Kurzgesagt – In a Nutshell 

Sources – Ozempic

Disclaimer: This video is for educational purposes only and does not provide medical advice. While we mention Ozempic and Mounjaro as examples of GLP-1 agonist medications, they differ from other brands (Wegovy, Zepbound) in their approved uses and formulations. For instance, Ozempic and Mounjaro are not specifically approved for weight loss in the absence of other conditions such as e.g. type 2 diabetes, while Wegovy and Zepbound are. Always consult a qualified healthcare professional before starting or changing any medication or treatment.

We thank the following experts for their critical reading, feedback and corrections:

– Prof. Daniel J. Drucker

University of Toronto, Canada

– Dr. Ziyad Al-Aly

Washington University School of Medicine, USA

– Areesha Moiz, MSc

Jewish General Hospital, Montreal, Canada

– More than one in eight US adults have tried the drugs, for the first time in history the country’s obesity rate actually fell.

This statistic refers to people who have used the drug for any reason, including losing weight or treating a chronic disease like diabetes or heart disease.

#Alex Montero, Grace Sparks, Marley Presiado, and Liz Hamel. KFF Health Tracking Poll May 2024: The Public’s Use and Views of GLP-1 Drugs. 2024

https://www.kff.org/health-costs/kff-health-tracking-poll-may-2024-the-publics-use-and-views-of-glp-1-drugs/

Quote: “The latest KFF Health Tracking Poll finds that about one in eight adults (12%) say they have ever taken a GLP-1 agonist – an increasingly popular class of prescription drugs used for weight loss and to treat diabetes or prevent heart attacks or strokes for adults with heart disease – including 6% who say they are currently taking such a drug. The share who report ever taking these drugs rises to four in ten (43%) among adults who have been told by a doctor that they have diabetes, a quarter who have been told they have heart disease, and one in five (22%) who have been told by a doctor that they are overweight or obese in the past five years1.”

The below graph published by Financial Times is based on publicly available data from the NHANES (National Health and Nutrition Examination) Surveys published by the CDC (Centers for Disease Control and Prevention). The survey data can be found here: https://wwwn.cdc.gov/nchs/nhanes/default.aspx (for years older than 1999, click on the left panels “NAHNES III” and below).

#Burn-Murdoch J. We may have passed peak obesity. Financial Times (2024)

https://www.ft.com/content/21bd0b9c-a3c4-4c7c-bc6e-7bb6c3556a56 

Quote: “Around the world, obesity rates have been stubbornly climbing for decades, if anything accelerating in recent years. But now newly released data finds that the US adult obesity rate fell by around two percentage points between 2020 and 2023.”

#National Center for Health Statistics. Obesity and Severe Obesity Prevalence in Adults: United States, August 2021–August 2023. (2024)

https://www.cdc.gov/nchs/products/databriefs/db508.htm 

#Rader B, Hazan R, Brownstein JS. Changes in Adult Obesity Trends in the US. JAMA Health Forum. 2024

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2827712

Quote: “A total of 16 743 822 unique adults (78.4% aged 26-75 years; 51.3% female and 48.7% male) (Table) contributed 47 939 382 BMI measurements. Mean (SD) population BMI rose annually from 2013 (29.65 [1.99]) to 2021 (30.23 [2.04]), plateaued in 2022 (30.24 [2.04]), and decreased slightly in 2023 (30.21 [1.99]). This same pattern was seen in percent changes of adults with obesity (Figure, A).

[...]

A decrease in obesity prevalence was observed in the South, among individuals aged 66 to 75 years, and among females (Figure, B-E). The 2023 decline in obesity prevalence was also seen in a sensitivity analysis using unweighted data (46.2%, 46.0%, and 45.6% in 2021, 2022, and 2023, respectively).

[...]

These findings suggest that BMI and obesity prevalence in the US decreased in 2023 for the first time in more than a decade. The most notable decrease was in the South, which had the highest observed per capita GLP-1RA dispensing rate.”

#Bartelt K, Barkley E, Allen S, Longo J. After a Decade of Increase, Obesity and Severe Obesity Have Trended Back Down. Epic Research. 2025

https://www.epicresearch.org/articles/after-a-decade-of-increase-obesity-and-severe-obesity-have-trended-back-down

Quote: “We found that the percentage of adults classified as obese (BMI of 30 or greater) increased from around 40% in 2010 to around 45% in 2020, a 13.6% increase, and this rate remained fairly stable through 2024. The rate of severe obesity (BMI of 40 or greater) increased from 8.5% of patients in 2010 to 10.7% in 2021, followed by a downward trend to 10.3% in 2024.”

– At its core being overweight or obese is a mismatch between how much you eat and how much your body needs. Eat more calories than you burn, and your body will store them as fat. Eat less, and you’ll lose it.

The "calories in, calories out" (CICO) model is a foundational concept in weight loss management, emphasizing that weight loss occurs when calorie expenditure exceeds calorie intake. However, recent research shows that the relationship between calorie intake, calorie expenditure and weight loss is more complex, involving physiological adaptations, diet composition, and behavioral factors.

#Kim JY. Optimal Diet Strategies for Weight Loss and Weight Loss Maintenance. J Obes Metab Syndr. 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8017325/ 

Quote: “Obesity has become one of the most important public health problems worldwide, which suggests the need for evidence-based dietary strategies for weight loss and its maintenance. Weight management depends upon complex factors such as amount of food eaten, type of food eaten, and timing of meals. In this review, we identified evidence-based dietary strategies for weight management based on these three components. An energy deficit is the most important factor in weight loss. A low-calorie diet with a low fat or carbohydrate content has been recommended; however, in some cases, a very-low-calorie diet is required for a short period. Some macronutrient composition-based diets, such as the ketogenic diet or high-protein diet, could be considered in some cases, although the potential risks and long-term effectiveness remain unknown. Meal timing is also an important factor in weight management, and higher-calorie breakfasts in combination with overnight fasting may help to prevent obesity. Our review indicated that there is no single best strategy for weight management. Hence, strategies for weight loss and its maintenance should be individualized, and healthcare providers must choose the best strategy based on patient preferences.”

#Ludwig DS, Ebbeling CB. The Carbohydrate-Insulin Model of Obesity: Beyond "Calories In, Calories Out". JAMA Intern Med. 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6082688/ 

Quote: “Despite intensive research, the causes of the obesity epidemic remain incompletely understood and conventional calorie-restricted diets continue to lack long-term efficacy. According to the Carbohydrate-Insulin Model (CIM) of obesity, recent increases in the consumption of processed, high-glycemic load carbohydrates produce hormonal changes that promote calorie deposition in adipose tissue, exacerbate hunger and lower energy expenditure. Basic and genetic research provides mechanistic evidence in support of the CIM. In animals, dietary composition has been clearly demonstrated to affect metabolism and body composition, independently of calorie intake, consistent with CIM predictions. Meta-analyses of behavioral trials report greater weight loss with reduced-glycemic load versus low-fat diets, though these studies characteristically suffer from poor long-term compliance. Feeding studies have lacked the rigor and duration to test the CIM, but the longest such studies tend to show metabolic advantages for low-glycemic load vs low-fat diets. Beyond the type and amount of carbohydrate consumed, the CIM provides a conceptual framework for understanding how many dietary and non-dietary exposures might alter hormones, metabolism and adipocyte biology in ways that could predispose to obesity. Pending definitive studies, the principles of a low-glycemic load diet offer a practical alternative to the conventional focus on dietary fat and calorie restriction.”

#Hall KD, Guo J. Obesity Energetics: Body Weight Regulation and the Effects of Diet Composition. Gastroenterology. 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5568065/ 

Quote: “Weight changes are accompanied by imbalances between calorie intake and expenditure. This fact is often misinterpreted to suggest that obesity is caused by gluttony and sloth and can be treated by simply advising people to eat less and move more. Rather various components of energy balance are dynamically interrelated and weight loss is resisted by counterbalancing physiological processes. While low-carbohydrate diets have been suggested to partially subvert these processes by increasing energy expenditure and promoting fat loss, our meta-analysis of 32 controlled feeding studies with isocaloric substitution of carbohydrate for fat found that both energy expenditure (26 kcal/d; P <.0001) and fat loss (16 g/d; P <.0001) were greater with lower fat diets. We review the components of energy balance and the mechanisms acting to resist weight loss in the context of static, settling point, and set-point models of body weight regulation, with the set-point model being most commensurate with current data.”

#Ludwig, D.S., Apovian, C.M., Aronne, L.J. et al. Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models. Eur J Clin Nutr. 2022.

https://www.nature.com/articles/s41430-022-01179-2

Quote: “The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake (“eat less”) and increase energy expenditure (“move more”). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on “complex endocrine, metabolic, and nervous system signals” that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, “ultra-processed” foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body’s metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.”

– For most of our history, food was scarce. So when our ancestors found a calorie bomb, binging on it was the best of ideas. The more sugar, fat and salt the better! Our brains are wired to LOVE those foods, they bring pleasure, enjoyment and mental release. This helped us survive in a world where food was the most important thing to worry about each day.

And then the world changed overnight and suddenly food was cheap, calorie-dense and hyperpalatable. Our ancient biology hijacked our modern behavior. Most of us can’t help ourselves and overeat regularly.

#Wiss DA, Avena N, Rada P. Sugar Addiction: From Evolution to Revolution. Front Psychiatry. 2018

https://pmc.ncbi.nlm.nih.gov/articles/PMC6234835/ 

Quote: “Adipose tissue in mammals play an important role in survival by preparing the body for periods of famine (29). From an evolutionary perspective, the increase in body fat prepared animals for times of food scarcity, in fact, those accumulating body fat had an advantage compared to those that did not (30). However, this occurred in times when humans had insecure food supply (hunter-gatherer) and could spend many days on a hypocaloric diet. During prehistoric times, the excessive increase in body weight was dampened by physical activity needed in the search of food, moreover, excessive fat would mean, as a predator, lower chances of catching the prey and vice versa (29). So, even if copious quantities of food were eaten, there was a natural brake mediated by physical activity.

When did this panorama change? The first change was the advent of agriculture and animal domestication ~10,000 years ago, leading people to become producers by gathering and securing food supply (31). Of course, farming depended on climate and plagues which could decimate crops resulting in famine (3). The second change was the industrialization of food supply (industrial revolution of the nineteen century) allowing for mass production of flour and sugar (32), with the ulterior manufacturing, in the last decades, of processed and ultra-processed foods that are inexpensive and highly caloric (abundant sugars, salts, fats) (11, 33). These two developments are linked to food availability and how food is refined and commercialized. Meanwhile, a third important revolution happened over the past few decades: the arrival and public accessibility of automobiles, television sets, and later the computer leading us toward a sedentary lifestyle (7). When all three transformations are combined, we can see that caloric intake has risen while calorie expenditure has significantly decreased, leading to the obesity epidemic.

Although humans have culturally and technologically evolved, our genome has changed very little in the last 10,000 years (4). This means that our brain circuitry is still programmed to eat more in times of food abundance preparing for periods of starvation (31).”

– Today over 40% of adults are overweight, and obesity affects one billion humans and kills almost 4 million annually.

In 2022, roughly one billion people globally (890 million adults, and 160 million children and adolescents) were estimated to live with obesity. The fraction of adults living with obesity globally was recently estimated to be 43% (2022, adults >21 yrs old, WHO) and 45% (2021, adults >25 yrs old, The Lancet).

#World Health Organization – Obesity and overweight. Retrieved October 2025

https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight

Quote: “In 2022, 2.5 billion adults aged 18 years and older were overweight, including over 890 million adults who were living with obesity. This corresponds to 43% of adults aged 18 years and over (43% of men and 44% of women) who were overweight; an increase from 1990, when 25% of adults aged 18 years and over were overweight. Prevalence of overweight varied by region, from 31% in the WHO South-East Asia Region and the African Region to 67% in the Region of the Americas. [...] While just 2% of children and adolescents aged 5–19 were obese in 1990 (31 million young people), by 2022, 8% of children and adolescents were living with obesity (160 million young people).”

#Ng, M et al. Global, regional, and national prevalence of adult overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet. 2025

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00355-1/fulltext 

Quote: “In 2021, an estimated 2·11 billion (95% UI 2·09–2·13) adults aged 25 years and older worldwide were affected by overweight and obesity—almost half of the total adult population (45·1% [44·7–45·4]).”

An estimate from 2021 puts global annual deaths from obesity at around 3.71 million. Since obesity rates have increased significantly since then, we rounded this number up.

#Our World in Data. Deaths from obesity, by age, World, 1990 to 2021. Retrieved October 2025

https://ourworldindata.org/grapher/deaths-from-obesity-by-age 

– If trends continue, by 2050 one in three adults on Earth will be obese and half of humanity will be overweight.

By 2050, roughly 60% of adults and a third of children and adolescents globally are projected to be at least overweight. Additionally, by 2050 1 in 3 adults over the age of 25 globally is projected to be obese.

#Ng, M et al. Global, regional, and national prevalence of adult overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet. 2025

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00355-1/fulltext 

Quote: “The age-standardised prevalence of overweight and obesity is forecasted to increase by 30·7% (95% UI 17·8–36·3) globally over the next 30 years, with nearly 60% of adults expected to have overweight and obesity by 2050 (figure 2; appendix 1 pp 49–50). [...] Specific to obesity, age-standardised prevalence is forecasted to increase by 68·3% (95% UI 42·6–80·5) globally, with approximately 1 in 3 adults over the age of 25 expected to experience obesity by 2050, among whom about a quarter will be over the age of 65 (see appendix 1 pp 51–53).”

#Kerr, JA et al. Global, regional, and national prevalence of child and adolescent overweight and obesity, 1990-2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet. 2025

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00397-6/fulltext 

Quote: “If current trends continue, we forecast that around a third of the world's children and adolescents will have overweight or obesity by 2050 (tables 1, 2; appendix 1 pp 45–53), equating to 356 million (95% UI 295–411) young people aged 5–14 years and 390 million (331–440) aged 15–24 years (total 746 million [627–851]). Of those, 360 million (278–422) children and adolescents would have obesity by 2050 (tables 1, 2), the result of a 120·7% (80·7–141·6) increase in prevalence. Globally, 9·1% (8·4–9·7) of those aged 5–14 years are forecasted to have obesity by 2030, increasing to 15·6% (12·7–17·2), or 186 million individuals [141–221]), by 2050.”

– So almost everybody who loses weight struggles to keep it that way or puts back on even more.

Weight maintenance after weight loss is challenging, and it is not just about willpower. There are also various physiological factors at play that make your body “want” to regain the lost weight.

#van Baak, M.A., Mariman, E.C.M. Obesity-induced and weight-loss-induced physiological factors affecting weight regain. Nat Rev Endocrinol  (2023)

https://www.nature.com/articles/s41574-023-00887-4 

Quote: “Weight regain after successful weight loss resulting from lifestyle interventions is a major challenge in the management of overweight and obesity. Knowledge of the causal mechanisms for weight regain can help researchers and clinicians to find effective strategies to tackle weight regain and reduce obesity-associated metabolic and cardiovascular complications. This Review summarizes the current understanding of a number of potential physiological mechanisms underlying weight regain after weight loss, including: the role of adipose tissue immune cells; hormonal and neuronal factors affecting hunger, satiety and reward; resting energy expenditure and adaptive thermogenesis; and lipid metabolism (lipolysis and lipid oxidation). We describe and discuss obesity-associated changes in these mechanisms, their persistence during weight loss and weight regain and their association with weight regain. Interventions to prevent or limit weight regain based on these factors, such as diet, exercise, pharmacotherapy and biomedical strategies, and current knowledge on the effectiveness of these interventions are also reviewed.”

– Many eating behaviors – eat now or later, chocolate or vegetables –  are actually governed by an orchestra of hormones that are not within your control. You are not hungry in the evening because you decide to be or because this is when your body needs energy, but because your body releases certain hormones.

#Yeung AY, Tadi P. Physiology, Obesity Neurohormonal Appetite And Satiety Control. [Updated 2023 Jan 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025

https://www.ncbi.nlm.nih.gov/books/NBK555906/ 

Quote: “The feelings of appetite and satiety involve complex interactions between hormones from the gastrointestinal tract to the hypothalamus and vv feedback. Within the hypothalamus are specific regions where hormones interact to produce sensations of appetite and satiety, leading to food consumption or a feeling of fullness. Through the interactions of ghrelin and leptin, the hypothalamus can regulate the sensation of hunger and satiety, leading to energy homeostasis. Ghrelin, termed the "hunger hormone," was initially discovered through its receptor, the growth hormone secretagogue receptor, before explaining its role as a growth-hormone-releasing peptide.[1] 

Leptin was discovered primarily as a signal in regulating body weight.[2] However, the roles of these hormones in regulating appetite and satiety were not explicitly known until research showed a correlation between a rise in plasma levels of ghrelin before meals and a subsequent decrease in plasma levels of ghrelin after meals and a subsequent change in plasma leptin levels.[3] Together, ghrelin and leptin signals regulate our sensations of hunger and satiety by sending signals to different nuclei within the hypothalamus for food intake. An imbalance or dysregulation of these hormones may drastically affect the body's energy homeostasis.”

– And it turns out your fat is one of the major regulators of this orchestra.

If you are overweight or obese, the excess fat is throwing your hormonal orchestra out of tune. This may make you more hungry or push you to overeat more, creating insulin resistance that causes type 2 diabetes and so on. We made a video if you want details.

With a healthy amount of fat, the satiety hormone leptin tells your brain when you have enough energy storage, can eat less and spend more energy. But if you have too much fat, instead of becoming less hungry, your brain becomes resistant against the constant flood of leptin. This breaks your internal food “thermostat” and increases feelings of hunger even when you have had enough food.

#Gruzdeva O, Borodkina D, Uchasova E, Dyleva Y, Barbarash O. Leptin resistance: underlying mechanisms and diagnosis. Diabetes Metab Syndr Obes. 2019

https://pmc.ncbi.nlm.nih.gov/articles/PMC6354688/

Quote: “Leptin is an adipocyte-secreted hormone that regulates the appetite and represents a key factor in the development of obesity, a serious medical, social, and economic problem in modern society.1,2 More than 20 years ago, leptin and its receptors were identified as key regulators of body weight and energy homeostasis. A minor increase in leptin concentration reduces the appetite and leads to a decrease in body weight;3 however, in obesity, despite increased leptin concentration, the efficacy of the anorexic effect of leptin is decreased,1,3 with leptin resistance developing due to a defect in intracellular signaling associated with the leptin receptor or decreases in leptin transport across the blood–brain barrier (BBB).4”

#Scheja, Ludger, and Joerg Heeren. “The endocrine function of adipose tissues in health and cardiometabolic disease.” Nature Reviews. Endocrinology (2019)
https://pubmed.ncbi.nlm.nih.gov/31296970/

Quote: “In healthy conditions in humans and rodents, circulating leptin levels correlate positively with adipose tissue mass and leptin levels decrease sharply during prolonged fasting34, but do not substantially change between meals35. Thus, low plasma leptin levels can be regarded as an endocrine signal reflecting depleted adipose tissue energy stores and high energy demand. In line with this notion, low plasma leptin concentration not only fosters

increased energy intake but is also causally involved in starvation-associated alterations such as increased corticosterone and decreased thyroid hormone levels, gonadal hypoactivity and suppression of the immune system36.

Leptin is expressed in all types of adipose tissues, with a preference for subcutaneous WAT in humans37, and is predominantly regulated at the transcriptional level38. In the fasted state, the sympathetic nervous system acting on adipocyte β-adrenergic receptors is the principal leptin-lowering mechanism39–41. By this mechanism, the secretion of leptin is tightly coupled to nutritional state and thus can mediate physiological adaptations.”

#Chait A, den Hartigh LJ. Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease. Front Cardiovasc Med. 2020
https://pmc.ncbi.nlm.nih.gov/articles/PMC7052117/#s6
Quote: “Abundant evidence indicates that adiposity and adipose tissue inflammation are associated with insulin resistance, which refers to a reduced response to binding of insulin to its receptor in peripheral tissues such as adipose tissue and skeletal muscle. This differs from glucose effectiveness, which is uptake of glucose by peripheral tissues in an insulin-independent manner. Insulin inhibits hepatic glucose output and stimulates lipogenesis in the liver, both of which are reduced in the presence of insulin resistance. Such desensitization of insulin signaling pathways also inhibits glucose uptake in peripheral tissues and stimulates lipolysis in adipose tissue. To compensate for reduced insulin sensitivity, insulin secretion is increased in order to maintain euglycemia. If the pancreatic beta cells are unable to secrete sufficient insulin to compensate for the reduced insulin sensitivity (termed beta cell dysfunction), hyperglycemia will ensue, leading to glucose intolerance and eventually T2DM (366). While the precise mechanisms that lead to beta cell dysfunction are not completely understood, ectopic fat accumulation may contribute, as discussed earlier. Nonetheless, ample evidence suggests that excess adiposity and adipose tissue inflammation contribute to insulin resistance [reviewed in (64, 367)]. Many studies have demonstrated that excess adiposity is correlated with insulin resistance in humans. Cross-sectional studies in men of European, Asian Indian, and American descent have shown that total, visceral, and subcutaneous adiposity, BMI, and waist circumference are all negatively associated with insulin sensitivity (368, 369). As noted earlier, adiposity, especially visceral adiposity, is characterized by adipose tissue inflammation.”

For further information on the subject, you can watch our recent video on Fat: 

https://www.youtube.com/watch?v=sOsqXKr4l30 

And you can also check out our sources for that video: https://sites.google.com/view/sources-fat/

– But there is one specific hormone that plays its tune quietly in the background, even in obese people – the “glucagon-like peptide-1”, or GLP-1.

It is one of the hormones your body releases after a meal. It tells your pancreas to release more insulin to keep blood sugar in check and slows down your digestion to keep food in your stomach. And in your brain, it increases your feeling of fullness and being satisfied – curbing your appetite.

#Tudurí E, López M, Diéguez C, Nadal A, Nogueiras R. Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets. Trends Endocrinol Metab. 2016

https://pubmed.ncbi.nlm.nih.gov/27062006/ 

Quote: “Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors. In this review, we focus on the pancreatic effects exerted by current GLP-1 derivatives used to treat diabetes. Based on the results from in vitro and in vivo studies in humans and animal models, we describe the specific actions of GLP-1 analogs on the synthesis, processing, and secretion of insulin, islet morphology, and β cell proliferation and apoptosis.”

#Lee YS, Jun HS. Anti-diabetic actions of glucagon-like peptide-1 on pancreatic beta-cells. Metabolism. 2014

https://pubmed.ncbi.nlm.nih.gov/24140094/ 

Quote: “Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L-cells in response to nutrients. GLP-1 lowers blood glucose levels by stimulating insulin secretion from pancreatic beta-cells in a glucose-dependent manner. In addition, GLP-1 slows gastric emptying, suppresses appetite, reduces plasma glucagon, and stimulates glucose disposal, which are beneficial for glucose homeostasis. Therefore, incretin-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase IV, an enzyme which inactivates GLP-1, have been developed for treatment of diabetes. This review outlines our knowledge of the actions of GLP-1 on insulin secretion and biosynthesis, beta-cell proliferation and regeneration, and protection against beta-cell damage, as well as the involvement of recently discovered signaling pathways of GLP-1 action, mainly focusing on pancreatic beta-cells.”

#Leech CA, Dzhura I, Chepurny OG, et al. Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic β cells. Prog Biophys Mol Biol. 2011

https://pmc.ncbi.nlm.nih.gov/articles/PMC3200499/ 

Quote: “Insulin secretion from pancreatic β cells is stimulated by glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal. GLP-1 mimetics (e.g., Byetta) and GLP-1 analogs (e.g., Victoza) activate the β cell GLP-1 receptor (GLP-1R), and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus (T2DM).”

#Kim KS, Park JS, Hwang E, et al. GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans. Science. 2024

https://pubmed.ncbi.nlm.nih.gov/38935778/ 

Quote: “Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMHGLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMHGLP-1R neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARCNPY/AgRP neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.”

– These effects are usually modest. Once in your bloodstream, GLP-1 disappears in barely two minutes, its song quickly fading away.

#Lee S, Lee DY. Glucagon-like peptide-1 and glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes. Ann Pediatr Endocrinol Metab. 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5401818/ 

Quote: “Native GLP-1 has a very short half-life (about 2 minutes) because of rapid degradation by the endogenous enzymes dipeptidyl-peptidase-IV (DPP-4)67) and neutral endopeptidase (NEP)68).”

#Sharma D, Verma S, Vaidya S, Kalia K, Tiwari V. Recent updates on GLP-1 agonists: Current advancements & challenges. Biomed Pharmacother. 2018

https://www.sciencedirect.com/science/article/pii/S0753332218327537

Quote: “Glucagon-like peptide (GLP)-1 is an incretin hormone exhibiting several pharmacological actions such as neuroprotection, increased cognitive function, cardio-protection, decreased hypertension, suppression of acid secretion, increase in lyposis, and protection from inflammation. The most potent actions are glucose-dependent insulinotropic and glucagonostatic actions, stimulation of β-cell proliferation, enhanced insulin secretion and reduced weight gain in patients with type-2 diabetes pertaining to blood glucose control. Despite all these actions, its short half-life (around 2∼min) and degradation by a dipeptidyl peptidase-4 enzyme (DPP-4) limits the therapeutic utility of GLP1. In this review, we have discussed DPP IV-resistant analogs of GLP-1 currently present in clinical trials such as Exenatide, Liraglutide, Semaglutide, Efpeglenatide, Exenatide ER, Ittca 650 (Intarcia), Dulaglutide, Albiglutide, and Lixisenatide. Moreover, we have also discussed in detail the pharmacology, signaling mechanisms, and pharmacokinetic properties (Cmax, Tmax, T1/2, Vd, and Bioavailability) of DPP IV-resistant analogs of (GLP-1). Interestingly, GLP-1 agonist drugs have shown better potential to treat type-2 diabetes mellitus (T2DM) as compared to currently used drugs in clinics without causing the side effects of hypoglycemia and weight gain.”

#Nilsen, J., Aaen, K.H., Benjakul, S. et al. Enhanced plasma half-life and efficacy of engineered human albumin-fused GLP-1 despite enzymatic cleavage of its C-terminal end. Commun Biol (2025)

https://www.nature.com/articles/s42003-025-08249-8

Quote: “One such example is glucagon-like peptide 1 (GLP-1) (3.3 kDa), a small peptide hormone with a plasma half-life of only two minutes due to enzymatic degradation by dipeptidyl peptidase-4 (DDP-4) in the blood and rapid excretion through the kidneys16,17,18,19.”

#Hui H, Farilla L, Merkel P, Perfetti R. The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects. Eur J Endocrinol. 2002

https://pubmed.ncbi.nlm.nih.gov/12039708/ 

Quote: “The incretin hormone glucagon-like peptide-1 (GLP-1) is capable of ameliorating glucose-dependent insulin secretion in subjects with diabetes. However, its very short half-life (1.5-5 min) in plasma represents a major limitation for its use in the clinical setting. The present study was designed to characterize the duration of the effect of GLP-1 in the Zucker diabetic fatty (ZDF) rat. ZDF rats were subjected to a 48 h infusion of human GLP-1 (30 pmol/kg per min), followed by an i.p. glucose tolerance test (IPGTT) (1 g/kg body weight), 2 h after removing the infusion pump. At 15 min from the beginning of the test, GLP-1-treated animals had lower plasma glucose levels (442+/-38 mg/dl) than saline-infused controls (583+/-63 mg/dl, P<0.01). This was reflected in the higher insulin levels attained in the GLP-1-treated animals (1999+/-163 vs 1250+/-51 pmol/l, GLP-1 vs saline respectively, P<0.01). Repetition of the IPGTT on day 3, 9 and 16 from the removal of the infusion pump revealed a surprising lasting 'memory' of the exposure to GLP-1. Indeed, the best insulin secretory response was observed approximately 1 week after discontinuation of the GLP-1 infusion, and lasted up to 3 weeks from the early exposure to GLP-1. Detection of fasting plasma levels of GLP-1 during the 3 weeks of the experiment showed a very rapid decline, consistent with the data reported by others. Our findings provide evidence for a long-lasting beneficial effect of GLP-1 that persists for weeks even when the circulating levels of GLP-1 are back to normal.”

– So one day scientists had an idea – what if we made artificial copies of GLP-1, that play the same song but louder and much longer? A GLP-1 signal that stays in your body would boost insulin and silence appetite. The first artificial GLP-1 was approved in 2005 for diabetes and in 2014 for obesity, but the revolution came with semaglutide and tirzepatide – Ozempic and Mounjaro. 

An “agonist” is a drug that binds to a receptor in your body and activates some biological process or response. It is the opposite of an antagonist, which binds to a receptor but does not activate it, thus blocking the receptor and preventing or reducing a biological response that would otherwise occur. GLP-1 agonists mimic the GLP-1 that naturally occurs in your body, bind to the GLP-1 receptor and activate it.

The first GLP-1 agonist approved for treating diabetes was Exenatide in 2005, and the first one approved for the treatment of obesity in 2014 was Liraglutide. Both were originally formulated and approved as subcutaneous injections.

#Bond A. Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus. Proc (Bayl Univ Med Cent). 2006

https://pmc.ncbi.nlm.nih.gov/articles/PMC1484540/ 

Quote: “Exenatide (Byetta) is the first in a new class of incretin peptide mimetics (glucagon-like polypeptide-1 [GLP-1] receptor agonists) available in the USA. It was approved by the Food and Drug Administration (FDA) in April 2005 for adjunctive glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea (2).”

#Mary K. Caffrey. Liraglutide Approved Under New Name to Treat Obesity. Evidence-Based Diabetes Management. 2015

https://www.ajmc.com/view/liraglutide-approved-under-new-name-to-treat-obesity 

Quote: “On December 23, 2014, the FDA approved liraglutide, under the name Saxenda, to treat obesity, after having previously approved it under the name Victoza to treat type 2 diabetes mellitus (T2DM).

As Saxenda, the glucagon-like peptide-1 (GLP-1) receptor agonist will be approved for adults with a body mass index (BMI) of 30 or higher, or for adults with a BMI of 27 or higher plus at least 1 other comorbidity, such as T2DM or high cholesterol.”

Semaglutide was first approved in 2017 for treatment of type 2 diabetes (brand name Ozempic), and in 2021 for chronic weight management (brand name Wegovy).

#Dhillon, S. Semaglutide: First Global Approval. Drugs (2018). 

https://doi.org/10.1007/s40265-018-0871-0 

Quote: “Novo Nordisk has developed a subcutaneous formulation of semaglutide (Ozempic®), a modified human glucagon-like peptide-1 (GLP-1) analogue, for the treatment of type 2 diabetes mellitus. It has been developed using Novo Nordisk’s proprietary protein-acylation technology, and is administered using an injection device. Semaglutide lowers blood glucose by stimulating the release of insulin and also lowers body weight. Once-weekly subcutaneous semaglutide has recently been approved in the US, Puerto Rico and Canada, and has received a positive opinion in the EU for the treatment of patients with type 2 diabetes. It will be launched as the Ozempic® Pen, a pre-filled device. Semaglutide is also under regulatory review in Japan and Switzerland for the treatment of type 2 diabetes. Clinical development for obesity, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease is underway worldwide. This article summarizes the milestones in the development of semaglutide leading to this first approval for type 2 diabetes.”

#FDA Approves Prescription Weight Loss Therapy for Adults With Obesity. Pharmacy Times (2021)

https://www.pharmacytimes.com/view/fda-approves-prescription-weight-loss-therapy-for-adults-with-obesity 

Quote: “Officials with the FDA have approved the new drug application (NDA) for semaglutide injection (Wegovy; Novo Nordisk) 2.4 mg for adults with obesity (BMI ≥30) or overweight BMI ≥27). According to Novo Nordisk, this novel drug is the only prescription weight-loss medication with once-weekly dosing.”

Tirzepatide was first approved in 2022 for treatment of type 2 diabetes (brand name Mounjaro), and in 2023 for chronic weight management (brand name Zepbound).

#Syed, Y.Y. Tirzepatide: First Approval. Drugs (2022)

https://doi.org/10.1007/s40265-022-01746-8

Quote: “Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Native GIP and GLP-1 are incretin hormones that stimulate insulin secretion and decrease glucagon secretion. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. This article summarizes the milestones in the development of tirzepatide leading to this first approval for T2DM.”

#Food and Drug Administration. FDA Approves New Medication for Chronic Weight Management.023

https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management

Quote: “Today, the U.S. Food and Drug Administration approved Zepbound (tirzepatide) injection for chronic weight management in adults with obesity (body mass index of 30 kilograms per square meter (kg/ m2) or greater) or overweight (body mass index of 27 kg/m2 or greater) with at least one weight-related condition (such as high blood pressure, type 2 diabetes or high cholesterol) for use, in addition to a reduced calorie diet and increased physical activity. Tirzepatide, the active ingredient in Zepbound, is already approved under the trade name Mounjaro to be used along with diet and exercise to help improve blood sugar (glucose) in adults with type 2 diabetes mellitus.”

– Really powerful GLP-1 agonists that play their songs in your bloodstream for up to a week.

Medications typically get metabolized gradually over time. A popular metric for the stability of medications in the blood stream is the half-life (t½), i.e. the time it takes for the concentration of the drug in the plasma or the total amount in the body to be reduced by 50%.

#Yang XD, Yang YY. Clinical Pharmacokinetics of Semaglutide: A Systematic Review. Drug Des Devel Ther. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11215664/ 

Quote: “Purpose

The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use.

Methodology

The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies.

Results

Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug–drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this.

Conclusion

This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.

[...]

A t1/2 of approximately 1 week was observed following both oral and subcutaneous administrations, demonstrating that the elimination phase was similar, irrespective of the route of administration.”

#Schneck K, Urva S. Population pharmacokinetics of the GIP/GLP receptor agonist tirzepatide. CPT Pharmacometrics Syst Pharmacol. 2024.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10962491/ 

Quote: “Tirzepatide is a first‐in‐class glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist approved as for the treatment of type 2 diabetes mellitus. A population‐based pharmacokinetic (PK) model was developed from 19 pooled studies. Tirzepatide pharmacokinetics were well‐described by a two‐compartment model with first order absorption and elimination. The tirzepatide population PK model utilized a semimechanistic allometry model to describe the relationship between body size and tirzepatide PK. The half‐life of tirzepatide was ~5 days and enabled sustained exposure with once‐weekly subcutaneous dosing. The covariate analysis suggested that adjustment of the dose regimen based on demographics or subpopulations was unnecessary. The tirzepatide PK model can be used to predict tirzepatide exposure for various scenarios or populations.”

– They send out a loud and steady signal that dials down your appetite 24/7. You still enjoy food, but you feel full and satisfied much sooner, making it easy to not overeat. And since the song never really switches off, you feel less hungry throughout your day, making you eat less often.

#Kim KS, Park JS, Hwang E, et al. GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans. Science. 2024

https://pubmed.ncbi.nlm.nih.gov/38935778/ 

Quote: “Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMHGLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMHGLP-1R neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARCNPY/AgRP neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.”

#Cheney C, Hunter K, Klein M. Impact of GLP-1 Receptor Agonists on Perceived Eating Behaviors in Response to Stimuli. Diabetes Metab Syndr Obes. 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC12056664/

Quote: “Background

Several Glucagon-like peptide-1 (GLP-1) receptor agonists are FDA-approved for weight loss in patients with obesity primarily through targeting gastrointestinal pathways to reduce caloric intake; however, less is known about the GLP-1 receptor agonist impact on the behavioral aspects of eating. Our study investigated how patients’ perceived eating behaviors evolve in response to different stimuli after initiating a GLP-1 receptor agonist. We hypothesized that participants reported eating behaviors are more in tune with their physiological cues (hunger and satiety) and less influenced by emotional, situational, and external sensory cues after starting their GLP-1 receptor agonists.

Materials and Methods

This was a survey-based cross-sectional study that included 101 participants with BMI >27 who were prescribed a GLP-1 receptor agonist medication. The survey inquired about participants’ perspectives on their eating behaviors before and after starting GLP-1 receptor agonists. The survey was created through Google Forms and consisted of 31 questions in a multiple-choice format. A paired T-test was used to compare the participants’ numerical scores for a given question before and after starting the GLP1 receptor agonist.

Results

Participants reported feeling significantly more cognizant of their hunger cues and a significant reduction in the frequency with which they ate past the point of feeling full. Participants also reported a significant reduction in the frequency with which they desired to eat food in response to external sensory cues and situational cues. In addition, participants reported a significant reduction in the frequency of consuming food in excess in response to emotional cues.

Conclusion

Together, these results suggest that GLP-1 receptor agonists may promote substantial weight loss through improved perceived regulation of eating behavior, supporting a state in which physiological cues have a greater influence on food intake than emotional, external, sensory, and situational cues.”

#Salvador R, Moutinho CG, Sousa C, et al. Semaglutide as a GLP-1 Agonist: A Breakthrough in Obesity Treatment. Pharmaceuticals (Basel). 2025

https://pmc.ncbi.nlm.nih.gov/articles/PMC11944337/ 

Quote: “The administration of subcutaneous or oral SMG, in addition to its effects on reducing HbA1c concentration and on cardiovascular, renal, and hepatic variables, has a significant effect on body weight reduction. The effect on body composition has been shown to be dose-dependent, with higher doses having a superior effect on weight loss. The effect on body composition was not only absolute weight loss but also a reduction in waist circumference [155,156,157]. To the same extent, subcutaneous (2.4 mg) or oral (50 mg) SMG has an effect on reducing ad libitum energy intake, appetite and satiety, and food cravings, while also improving the control of food intake [100,158,159].”

– How intensely you feel hunger is largely genetic, so especially people who suffer from food noise, a constant urge to eat, feel a huge psychological relief from the drug. Finally their body stopped screaming at them.

Hunger and appetite are complex traits influenced by both genetic and environmental factors. Research has uncovered genes and biological pathways that regulate food intake, satiety, and susceptibility to overeating, highlighting the heritable component of eating behaviors. However, the relationship between genetics and feelings of hunger is complex, and many aspects of it are not yet well understood.

#Merino, J., Dashti, H.S., Sarnowski, C. et al. Genetic analysis of dietary intake identifies new loci and functional links with metabolic traits. Nat Hum Behav (2022).

https://doi.org/10.1038/s41562-021-01182-w 

Quote: “Dietary intake is a major contributor to the global obesity epidemic and represents a complex behavioural phenotype that is partially affected by innate biological differences. Here, we present a multivariate genome-wide association analysis of overall variation in dietary intake to account for the correlation between dietary carbohydrate, fat and protein in 282,271 participants of European ancestry from the UK Biobank (n = 191,157) and Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 91,114), and identify 26 distinct genome-wide significant loci. Dietary intake signals map exclusively to specific brain regions and are enriched for genes expressed in specialized subtypes of GABAergic, dopaminergic and glutamatergic neurons. We identified two main clusters of genetic variants for overall variation in dietary intake that were differently associated with obesity and coronary artery disease. These results enhance the biological understanding of interindividual differences in dietary intake by highlighting neural mechanisms, supporting functional follow-up experiments and possibly providing new avenues for the prevention and treatment of prevalent complex metabolic diseases.”

#Farooqi S. Obesity and thinness: insights from genetics. Philos Trans R Soc Lond B Biol Sci. 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10475868/ 

Quote: “Genetic disruption of key molecular components of the hypothalamic leptin–melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people who carry these mutations have shown that the adipose tissue-derived hormone leptin primarily acts to defend against starvation. A lack of leptin causes an intense drive to eat and increases the rewarding properties of food, demonstrating that human appetite has a strong biological basis. Genetic studies in clinical- and population-based cohorts of people with obesity or thinness continue to provide new insights into the physiological mechanisms involved in weight regulation and identify molecular targets for weight loss therapy.”

#Hayashi D, Edwards C, Emond JA, et al. What Is Food Noise? A Conceptual Model of Food Cue Reactivity. Nutrients. 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10674813/ 

Quote: “As GLP-1 receptor agonists, like semaglutide, emerge as effective treatments for weight management, anecdotal reports from patients and clinicians alike point to a reduction in what has been colloquially termed “food noise”, as patients report experiencing less rumination and obsessive preoccupation about food. In this narrative review, we discuss concepts used in studies to investigate human eating behavior that can help elucidate and define food noise, particularly food cue reactivity. We propose a conceptual model that summarizes the main factors that have been shown to determine the magnitude of the reactivity elicited by external and internal food cues and how these factors can affect short- and long-term behavioral and clinical outcomes. By integrating key research conducted in this field, the Cue–Influencer–Reactivity–Outcome (CIRO) model of food cue reactivity provides a framework that can be used in future research to design studies and interpret findings related to food noise and food cue reactivity.”

– Many people try a crash diet at some point in their lifetime. It’s not that crash diets don’t work, they do! You can lose 20% of your weight in 3 months – from 95 to 75 kilos, or 130 to 105. 

Crash diets are also called “very low-calorie diets” (VLCDs), and as the name suggests, they are based around severe caloric deficits sustained over several weeks or months. There are numerous variations on how to achieve a caloric deficit, i.e. what and how much one should eat as part of a specific VLCD.

The weight loss achieved for VLCDs varies with the type of diet, the duration of the diet, the starting weight, and also between people and study cohorts. As an illustrative example, we cite numbers commonly achieved by the “Very Low-Calorie Ketogenic Diet” within 3-6 months, which severely restricts calories (<800 kcal/day) while also limiting the fraction of carbohydrates per meal.

#Muscogiuri G, El Ghoch M, Colao A, et al. European Guidelines for Obesity Management in Adults with a Very Low-Calorie Ketogenic Diet: A Systematic Review and Meta-Analysis. Obes Facts. 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8138199/

Quote: “Bruci et al. [25] conducted a prospective observational noncontrolled real-life study including 92 patients (mean age = 51.3 ± 12.2 years; BMI 33.85 ± 5.84) with obesity and mild kidney failure and who underwent nearly 3 months of VLCKD. Anthropometric, body composition, and biochemical data were obtained before and after the dietary intervention. A significant reduction in body weight (92.40 ± 18.31 vs. 76.82 ± 14.95 kg; p < 0.0001), FM (35.63 ± 9.93 vs. 24.40 ± 9.00 kg; p < 0.0001), and FFM (56.77 ± 13.40 vs. 52.42 ± 10.89 kg; p < 0.0001) was observed, accompanied by improvements in glycemia (95.32 ± 13.26 vs. 88.25 ± 10.24 mg/dL; p = 0.002) and HbA1c (5.65 ± 0.81 vs. 5.33 ± 0.39%; p < 0.0001) and a reduction in total cholesterol (206.91 ± 45.65 vs. 184.46 ± 41.17 mg/dL; p = 0.004) and TG (156.44 ± 90.87 vs. 102.62 ± 35.71 mg/dL; p = 0.003).

[...]

Goday et al. [28] conducted a controlled trial including 89 adult patients with obesity and type 2 diabetes randomly allocated to either VLCKD (n = 45; mean age = 54.89 ± 8.81 years and BMI 33.25 ± 1.52) or standard LCD based on American Diabetes Association (ADA) guidelines (n = 45; mean age = 54.17 ± 7.97 years and BMI 32.88 ± 1.60). Clinical outcomes were assessed at baseline and at the 4-month follow-up. A significant reduction in body weight (91.5 ± 11.4 vs. 76.8 ± 9.1 kg; p < 0.0001), WC (108.1 ± 8.6 vs. 96.1 ± 7.6 cm; p < 0.0001), fasting glycemia (136.9 ± 34.4 vs. 108.9 ± 20.4 mg/dL; p < 0.0001), HbA1c (6.9 ± 1.1 vs. 6.0 ± 0.7% total Hb; p < 0.0001), the HOMA-IR index (6.9 ± 4.4 vs. 3.5 ± 1.9; p < 0.0001), and TG (150.5 ± 54.4 vs. 114.6 ± 57.2 mg/dL; p = 0.004) was observed with a VLCKD. On the other hand, a reduction only in WC (105.8 ± 8.5 vs. 100.4 ± 9.2 cm; p = 0.048) and the HOMA-IR index (5.8 ± 2.9 vs. 4.6 ± 2.5; p = 0.001) was observed in the LCD group.

[...]

Gomez-Arbelaez et al. [29] conducted a prospective interventional noncontrolled study in 20 adult patients with obesity (mean age 47.2 ± 10.2 years and BMI 35.5 ± 4.4) and who underwent a nutritional intervention based on a VLCKD. Anthropometric and body composition assessments were conducted at baseline and at a mean of 40, 90, and 120 days. At the 6-month follow-up, significant weight loss (95.9 ± 16.3 vs. 75.1 ± 11.8 kg; p < 0.05) and a reduction in WC (109.4 ± 12.8 vs. 88.6 ± 10.1 cm; p < 0.05), FM (42.2 ± 9.1 vs. 25.7 ± 5.8 kg; p < 0.05), and FFM (52.8 ± 10.2 vs. 49.0 ± 9.7 kg; p < 0.05) were observed.”

– But such a sudden drop is not very healthy, and for the vast majority, the weight will come back within a year.

Various health risks can be associated with rapid and excessive weight loss, as caused by e.g. crash diets or other dietary interventions. However, the risks vary a lot between diets and how people execute them (for example, exactly how large the caloric deficit is and how long it is sustained). Professional combat athletes may undergo severe weight-loss regimes as part of their preparation for competitions, and those come with their own health risks we will not discuss here since this is not what we are talking about in this video. The most notable risk for non-athlete, “regular” people undergoing crash-diets is the loss of muscle mass and bone density.

Additionally, rapid weight loss through some very low caloric diets is not recommended for some groups of people, such as pregnant women, those with type 1 diabetes, kidney failure, cardiac arrhythmia, or frail older adults due to heightened risk of complications.

#Cava E, Yeat NC, Mittendorfer B. Preserving Healthy Muscle during Weight Loss. Adv Nutr. 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5421125/ 

Quote: “Weight loss is the cornerstone of therapy for people with obesity because it can ameliorate or completely resolve the metabolic risk factors for diabetes, coronary artery disease, and obesity-associated cancers. The potential health benefits of diet-induced weight loss are thought to be compromised by the weight-loss–associated loss of lean body mass, which could increase the risk of sarcopenia (low muscle mass and impaired muscle function). The objective of this review is to provide an overview of what is known about weight-loss–induced muscle loss and its implications for overall physical function (e.g., ability to lift items, walk, and climb stairs). The currently available data in the literature show the following: 1) compared with persons with normal weight, those with obesity have more muscle mass but poor muscle quality; 2) diet-induced weight loss reduces muscle mass without adversely affecting muscle strength; 3) weight loss improves global physical function, most likely because of reduced fat mass; 4) high protein intake helps preserve lean body and muscle mass during weight loss but does not improve muscle strength and could have adverse effects on metabolic function; 5) both endurance- and resistance-type exercise help preserve muscle mass during weight loss, and resistance-type exercise also improves muscle strength. We therefore conclude that weight-loss therapy, including a hypocaloric diet with adequate (but not excessive) protein intake and increased physical activity (particularly resistance-type exercise), should be promoted to maintain muscle mass and improve muscle strength and physical function in persons with obesity.”

#Kim JY. Optimal Diet Strategies for Weight Loss and Weight Loss Maintenance. J Obes Metab Syndr. 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8017325/ 

Quote: “Traditionally, a very-low-calorie diet (VLCD), which provides <800 kcal a day, is not recommended for routine weight management and should only be used in limited circumstances along with medical monitoring according to obesity guidelines.12 However, a recent review suggested that a VLCD used in combination with behavioral programs can provide greater long-term weight loss than behavioral programs alone, and that it is tolerable and has few adverse effects.17 Additionally, a VLCD with meal replacement is effective for achieving diabetes remission in individuals with obesity lasting for at least 2 years.18,19 Another form of the VLCD—the very-low-calorie ketogenic diet (VLCKD)—has been proposed as a promising option for significant weight loss in a short duration of time and stability for 2 years.20 The VLCKD consists of very-low-calorie (<700–800 kcal/day) and low-carbohydrate (<30–50 g/day) intake along with adequate protein consumption (equivalent to 0.8–1.2 g/day/kg of ideal body weight) for a short period, followed by a gradual switch to a low-calorie diet. The VLCKD program is recommended by the Italian Society of Endocrinology in cases of severe obesity, sarcopenic obesity, obesity associated with T2DM, hypertriglyceridemia, and hypertension.21 However, this program is contraindicated in pregnant women; those with type 1 diabetes mellitus (T1DM), kidney failure, or cardiac arrhythmia; and older patients with frailty.”

#Zhao, Q., Khedkar, S.V. & Johnson, K.C. Weight Loss Interventions and Skeletal Health in Persons with Diabetes. Curr Osteoporos Rep (2022)

https://link.springer.com/article/10.1007/s11914-022-00744-9 

Quote: “Purpose of Review

Weight loss is recommended for improving glycemic control and reducing cardiovascular risk factors in persons with diabetes. However, both diabetes and weight loss have been associated with detrimental skeletal health. This review aims to summarize recent study findings on the effects of lifestyle interventions for weight loss on skeletal health among persons with type 2 diabetes (T2D).

Recent Findings

A few large-scale observational studies have demonstrated an increased fragility fracture risk associated with weight loss among persons with T2D. Randomized control trials in persons with T2D also have shown that intentional lifestyle interventions for weight loss are associated with a greater decrease in bone mineral density (BMD) and an increase in the risk of fracture. The biological mechanisms underlying the compromised bone health during lifestyle interventions for weight loss are complex and not yet conclusive. However, there is evidence to suggest that bone loss and increased fracture risk during intentional weight loss may be mitigated by some intervention approaches, such as high protein intake, calcium supplementation, and resistance and balance training.

Summary

There is still a lack of studies investigating the effects of different interventions for weight loss on skeletal health among persons with T2D. However, certain types of diet and physical activity intervention combined with bone monitoring and fracture risk prediction may help achieve weight loss goals and maintain skeletal health among persons with T2D during intentional weight loss.”

Any diet that involves a temporary change in nutritional intake suffers the risk of weight regain after the diet is over. Below we cite some evidence for common and significant weight regain for both specifically “crash diets” (very-low-calorie diets) and “any diet”, i.e. a temporary dietary intervention used for the purpose of weight reduction.

#Saris, W.H.M. Very-Low-Calorie Diets and Sustained Weight Loss. Obesity Research (2001)

https://onlinelibrary.wiley.com/doi/10.1038/oby.2001.134 

Quote: “Objective: To review of the literature on the topic of very-low-calorie diets (VLCDs) and the long-term weight-maintenance success in the treatment of obesity.

Research Methods and Procedures: A literature search of the following keywords: VLCD, long-term weight maintenance, and dietary treatment of obesity.

Results: VLCDs and low-calorie diets with an average intake between 400 and 800 kcal do not differ in body weight loss. Nine randomized control trials, including VLCD treatment with long-term weight maintenance, show a large variation in the initial weight loss regain percentage, which ranged from −7% to 122% at the 1-year follow-up to 26% to 121% at the 5-year follow-up. There is evidence that a greater initial weight loss using VLCDs with an active follow-up weight-maintenance program, including behavior therapy, nutritional education and exercise, improves weight maintenance.

Conclusions: VLCD with active follow-up treatment seems to be one of the better treatment modalities related to long-term weight-maintenance success.”

#Vink, R.G., Roumans, N.J.T., Arkenbosch, L.A.J., et al. The effect of rate of weight loss on long-term weight regain in adults with overweight and obesity. Obesity (2016)

https://onlinelibrary.wiley.com/doi/full/10.1002/oby.21346 

Quote: “While a dietary intervention (DI) can achieve significant weight loss, the greatest challenge is the seemingly inevitable weight regain in the following years. One year after weight loss, ∼20% of individuals were able to remain weight stable, when weight stable was defined as an intentional weight loss of ≥10% maintained for at least 1 year 3, 4. In a more recent study, participants regained on average ∼70% of their lost weight over 2 years following diet-induced weight loss 5. Insight in the etiology of weight regain and long-term weight management are therefore strongly needed.”

#Flore G, Preti A, Carta MG, et al. Weight Maintenance after Dietary Weight Loss: Systematic Review and Meta-Analysis on the Effectiveness of Behavioural Intensive Intervention. Nutrients. 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC8953094/ 

Quote: “After a low-calorie diet, only 25% of patients succeed in maintaining the result of weight loss for a long time. This systematic review and meta-analysis aims to explore whether patients undergoing intensive intervention during the maintenance phase have a greater preservation of the weight achieved during the previous slimming phase than controls. A bibliographic search was conducted using PubMed, Scopus, and Cochrane databases for clinical trials and randomised, controlled trials investigating the role of choice in weight-loss-maintenance strategies. Only studies with a follow-up of at least 12 months were considered. A total of eight studies, for a total of 1454 patients, was identified, each comparing a group that followed a more intensive protocol to a control group. Our metanalysis highlighted that an intensive approach even in the maintenance phase could be important to ensure greater success in the phase following the weight-loss period. However, it should be pointed out that the improvement was not so different from the trend of the respective controls, with a non-statistically significant mean difference of the effect size (0.087; 95% CI −0.016 to 0.190 p = 0.098). This finding, along with the observation of a weight regain in half of the selected studies, suggests this is a long work that has to be started within the weight-loss phase and reinforced during the maintenance phase. The problem of weight control in patients with obesity should be understood as a process of education to a healthy lifestyle and a balanced diet to be integrated in the context of a multidisciplinary approach.”

– Diets that are sustainable are actually not diets but long term lifestyle changes. But this is painfully slow, so a lot of people quit out of frustration. And among those disciplined enough, results are pretty modest – 5 to 10% of weight lost in a year.

#Finucane FM, Gibson I, Hughes R, et al. Factors associated with weight loss and health gains in a structured lifestyle modification programme for adults with severe obesity: a prospective cohort study. Front Endocrinol (Lausanne). 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10616877/ 

Quote: “Background: Individual responses to behavioural weight loss interventions can vary significantly, and a better understanding of the factors associated with successful treatment might help to target interventions for those who will benefit the most. We sought to identify demographic and clinical characteristics that predicted intervention “success” (defined as ≥5% weight loss) and other health gains in patients with severe obesity attending a ten-week structured lifestyle modification programme.

Methods: We conducted a prospective cohort study of all 1122 patients (751 (66.9%) female, mean age 47.3 ± 11.9 years, mean body mass index (BMI) 46.7 ± 7.8 kgm-2) referred from our hospital-based obesity clinic, who started the structured lifestyle programme between 2012-2019. We compared routine clinical measures such as weight, fitness, blood pressure, lipids and HbA1c at baseline and follow-up. We also used validated questionnaires to quantify anxiety, depression and health-related quality of life.

Results: Of 1122 patients who started, 877 (78.2%) completed the programme and attended for follow up. Of these, 12.8% lost ≥5% body weight. The amount of weight lost was a strong and consistent predictor of improvements in metabolic, cardiovascular, and mental health, even after adjusting for age, sex, programme attendance and baseline fitness. Older age, male sex, being physically active and having lower anxiety and depression scores at baseline predicted greater weight loss. Younger age, depression and longer wait time to start the intervention were associated with drop-out.

Conclusions: In adults with severe obesity completing a structured lifestyle modification programme, older age and good mental health were associated with programme completion and attaining ≥5% weight loss. The magnitude of weight lost was a strong predictor of improvements in cardiovascular, metabolic and mental health associated with programme completion.”

#Kaikkonen KM, Korpelainen R, Vanhala ML, Keinänen-Kiukaanniemi SM, Korpelainen JT. Long-term effects on weight loss and maintenance by intensive start with diet and exercise. Scand J Med Sci Sports. 2023

https://onlinelibrary.wiley.com/doi/10.1111/sms.14269 

Quote: “This 36-month study aimed to determine whether exercise intervention added to weight loss treatment in the beginning or at 6 months is effective for weight loss and long-term weight maintenance. A total of 120 obese adults (body mass index >30) were randomly assigned to intensified behavioral modification (iBM), iBM+ additional exercise from 0 to 3 months (CWT1), iBM+ additional exercise from 6 to 9 months (CWT2), and a control group (CON). Questionnaires and measurements were collected at baseline, 3, 9, 24, and 36 months. The intervention consisted of an 12 months intensified weight-loss period followed by a 24 months weight-maintenance period. Eighty (67%) subjects (mean age 46.0 years, BMI 36.2) completed the trial. Compared with the control group, all three intervention groups had significant weight loss during the 36-month intervention period (p < 0.001). The achieved weight loss remained significant at 36 months in the iBM (−6.8%, p < 0.001), the CWT1 (−5.8%, p < 0.001), and the CWT2 group (−3.9%, p < 0.001). The CWT1 group showed significant reduction in waist circumference at 9 months (−11.3 cm, p < 0.001), at 24 months (−8.8 cm, p < 0.001), and at 36 months (−8.7 cm, p < 0.001). Intensified behavioral modification alone and with exercise resulted in clinically significant weight loss and long-term weight maintenance. The addition of exercise at the onset promoted greater reductions in waist circumference. In the treatment of obesity, including severe obesity, more intensive lifestyle interventions with exercise should be incorporated.”

#Lv N, Azar KMJ, Rosas LG, Wulfovich S, Xiao L, Ma J. Behavioral lifestyle interventions for moderate and severe obesity: A systematic review. Prev Med. 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5503454/ 

Quote: “Moderate and severe obesity (BMI ≥ 35 kg/m2) affect 15% of US adults, with a projected increase over the next two decades. This study reviews evidence of behavioral lifestyle interventions for weight loss in this population. We searched PubMed, PsychInfo, CINAHL®, and Scopus through February 2016 for experimental and quasi-experimental studies that tested a dietary and/or physical activity intervention with a behavioral modification component versus a comparator; and had ≥ six-month follow-up and a weight-related primary outcome. Twelve studies representing 1862 participants (mean BMI 37.5–48.3, mean age 30–54 years) were included. Nine studies compared different behavioral interventions and three tested behavioral intervention(s) versus pharmacological or surgical treatments. Among the 25 behavioral interventions in the 12 studies, 18 reported percent of participants achieving clinically significant weight loss up to 12 months (32–97% achieving 5% or 3–70% achieving 10%). Three studies measured other cardiometabolic risk factors, but showed no significant risk reduction. Seven interventions with greater effectiveness (i.e., at least 31% achieving ≥ 10% or 62% achieving ≥ 5% weight loss up to one year) included multiple components (diet, physical activity, and behavioral strategies), long duration (e.g., one year), and/or intensive contacts (e.g., inpatient stays for clinic-based interventions, weekly contacts for community-based ones). Evidence for the effectiveness of behavioral interventions versus pharmacological or surgical treatment was limited. Comprehensive and intensive behavioral interventions can result in clinically significant, albeit modest, weight loss in this obese subpopulation but may not result significant improvements in other cardiometabolic risk factors. More research on scalable and sustainable interventions is needed.”

#Webb VL, Wadden TA. Intensive Lifestyle Intervention for Obesity: Principles, Practices, and Results. Gastroenterology. 2017

https://www.gastrojournal.org/article/S0016-5085(17)30139-7/fulltext 

Quote: “Using the Guidelines for the Management of Overweight and Obesity in Adults as a framework, this article reviews intensive lifestyle interventions for weight loss. The Guidelines recommend a minimum of 6 months of high-intensity, comprehensive lifestyle intervention, consisting of a reduced-calorie diet, increased physical activity, and behavior therapy. Persons with obesity typically lose approximately 8 kg (approximately 8% of initial weight) with this approach, accompanied by improvements in health and quality of life. To prevent weight regain, the Guidelines recommend a 1-year weight loss maintenance program that includes at least monthly counseling with a trained interventionist. Lifestyle interventions usually are delivered in-person; however, treatment increasingly is being disseminated through community- and commercial-based programs, as well as delivered by telephone, Internet, and smartphone platforms. These latter modalities expand treatment reach but usually produce smaller weight losses than in-person interventions. The review concludes with an examination of challenges in weight management.”

#Wadden TA, Webb VL, Moran CH, Bailer BA. Lifestyle modification for obesity: new developments in diet, physical activity, and behavior therapy. Circulation. 2012

https://pmc.ncbi.nlm.nih.gov/articles/PMC3313649/ 

Quote: “Expert panels sponsored by both the World Health Organization and the National Institutes of Health have recommended that obese adults (ie, body mass index ≥30 kg/m2), as well as those who are overweight (body mass index of 25–29.9 kg/m2) and have comorbid conditions, lose 10% of their initial weight.1,2 A comprehensive program of lifestyle modification is considered the first option for achieving this goal.2 Lifestyle modification, also referred to as behavioral weight control, includes 3 primary components: diet, exercise, and behavior therapy.3 This narrative review examines weight losses achieved with this approach, as well as new developments with each of the 3 components.

[...]

A comprehensive program of lifestyle modification produces a 7% to 10% reduction in initial weight that is associated with clinically meaningful improvements in several CVD risk factors, including the prevention of type 2 diabetes.”

– The new drugs change that completely. In 3 months you can lose 10% of your initial weight. Three months later, over 15. And after a year, you may reach more than 20% – a level of weight loss that used to only really be achievable through bariatric surgery.

The rates and amount of weight loss on GLP-1 agonists depends on the specific drug used, its dosage, administration route (oral vs. subcutaneous), frequency of administration, duration of treatment, and whether or not lifestyle interventions are implemented at the same time (and to what degree they are adhered to).

The numbers we use here are based on a recent, large randomized controlled trial on the efficacy of 15 mg Tirzepatide administered once weekly.

#Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022

https://www.nejm.org/doi/full/10.1056/NEJMoa2206038 

“Effect of Once-Weekly Tirzepatide, as Compared with Placebo, on Body Weight.

[...] Panel B shows the percent change in body weight according to weeks since randomization, derived from a mixed model for repeated measures (MMRM) analysis for the efficacy estimand; week 72 estimates for the treatment-regimen estimand are also shown.”

There is also a recent meta-analysis summarizing weight loss outcomes across both commercially available and pre-market GLP-1 agonists tested in clinical trials.

#Areesha Moiz, Kristian B. Filion, Helia Toutounchi, et al. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials. Ann Intern Med. 2025

https://www.weniger-kg.de/wp-content/uploads/10.7326_ANNALS-24-01590.pdf 

Quote: “A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m2; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare.”

Typical weight loss achieved with bariatric surgery depends on the type of surgery, the age of the patient, pre-surgery BMI and other factors. Through the most common type of bariatric surgery (gastric sleeve) it is not uncommon to achieve long-term weight loss results in excess of 20% within 1 year post-operation.

#Masry, M.A.M.E., Fiky, M.A.M.E. Long-Term Outcome of Laparoscopic Sleeve Gastrectomy (LSG) on Weight Loss in Patients with Obesity: a 5-Year and 11-Year Follow-Up Study. Obes Surg (2023)

https://link.springer.com/article/10.1007/s11695-023-06781-2 

Quote: “At the 1-year follow-up, data on 860 patients were available, while at the 5-year and 11-year follow-ups, data on 193/548 and 48/93 patients, respectively, were available.

The patients’ mean BMI at the 1-year follow-up was 29.76 ± 5.75 kg/m2, the mean EBWL% [excess body weight loss] was 84.57 ± 18.41%, and the mean TWL% [total weight loss] was 35.14 ± 6.51%.”

– We can’t stress enough how unhealthy obesity is, causing everything from diabetes to heart attacks and cancer. 

Diabetes:

#Garg C, Daley SF. Obesity and Type 2 Diabetes. [Updated 2025 Jun 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025

https://www.ncbi.nlm.nih.gov/books/NBK592412/ 

Quote: “The lifetime risk of developing diabetes in men aged 18 or older increases from 7% to 70% as the body mass index (BMI) increases from less than 18.5 kg/m2 to over 35 kg/m2. In women, the risk increases from 12% to 74% across the same BMI values.[3] Given this strong association, diabetes screening is recommended for all patients with obesity. Managing obesity is crucial for both the prevention and treatment of T2D. Weight loss leads to a significant reduction in the incidence of diabetes in at-risk populations. In a study, lifestyle modifications, including modest weight reduction (5%-10% of baseline weight) and at least 150 minutes of physical activity per week, led to over a 50% reduction in the incidence of diabetes.[4]”

Heart attacks:

#Leggio, M., Lombardi, M., Caldarone, E. et al. The relationship between obesity and hypertension: an updated comprehensive overview on vicious twins. Hypertens Res (2017)
https://doi.org/10.1038/hr.2017.75
Quote: “There is a clearly established link between obesity and hypertension.28,29,56,57 The accumulation of excess adipose tissue initiates a cascade of events that give rise to an elevated blood pressure; obesity-induced hypertension is a common pathway in both children and adults.29,58,59 Pathogenetic factors and pathophysiological mechanisms linking obesity to hypertension (Figure 1) are described and reviewed herein as they provide the basis for a rational therapeutic strategy. 

[...]

Hypertension is a complex phenotype that arises from numerous genetic, environmental (including air pollution26), behavioral and even social origins, and obesity is one of the most prevalent risk factors for its development. Regardless of its etiology, however, hypertension is a highly prevalent and highly significant risk factor for the development of all manifestations of cardiovascular disease, including coronary heart disease, stroke, heart failure, aortic and peripheral arterial disease, and valvular heart disease. The association of hypertension with cardiovascular risk in the short and long term is unequivocally established. The association of obesity with short-term cardiovascular disease event rates (for example, in the next 10 years) is more difficult to establish, largely because the major effects of obesity appear to act through more proximal risk factors, such as diabetes, dyslipidemia and hypertension. However, longer-term studies of obesity and cardiovascular disease do indicate risk for cardiovascular disease associated with obesity independent of these other risk factors.”

#Parvanova, Aneliya et al. “Mechanisms and treatment of obesity-related hypertension-Part 1: Mechanisms.” Clinical Kidney Journal 2023
https://pubmed.ncbi.nlm.nih.gov/38186879/
Quote: “Obesity, especially when associated with increased visceral and ectopic fat expansion, is a major cause of hypertension and related cardiovascular and kidney injury. Obesity-related hypertension is initiated by increased renal sodium reabsorption and plasma volume expansion due to renal compression by perirenal/sinus fat and moderate increases in systemic/renal SNS and RAAS activity sustained by a complex interplay among hyperleptinemia, AngII, intermedin, adrenomedullin, and impaired baroreceptor and chemoreceptor reflexes. This manuscript overviews a series of pathophysiological mechanisms involved in the pathogenesis of obesity-related hypertension—such as leptin resistance, impaired baroreceptor and chemoreceptor reflexes, increased renal sympathetic nervous activity, mitochondrial dysfunction, the regulatory role of intermedin, adrenomedullin and sPRR—that could be the target of specific and selective therapeutic interventions in the innovative context of precision medicine.”

Cancer:

#Islami, Farhad et al. “Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States, 2019.” CA: a cancer journal for clinicians (2024)
https://pubmed.ncbi.nlm.nih.gov/38990124/
Quote: “In 2019, an estimated 40.0% (713,340 of 1,781,649) of all incident cancers (excluding nonmelanoma skin cancers) and 44.0% (262,120 of 595,737) of all cancer deaths in adults aged 30 years and older in the United States were attributable to the evaluated risk factors. Cigarette smoking was the leading risk factor contributing to cancer cases and deaths overall (19.3% and 28.5%, respectively), followed by excess body weight (7.6% and 7.3%, respectively), and alcohol consumption (5.4% and 4.1%, respectively). For 19 of 30 evaluated cancer types, more than one half of the cancer cases and deaths were attributable to the potentially modifiable risk factors considered in this study. Lung cancer had the highest number of cancer cases (201,660) and deaths (122,740) attributable to evaluated risk factors, followed by female breast cancer (83,840 cases), skin melanoma (82,710), and colorectal cancer (78,440) for attributable cases and by colorectal (25,800 deaths), liver (14,720), and esophageal (13,600) cancer for attributable deaths. Large numbers of cancer cases and deaths in the United States are attributable to potentially modifiable risk factors, underscoring the potential to substantially reduce the cancer burden through broad and equitable implementation of preventive initiatives.”

#Pati Sukanya, Wadeed Irfan, Ahmad Jameel, et al. Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management. Cancers (2023)
https://doi.org/10.3390/cancers15020485
Quote: “Background: Obesity or excess body fat is a major global health challenge that has not only been associated with diabetes mellitus and cardiovascular disease but is also a major risk factor for the development of and mortality related to a subgroup of cancer. This review focuses on epidemiology, the relationship between obesity and the risk associated with the development and recurrence of cancer and the management of obesity. Methods: A literature search using PubMed and Google Scholar was performed and the keywords ‘obesity’ and cancer’ were used. The search was limited to research papers published in English prior to September 2022 and focused on studies that investigated epidemiology, the pathogenesis of cancer, cancer incidence and the risk of recurrence, and the management of obesity. Results: About 4–8% of all cancers are attributed to obesity. Obesity is a risk factor for several major cancers, including post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancer. Excess body fat results in an approximately 17% increased risk of cancer-specific mortality. The relationship between obesity and the risk associated with the development of cancer and its recurrence is not fully understood and involves altered fatty acid metabolism, extracellular matrix remodeling, the secretion of adipokines and anabolic and sex hormones, immune dysregulation, and chronic inflammation. Obesity may also increase treatment-related adverse effects and influence treatment decisions regarding specific types of cancer therapy. Structured exercise in combination with dietary support and behavior therapy are effective interventions. Treatment with glucagon-like peptide-1 analogues and bariatric surgery result in more rapid weight loss and can be considered in selected cancer survivors. Conclusions: Obesity increases cancer risk and mortality. Weight-reducing strategies in obesity-associated cancers are important interventions as a key component of cancer care. Future studies are warranted to further elucidate the complex relationship between obesity and cancer with the identification of targets for effective interventions.” 

#NIH, National Cancer Institute. Obesity and Cancer. January 28, 2025
https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet
Quote: “A 2024 study examined whether the increasing incidence of early-onset cancers over the period 2000 to 2012 worldwide could be explained by increasing rates of obesity among young adults over this period (46). Six of nine obesity-related cancers increased in incidence among young adults during this period, and for four of these cancers (colon, rectal, pancreatic, and kidney), this rise was associated with increases in body weight. This finding suggests a possible link between the obesity epidemic and the rising incidence in these early-onset cancers worldwide (46). Obesity has also been linked to increased risks of early-onset breast cancer in Black women (47, 48).” 

#Steele CB, Thomas CC, Henley SJ, et al. Vital Signs: Trends in Incidence of Cancers Associated with Overweight and Obesity — United States, 2005–2014. MMWR Morb Mortal Wkly Rep 2017
https://www.cdc.gov/mmwr/volumes/66/wr/mm6639e1.htm
Quote: “Results: In 2014, approximately 631,000 persons in the United States received a diagnosis of a cancer associated with overweight and obesity, representing 40% of all cancers diagnosed. Overweight- and obesity-related cancer incidence rates were higher among older persons (ages ≥50 years) than younger persons; higher among females than males; and higher among non-Hispanic black and non-Hispanic white adults compared with other groups. Incidence rates for overweight- and obesity-related cancers during 2005–2014 varied by age, cancer site, and state. Excluding colorectal cancer, incidence rates increased significantly among persons aged 20–74 years; decreased among those aged ≥75 years; increased in 32 states; and were stable in 16 states and the District of Columbia.”

#Pati S, Irfan W, Jameel A, Ahmed S, Shahid RK. Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management. Cancers (Basel). 2023
https://pmc.ncbi.nlm.nih.gov/articles/PMC9857053/
Quote: “Results: About 4–8% of all cancers are attributed to obesity. Obesity is a risk factor for several major cancers, including post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancer. Excess body fat results in an approximately 17% increased risk of cancer-specific mortality. The relationship between obesity and the risk associated with the development of cancer and its recurrence is not fully understood and involves altered fatty acid metabolism, extracellular matrix remodeling, the secretion of adipokines and anabolic and sex hormones, immune dysregulation, and chronic inflammation.” 

#Sun, Ming et al. Body mass index and risk of over 100 cancer forms and subtypes in 4.1 million individuals in Sweden: the Obesity and Disease Development Sweden (ODDS) pooled cohort study. The Lancet Regional Health – Europe. 2024

https://pubmed.ncbi.nlm.nih.gov/39253735/
Quote: “The findings of this study have important public health implications. Established obesity-related cancers accounted for 25% of all cancer cases in this study, and the proportion increased to 40% when potential obesity-related cancers were added. Therefore, a substantial proportion of cancers could potentially be prevented by implementing public health measures enabling and advocating a healthy lifestyle to keep a normal weight, or to reduce weight with the same measures or by obesity treatment. Cancer risk has been shown to reduce after bariatric surgery of individuals with obesity, which could be an effect of the resulting weight loss.35 Nevertheless, our findings, particularly of rarer cancers, should be verified in future studies and in updated systematic reports weighing the total epidemiological and biological mechanistic evidence to conclude which cancers are likely to be caused by obesity.”

#Safizadeh F, Mandic M, Hoffmeister M, Brenner H. Reevaluating the fraction of cancer attributable to excess weight: overcoming the hidden impact of prediagnostic weight loss. Eur J Epidemiol. 2024
https://link.springer.com/article/10.1007/s10654-024-01146-0
Quote: “A study evaluating the proportion of cancer cases attributable to modifiable riskfactors in the United States estimated that 7.8% (men: 4.8%, women:10.9%) of cancer cases in 2014 were attributable to excess weight [11]. The higher PAF estimates compared to the study of Brown et al. for the UK for 2015 may primarily reflect the much higher prevalence of obesity in the United States. This prevalence have further increased in recent years, with 30.7% and 42.4% of adults being overweight and obese in the US in 2017–2018 [35], and 37.9% and 25.9% of adults being overweight and obese in the UK in 2021 [36], respectively. It is plausible to assume that due consideration of prediagnostic weight loss would likewise have led to higher PAF estimates for the US in 2014, and that these PAFs further increased in the meantime due to the ongoing obesity epidemic in the past decades.”

#Avgerinos KI, Spyrou N, Mantzoros CS, Dalamaga M. Obesity and cancer risk: Emerging biological mechanisms and perspectives. Metabolism. 2019
https://pubmed.ncbi.nlm.nih.gov/30445141/
Quote: “Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype.”

– Treatment with semaglutide cuts your risk of stroke or heart attack by 20%.

This reduction in the risk of primary cardiovascular end-point events, such as strokes and heart attacks, was shown in a large randomized trial in patients with obesity and pre-existing cardiovascular disease treated with either placebo or semaglutide. It is unclear whether the cardiovascular-protective effect is also present in people who are not obese and/or do not have pre-existing cardiovascular problems.

The study reports the risk reduction of 20% after the median treatment time of 34 months (2-3 years), but as observed in Fig. 1A shown below, the placebo and semaglutide treatment “arms” diverge much earlier than that, suggesting an effect is already present a few months into treatment. 

Of note: this study was funded by Novo Nordisk, the drug company producing the tested semaglutide.

#Lincoff AM, Brown-Frandsen K, Colhoun HM,  et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023

https://www.nejm.org/doi/10.1056/NEJMoa2307563 

Quote: “Background

Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.

Methods

In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.

Results

A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).

Conclusions

In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.)”

There is also evidence that albiglutide (a GLP-1 agonist used to treat type 2 diabetes) can help prevent strokes of heart attacks in people with diabetes and cardiovascular disease:

#Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32261-X/abstract 

Quote: “Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68-0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.”

– 17 months of tirzepatide crashes your chances of developing diabetes by 66%. 

The study we are referring to (cited below) predicts the risk of developing diabetes after 72 weeks of treatment with Tirzepatide.

#Hankosky ER, Wang H, Neff LM, et al. Tirzepatide reduces the predicted risk of developing type 2 diabetes in people with obesity or overweight: Post hoc analysis of the SURMOUNT-1 trial. Diabetes Obes Metab. 2023

https://doi.org/10.1111/dom.15269 

Quote: “The median relative risk reductions at week 72 ranged from 60.3% to 69.0% for the tirzepatide treatment groups versus 10.8% for the placebo group (Figure 1B). The difference in risk reduction between tirzepatide dose groups (5, 10 and 15 mg) and placebo was −11.7%, −13.7% and −14.0%, respectively (p < .001 for all).”

A different study on Tirzepatide also reports incidence rate reductions for new-onset diabetes after several months/years of treatment.

#Pardeshi G, Kumbhar UT, Kaviprawin M, et al. Effect of Tirzepatide on the Risk of Developing Type 2 Diabetes Mellitus Among the People Living With Obesity or Overweight: A Systematic Review. Clin Obes. 2025

https://onlinelibrary.wiley.com/doi/10.1111/cob.70042 

Quote: “Tirzepatide provides superior efficacy in weight reduction and metabolic control compared to existing therapies. The present systematic review assessed the effect of Tirzepatide on the risk of developing type 2 diabetes mellitus (T2DM) among people living with obesity or overweight. Six major databases [MEDLINE (PubMed), ClinicalTrials.gov, EMBASE, Scopus, Web of Science and Cochrane Library] were searched for potential studies published till 10 July 2025. Two-stage dual screening with third-person adjudication was adopted for screening of studies. PROSPERO ID: CRD42024614466. RoB 2.0 and the Newcastle-Ottawa Scale were used to assess the quality of randomised controlled trials (RCTs) and cohort studies, respectively. Database search yielded 2601 studies, among which three studies were eligible (one RCT and two cohort studies) for systematic review. The hazard ratio (HR) for the new-onset diabetes at 12 months following the Tirzepatide intake was significantly lower than that of the Semaglutide group of patients (HR = 0.73, p < 0.001 [95% CI: 0.58-0.92]). The risk of the new-onset diabetes for 176 weeks (HR = 0.07, p < 0.001 [95% CI: < 0.01-0.1]) and 193 weeks (HR = 0.12, p < 0.001 [95% CI: 0.1-0.2]) following the Tirzepatide intake was significantly lower than that of the placebo group of patients. Tirzepatide might have significant efficacy in the prevention of T2DM in patients with obesity or overweight.”

– They also reduce sleep apnoea, improve kidney and liver function, lower inflammation, cut cancer risk, and may potentially slow Alzheimer's.

General overview of health benefits of GLP-1 drugs: 

#Daniel J. Drucker. The benefits of GLP-1 drugs beyond obesity. Science (2024).

https://www.glucagon.com/pdfs/Druckerscience.adn4128.pdf 

Quote: “Glucagon-like peptide–1 (GLP-1) is secreted from gut endocrine cells in response to food ingestion and acts as an incretin hormone to potentiate glucose-dependent insulin secretion. Pharmacological GLP-1 receptor (GLP- 1R) activation reduced glucagon secretion (which raises blood glucose) and gastric emptying, leading to the development of GLP-1 therapies for the treatment of type 2 diabetes (T2D). GLP-1R is expressed on several pancreatic islet cell types and within multiple regions of the central nervous system. Subsequent studies revealed that exogenous GLP-1 administration inhibited food intake through brain GLP-1R activation in animals and humans, leading to weight loss. The decades-long use of GLP-1 medicines, principally acylated peptides such as liraglutide and semaglutide, for the treatment of obesity and T2D (1) has revealed that they also exert pleiotropic actions beyond glucose and weight control, such as reduction of heart and kidney diseases. There are several potential mechanisms underlying these benefits, such as reducing systemic inflammation (2), which have implications for future clinical applications and drug development.”

Sleep apnoea:

#Kow CS, Ramachandram DS, Hasan SS, Thiruchelvam K. Efficacy and safety of GLP-1 receptor agonists in the management of obstructive sleep apnea in individuals without diabetes: A systematic review and meta-analysis of randomized, placebo-controlled trials. Sleep Med. 2025

https://doi.org/10.1016/j.sleep.2025.02.010 

Quote: “Introduction

Obstructive sleep apnea (OSA) is a common sleep disorder that disrupts breathing during sleep. While continuous positive airway pressure therapy is the standard treatment, poor adherence has led to exploration of alternative treatments. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce body weight and may help manage OSA. This systematic review and meta-analysis evaluated the efficacy and safety of GLP-1 RAs in individuals with OSA and elevated body weight who are without diabetes.

Methods

A systematic search was conducted in September 2024 across multiple databases. Randomized controlled trials (RCTs) evaluating GLP-1 RAs for OSA in adults with a body mass index (BMI) ≥30 kg/m2 were included. The primary outcomes were changes in the apnea-hypopnea index (AHI) and overall adverse events. Meta-analyses were performed using a random-effects model.

Results

Three RCTs were included in the analysis. Pooled results showed that GLP-1 RA treatment significantly reduced AHI compared to placebo, with a weighted mean difference (WMD) of −16.6 events per hour (95 % confidence interval [CI]: −27.9 to −5.3). However, GLP-1 RAs were associated with a higher frequency of adverse events, with an odds ratio (OR) of 1.62 (95 % CI: 1.16 to 2.24) compared to placebo.

Conclusion

GLP-1 RAs effectively reduce OSA severity, offering a promising alternative for individuals with OSA and elevated body weight. However, the increased risk of side effects must be considered. Further long-term studies are needed to confirm the sustained benefits and safety of GLP-1 RAs in OSA management.”

Kidney function:

#Badve, Sunil V et al. Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. The Lancet Diabetes & Endocrinology. 2025

https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00271-7/abstract 

Quote: “Background

GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACE) and can also have kidney benefits. However, whether GLP-1 receptor agonists improve clinically important kidney outcomes remains uncertain. We aimed to comprehensively assess the effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes by performing a meta-analysis of randomised controlled trials.

Methods

For this meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials that included at least 500 participants with type 2 diabetes, compared a GLP-1 receptor agonist with placebo with at least 12 months of follow-up, and reported a primary clinical kidney or cardiovascular outcome, from database inception to March 26, 2024. Post hoc, we included the SELECT trial (NCT03574597), which enrolled participants with cardiovascular disease and a BMI of 27 kg/m2 or more without diabetes. Study-level summary data were extracted independently by two authors for inclusion in this random-effects analysis. The main kidney outcome was a composite outcome, consisting of kidney failure (kidney replacement therapy or a persistent estimated glomerular filtration rate [eGFR] <15 mL/min per 1·73 m2), a sustained reduction in eGFR by at least 50% or the nearest equivalent, or death from kidney failure. The main cardiovascular outcome was MACE, consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. This study is registered with PROSPERO, CRD42024528864.

Findings

Of the 5140 records identified through the literature search, 11 trials, involving 85 373 participants (29 386 female, 55 987 male), were included in the meta-analysis. In participants with type 2 diabetes (67 769), GLP-1 receptor agonists reduced the composite kidney outcome by 18% compared with placebo (hazard ratio [HR] 0·82, 95% CI 0·73–0·93; I2 =26·41%), kidney failure by 16% (HR 0·84, 0·72–0·99; I2 =0%), MACE by 13% (HR 0·87, 0·81–0·93; I2 =49·75%), and all-cause death by 12% (HR 0·88, 0·83–0·93; I2 =0%). The effect on the composite kidney outcome (HR 0·81, 95% CI 0·72–0·92; I2 =23·11%), kidney failure (HR 0·84, 0·72–0·98; I2 =0%), MACE (HR 0·86, 0·80–0·92; I2 =48·9%), and all-cause death (HR 0·87, 0·82–0·91; I2 =0%) was similar when the SELECT trial was included, with no evidence of heterogeneity between this trial and those including participants with type 2 diabetes (pheterogeneity >0·05). There was no difference in the risk of serious adverse events, including acute pancreatitis and severe hypoglycaemia, between the GLP-1 receptor agonist and placebo groups (risk ratio [RR] 0·95, 95% CI 0·90–1·01; I2 =88·5%). However, treatment discontinuation due to adverse events occurred more frequently in the GLP-1 receptor agonist groups (RR 1·51, 95% CI 1·18–1·94; I2 =96·3%).

Interpretation

We found evidence that GLP-1 receptor agonists significantly reduce clinically important kidney events, kidney failure, and cardiovascular events.”

Liver function:

#Liao C, Liang X, Zhang X, Li Y. The effects of GLP-1 receptor agonists on visceral fat and liver ectopic fat in an adult population with or without diabetes and nonalcoholic fatty liver disease: A systematic review and meta-analysis. PLoS One. 2023

https://pmc.ncbi.nlm.nih.gov/articles/PMC10449217/ 

Quote: “Aim

To uncover the effect of GLP-1 receptor agonists (GLP-1 RAs) on the visceral- and hepatic fat content of adults.

Methods

PubMed, EMBASE, Cochrane Library, and Web of Science were searched from inception until November 2022. Randomized controlled trials (RCTs) of GLP-1Ras was extracted, including reports of effects on visceral adipose tissue and hepatic fat content in individuals with type 2 diabetes, non-type 2 diabetes, NAFLD (non-alcoholic fatty liver disease), and non-NAFLD. Meta-analyses used random-effects models.

Results

1736 individuals in the 30 qualified RCTs were included, comprising 1363 people with type 2 diabetes and 318 with NFLD. GLP-1 RAs reduced visceral adipose tissue (standard mean difference [SMD] = -0.59, 95% CI [-0.83, -0.36], P<0.00001) and hepatic fat content (weighted mean difference [WMD] = -3.09, 95% CI [-4.16, -2.02], P<0.00001) compared to other control treatment. Subgroup analysis showed that GLP-1Ras dramatically decreased visceral fat in patients with type 2 diabetes (SMD = -0.49, 95% CI [-0.69, -0.29] P<0.00001), NAFLD (SMD = -0.99, 95% CI [-1.64, -0.34] P = 0.003), non-type 2 diabetes (SMD = -1.38, 95% CI [-2.44, -0.32] P = 0.01), and non-NAFLD (SMD = -0.53, 95% CI [-0.78, -0.28] P<0.0001). GLP-1Ras reduced the liver fat level of type 2 diabetes (WMD = -3.15, 95% CI [-4.14, -2.15] P<0.00001), NAFLD (WMD = -3.83, 95% CI [-6.30, -1.37] P = 0.002), and type 2 diabetes with NAFLD (WMD = -4.27, 95% CI [-6.80, -1.74] P = 0.0009), while showed no impact on the hepatic fat content in non-Type 2 diabetes (WMD = −12.48, 95% CI [−45.19, 20.24] P = 0.45).

Conclusions

LP-1 RAs significantly reduce visceral- and liver fat content in adults.”

#Kanwal F, Kramer JR, Li L, et al. GLP-1 Receptor Agonists and Risk for Cirrhosis and Related Complications in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease. JAMA Intern Med. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11406452/ 

Quote: “Question

Is use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) associated with lower incidence of cirrhosis and its complications in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)?

Findings

In this cohort study of 16 058 patients (14 606 without and 1452 with cirrhosis), GLP-1 RA use was associated with a statistically significant reduction in the risk of progression to cirrhosis and its complications in patients with MASLD and diabetes than use of an active comparator treatment. The chemopreventive benefit was limited to patients who initiated GLP-1 RAs earlier in the disease course; patients who started GLP-1 RAs after they had already progressed to cirrhosis did not have lower rates of progression to hepatic decompensation or hepatocellular cancer.

Meaning

If confirmed by clinical trials, GLP-1 RAs show promise as chemopreventive agents for cirrhosis and its complications in patients with MASLD and diabetes.”

#Nevola, R.; Epifani, R.; Imbriani, S.; et al. GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int. J. Mol. Sci. 2023

https://www.mdpi.com/1422-0067/24/2/1703 

Quote: “To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.”

#Lee, H.A.; Kim, H.Y. Therapeutic Mechanisms and Clinical Effects of Glucagon-like Peptide 1 Receptor Agonists in Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2023

https://www.mdpi.com/1422-0067/24/11/9324 

Quote: “Nonalcoholic fatty liver disease (NAFLD) can lead to liver fibrosis and cirrhosis. Recently, glucagon-like peptide 1 receptor agonists (GLP-1RAs), a class of drugs used to treat type 2 diabetes and obesity, have shown therapeutic effects against NAFLD. In addition to reducing blood glucose levels and body weight, GLP-1RAs are effective in improving the clinical, biochemical, and histological markers of hepatic steatosis, inflammation, and fibrosis in patients with NAFLD. Additionally, GLP-1RAs have a good safety profile with minor side effects, such as nausea and vomiting. Overall, GLP-1RAs show promise as a potential treatment for NAFLD, and further studies are required to determine their long-term safety and efficacy.”

Inflammation:

#Ngabea Murtala, Igbayilola Yusuff Dimeji. GLP-1 Receptor Agonists and Inflammatory Pathway Modulation: Dual Targeting of Metabolic and Immune Dysfunction in Insulin Resistance. Biochemical and Biophysical Research Communications. 2025

https://doi.org/10.1016/j.bbrc.2025.152822 

Quote: “Because of their extensive effects on glycaemic management and weight loss, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are showing promise as therapeutic agents in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Their therapeutic use over the past few years is no longer restricted to glucose metabolism only, but increasingly, more evidence is suggesting their anti-inflammatory actions. Low-grade inflammation for prolonged periods is a important participant in the pathogenesis of insulin resistance and metabolic syndrome. It has been demonstrated that GLP-1RAs influence immune functions and suppress inflammation via influencing key signalling pathways, such as c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and the nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome. These signaling pathways are involved in cellular stress responses and cytokine production resulting in insulin resistance. By modulating both inflammatory and metabolic targets, GLP-1RAs are a potential class of immunometabolic modulators. This mini-review emphasizes the dual impact of GLP-1RAs and their therapeutic application in the overall management of insulin resistance and metabolic disorders.”

#Wong CK, McLean BA, Baggio LL, et al. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab. 2024

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00420-5 

Quote: “Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.”

#Daniel J. Drucker. The benefits of GLP-1 drugs beyond obesity. Science (2024)

https://www.glucagon.com/pdfs/Druckerscience.adn4128.pdf 

Quote: “Glucagon-like peptide–1 (GLP-1) is secreted from gut endocrine cells in response to food ingestion and acts as an incretin hormone to potentiate glucose-dependent insulin secretion. Pharmacological GLP-1 receptor (GLP- 1R) activation reduced glucagon secretion (which raises blood glucose) and gastric emptying, leading to the development of GLP-1 therapies for the treatment of type 2 diabetes (T2D). GLP-1R is expressed on several pancreatic islet cell types and within multiple regions of the central nervous system. Subsequent studies revealed that exogenous GLP-1 administration inhibited food intake through brain GLP-1R activation in animals and humans, leading to weight loss. The decades-long use of GLP-1 medicines, principally acylated peptides such as liraglutide and semaglutide, for the treatment of obesity and T2D (1) has revealed that they also exert pleiotropic actions beyond glucose and weight control, such as reduction of heart and kidney diseases. There are several potential mechanisms underlying these benefits, such as reducing systemic inflammation (2), which have implications for future clinical applications and drug development.”

Cancer risk:

#Dai H, Li Y, Lee YA, Lu Y, et al. GLP-1 Receptor Agonists and Cancer Risk in Adults With Obesity. JAMA Oncol. 2025

https://pubmed.ncbi.nlm.nih.gov/40839273/ 

Quote: “Importance: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely prescribed for glycemic control in type 2 diabetes and have recently gained popularity for weight management. However, their long-term impact on cancer risk remains uncertain. Understanding this association is crucial for patient safety.

Objective: To compare the incidence of 14 cancers among adults with obesity prescribed GLP-1RAs vs nonusers.

Design, setting, and participants: This retrospective cohort study followed a target trial emulation design using 2014 to 2024 electronic health record data from OneFlorida+, a multicenter health research network that integrates real-world clinical data from diverse health care settings. Adults 18 years or older eligible for antiobesity medications without prior cancer history were included. Participants were categorized as GLP-1RA users or nonusers, matched 1:1 using propensity scores.

Exposure: Individuals taking vs not taking GLP-1RAs.

Main outcomes and measures: The primary outcomes were the incidence of 14 cancer types, including 13 obesity-associated cancers (liver, thyroid, pancreatic, bladder, colorectal, kidney, breast, endometrial, meningioma, upper gastrointestinal, ovarian, multiple myeloma, and prostate) and lung cancer.

Results: A total of 86 632 matched adults (mean [SD] age, 52.4 [14.5] years; 68.2% female) were included, comprising 43 317 GLP-1RA users and 43 315 otherwise eligible nonusers. The incidence rates of the 14 cancers were 13.6 vs 16.4 per 1000 person-years, respectively, indicating a significantly lower overall cancer risk among individuals taking GLP-1RAs (hazard ratio [HR], 0.83 [95% CI, 0.76-0.91]; P = .002) compared with nonusers. In particular, taking GLP-1RAs was associated with a reduced risk of endometrial cancer (HR, 0.75 [95% CI, 0.57-0.99]; P = .05), ovarian cancer (HR, 0.53 [95% CI, 0.29-0.96]; P = .04), and meningioma (HR, 0.69 [95% CI, 0.48-0.97]; P = .05). However, GLP-1RAs were associated with a marginally nonsignificant increased risk of kidney cancer (HR, 1.38 [95% CI, 0.99-1.93]; P = .04).

Conclusions and relevance: This retrospective cohort study found that taking GLP-1RAs was associated with a reduced overall risk of cancer, including lower risks of endometrial, ovarian, and meningioma cancers, among patients with obesity or overweight. However, taking GLP-1RAs may be associated with an increased risk of kidney cancer, highlighting the need for longer-term follow-up to clarify the underlying mechanisms and clinical implications of these findings.”

#Wang L, Xu R, Kaelber DC, Berger NA. Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes. JAMA Netw Open. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11227080/ 

Quote: “Question

Is there clinical evidence supporting the potential benefits of glucagon-like peptide receptor agonists (GLP-1RAs) for the prevention of 13 obesity-associated cancers (OACs)?

Findings

This cohort study of more than 1.6 million patients with type 2 diabetes (T2D) who had no prior diagnosis of 13 OACs found that patients with T2D treated with GLP-1RAs vs insulin had a significant risk reduction in 10 of 13 OACs, including esophageal, colorectal, endometrial, gallbladder, kidney, liver, ovarian, and pancreatic cancer as well as meningioma and multiple myeloma. No decrease in cancer risk was associated with GLP-1RAs compared with metformin.

Meaning

This study provides clinical data suggesting that GLP-1RAs may reduce the risk of specific OACs compared with insulins.”

Alzheimers:

There are no large randomized controlled trials yet that look at how GLP-1 agonist drugs affect Alzheimer risks, but there is some preclinical evidence suggesting a protective effect.

#Teixeira, L.C.R.; Luizon, M.R.; Gomes, K.B. Exploring the Role of GLP-1 Receptor Agonists in Alzheimer’s Disease: A Review of Preclinical and Clinical Evidence. Receptors 2025

https://www.mdpi.com/2813-2564/4/1/2 

Quote: “Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including dulaglutide, liraglutide, semaglutide, and exenatide, are effective treatments for type 2 diabetes mellitus (T2DM) and obesity. These agents mimic the action of the endogenous incretin glucagon-like peptide-1 (GLP-1) by enhancing insulin secretion, inhibiting glucagon release, and promoting weight loss through appetite suppression. GLP-1RAs have recently been suggested to have neuroprotective effects, suggesting their potential as treatment for neurodegenerative disorders, such as Alzheimer’s disease (AD). AD and T2DM share several common pathophysiological mechanisms, including insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction. These shared mechanisms suggest that therapeutic agents targeting metabolic dysfunction may also be beneficial for neurodegenerative conditions. Preclinical studies on GLP-1RAs in AD models, both in vitro and in vivo, have demonstrated promising neuroprotective effects, including reductions in amyloid-beta accumulation, decreased tau hyperphosphorylation, improved synaptic plasticity, and enhanced neuronal survival. Despite the encouraging results from preclinical models, several challenges need to be addressed before GLP-1RAs can be widely used for AD treatment. Ongoing clinical trials are investigating the potential cognitive benefits of GLP-1RAs in AD patients, aiming to establish their role as a therapeutic option for AD. This review aimed to examine the current literature on preclinical and clinical studies investigating GLP-1 receptor agonists as potential therapeutic agents for AD.”

#Tang H, Donahoo WT, DeKosky ST, et al. GLP-1RA and SGLT2i Medications for Type 2 Diabetes and Alzheimer Disease and Related Dementias. JAMA Neurol. 2025

https://bsmedia.business-standard.com/_media/bs/data/general-file-upload/2025-04/GLP-1RA%20and%20SGLT2i%20Medications%20for%20Type%202%20Diabetes.pdf 

Quote: “Importance: The association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) and risk of Alzheimer disease and related dementias (ADRD) remains to be confirmed.

Objective: To assess the risk of ADRD associated with GLP-1RAs and SGLT2is in people with type 2 diabetes (T2D).

Design, setting, and participants: This target trial emulation study used electronic health record data from OneFlorida+ Clinical Research Consortium from January 2014 to June 2023. Patients were 50 years or older with T2D and no prior diagnosis of ADRD or antidementia treatment. Among the 396 963 eligible patients with T2D, 33 858 were included in the GLP-1RA vs other glucose-lowering drug (GLD) cohort, 34 185 in the SGLT2i vs other GLD cohort, and 24 117 in the GLP-1RA vs SGLT2i cohort.

Exposures: Initiation of treatment with a GLP-1RA, SGLT2i, or other second-line GLD.

Main outcomes and measures: ADRD was identified using clinical diagnosis codes. Hazard ratios (HRs) with 95% CIs were estimated using Cox proportional hazard regression models with inverse probability of treatment weighting (IPTW) to adjust for potential confounders.

Results: This study included 33 858 patients in the GLP-1RA vs other GLD cohort (mean age, 65 years; 53.1% female), 34 185 patients in the SGLT2i vs other GLD cohort (mean age, 65.8 years; 49.3% female), and 24 117 patients in the GLP-1RA vs SGLT2i cohort (mean age, 63.8 years; 51.7% female). In IPTW-weighted cohorts, the incidence rate of ADRD was lower in GLP-1RA initiators compared with other GLD initiators (rate difference [RD], -2.26 per 1000 person-years [95% CI, -2.88 to -1.64]), yielding an HR of 0.67 (95% CI, 0.47-0.96). SGLT2i initiators had a lower incidence than other GLD initiators (RD, -3.05 per 1000 person-years [95% CI, -3.68 to -2.42]), yielding an HR of 0.57 (95% CI, 0.43-0.75). There was no difference between GLP-1RAs and SGLT2is, with an RD of -0.09 per 1000 person-years (95% CI, -0.80 to 0.63) and an HR of 0.97 (95% CI, 0.72-1.32).

Conclusion and relevance: In people with T2D, both GLP-1RAs and SGLT2is were statistically significantly associated with decreased risk of ADRD compared with other GLDs, and no difference was observed between both drugs.”

#Wang W, Wang QQ, Qi X, et al. Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. Alzheimer's Dement. 2024

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14313 

Quote: “INTRODUCTION

Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking.

METHODS

We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan–Meier survival analyses.

RESULTS

Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups.

DISCUSSION

These findings support further studies to assess semaglutide's potential in preventing AD.

Highlights

Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs.

Semaglutide was associated with significantly lower AD-related medication prescriptions.

Similar reductions were seen across obesity status, gender, and age groups.

Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM.

These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.”

#Liang Y, Doré V, Rowe CC, Krishnadas N. Clinical Evidence for GLP-1 Receptor Agonists in Alzheimer’s Disease: A Systematic Review. Journal of Alzheimer’s Disease Reports. 2024

https://journals.sagepub.com/doi/10.3233/ADR-230181 

Quote: “Background:

Alzheimer’s disease (AD) is the most common cause of dementia. While preclinical studies have shown benefits of glucagon-like peptide 1 receptor agonists (GLP-1 RA) in targeting core AD pathology, clinical studies are limited.

Objective:

A systematic review was performed to evaluate GLP-1 RAs in AD for their potential to target core AD pathology and improve cognition.

Methods:

Searches were conducted via three different databases (PubMed, Embase, and Cochrane Library). Search terms included Medical Subject Headings (MeSH) terms: ‘glucagon-like peptide 1 receptor agonist’ and ‘Alzheimer’s disease’, as well as entry terms ‘GLP-1 RA’, ‘AD’, and three types of GLP-1 RA: ‘liraglutide’, ‘exenatide’, and ‘lixisenatide’.

Results:

A total of 1,444 studies were screened. Six articles that met criteria were included (four randomized control trials [RCTs] and two protocol studies). Two RCTs with amyloid-β and tau biomarker endpoints did not observe an end of treatment difference between the placebo and treated groups. In three RCTs with cognitive endpoints, there was no end of treatment difference between placebo and treated groups. GLP-1 RA showed metabolic benefits, such as lower body mass index and improved glucose levels on oral glucose tolerance tests in treated groups. GLP-1 RA may mitigate the decline in cerebral glucose metabolism and show enhanced blood-brain glucose transport capacity using 18F-FDG PET, however, more data is needed.

Conclusions:

GLP-1 RA therapy did not alter amyloid-β and tau biomarkers nor show improvements in cognition but showed potential metabolic and neuroprotective benefits.”

– They might even boost fertility, as obesity often disrupts hormones and increases complications during pregnancy.

How fertility is affected by treatment with GLP-1 agonists is an active area of research. Some early findings in people with obesity, diabetes and/or PCOS (polycystic ovarian syndrome) suggest that treatment with GLP-1 agonists can increase fertility. Notably, most evidence points to indirect effects of GLP-1 agonists on fertility, by e.g. leading to weight loss, which then increases fertility. However, in women there is a lack of studies in patients without PCOS.

#Tabeau, Adrianna, Pawlik, Agnieszka, Dudek, Patryk, et al. Improving Reproductive Outcomes in PCOS: The Emerging Role of GLP-1 Receptor Agonists. Journal of Education, Health and Sport. Online. 25 March 2025

https://apcz.umk.pl/JEHS/article/view/59347 

Quote: “Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder affecting a significant proportion of women of reproductive age. It is associated with infertility, metabolic abnormalities, and hormonal imbalances, including insulin resistance and hyperandrogenism. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as exenatide and liraglutide, have shown promise in improving reproductive outcomes in women with PCOS. This review evaluates the potential benefits of GLP-1 RAs in enhancing fertility, with a focus on menstrual regularity, ovulation rates, pregnancy rates, and metabolic outcomes. Studies have indicated that GLP-1 RAs improve insulin sensitivity, reduce BMI, waist circumference, and testosterone levels, and contribute to higher natural pregnancy rates. Despite the promising results, the long-term safety of GLP-1 RAs, particularly during pregnancy, remains uncertain. Patients using GLP-1 RAs are advised to use contraception, as the safety profile during pregnancy is still under investigation. Further research is necessary to establish the long-term effects and safety of these medications in women with PCOS. Overall, GLP-1 RAs offer a potential therapeutic approach for improving fertility and metabolic health in women with PCOS.”

#Zhou, L., Qu, H., Yang, L. et al. Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: a meta-analysis and systematic review. BMC Endocr Disord 23, 245 (2023)

https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-023-01500-5 

Quote: “Purpose

This study was aimed to assess the effectiveness of Glucagon-like peptide 1 receptor agonists on pregnancy rate, menses, anthropometric and hormonal parameters in PCOS patients.

Methods

We conducted searches of the published literature in PubMed, EMBASE, Cochrane Library, Web of Science up to September 2022. Data from randomized controlled trials were obtained to assess the effects of GLP1RAs in PCOS women. Weighted mean difference, standardized mean difference, and risks ratio were employed for effect size estimation using a random-effects model.

Results

A total of 840 patients with 469 individuals in GLP1RAs group and 371 individuals in control group from 11 RCTs were included. GLP1RAs usage was associated with an improvement in natural pregnancy rate (RR: 1.72, 95% CI 1.22 to 2.43, P = 0.002, I2 = 0%) and menstrual regularity (SMD: 1.72, 95% CI 0.60 to 2.85, P < 0.001, I2 = 95.6%). There were no statistically significant differences in total pregnancy rate, IVF pregnancy rate between two groups, but total PR elevated in a short time after GLP1RAs as shown in subgroup analysis. Randomization to GLP1RAs treatment was associated with great improvement in HOMA-IR, BMI, WC, SHBG and a slight reduction in TT compared to control group. A decrease in TBF was seen in European population. GLP1RAs monotherapy was not superior to metformin when it came to fT, DHEAS, FAI.

Conclusions

Prescription of GLP1RAs improves natural pregnancy rate, menstrual cyclicity and insulin sensitivity, anthropometrics, hormonal indexes in PCOS women.”

#Varnum, A.A.; Pozzi, E.; Deebel, N.A.; et al. Impact of GLP-1 Agonists on Male Reproductive Health—A Narrative Review. Medicina 2024

https://www.mdpi.com/1648-9144/60/1/50 

Quote: "Background and objective—Obesity is a prevalent health concern that notably impairs male fertility through hormonal disruptions and other pathophysiological alterations. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can significantly reduce weight. This narrative review synthesizes the existing literature discussing the impact of glucagon-like peptide-GLP-1 RAs on the male reproductive system, particularly on the hypothalamic–pituitary–gonadal axis and spermatogenesis, highlighting their potential impact on male fertility. Material and methods—PubMed database was used for the retrieval of English-language articles published up to November 2023. This non-systematic literature review predominantly concentrates on both pre-clinical and clinical studies pertaining to GLP-1 RAs, specifically exploring their impact on male reproductive hormones and sperm parameters. Results—GLP-1 receptors have been identified within the male reproductive system according to the existing literature. While the exact mechanisms are not well understood, they appear to be involved in glucose homeostasis and energy metabolism, both vital processes in spermatogenesis. Multiple clinical trials have demonstrated the efficacy of GLP-1 RAs for promoting weight loss. Recent studies show that the use of GLP-1 RAs in obese males may enhance sperm metabolism, motility, and insulin secretion in vitro, along with positive effects on the human Sertoli cells. Recent clinical trials discussed in this review demonstrate weight loss associated with GLP-1 RAs is correlated with improvements in sperm count, concentration, and motility. However, the direct impact of GLP-1 RAs on male reproductive hormones remains unclear, necessitating further research to confirm their potential role in treating male infertility. Conclusions—This narrative review summarizes the existing literature discussing the potential impact of GLP-1 RA on the male reproductive system, emphasizing their potential therapeutic role in addressing idiopathic infertility in obese men. Despite numerous studies exploring the influence of GLP-1 and GLP-1 RAs on reproductive hormones, testicular function, and spermatogenesis, further clinical trials are crucial to validate initial evidence. Longer follow-up periods are essential to address uncertainties regarding the long-term repercussions and outcomes of GLP-1 RA use. While this holds true, the current literature suggests that GLP-1RAs show promise as a potential therapeutic approach for improving sperm parameters in obese men.”

#Pavli P, Triantafyllidou O, Kapantais E, Vlahos NF, Valsamakis G. Infertility Improvement after Medical Weight Loss in Women and Men: A Review of the Literature. Int J Mol Sci. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC10856238/ 

Quote: “Infertility is a modern health problem. Obesity is another expanding health issue associated with chronic diseases among which infertility is also included. This review will focus on the effects of weight loss by medical therapy on fertility regarding reproductive hormonal profile, ovulation rates, time to pregnancy, implantation rates, pregnancy rates, normal embryo development, and live birth rates. We comprised medicine already used for weight loss, such as orlistat and metformin, and emerging medical treatments, such as Glucagon-Like Peptide-1 receptor agonists (GLP-1 RA). Their use is not recommended during a planned pregnancy, and they should be discontinued in such cases. The main outcomes of this literature review are the following: modest weight loss after medication and the duration of the treatment are important factors for fertility improvement. The fecundity outcomes upon which medical-induced weight loss provides significant results are the female reproductive hormonal profile, menstrual cyclicity, ovulation and conception rates, and pregnancy rates. Regarding the male reproductive system, the fertility outcomes that feature significant alterations after medically induced weight loss are as follows: the male reproductive hormonal profile, sperm motility, movement and morphology, weight of reproductive organs, and sexual function. The newer promising GLP-1 RAs show expectations regarding fertility improvement, as they have evidenced encouraging effects on improving ovulation rates and regulating the menstrual cycle. However, more human studies are needed to confirm this. Future research should aim to provide answers about whether medical weight loss therapies affect fertility indirectly through weight loss or by a possible direct action on the reproductive system.”

– Some of these benefits are a direct result of weight loss. But intriguingly, they sometimes occur regardless of how much weight has been lost, and some have been seen in patients who weren’t obese to begin with. We don’t know why yet, but it seems like turning up the GLP-1 signal is synchronizing the whole metabolic orchestra, restoring a balance between brain, gut and body.

#Deanfield J, Lincoff AM, Kahn SE, et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet. 2025

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01375-3/fulltext

Quote: “Background

The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk.

Methods

Patients aged at least 45 years, with a BMI of at least 27 kg/m2 were enrolled in 41 countries (804 sites) and randomised 1:1 to once-weekly semaglutide 2·4 mg or placebo. The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Adiposity measures included weight and waist circumference. In this analysis, risk of MACE occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and, in a separate analysis, all in-trial MACE were assessed between patients by adiposity changes over 104 weeks. This trial is registered with ClinicalTrials.gov, NCT03574597.

Findings

Semaglutide significantly reduced MACE incidence compared with placebo among 17 604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE—an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94–0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93–0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94–0·99]; p=0·007), but not bodyweight (0·99 [0·97–1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77–0·97] after adjustment for time-varying changes in waist circumference).

Interpretation

The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction.”

#Daniel J. Drucker. The benefits of GLP-1 drugs beyond obesity. Science (2024)

https://www.glucagon.com/pdfs/Druckerscience.adn4128.pdf 

Quote: “Glucagon-like peptide–1 (GLP-1) is secreted from gut endocrine cells in response to food ingestion and acts as an incretin hormone to potentiate glucose-dependent insulin secretion. Pharmacological GLP-1 receptor (GLP- 1R) activation reduced glucagon secretion (which raises blood glucose) and gastric emptying, leading to the development of GLP-1 therapies for the treatment of type 2 diabetes (T2D). GLP-1R is expressed on several pancreatic islet cell types and within multiple regions of the central nervous system. Subsequent studies revealed that exogenous GLP-1 administration inhibited food intake through brain GLP-1R activation in animals and humans, leading to weight loss. The decades-long use of GLP-1 medicines, principally acylated peptides such as liraglutide and semaglutide, for the treatment of obesity and T2D (1) has revealed that they also exert pleiotropic actions beyond glucose and weight control, such as reduction of heart and kidney diseases. There are several potential mechanisms underlying these benefits, such as reducing systemic inflammation (2), which have implications for future clinical applications and drug development.

[...]

GLP-1 medicines were studied in eight distinct cardiovascular outcome trials in people with T2D, and one trial in people with obesity. Long-acting GLP-1 medicines that are continuously present in the circulation reduced rates of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death in people with T2D and/or obesity. Subsequent trials demonstrated a benefit for semaglutide in people with heart failure with preserved injection fraction, with or without T2D (NCT04788511).

[...]

Interestingly, the cardioprotective effect of semaglutide observed in people with obesity developed within months of drug initiation, well before meaningful weight loss had been achieved in most trial participants. Furthermore, in the SELECT cardiovascular outcome trial (NCT03574597) studying semaglutide in people with obesity, the extent of weight loss did not correlate with the effects of the drug to reduce heart attacks, stroke, and cardiovascular death.”

– And as if that weren’t enough, GLP-1 drugs may also quiet other cravings – they seem to reduce the use of alcohol, nicotine, cannabis and opioids. Large trials are underway to confirm these effects. If the results hold, they could become something unprecedented: real anti-addiction drugs.

Evidence suggests that treatment with GLP-1 is associated with reduced use of alcohol, nicotine, cannabis and opioids, but the mechanisms behind this relationship are not clear yet. It is possible that some of these associations are indirect effects, such as e.g. a nausea side effect of a GLP-1 drug lowering the use of alcohol. But it also hypothesized that GLP-1 drugs might be tapping into the reward system of the brain, more directly affecting alcohol- and drug use and addiction.

Below, we cite studies for each addiction category. For a continuously updated general article on the scientific evidence around the use of GLP-1 in addiction, see here:

#Nicholas Reville and Zarinah Agnew. GLP-1 for Addiction: the Medical Evidence for Opioid, Nicotine, and Alcohol Use Disorder. Retrieved October 2025

https://recursiveadaptation.com/p/the-growing-scientific-case-for-using 

Quote: “This article is regularly updated as new research studies are published. We believe this is the most comprehensive and up-to-date review available of the scientific evidence and policy opportunities for GLP-1RAs and addiction reduction. Subscribe below (it’s free) to be notified when new research is released.”

Alcohol / Alcohol Use Disorder:

#Wang, W., Volkow, N.D., Berger, N.A. et al. Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population. Nat Commun (2024) https://doi.org/10.1038/s41467-024-48780-6

Quote: “Alcohol use disorders are among the top causes of the global burden of disease, yet therapeutic interventions are limited. Reduced desire to drink in patients treated with semaglutide has raised interest regarding its potential therapeutic benefits for alcohol use disorders. In this retrospective cohort study of electronic health records of 83,825 patients with obesity, we show that semaglutide compared with other anti-obesity medications is associated with a 50%-56% lower risk for both the incidence and recurrence of alcohol use disorder for a 12-month follow-up period. Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without type 2 diabetes. Similar findings are replicated in the study population with 598,803 patients with type 2 diabetes. These findings provide evidence of the potential benefit of semaglutide in AUD in real-world populations and call for further randomized clinical trials.”

#Hendershot CS, Bremmer MP, Paladino MB, et al. Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2025

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2829811 

Quote: “Question  Does the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide reduce alcohol consumption and craving in adults with alcohol use disorder (AUD)?

Findings  In this randomized clinical trial, relative to placebo, low-dose semaglutide reduced the amount of alcohol consumed during a posttreatment laboratory self-administration procedure. Over 9 weeks of treatment, semaglutide led to reductions in some but not all measures of weekly consumption, significantly reduced weekly alcohol craving relative to placebo, and led to greater relative reductions in cigarettes per day in a subgroup of participants with current cigarette use.

Meaning  These results justify larger clinical trials of incretin therapies for AUD.”

#Lähteenvuo M, Tiihonen J, Solismaa A, et al. Repurposing Semaglutide and Liraglutide for Alcohol Use Disorder. JAMA Psychiatry. 2025

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2825650

Quote: “Importance  Preliminary studies suggest that glucagon-like peptide-1 receptor (GLP-1) agonists, used to treat type 2 diabetes and obesity, may decrease alcohol consumption.

Objective  To test whether the risk of hospitalization due to alcohol use disorder (AUD) is decreased during the use of GLP-1 agonists compared with periods of nonuse for the same individual.

Design, Setting, and Participants  This cohort study was an observational study conducted nationwide in Sweden using data from January 2006 to December 2023. The population-based cohort was identified from registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. Participants were all residents aged 16 to 64 years who had a diagnosis of AUD.

Exposures  The primary exposure was use of individual GLP-1 agonists (compared with nonuse of GLP-1 agonists), and the secondary exposure was medications with indication for AUD.

Main Outcomes and Measures  The primary outcome was AUD hospitalization analyzed in a Cox regression within-individual model. Secondary outcomes were any substance use disorder (SUD)–related hospitalization, somatic hospitalization, and suicide attempt.

Results  The cohort included 227 866 individuals with AUD; 144 714 (63.5%) were male and 83 154 (36.5%) were female, with a mean (SD) age of 40.0 (15.7) years. Median (IQR) follow-up time was 8.8 (4.0-13.3) years. A total of 133 210 individuals (58.5%) experienced AUD hospitalization. Semaglutide (4321 users) was associated with the lowest risk (AUD: adjusted hazard ratio [aHR], 0.64; 95% CI, 0.50-0.83; any SUD: aHR, 0.68; 95% CI, 0.54-0.85) and use of liraglutide (2509 users) with the second lowest risk (AUD: aHR, 0.72; 95% CI, 0.57-0.92; any SUD: aHR, 0.78; 95% CI, 0.64-0.97) of both AUD and SUD hospitalization. Use of any AUD medication was associated with a modestly decreased risk (aHR, 0.98; 95% CI, 0.96-1.00). Semaglutide (aHR, 0.78; 95% CI, 0.68-0.90) and liraglutide (aHR, 0.79; 95% CI, 0.69-0.91) use were also associated with decreased risk of somatic hospitalizations but not associated with suicide attempts (semaglutide: aHR, 0.55; 95% CI, 0.23-1.30; liraglutide: aHR, 1.08; 95% CI, 0.55-2.15).

Conclusions and Relevance  Among patients with AUD and comorbid obesity/type 2 diabetes, the use of semaglutide and liraglutide were associated with a substantially decreased risk of hospitalization due to AUD. This risk was lower than that of officially approved AUD medications. Semaglutide and liraglutide may be effective in the treatment of AUD, and clinical trials are urgently needed to confirm these findings.”

#Quddos, F., Hubshman, Z., Tegge, A. et al. Semaglutide and Tirzepatide reduce alcohol consumption in individuals with obesity. Sci Rep (2023)

https://www.nature.com/articles/s41598-023-48267-2 

Quote: “Alcohol Use Disorder (AUD) contributes significantly to global mortality. GLP-1 (Glucagon-like peptide-1) and GLP-1/GIP (Glucose-dependent Insulinotropic Polypeptide) agonists, FDA-approved for managing type 2 diabetes and obesity, where the former has shown to effectively reduce the consumption of alcohol in animal models but no reports exist on the latter. In this report, we conducted two studies. In the first study, we conducted an analysis of abundant social media texts. Specifically, a machine-learning based attribution mapping of ~ 68,250 posts related to GLP-1 or GLP-1/GIP agonists on the Reddit platform. Secondly, we recruited participants (n = 153; current alcohol drinkers; BMI ≥ 30) who self-reported either taking Semaglutide (GLP-1 agonist), Tirzepatide (the GLP-1/GIP combination) for ≥ 30 days or, as a control group; no medication to manage diabetes or weight loss for a within and between subject remote study. In the social media study, we report 8 major themes including effects of medications (30%); diabetes (21%); and Weight loss and obesity (19%). Among the alcohol-related posts (n = 1580), 71% were identified as craving reduction, decreased desire to drink, and other negative effects. In the remote study, we observe a significantly lower self-reported intake of alcohol, drinks per drinking episode, binge drinking odds, Alcohol Use Disorders Identification Test (AUDIT) scores, and stimulating, and sedative effects in the Semaglutide or Tirzepatide group when compared to prior to starting medication timepoint (within-subjects) and the control group (between-subjects). In summary, we provide initial real-world evidence of reduced alcohol consumption in people with obesity taking Semaglutide or Tirzepatide medications, suggesting potential efficacy for treatment in AUD comorbid with obesity.”

#Qeadan F, McCunn A, Tingey B. The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis. Addiction. 2025

https://onlinelibrary.wiley.com/doi/10.1111/add.16679 

Quote: “Aims

This study aimed to estimate the strength of association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RA) and the incidence of opioid overdose and alcohol intoxication in patients with opioid use disorder (OUD) and alcohol use disorder (AUD), respectively. This study also aimed to compare the strength of the GIP/GLP-1 RA and substance use-outcome association among patients with comorbid type 2 diabetes and obesity.

Design

A retrospective cohort study analyzing de-identified electronic health record data from the Oracle Cerner Real-World Data.

Setting

About 136 United States of America health systems, covering over 100 million patients, spanning January 2014 to September 2022.

Participants

The study included 503 747 patients with a history of OUD and 817 309 patients with a history of AUD, aged 18 years or older.

Measurements

The exposure indicated the presence (one or more) or absence of GIP/GLP-1 RA prescriptions. The outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort. Potential confounders included comorbidities and demographic factors.

Findings

Patients with GIP/GLP-1 RA prescriptions demonstrated statistically significantly lower rates of opioid overdose [adjusted incidence rate ratio (aIRR) in OUD patients: 0.60; 95% confidence interval (CI) = 0.43–0.83] and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI = 0.40–0.63) compared to those without such prescriptions. When stratified by comorbid conditions, the rate of incident opioid overdose and alcohol intoxication remained similarly protective for those prescribed GIP/GLP-1 RA among patients with OUD and AUD.

Conclusions

Prescriptions of glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonists appear to be associated with lower rates of opioid overdose and alcohol intoxication in patients with opioid use disorder and alcohol use disorder. The protective effects are consistent across various subgroups, including patients with comorbid type 2 diabetes and obesity.”

There are also several large clinical trials underway to further study the effect of GLP-1 agonists on alcohol consumption:

• Study Details | NCT06409130 | Effects of NNC0194-0499, Cagrilintide, and Semaglutide Alone or in Combinations on Liver Damage and Alcohol Use in People With Alcohol-related Liver Disease | ClinicalTrials.gov

• Study Details | NCT05895643 | Does Semaglutide Reduce Alcohol Intake in Patients With Alcohol Use Disorder and Comorbid Obesity? | ClinicalTrials.gov 

• Study Details | NCT05892432 | Clinical Trial of Rybelsus (Semaglutide) Among Adults With Alcohol Use Disorder (AUD) | ClinicalTrials.gov 

• Study Details | NCT05520775 | Semaglutide for Alcohol Use Disorder | ClinicalTrials.gov

• Study Details | NCT06015893 | Semaglutide Therapy for Alcohol Reduction (STAR) | ClinicalTrials.gov 

Nicotine / Tobacco Use Disorder:

#William Wang, Nora D. Volkow, Nathan A. Berger, et al. Association of Semaglutide With Tobacco Use Disorder in Patients With Type 2 Diabetes: Target Trial Emulation Using Real-World Data. Ann Intern Med. 2024

https://www.acpjournals.org/doi/10.7326/M23-2718

Quote: “Background:

Reports of reduced desire to smoke in patients treated with semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) medication for type 2 diabetes mellitus (T2DM) and obesity, have raised interest about its potential benefit for tobacco use disorders (TUDs).

Objective:

To examine the association of semaglutide with TUD-related health care measures in patients with comorbid T2DM and TUD.

Design:

Emulation target trial based on a nationwide population-based database of patient electronic health records.

Setting:

United States, 1 December 2017 to 31 March 2023.

Participants:

Seven target trials were emulated among eligible patients with comorbid T2DM and TUD by comparing the new use of semaglutide versus 7 other antidiabetes medications (insulins, metformin, dipeptidyl-peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, thiazolidinediones, and other GLP-1RAs).

Measurements:

The TUD-related health care measures (medical encounter for diagnosis of TUD, smoking cessation medication prescriptions, and smoking cessation counseling) that occurred within a 12-month follow-up were examined using Cox proportional hazards and Kaplan–Meier survival analyses.

Results:

The study compared 222 942 new users of antidiabetes medications including 5967 of semaglutide. Semaglutide was associated with a significantly lower risk for medical encounters for TUD diagnosis compared with other antidiabetes medications, and was strongest compared with insulins (hazard ratio [HR], 0.68 [95% CI, 0.63 to 0.74]) and weakest but statistically significant compared with other GLP-1RAs (HR, 0.88 [CI, 0.81 to 0.96]). Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed in patients with and without a diagnosis of obesity. For most of the group comparisons, the differences occurred within 30 days of prescription initiation.

Limitation:

Documentation bias, residual confounding, missing data on current smoking behavior, body mass index, and medication adherence.

Conclusion:

Semaglutide was associated with lower risks for TUD-related health care measures in patients with comorbid T2DM and TUD compared with other antidiabetes medications including other GLP-1Ras, primarily within 30 days of prescription. These findings suggest the need for clinical trials to evaluate semaglutide’s potential for TUD treatment.”

#Yammine L, Green CE, Kosten TR, et al. Exenatide Adjunct to Nicotine Patch Facilitates Smoking Cessation and May Reduce Post-Cessation Weight Gain: A Pilot Randomized Controlled Trial. Nicotine Tob Res. 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8517504/

Quote: “Approved pharmacological treatments for smoking cessation are modestly effective, underscoring the need for improved pharmacotherapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the rewarding effects of nicotine in preclinical studies. We examined the efficacy of extended-release exenatide, a GLP-1R agonist, combined with nicotine replacement therapy (NRT, patch) for smoking cessation, craving, and withdrawal symptoms, with post-cessation body weight as a secondary outcome.

Methods

Eighty-four prediabetic and/or overweight smokers were randomized (1 : 1) to once-weekly placebo or exenatide, 2 mg, subcutaneously. All participants received NRT (21 mg) and brief smoking cessation counseling. Seven-day point prevalence abstinence (expired CO level ≤5 ppm), craving, withdrawal, and post-cessation body weight were assessed following 6 weeks of treatment. A Bayesian approach for analyzing generalized linear models yielded posterior probabilities (PP) to quantify the evidence favoring hypothesized effects of treatment on the study outcomes.

Results

Exenatide increased the risk for smoking abstinence compared to placebo (46.3% and 26.8%, respectively), (risk ratio [RR] = 1.70; 95% credible interval = [0.96, 3.27]; PP = 96.5%). Exenatide reduced end-of-treatment craving in the overall sample and withdrawal among abstainers. Post-cessation body weight was 5.6 pounds lower in the exenatide group compared to placebo (PP = 97.4%). Adverse events were reported in 9.5% and 2.3% of participants in the exenatide and placebo groups, respectively.

Conclusions

Exenatide, in combination with the NRT improved smoking abstinence, reduced craving and withdrawal symptoms, and decreased weight gain among abstainers. Findings suggest that the GLP-1R agonist strategy is worthy of further research in larger, longer duration studies.

Implications

Despite considerable progress in tobacco control, cigarette smoking remains the leading cause of preventable disease, disability, and death. In this pilot study, we showed that extended-release exenatide, a glucagon-like peptide-1 receptor agonist, added to the nicotine patch, improved abstinence and mitigated post-cessation body weight gain compared to patch alone. Further research is needed to confirm these initial positive results.”

#De Giorgi R, Koychev I, Adler AI, et al. 12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study. EClinicalMedicine. 2024

https://pmc.ncbi.nlm.nih.gov/articles/PMC11701436/ 

Quote: “Background

While semaglutide, approved for type-2 diabetes mellitus (T2DM), is being investigated as a treatment for brain disorders, concerns over adverse neuropsychiatric events have emerged. More data are therefore needed to assess the effects of semaglutide on brain health. This study provides robust estimates of the risk of neurological and psychiatric outcomes following semaglutide use compared to three other antidiabetic medications.

Methods

This retrospective cohort study used electronic health records from TriNetX US Collaborative Network, covering >100 million patients in the USA. Due to the exploratory nature of this study, we did not use a pre-registered protocol or statistical analysis plan. Three cohorts with T2DM prescribed semaglutide between 1st December 2017 and 31st May 2021 were propensity-score matched (1:1 using a greedy nearest-neighbour algorithm with calliper distance of 0.1) with cohorts receiving sitagliptin, empagliflozin, and glipizide. Using Cox regression analysis, we compared the risks of 22 neurological and psychiatric outcomes within one year since the index prescription: encephalitis, parkinsonism, cognitive deficit, dementia, epilepsy/seizure, migraine, insomnia, nerve disorder, myoneural junction/muscle disease, intracranial haemorrhage, ischaemic stroke, alcohol misuse, opioid misuse, cannabis misuse, stimulants misuse, nicotine misuse, psychosis, bipolar disorder, depression, anxiety, obsessive-compulsive disorder, and suicidality. Negative control outcomes (NCOs) were used to assess unmeasured confounding.

Findings

Each matched cohort included 23,386 (semaglutide vs sitagliptin), 22,584 (vs empagliflozin), and 19,206 (vs glipizide) patients. Semaglutide was not associated with an increased risk of neurological and psychiatric outcomes. Instead, after multiple-testing correction, semaglutide was associated with reduced risk for several such outcomes, notably cognitive deficit compared to sitagliptin (HR 0.72, 95% CI 0.64–0.80) and glipizide (HR 0.72, 95% CI 0.63–0.81), dementia compared to sitagliptin (HR 0.52, 95% CI 0.40–0.68), and nicotine misuse across most comparisons (HR 0.72, 95% CI 0.61–0.85 against glipizide; HR 0.77, 95% CI 0.65–0.90 against empagliflozin; HR 0.82, 95% CI 0.70–0.95 against sitagliptin, though the latter was no longer statistically significant after adjustment for multiple comparisons). Empagliflozin showed fewest differences from semaglutide. No differences in NCOs were observed between cohorts.

Interpretation

Semaglutide is not associated with higher 12-month risk of adverse neuropsychiatric outcomes compared to other antidiabetic medications. Potential beneficial associations with some outcomes, especially cognitive deficit and nicotine misuse, should stimulate validation in clinical trials.”

There is also a large clinical trial underway to further study the effect of GLP-1 agonists on nicotine use: https://clinicaltrials.gov/study/NCT05530577 

Cannabis Use Disorder:

#Wang, W., Volkow, N.D., Berger, N.A. et al. Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study. Mol Psychiatry 29, 2587–2598 (2024).

https://doi.org/10.1038/s41380-024-02498-5

Quote: “Cannabis is the most frequently used illicit drug in the United States with more than 45 million users of whom one-third suffer from a cannabis use disorder (CUD). Despite its high prevalence, there are currently no FDA-approved medications for CUD. Patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2D) and for weight management have reported reduced desire to drink and smoke. Preclinical studies have shown that semaglutide decreased nicotine and alcohol consumption. Preclinical and preliminary clinical evidence of semaglutide’s potential beneficial effects on various substance use disorders led us to evaluate if it pertained to CUD. In this retrospective cohort study of electronic health records (EHRs) from the TriNetX Analytics Network, a global federated health research network of approximately 105.3 million patients from 61 large healthcare organizations in the US, we aimed to assess the associations of semaglutide with both incident and recurrent CUD diagnosis compared to non-GLP-1RA anti-obesity or anti-diabetes medications. Hazard ratio (HR) and 95% confidence intervals (CI) of incident and recurrent CUD were calculated for 12-month follow-up by comparing propensity-score matched patient cohorts. The study population included 85,223 patients with obesity who were prescribed semaglutide or non-GLP-1RA anti-obesity medications, with the findings replicated in 596,045 patients with T2D. In patients with obesity (mean age 51.3 years, 65.6% women), semaglutide compared with non-GLP-1RA anti-obesity medications was associated with lower risk for incident CUD in patients with no prior history CUD (HR: 0.56, 95% CI: 0.42–0.75), and recurrent CUD diagnosis in patients with a prior history CUD (HR: 0.62, 95% CI: 0.46–0.84). Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without T2D. Similar findings were replicated in the study population with T2D when comparing semaglutide with non-GLP-1RA anti-diabetes medications for incident CUD (HR: 0.40, 95% CI: 0.29–0.56) and recurrent CUD (HR: 0.66, 95% CI: 0.42–1.03). While these findings provide preliminary evidence of the potential benefit of semaglutide in CUD in real-world populations, further preclinical studies are warranted to understand the underlying mechanism and randomized clinical trials are needed to support its use clinically for CUD.”

Opioid Use Disorder:

#Wang W, Volkow ND, Wang Q, et al. Semaglutide and Opioid Overdose Risk in Patients With Type 2 Diabetes and Opioid Use Disorder. JAMA Netw Open. 2024

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2824054 

Quote: “The study included 33 006 eligible patients: 3034 were prescribed semaglutide (mean [SD] age, 57.4 [11.0] years; 1714 [56.5%] female) and 29 972 were prescribed other antidiabetic medications. Semaglutide was compared with each antidiabetic medication class in patients with comorbid T2D and OUD. Before propensity-score matching, the semaglutide and comparison groups differed by age, sex, ethnicity, and comorbidity conditions, but characteristics were balanced after matching (Table). Semaglutide was associated with a significantly lower risk of opioid overdose during a 1-year follow-up compared with other antidiabetic medications, including other GLP-1RAs, with HRs ranging from 0.32 (95% CI, 0.12-0.89) to 0.58 (95% CI, 0.38-0.87) (Figure). The negative control outcome showed no difference between groups.”

#Qeadan F, McCunn A, Tingey B. The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis. Addiction. 2025

https://onlinelibrary.wiley.com/doi/10.1111/add.16679 

Quote: “Aims

This study aimed to estimate the strength of association between prescriptions of glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RA) and the incidence of opioid overdose and alcohol intoxication in patients with opioid use disorder (OUD) and alcohol use disorder (AUD), respectively. This study also aimed to compare the strength of the GIP/GLP-1 RA and substance use-outcome association among patients with comorbid type 2 diabetes and obesity.

Design

A retrospective cohort study analyzing de-identified electronic health record data from the Oracle Cerner Real-World Data.

Setting

About 136 United States of America health systems, covering over 100 million patients, spanning January 2014 to September 2022.

Participants

The study included 503 747 patients with a history of OUD and 817 309 patients with a history of AUD, aged 18 years or older.

Measurements

The exposure indicated the presence (one or more) or absence of GIP/GLP-1 RA prescriptions. The outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort. Potential confounders included comorbidities and demographic factors.

Findings

Patients with GIP/GLP-1 RA prescriptions demonstrated statistically significantly lower rates of opioid overdose [adjusted incidence rate ratio (aIRR) in OUD patients: 0.60; 95% confidence interval (CI) = 0.43–0.83] and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI = 0.40–0.63) compared to those without such prescriptions. When stratified by comorbid conditions, the rate of incident opioid overdose and alcohol intoxication remained similarly protective for those prescribed GIP/GLP-1 RA among patients with OUD and AUD.

Conclusions

Prescriptions of glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonists appear to be associated with lower rates of opioid overdose and alcohol intoxication in patients with opioid use disorder and alcohol use disorder. The protective effects are consistent across various subgroups, including patients with comorbid type 2 diabetes and obesity.”

A small clinical trial among some 25 participants reported a reduction in opioid cravings in people treated with liraglutide for 3 weeks:

#Bajaj S. Opioid cravings were reduced by anti-obesity drug in small study. Stat10. 2024

https://www.statnews.com/2024/02/17/opioid-cravings-glp1-weight-loss-liraglutide-penn-state/ 

Quote: “Among 20 patients for opioid use disorder, those on liraglutide experienced a 40% reduction in opioid cravings over the three-week study, with this effect evident at even the lowest liraglutide dose, according to data presented here at the American Association for the Advancement of Science conference.”

Link to trial results: https://clinicaltrials.gov/study/NCT04199728?tab=results

There are also several large clinical trials underway to further study the use of GLP-1 agonists for Opioid Use Disorder:

• Study Details | NCT06548490 | GLP-1R Agonist Treatment for Opioid Use Disorder | ClinicalTrials.gov

• Evaluation of Tirzepatide as an Adjunct to Buprenorphine for the treatment of opioid use disorder: A pragmatic, multi-site, double-blind, Randomized, placebo-controlled, trial (TAB). | National Institute on Drug Abuse (NIDA)

• https://clinicaltrials.gov/study/NCT06639464 

A recent review on hypotheses and preclinical evidence about the mechanism of GLP-1 affecting addiction:

#Marquez-Meneses, J.D.; Olaya-Bonilla, S.A.; Barrera-Carreño, S.; et al. GLP-1 Analogues in the Neurobiology of Addiction: Translational Insights and Therapeutic Perspectives. Int. J. Mol. Sci. 2025

https://www.mdpi.com/1422-0067/26/11/5338 

Quote: “Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction models involving alcohol, nicotine, psychostimulants, and opioids. In animal studies, glucagon-like peptide-1 receptor agonists consistently reduce drug intake, attenuate dopamine release in reward circuits, and decrease relapse-like behavior. Clinical and observational studies provide preliminary support for these findings, particularly among individuals with comorbid obesity or insulin resistance. However, several translational barriers remain, including limited blood–brain barrier penetration, species differences in pharmacokinetics, and variability in treatment response due to genetic and metabolic factors. Ethical considerations and methodological heterogeneity further complicate clinical translation. Future directions include the development of central nervous system penetrant analogues, personalized medicine approaches incorporating pharmacogenomics, and rigorously designed trials in diverse populations. Glucagon-like peptide-1 receptor agonists may offer a novel therapeutic strategy that addresses both metabolic and neuropsychiatric dimensions of addiction, warranting further investigation to define their role in the evolving landscape of substance use disorder treatment.”

– But of course there are side effects. Most commonly nausea, vomiting, diarrhea and constipation – not fun, but usually harmless and fleeting for the vast majority of patients. More serious stuff like pancreatitis, kidney problems or gallbladder disease do happen, but for well under 5% of people.

#Areesha Moiz, Kristian B. Filion, Helia Toutounchi, et al. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials. Ann Intern Med. 2025

https://www.weniger-kg.de/wp-content/uploads/10.7326_ANNALS-24-01590.pdf 

Quote: “Adverse events were commonly reported in most participants for both the active treatment and placebo groups (Table 4). The majority were GI disorders (most commonly nausea, diarrhea, constipation, and vomiting), which occurred more frequently in the active groups than the placebo groups. Across all RCTs, the majority of GI disorders were transient, related to dose escalation, and mild to moderate in severity. No serious GI disorders, such as bowel obstruction or gastroparesis, were reported.Most AEs did not require treatment discontinuation. In addition, most treatment discontinuations occurred during the dose-escalation phase before the maintenance dose was reached. Select SAEs of interest included severe GI events, biliary disorders (cholecystitis and cholelithiasis), pancreatitis, and psychiatric disorders. These outcomes were inconsistently reported across RCTs but were rare (severe GI and biliary disorders, ≤3.5%; pancreatitis, <2%; psychiatric disorders, ≤15% [including less severe events, such as insomnia and mood alterations]) in those that did report them (Supplement Table 5, available at Annals.org). Trialspecific safety outcomes are reported by dose in Supplement Table 6 (available at Annals.org). Overall, there were no clear dose-dependent relationships.”

#Reiss, A.B.; Gulkarov, S.; Lau, R.; et al. Weight Reduction with GLP-1 Agonists and Paths for Discontinuation While Maintaining Weight Loss. Biomolecules 2025

https://www.mdpi.com/2218-273X/15/3/408 

Quote: “GLP-1 medications can cause a range of side effects related to the gastrointestinal system as well as changes in muscle mass and effects on the appearance of the face and loss of hair (Figure 2). The most common detrimental consequences of the GLP-1 class are gastrointestinal. The most often reported side effects are nausea and vomiting which are a result of activation of specific GLP-1 receptors in the hindbrain and these symptoms can be mitigated with gradual dose escalation [155,156,157]. In addition to nausea and vomiting, other GI-related side effects include diarrhea, constipation, dyspepsia, decreased appetite, and abdominal pain [158,159,160]. It is estimated that around 80–90% of patients will develop an adverse effect from the use of this class.

Figure 2. Adverse effects of GLP-1 class drugs. Gastrointestinal issues are common, ranging from nausea and diarrhea to rarer and more severe consequences such as pancreatitis. Rapid weight loss due to the use of GLP-1 drugs is associated with biliary disease, sarcopenia, and alopecia. Rapid weight loss can also lead to what is known as an “Ozempic face”, where the cheeks become hollowed out, and wrinkles, as well as eye bags, become more pronounced.

A more serious gastrointestinal concern is that of pancreatitis. Early studies on patients with type 2 diabetes treated with incretin therapy including GLP-1s and dipeptidyl peptidase-4 (DPP4) inhibitors did demonstrate an association between drug usage and the development of pancreatitis [159]. GLP-1R analogs have been associated with lipase and amylase suggesting a mechanism of pancreatic inflammation [161,162]. In fact, the package insert for semaglutide suggests an increase of 13% for amylase and 22% for lipase and the dual incretin agonist tirzepatide suggests a 38% increase and lipase upwards of a 42% increase [163]. Despite this, animal studies have demonstrated decreases in pancreatic secretion in response to GLP-1 elevation, therefore the mechanism behind this potential interaction of GLP-1 receptor analogs and pancreatitis remains elusive [164]. It is important to note that these studies mostly included dipeptidyl peptidase-4 DPP4 and early GLP-1s, exenatide, and liraglutide. Furthermore, patients with type 2 diabetes are inherently at higher risk of pancreatitis [165]. The large and long-duration GLP-1 cardiovascular outcome trials did not show an increase in pancreatitis [166]. Recent trials on the newer GLP-1 agents including tirzepatide and semaglutide specific to weight loss have not demonstrated increased rates of pancreatitis, although product labeling still instructs avoidance in patients with a history of pancreatitis [167,168,169].

Rapid weight loss has long been associated with biliary disease, sarcopenia, and alopecia [170,171,172,173,174]. As the newer agents in the GLP class have become incredibly potent where users are losing an estimated 15-20% of body weight, with much of the weight loss occurring in the initial weeks of initiating the drug [175,176]. It is thus not surprising that these same side effects of rapid weight loss are seen as a class effect. The rapid weight loss can be visualized in many areas of the body and one of these manifestations known as “Ozempic face” occurs when fat pads in the face are rapidly depleted [177,178]. Patients should be aware of these potential unwanted effects and, to minimize loss of muscle mass, encouraged to participate in resistance exercises and increase protein intake [179].

While these cosmetic findings are an issue, the loss of lean body mass is another area of concern [180]. The landmark GLP-1 drug trial for semaglutide, STEP 1 (semaglutide treatment effect in people with obesity), demonstrates a significant loss of total lean body mass [132], which has been further corroborated by other investigators [181]. Tirzepatide has demonstrated total lean mass loss as well, although additional studies are needed to determine the impact of this [134,182]. The question of whether the ratio between fat mass and lean body mass is disrupted or maintained during weight loss with GLP-1 agonists is still unresolved [183,184]. Studies to clarify this issue would particularly be needed for patients who are afflicted with sarcopenic obesity, a condition of a mismatch between muscle and fat mass.”

– Apart from this, the main downside of GLP-1 drugs may come from their greatest strength – rapid weight loss. If you don’t actively check what you eat, taking these drugs is just like an unhealthy crash diet. Any steep calorie deficit requires resistance training and plenty of protein, or else you’ll lose a lot of muscle along with the fat.

Loss of muscle mass is a common problem during weight loss, regardless of intervention type (a specific diet, physical exercise, surgery, a drug, or a combination of these). Some evidence suggests that there is less loss of muscle when the weight is lost through the use of GLP-1 agonists as opposed to bariatric surgery or a pure dietary intervention, but this is an active area of research. In any case, strength training and high protein diets can help mitigate some of these losses.

#Anyiam O, Ardavani A, Rashid RSA, Panesar A, Idris I. How do glucagon-like Peptide-1 receptor agonists affect measures of muscle mass in individuals with, and without, type 2 diabetes: A systematic review and meta-analysis. Obesity Reviews. 2025

https://onlinelibrary.wiley.com/doi/10.1111/obr.13916 

Quote: “Glucagon-like peptide-1 receptor agonists (GLP1RAs) are used for the management of type 2 diabetes (T2DM) and obesity. GLP1RAs induce significant weight loss but concerns have been raised regarding the associated effects on muscle mass (MM). We therefore conducted a systematic review and meta-analysis assessing the effects of GLP1RAs on various measures of MM in individuals living with overweight or obesity, with and without T2DM. Comprehensive search of Medline, Pubmed, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar was performed. Studies involving cohorts with a mean age over 40 years and a mean body mass index over 25 kg.m-2 were included. The primary outcome was any measure used to estimate MM, whilst fat mass (FM) and total body weight were included as secondary outcomes. Thirty-eight publications, involving 1735 participants, were included in the review. Separate meta-analyses were performed for studies involving participants with T2DM and individuals without T2DM (non-DM). In individuals with T2DM, GLP1RAs induced a non-significant mean reduction in MM measures (-0.74 kg, 95% CI: -1.61, 0.14, p = 0.10), despite significantly reducing FM (-3.18 kg, 95% CI: -4.09, -2.28, p < 0.0001). In the non-DM analysis, a significant mean reduction in MM measures was observed (-1.41 kg, 95% CI: -2.12, -0.71, p = 0.0001), however, this was significantly less than the reduction in FM (-6.02 kg, 95% CI: -7.53, -4.50, p < 0.0001). In both populations, the reduction in measures of MM accounted for less than 20% of the total weight reduction. These findings provide some clarity to clinicians that use GLP1RAs to manage individuals with T2DM and/or obesity, however, further more detailed analysis of the impact of these medications on functional skeletal muscle is required.

[...]

In conclusion, this meta-analysis demonstrated that when used in individuals with T2DM, GLP1RAs do not induce a significant reduction in measures used to estimate muscle mass, despite significant reductions observed in weight and fat mass. In individuals with obesity, a significant reduction in muscle mass measures was observed, however, this was significantly less than the corresponding reduction in fat mass. In both cases, the mean reduction in measures of muscle mass constituted less than 20% of total weight loss, which appears to be less than the amount reported from bariatric surgery and dietary interventions.”

#Neeland IJ, Linge J, Birkenfeld AL. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes Obes Metab. 2024

https://doi.org/10.1111/dom.15728 

Quote: “Weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic polypeptide receptor agonists is coming closer to the magnitudes achieved with surgery. However, with greater weight loss there is concern about potential side effects on muscle quantity (mass), health and function. There is heterogeneity in the reported effects of GLP-1-based therapies on lean mass changes in clinical trials: in some studies, reductions in lean mass range between 40% and 60% as a proportion of total weight lost, while other studies show lean mass reductions of approximately 15% or less of total weight lost. There are several potential reasons underlying this heterogeneity, including population, drug-specific/molecular, and comorbidity effects. Furthermore, changes in lean mass may not always reflect changes in muscle mass as the former measure includes not only muscle but also organs, bone, fluids, and water in fat tissue. Based on contemporary evidence with the addition of magnetic resonance imaging-based studies, skeletal muscle changes with GLP-1RA treatments appear to be adaptive: reductions in muscle volume seem to be commensurate with what is expected given ageing, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and severity of disease may influence the selection of appropriate candidates for these therapies due to risk of sarcopenia. To further improve muscle health during weight loss, several pharmacological treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. Future research on GLP-1-based and other therapies designed for weight loss should focus on more accurate and meaningful assessments of muscle mass, composition, as well as function, mobility or strength, to better define their impact on muscle health for the substantial number of patients who will likely be taking these medications well into the future.”

#Sargeant JA, Henson J, King JA, et al. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab. 2019

https://doi.org/10.3803/EnM.2019.34.3.247 

Quote: “Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.

[...]

Consequently, although yielding a more favorable body composition, the potential LBM and skeletal muscle loss associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. A more rapid decline in skeletal muscle and consequential increased risk of sarcopenia is concerning, particularly as individuals prescribed these therapies are usually already vulnerable to an increased risk of physical frailty (i.e., those with T2DM and/or obesity) [75]. In turn, strategies to preserve or increase skeletal muscle and physical function in these individuals (e.g., through structured exercise training), are of importance. It is also important to state that the absolute mass of skeletal muscle is not the only factor to consider, and improving muscular function (strength, endurance, flexibility etc.) remains critical to improve physical function and performance in tasks of daily living; to impact positively on an individual's quality of life.”

#Cava E, Yeat NC, Mittendorfer B. Preserving Healthy Muscle during Weight Loss. Adv Nutr. 2017

https://pmc.ncbi.nlm.nih.gov/articles/PMC5421125/ 

Quote: “Weight loss is the cornerstone of therapy for people with obesity because it can ameliorate or completely resolve the metabolic risk factors for diabetes, coronary artery disease, and obesity-associated cancers. The potential health benefits of diet-induced weight loss are thought to be compromised by the weight-loss–associated loss of lean body mass, which could increase the risk of sarcopenia (low muscle mass and impaired muscle function). The objective of this review is to provide an overview of what is known about weight-loss–induced muscle loss and its implications for overall physical function (e.g., ability to lift items, walk, and climb stairs). The currently available data in the literature show the following: 1) compared with persons with normal weight, those with obesity have more muscle mass but poor muscle quality; 2) diet-induced weight loss reduces muscle mass without adversely affecting muscle strength; 3) weight loss improves global physical function, most likely because of reduced fat mass; 4) high protein intake helps preserve lean body and muscle mass during weight loss but does not improve muscle strength and could have adverse effects on metabolic function; 5) both endurance- and resistance-type exercise help preserve muscle mass during weight loss, and resistance-type exercise also improves muscle strength. We therefore conclude that weight-loss therapy, including a hypocaloric diet with adequate (but not excessive) protein intake and increased physical activity (particularly resistance-type exercise), should be promoted to maintain muscle mass and improve muscle strength and physical function in persons with obesity.”

#Marwa Al-Badri, Abd Almasih Barbar Askar, Abdelrahman Khater, et al. 14-PUB: The Effect of Structured Intensive Lifestyle Intervention on Muscle Mass in Patients with Type 2 Diabetes Receiving GLP-1 Receptor Agonists. Diabetes. 2024

https://diabetesjournals.org/diabetes/article/73/Supplement_1/14-PUB/156089/14-PUB-The-Effect-of-Structured-Intensive 

Quote: “Glucagon-like-peptide-1 receptor agonists (GLP-1RAs) emerged as an important treatment option for type 2 diabetes (T2D) for their dual efficacy in improving glycemia and reducing body weight. However, they significantly reduce fat free mass (FFM), a surrogate for muscle mass, putting patients at a higher risk for sarcopenia and its sequelae. It is unknown whether structured intensive lifestyle intervention (sILI), that includes higher protein intake and strength exercises, can mitigate muscle mass loss with GLP-1RA use. We retrospectively evaluated 53 patients with T2D enrolled in a 12-week multidisciplinary sILI (mean age 58.17±11.3 years; 51% male; weight 104.3±19.7 kg; BMI 36.1±5.6 kg/m2, A1C 7.4±1.3%) and divided them into two groups: group 1, already taking GLP-1RA (n=32), and group 2, not on GLP-1RA (n=21). Both groups were instructed to follow a hypocaloric structured medical nutrition therapy plan with increased protein intake to 1-1.5 gm/kg of adjusted body weight. They were also instructed to exercise for 360 minutes/week with more emphasis on strength exercises. Body composition was analyzed by bioelectrical impedance. At 12 weeks, group 1 lost 7.4±4.5 kg (p<0.001) and group 2 lost 6.2±5.4 kg (p<0.001), and their A1C decreased by 0.84%±1.1% (p<0.001) and by 1%±1.06% (p<0.001) respectively, with no differences between groups over time. Group 1 had no change in FFM compared to baseline while group 2 lost 1.4±2.6 kg (p<0.05). There was no difference in FFM loss between groups over time (p=0.28). Our findings suggest that increasing protein intake and strength exercises, as part of sILI, may mitigate the deleterious effect of GLP-1RA on muscle mass in patients with T2D. These results support recommending an increase in protein intake and incorporation of strength exercises when GLP-1RA is prescribed for patients with T2D to minimize muscle mass loss. Further research is needed to validate these findings in a randomized prospective study.W

– That’s harmful at any age, but especially after 40, when building muscle gets harder and the risk of falls starts to rise.

On average, people lose muscle mass as they age. At the same time, building more muscle mass through e.g. resistance training becomes harder as people age.

#Heymsfield SB, Fearnbach N. Can increasing physical activity prevent aging-related loss of skeletal muscle? Am J Clin Nutr. 2021

https://pmc.ncbi.nlm.nih.gov/articles/PMC8574632/ 

Quote: “Skeletal muscle (SM) mass increases from birth to the third decade and then declines from peak levels thereafter at variable rates with acceleration in the later decades (1–4).”

#Silva AM, Shen W, Heo M, et al. Ethnicity-related skeletal muscle differences across the lifespan. Am J Hum Biol. 2010

https://pmc.ncbi.nlm.nih.gov/articles/PMC2795070/ 

#Straight CR, Fedewa MV, Toth MJ, Miller MS. Improvements in skeletal muscle fiber size with resistance training are age-dependent in older adults: a systematic review and meta-analysis. J Appl Physiol (1985). 2020

https://pmc.ncbi.nlm.nih.gov/articles/PMC7473942/ 

Quote: “As studies examining the hypertrophic effects of resistance training (RT) at the cellular level have produced inconsistent results, we performed a systematic review and meta-analysis to investigate muscle fiber size before and after a structured RT intervention in older adults. A random-effects model was used to calculate mean effect size (ES) and 95% confidence intervals (CI). Thirty-five studies were included (age range: 59.0–88.5 yr), and 44 and 30 effects were used to estimate RT impact on myosin heavy chain (MHC) I and II fiber size. RT produced moderate-to-large increases in MHC I (ES = +0.51, 95%CI +0.31 to +0.71; P < 0.001) and II (ES = +0.81, 95%CI +0.56 to +1.05; P < 0.001) fiber size, with men and women having a similar response. Age was negatively associated with change in muscle fiber size for both fiber types (MHC I: R2 = 0.11, β = −0.33, P = 0.002; MHC II: R2 = 0.10, β = −0.32, P = 0.04), indicating a less robust hypertrophic response as age increases in older adults. Unexpectedly, a higher training intensity (defined as percentage of one-repetition maximum) was associated with a smaller increase in MHC II fiber size (R2 = 15.09%, β = −0.39, P = 0.01). Notably, MHC II fiber subtypes (IIA, IIX, IIAX) were examined less frequently, but RT improved their size. Overall, our findings indicate that RT induces cellular hypertrophy in older adults, although the effect is attenuated with increasing age. In addition, hypertrophy of MHC II fibers was reduced with higher training intensity, which may suggest a failure of muscle fibers to hypertrophy in response to high loads in older adults.”

#Amiri A, Dong X, Frith K. Risk of Falls in adults 45-64 years old in the United States. Public Health Nurs. 2022

https://onlinelibrary.wiley.com/doi/10.1111/phn.13116 

Quote: “Falls among the older adults (64+ years old [YO]) are considered public health issues. However, fall prevention in middle adulthood (age 45–64) has received less attention. We studied the associations between the number of falls and fall-related injuries and indicators for socio-demographics, chronic diseases, and difficulties in conducting activities in two age groups, 45–64 YO and 64+. In this secondary data analysis, we used the Behavioral Risk Factor Surveillance System (BRFSS) 2018 data. The study showed respondents in the 45–64 YO have higher average falls and fall-related injuries than those 64+ (P < .001). Variables that link to more falls and fall-related injuries in 64+ correspond to more falls and fall-related injuries in 45–64 YO. The finding indicates that the odds of falls and fall-related injuries are comparable across age groups when considering demographic characteristics. However, odds of falling in the presence of arthritis and asthma are higher for respondents in 45–64 YO than the 64+ YO. The risk of falls and fall-related injuries are not specific to older adults. Factors that matter to the number of falls and fall-related injuries in the older adults also count in the younger age group. Nurses are asked to validate available fall assessment tools for adults 45–64 years old and evaluate all clients over 45 for fall risk.”

– After about a year the weight loss slows down and eventually stops in most people.

Tirzepatide:

#Jastreboff AM, le Roux CW, Stefanski A, et al. Tirzepatide for Obesity Treatment and Diabetes Prevention. N Engl J Med. 2025

https://internetbookofemergencymedicine.com/wp-content/uploads/2025/05/tirzepatide-for-obesity-treatment-and-diabetes-prevention.pdf 

#Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024

https://jamanetwork.com/journals/jama/fullarticle/2812936

#Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022

https://www.nejm.org/doi/full/10.1056/NEJMoa2206038 

Semaglutide:

#Ryan, D.H., Lingvay, I., Deanfield, J. et al. Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial. Nat Med (2024) https://doi.org/10.1038/s41591-024-02996-7

#Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021

https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

– At this point you usually stop using the medication.

Here we are specifically referring to getting GLP-1 agonists prescribed for weight loss management. The typical treatment duration in clinical trials and real-life practice depends on the type of drug and can vary strongly. Treatment duration for weight loss ranges from about 4 months to 2 years. Longer treatment is generally associated with greater and more sustained weight loss. Most randomized controlled trials use treatment periods between 26 and 72 weeks (6 months to 1.5 years) for common drugs like liraglutide, semaglutide, and tirzepatide. Never start or stop taking prescribed medication without consulting a medical professional.

#Areesha Moiz, Kristian B. Filion, Helia Toutounchi, et al. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials. Ann Intern Med. 2025

https://www.weniger-kg.de/wp-content/uploads/10.7326_ANNALS-24-01590.pdf 

Quote: “A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m2; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare.”

– If you used that time to change your eating habits you have a really good chance of keeping the lost weight off! 

Weight regain after stopping a weight-loss intervention is a common problem regardless of the type of intervention, such as a specific diet, physical exercise, surgery, a drug, or a combination of these. Sustained dietary changes, combined with behavioral and lifestyle interventions, can help prevent this rebound, but they are not a guarantee. 

#Reiss, A.B.; Gulkarov, S.; Lau, R.; et al. Weight Reduction with GLP-1 Agonists and Paths for Discontinuation While Maintaining Weight Loss. Biomolecules 2025

https://www.mdpi.com/2218-273X/15/3/408 

Quote: “The use of GLP-1 drugs as a weight loss tool is prevalent and effective, but it is preferable to find ways to keep the weight off without a lifetime of drug treatment and this is an area that needs attention [298]. Lifestyle interventions alone are not durable for most people [299,300]. Studies are clearly needed to find ways to support withdrawal of pharmacotherapy without weight rebound using a multi-disciplinary approach which would likely involve behavioral change, nutritional guidance, structured physical activity, and perhaps peer support groups [301,302,303,304,305].”

– But about 25% regain a significant chunk, and some 20% put back on all of it.

#Bartelt K, Mast C, Deckert J, Gracianette M, Joyce B. Many Patients Maintain Weight Loss a Year After Stopping Semaglutide and Liraglutide. Epic Research. Accessed on October 27, 2025. https://epicresearch.org/articles/many-patients-maintain-weight-loss-a-year-after-stopping-semaglutide-and-liraglutide 

Full report: https://media.epic.com/epicresearch/wordpressmedia/pdfs/many-patients-maintain-weight-loss-a-year-after-stopping-semaglutide-and-liraglutide.pdf 

In a recent large randomized controlled trial of Tirzepatide (SURMOUNT-4), people on average regained ⅔ of the weight they had lost within one year of being put on a placebo:

#Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024

https://jamanetwork.com/journals/jama/fullarticle/2812936

– The newest generation of drugs is just too new so there is no long-term data. 

In the US and for the treatment of type 2 diabetes, semaglutide (Ozempic) was first approved in 2017, and Tirzepatide (Mounjaro) in 2022.

#Dhillon, S. Semaglutide: First Global Approval. Drugs (2018). 

https://doi.org/10.1007/s40265-018-0871-0 

Quote: “Novo Nordisk has developed a subcutaneous formulation of semaglutide (Ozempic®), a modified human glucagon-like peptide-1 (GLP-1) analogue, for the treatment of type 2 diabetes mellitus. It has been developed using Novo Nordisk’s proprietary protein-acylation technology, and is administered using an injection device. Semaglutide lowers blood glucose by stimulating the release of insulin and also lowers body weight. Once-weekly subcutaneous semaglutide has recently been approved in the US, Puerto Rico and Canada, and has received a positive opinion in the EU for the treatment of patients with type 2 diabetes. It will be launched as the Ozempic® Pen, a pre-filled device. Semaglutide is also under regulatory review in Japan and Switzerland for the treatment of type 2 diabetes. Clinical development for obesity, non-alcoholic steatohepatitis and non-alcoholic fatty liver disease is underway worldwide. This article summarizes the milestones in the development of semaglutide leading to this first approval for type 2 diabetes.”

#Syed, Y.Y. Tirzepatide: First Approval. Drugs (2022)

https://doi.org/10.1007/s40265-022-01746-8

Quote: “Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Native GIP and GLP-1 are incretin hormones that stimulate insulin secretion and decrease glucagon secretion. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. This article summarizes the milestones in the development of tirzepatide leading to this first approval for T2DM.”

In the US and for weight management, semaglutide (Wegovy) was first approved in 2021, and Tirzepatide (Zepbound) in 2023.

#FDA Approves Prescription Weight Loss Therapy for Adults With Obesity. Pharmacy Times (2021)

https://www.pharmacytimes.com/view/fda-approves-prescription-weight-loss-therapy-for-adults-with-obesity 

Quote: “Officials with the FDA have approved the new drug application (NDA) for semaglutide injection (Wegovy; Novo Nordisk) 2.4 mg for adults with obesity (BMI ≥30) or overweight BMI ≥27). According to Novo Nordisk, this novel drug is the only prescription weight-loss medication with once-weekly dosing.”

#Food and Drug Administration. FDA Approves New Medication for Chronic Weight Management.023

https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management

Quote: “Today, the U.S. Food and Drug Administration approved Zepbound (tirzepatide) injection for chronic weight management in adults with obesity (body mass index of 30 kilograms per square meter (kg/ m2) or greater) or overweight (body mass index of 27 kg/m2 or greater) with at least one weight-related condition (such as high blood pressure, type 2 diabetes or high cholesterol) for use, in addition to a reduced calorie diet and increased physical activity. Tirzepatide, the active ingredient in Zepbound, is already approved under the trade name Mounjaro to be used along with diet and exercise to help improve blood sugar (glucose) in adults with type 2 diabetes mellitus.”

– The first GLP-1’s from 2005 haven’t shown major issues. 

The first approved GLP-1 agonist was exenatide for the treatment of type 2 diabetes in 2005. It was introduced in 2005 as a twice-daily injection. Since then, dosing options have expanded to include a once-weekly formulation. Both formulations are still regularly prescribed today and are considered safe.

#Inaishi J, Saisho Y. Exenatide Once Weekly for Management of Type 2 Diabetes: A Review. Clin Pharmacol. 2022

https://pmc.ncbi.nlm.nih.gov/articles/PMC9004502/

Quote: “Exenatide is one of the exendin-based glucagon-like peptide 1 receptor agonists (GLP-1RAs) and is currently available in two formulations, ie, exenatide twice daily (BID), a short-acting GLP-1RA, and exenatide once weekly (QW), a long-acting GLP-1RA. Clinical efficacy and safety of exenatide 2 mg QW in patients with type 2 diabetes (T2DM) has been demonstrated in the DURATION study program. Exenatide QW has been shown to achieve greater HbA1c reduction compared with exenatide BID, with less injection frequency and greater treatment satisfaction. However, exenatide QW failed to show a significant cardiovascular risk reduction in a cardiovascular outcome trial (CVOT), the EXSCEL trial, while other GLP-1RAs have shown positive CV outcomes. Furthermore, exenatide QW has been shown to be inferior to liraglutide and semaglutide with respect to HbA1c or body weight reduction in the head-to-head trials. Thus, although the long-term efficacy and safety of exenatide QW have been demonstrated, exenatide QW might be selected with lower priority within the class of GLP1-RAs for the management of T2DM, especially for patients at high CV risk. On the other hand, exenatide QW is now expected to be a treatment option for children with T2DM or patients with Parkinson’s disease. This review provides an overview of the current evidence regarding the clinical efficacy and safety of exenatide QW and discusses the current perspectives on exenatide QW for treatment of T2DM.”

– A recent study modeled what would happen if millions of US adults who are obese or overweight got GLP-1 drugs for life. In just 2 years, about 50% of all obesity in the country would vanish. Over the years, it would prevent 26 million cases of diabetes, 13 million cases of heart disease, and 5.5 million premature deaths.

The study modeled these outcomes based on a hypothetical scenario where 126 million eligible US adults take either semaglutide or tirzepatide for the rest of their lives. “Eligible” people in the study are “aged 20 to 79 years who would meet the following clinical trial inclusion criteria for these drugs: (1) had a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 30 or greater or (2) had a BMI between 27 and 29.9 and at least 1 weight-related comorbidity (ie, diabetes, hypertension, dyslipidemia, or cardiovascular disease).”

For reporting the predicted outcomes, we are using just the numbers for tirzepatide. The study reports outcomes per 100,000 people, and here we extrapolate to the focal population of 126 million eligible people. Our calculations are based on the numbers shown in Table 2 of the study, cited below.

Obesity cases averted

Tirzepatide: 45,609 cases averted per 100,000 * 1,260 (126 M/100k) = 57,467,340 (which is ~45% of the eligible 126 million US adults)

Diabetes cases averted

Tirzepatide: 20,854 cases averted per 100,000 * 1,260 (126 M/100k) = 26,276,040

Cardiovascular disease cases averted

Tirzepatide: 10,655 cases averted per 100,000 * 1,260 (126 M/100k) = 13,425,300

Premature deaths averted

Tirzepatide: 1,495 (diabetes) + 2,897 (cardiovascular) = 4,482 cases averted per 100,000 * 1,260 (126 M/100k) = 5,647,320

#Hwang JH, Laiteerapong N, Huang ES, Kim DD. Lifetime Health Effects and Cost-Effectiveness of Tirzepatide and Semaglutide in US Adults. JAMA Health Forum. 2025

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2831205 

Quote: “Importance  Newer antiobesity medications lead to greater weight loss and lower cardiometabolic risks. However, the high costs of these medications have raised policy questions about their value and coverage decisions.

Objective  To compare the cost-effectiveness of 4 antiobesity medications with lifestyle modification vs lifestyle modification alone in the US.

Design, Setting, and Participants  A lifetime cost-effectiveness analysis was conducted in 2024 using the validated Diabetes, Obesity, Cardiovascular Disease Microsimulation model for US adults. Data were included from the 2017-2020 National Health and Nutrition Examination Survey of 4823 individuals (representing 126 million eligible US adults) aged 20 to 79 years who would meet clinical trial inclusion criteria for antiobesity medications. Individual-level simulations projected long-term cardiometabolic outcomes, quality-adjusted life-years (QALYs), and health care expenditures. Probabilistic sensitivity analyses, subgroup analyses (across body mass index [BMI] categories [≥30 or ≥27 and at least 1 weight-related comorbidity], presence of comorbidities), and multiple scenario analyses (varying treatment discontinuation rates, value-based pricing benchmarks) were conducted. Future costs and QALYs were discounted at 3% annually.

Interventions  Lifestyle modification with naltrexone-bupropion, phentermine-topiramate, semaglutide, or tirzepatide vs lifestyle modification alone.

Main Outcomes and Measures  Obesity, diabetes, and cardiovascular disease cases averted, life-years and QALYs gained, costs incurred (2023 US dollars), and incremental cost-effectiveness ratios.

Results  Among the 126 million eligible US adults, the mean age was 48 (SE, 0.5) years; 51% were female; and the initial mean BMI was 34.7 (SE, 0.2); and 85% had at least 1 weight-related comorbidity. Over a lifetime, tirzepatide would avert 45 609 obesity cases (95% uncertainty interval [UI], 45 092-46 126) per 100 000 individuals and semaglutide would avert 32 087 cases (95% UI, 31 292-32 882) per 100 000 individuals. Tirzepatide would reduce 20 854 incident cases of diabetes (95% UI, 19 432-22 276) per 100 000 individuals and semaglutide would reduce 19 211 cases (95% UI, 17 878-20 544) per 100 000 individuals. Tirzepatide would reduce 10 655 cardiovascular disease cases (95% UI, 10 124-11 186) per 100 000 individuals and semaglutide would reduce 8263 cases (95% UI, 7738-8788) per 100 000 individuals. Despite the largest incremental QALY gains of 0.35 for tirzepatide and 0.25 for semaglutide among all antiobesity medications, the incremental cost-effectiveness ratios were $197 023/QALY and 467 676/QALY, respectively. To reach the $100 000/QALY threshold, their prices would require additional discounts by 30.5% for tirzepatide and 81.9% for semaglutide from their current net prices. Naltrexone-bupropion was cost saving due to its lower cost and had an 89.1% probability of being cost-effective at $100 000/QALY, whereas phentermine-topiramate had a 23.5% probability of being cost-effective at $100 000/QALY. Tirzepatide and semaglutide both had a 0% probability across all QALY threshold ranges examined ($100 000-$200 000/QALY).

Conclusions and Relevance  This economic evaluation found that although tirzepatide and semaglutide offered substantial long-term health benefits, they were not cost-effective at current net prices. Efforts to reduce the net prices of new antiobesity medications are essential to ensure equitable access to highly effective antiobesity medications.”

– And new drugs that are in final trials promise to work even better.

There are various new GLP-1 (and other glucagon hormone receptor) agonists currently in development. One example is Retatrutide, which yielded 17.5% weight reduction in 24 weeks in a phase II clinical trial. It is currently being tested in a phase III clinical trial (https://trials.lilly.com/en-US/trial/405675).

#Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023

https://www.nejm.org/doi/10.1056/NEJMoa2301972

Quote: “Background

Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose–response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known.

Methods

We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed.

Results

We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was −7.2% in the 1-mg group, −12.9% in the combined 4-mg group, −17.3% in the combined 8-mg group, and −17.5% in the 12-mg group, as compared with −1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was −8.7% in the 1-mg group, −17.1% in the combined 4-mg group, −22.8% in the combined 8-mg group, and −24.2% in the 12-mg group, as compared with −2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter.

Conclusions

In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.)”