Diabetes is a global epidemic affecting more than 240 million people worldwide. The incidence of this disease is growing at an alarming rate, with 380 million cases predicted by 2025. Each year over 3.8 million people die from complications of diabetes, including heart disease, stroke and kidney failure. The vast majority (90–95%) of cases are type 2 diabetes, largely resulting from the increasing prevalence of obesity and sedentary lifestyles. Despite the availability of a range of agents to treat type 2 diabetes, glucose control remains suboptimal, with less than 50% of patients achieving stated glycemic goals. 

In addition, current therapies have limited durability and/or are associated with significant side effects such as GI intolerance, hypoglycemia, weight gain, lactic acidosis and edema. Thus, significant unmet medical needs remain. 

In particular, safer, better tolerated medications which provide increased efficacy and long-term durability are desired. Insulin secretagogues represent a promising new approach to the treatment of this disease.

All sulfonylureas are taken orally

• These drugs exert their hypoglycaemic effects by stimulating insulin secretion from the pancreatic beta-cell.

• Their primary mechanism of action is to close ATP-sensitive K-channels in the beta-cell plasma membrane, and so initiate a chain of events which results in insulin release. Recent studies have shown that the beta-cell ATP-sensitive K-channel is a complex of two proteins: a pore-forming subunit (Kir6.2) and a drug-binding subunit (SUR1) which functions as the receptor for sulfonylureas.

• This review summarizes recent advances in our understanding of the molecular mechanism of sulfonylurea action, focusing on the relationship between the sulfonylurea receptor and the K-ATP channel.

1. Antacids may increase the absorption of all the sulfonylureas and hence produce higher peak concentrations of the drugs and a risk of temporary hypoglycaemia.

2. Chlorpropamide has an additional interaction with alcohol which can produce significant facial flushing.

3. Sulfonylureas are highly protein bound drugs and may be displaced  from blood protein binding sites by drug such as 𝐭𝐡𝐞 𝐧𝐨𝐧-𝐬𝐭𝐞𝐫𝐨𝐢𝐝𝐚𝐥 𝐚𝐧𝐭𝐢-𝐢𝐧𝐟𝐥𝐚𝐦𝐦𝐚𝐭𝐨𝐫𝐲 𝐝𝐫𝐮𝐠𝐬. The can cause a short-term 𝐢𝐧𝐜𝐫𝐞𝐚𝐬𝐞 in free (unbound) sulfonylurea and hence temporary 𝐡𝐲𝐩𝐨𝐠𝐥𝐲𝐜𝐚𝐞𝐦𝐢𝐚.

4. Interactions with sulfonylureas are due to the induction or inhibition of cytochrome P450 enzymes in the liver.

• Potential interactions between sulfonylureas or repaglinide and drugs which alter hepatic enzymes:

• 𝐈𝐧𝐝𝐮𝐜𝐞𝐫𝐬 of metabolism (reduce concentration of hypoglycaemic drug):

1. Phenytoin

2. Phenobarbitone

3. Rifabutin

4. Rifampicin

• 𝐈𝐧𝐡𝐢𝐛𝐢𝐭𝐨𝐫𝐬 of metabolism (increase concentration of hypoglycaemic drug)

1. Allopurinol

2. Chloramphenicol

3. Cimetidine

4. Erythromycin

• Some of the common side effects include:

1. Diarrhea                                            6. Sore throat

2. Nausea                                               7. Muscle pain

3. Vomiting                                           8. Headache

4. Stomach upset                              9. Loss of appetite

5. Abdominal pain                           10. Weakness   

• Other rare side effects include:

1. Upper respiratory tract infection

2. Dizziness (feeling faint, weak, or unsteady)

3. Asthenia (abnormal physical weakness or lack of energy)

4. Leukopenia (low white blood cells)

5. Anemia (low number of red blood cells)

6. Hypoglycemia (low blood sugar level)

Meglitinide derivatives are administered orally three times a day.

• Excretion:

Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within 6 hours after dosing, approximately 75% of the administered 14C-nateglinide was recovered in the urine. Eighty-three percent of the 14C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C-nateglinide was excreted in the urine as parent compound. In all studies of healthy volunteers and patients with Type 2 diabetes, nateglinide plasma concentrations declined rapidly with an average elimination half-life of approximately 1.5 hours. Consistent with this short elimination half-life, there was no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.

• The mechanism of action of meglitinide analogs involves binding to beta-cell receptors in the pancreas responsible for insulin secretion.

• Upon ingestion, the drug is absorbed in the gastrointestinal tract, enters the bloodstream, and reaches the pancreas. Meglitinide analogs bind to beta-cell receptors in the pancreas and stimulate insulin secretion.

• This stimulation leads to increased insulin secretion in the pancreas and, consequently, the regulation of blood sugar levels.

1. CYP2C8 enzyme inhibitors: Taking these medications with meglitinide analogs may increase the concentration of the latter in the blood, leading to an increased risk of hypoglycemia (low blood sugar). It is important to consult a healthcare provider before taking any of these medications along with meglitinide analogs.

2. Certain antifungal medications such as ketoconazole and fluconazole: Taking these medications with meglitinide analogs may increase the concentration of the latter in the blood and increase the risk of hypoglycemia. It may be necessary to adjust the dose of meglitinide analogs or switch to an alternative medication while taking these antifungal medications.

3. Some nonsteroidal anti-inflammatory drugs (NSAIDs): Taking NSAIDs with meglitinide analogs may increase the effects of the latter and raise the risk of hypoglycemia. It is advisable to consult a healthcare provider before taking NSAIDs with meglitinide analogs.

4. Certain anticoagulant medications such as warfarin: Taking meglitinide analogs with these medications may increase the risk of bleeding. Close monitoring of clotting levels is necessary when using these medications with meglitinide analogs.

1. Diarrhea

2. Nausea

3. Vomiting

4. Stomach upset/pain

5. Muscle/joint pain

6. Headache

7. Weakness