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Samuel E. Crockett Chair in Diabetes Research
AdventHealth Diabetes Institute
Senior Investigator and Diabetes Program Lead
AdventHealth Translational Research Institute
Adjunct Professor of Medicine
Johns Hopkins University School of Medicine
Richard E. Pratley, MD, has disclosed that he has received consulting fees from Corcept Therapeutics, Merck, Novo Nordisk, Pfizer, Sanofi, Scohia, and Sun Pharmaceutical; funds for research support from Hanmi, Metavention, Novo Nordisk, Poxel, and Sanofi; and fees for non-CME/CE services from Novo Nordisk.
Sodium glucose cotransporter 2 (SGLT2) inhibitors are potent, highly specific inhibitors of SGLT2, which is expressed almost exclusively in the proximal tubule of the kidney. Currently, 4 SGLT2 inhibitors that are taken orally (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) are approved by the FDA for the treatment of type 2 diabetes (T2D).
Inhibition of SGLT2 increases renal glucose excretion, thereby reducing plasma glucose levels. SGLT2 inhibition also causes a modest natriuretic and diuretic effect that contributes to a decrease in blood pressure. The obligate glucosuria and natriuresis also lead to weight loss. In phase III trials, SGLT2 inhibitors reduced A1C by 0.6% to 0.8%, systolic blood pressure by 3-5 mm Hg, and weight by 3-4 kg (~6.5-8.5 lb), on average.
Cardiovascular Outcomes Trials With the SGLT2 Inhibitors
As a condition of approval by the FDA, the cardiovascular safety of all 4 SGLT2 inhibitors have been studied in dedicated double-blind, randomized, placebo-controlled cardiovascular outcome trials (CVOTs), where patients were followed for a median of 2.4-4.2 years:
In these trials, significant reductions in major adverse cardiovascular events were seen with canagliflozin and empagliflozin. Empagliflozin also significantly reduced cardiovascular death and all-cause mortality. A consistent finding across all 4 studies has been a reduction in hospitalization for heart failure.
In addition to examining cardiovascular benefits, each of these studies also assessed composite kidney outcomes, which consisted of hard outcomes such as end-stage kidney disease, transplant, kidney-related death, and a decline in estimated glomerular filtration rate (eGFR). However, different definitions of eGFR decline were used in each trial. These different definitions affect the number of kidney events that accrue, and as a consequence, it is difficult to directly compare kidney outcomes across trials.
Recently, consensus on definitions of endpoints for clinical trials of kidney failure has been proposed. This consensus definition includes a sustained ≥40% decline in eGFR from baseline, in addition to kidney-related death and need for transplant or kidney replacement therapy. Therefore, McGuire and colleagues, including myself, recently performed a meta-analysis across the 4 SGLT2 CVOTs using this definition of kidney failure. In this meta-analysis, SGLT2 inhibition was associated with a significant 38% reduction in the composite renal endpoint (HR: 0.62; 95% CI: 0.56-0.70), which was quite consistent across trials, even though the proportion of patients with established CKD at baseline was relatively small, ranging from 7% in DECLARE-TIMI to 26% in EMPA-REG OUTCOME.
Recommendations in Practice
The decreased risk of CKD progression seen with SGLT2 inhibitors has been attributed to both glucose lowering as well as several glucose-independent mechanisms. Because of the consistency and significance of effect across these trials, the American Diabetes Association and the Kidney Disease Improving Global Outcomes organization modified their recommendations to include the use of an SGLT2 inhibitor in patients with T2D and CKD, regardless of glycemic status. Thus, all patients with T2D should have their kidney function assessed on a regular basis with measurement of eGFR and urine microalbumin-to-creatinine ratio. If evidence of kidney dysfunction is apparent, treatment with an SGLT2 inhibitor should be initiated, unless the medications are contraindicated.
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