10, 11, 12, 13, 14 SGLT2 Activity as a Therapeutic Target for DKD Research on various aspects of diabetes pathophysiology has led to new insights of the disease process, including the role of the kidney in glucose homeostasis and the discovery of additional therapeutic targets.15, 16 One such example is sodium glucose co-transporter-2 (SGLT2), which is part of a class of membrane-bound proteins that reabsorb glucose back into the body from urine.17, 18 Around 90% of glucose filtered form the kidneys is reabsorbed in the brush-border of cells in the proximal convoluted tubule by SGLT2 (Figure 1).17, 18, 19 With development of diabetes, there is an upregulation of SGLT2 transporters.20 This activity leads to increased glucose reabsorption. Additional sodium and chloride are also reabsorbed; thus less sodium and chloride in the tubules is presented to the microcirculation regulator (macula densa) of the glomerulus (filtering device of the kidney). Decreased sodium presented to the macula densa results in a dilation of the incoming arterioles to the glomerulus and constriction of the outgoing arterioles of the glomerulus, which turn leads to increased pressure within the glomerulus and a condition called “hyperfiltration,” causing further damage.18,19,21,22,23 Inhibition of the SGLT2 transporters is believed to reverse this process, resulting in less reabsorption of sodium and chloride. This activity leads to more sodium and chloride within the tubules, and in turn the macula densa. This action results in a reduction of blood flow into the glomerulus and a decrease in pressure within the glomerulus. This activity is considered one of the underlying benefits of SGLT2 inhibition.7,19,24,25,26 Figure 1: Glucose Reabsorption by the Kidney.18 SGLT2 transporters are upregulated in diabetes.18 This upregulation results in less sodium and chloride travelling to the distal tubule and initiates signaling from the macular densa, which leads to changes in microcirculation of the glomerulus with greater inflow (dilation of a‑ erent arteriole) and less outflow (constriction of e‑ erent arteriole). This activity results in an increase in glomerular pressure. One of root causes of DKD is believed to be an abnormally functioning SGLT2 system.19 SGLT2 inhibitors block the reabsorption of glucose, sodium and chloride, which results in more sodium and chloride being presented to the macular densa. This activity results in microvascular changes including a constriction of the a‑ erent arteriole and leads to a decrease in glomerular pressure. Glucose is then excreted into the urine. A decrease in glomerular pressure by changing microcirculation (a‑ erent constriction or e‑ erent dilation) may lead to a small decrease in eGFR, however the chronic e‑ ect may help preserve kidney function.19 REVIEW – SGLT2 inhibitors in type 2 diabetes mellitus Drugs in Context Figure 1. Glucose reabsorption by the kidney. Normally, SGLT2 reabsorbs most of the glucose filtered by the kidney. SGLT2 inhibitors reduce renal reabsorption of glucose, resulting in increased glucose excretion and lowering of plasma glucose concentration. Glucose ltration Reduced glucose reabsorption Glomerulus Loop of Henle Proximal tubule Distal tubule Collecting duct Increased glucose excretion SGLT2 SGLT2 inhibitors Reproduced with permission from Freeman JS. Review of insulin-dependent and insulin-independent agents for treating patients with type 2 diabetes mellitus and potential role for sodium-glucose co-transporter 2 inhibitors. Postgrad Med 2013;125(3):214–26. SGLT2, sodium-glucose co-transporter 2 Roleofthekidneyinglucoseglucose concentration [11]. This phenomenon results in several Table 1: Proposed Renal E ects of SGLT2 Inhibition7,19,26 Tubuloglomerular feedback Oxidative stress â Tubular fibrosis â â Intrarenal angiotensin > > > > > > > SGLT2 Inhibitors and Renal Outcomes in DKD Current SGLT2 inhibitors approved by the U.S. Food and Drug Administration (FDA) for lowering blood glucose levels in patients with type 2 diabetes include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. They are available as single-ingredient products and in combination with other diabetes medicines such as metformin. Studies have also shown possible benefits in addition to glucose lowering. Reductions in CV events with the use of SGLT2 inhibitors have been shown in the trials EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) and CANVAS (Canagliflozin Cardiovascular Assessment Study).27, 28 All drugs in the SGLT2 inhibitor class have been shown to reduce of hospitalization for heart failure, and canagliflozin and dapagliflozin have indications.29,30,31,32 Overall, these studies have supported the use of SGLT2 inhibitors in patients with type 2 diabetes to improve glycemic levels and reduce CV risk. SGLT2 inhibitor cardiovascular outcome trials (CVOTs) have shown a secondary, exploratory or ad hoc analysis reduction in renal composites (EMPA-REG OUTCOME, CANVAS Program, DECLARE TIMI 58) in patients with mild renal impairment (mean eGFR ~80 mL/min/1.73 m2 and median UACR of 300 to 5000 mg/g) and were treated with a maximally tolerated RAAS blockade agent. Participants entering the trial had a mean eGFR of 56 mL/min/1.73m2 and the median UACR was 927 mg/g. The primary outcome of the study was a