SGLT2 inhibitors reduce all-cause mortality

Patients taking sodium-glucose cotransporter-2 (SGLT2) inhibitors had significantly lower risk of all-cause mortality, according to a recent meta-analysis. It included 21 randomized clinical trials comparing almost 40,000 patients taking an SGLT2 inhibitor to more than 30,000 patients on other drugs. Most patients had type 2 diabetes mellitus (T2DM), but not all. The median trial duration was 104 weeks.

The study was published by Diabetes, Obesity and Metabolism on Dec. 7, 2020. The following commentary by Orly F. Kohn, MD, was published in the ACP Journal Club section of Annals of Internal Medicine on May 4.

SGLT2 inhibitors improve glycemic control by inhibiting reabsorption of glucose (and sodium) by the proximal tubules of the kidneys, allowing more of the filtered glucose to be excreted in the urine. Tubuloglomerular feedback results in normalization of afferent arteriole tone and reduces hyperfiltration. The benefits of SGLT2 inhibitors extend beyond their effect on lowering blood sugar. Numerous studies have found a benefit of these agents in terms of cardiovascular (CV), renal, and all-cause mortality in T2DM.

The meta-analysis by Silverii and colleagues assessed the reduction in all-cause mortality by the 4 SGLT2 inhibitors that have been approved by the U.S. Food and Drug Administration and/or European Medicines Agency. 25 trials enrolling <100 patients/group were reasonably excluded due to concern about heterogeneity; these trials would have contributed <7% of the entire population. Of the 21 included studies, 18 enrolled only patients with diabetes and 3 had a mix of patients. SGLT2 inhibitors overall, canagliflozin, dapagliflozin, and empagliflozin reduced all-cause mortality. No correlation was found between treatment effect on mortality and reduction in glycated hemoglobin.

Trials of SGLT2 inhibitors in patients with T2DM and atherosclerotic CV disease or risk factors also show promising protective effects on kidney function. Those studies did not assess kidney function as a primary outcome; patients had a range of estimated glomerular filtration rate (eGFR) levels (mostly >60 mL/min/1.73 m²) and albuminuria (ranging from none to macroalbuminuria) at baseline. CREDENCE was the first study of an SGLT2 inhibitor (canagliflozin) with a primary renal outcome. Study patients had diabetes with urine albumin-to-creatinine ratios (UACRs) >300 mg/g creatinine and eGFR [between] 30 and 89 mL/min/1.73 m² and were treated with renin–angiotensin blockade. There was an impressive 34% reduction in the renal-specific composite outcome of end-stage kidney disease, doubling in serum creatinine, or renal death. Subsequent meta-analysis showed a benefit with SGLT2 inhibitors in all eGFR subgroups, including patients with eGFRs 30 to 45 mL/min/1.73 m², and all UACR levels, in T2DM. Patients with T2DM and lower eGFR have less reduction in glycated hemoglobin with SGLT2 inhibitors yet benefit from a renoprotective effect.

The DAPA-CKD trial found that dapagliflozin reduced a composite outcome of a sustained decline of >50% in eGFR, end-stage kidney disease, or death from renal or CV causes in patients with proteinuric diabetes and nondiabetic kidney disease; the trial was stopped for efficacy. The subgroup analysis of DAPA-CKD by Wheeler and colleagues explored the possibility of a differential effect of dapagliflozin on kidney outcomes in patients with proteinuric CKD based on the presence (68%) or absence (32%) of T2DM. The cause of CKD was based on kidney biopsy in 13% of patients with T2DM and 36% of patients without T2DM. Most had eGFR <60 mL/min/1.73 m² and were taking angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). 14% of the patients with T2DM had nondiabetic kidney disease (defined by the investigator and often with a kidney biopsy). Analysis of outcomes by underlying cause of CKD showed a consistent effect of dapagliflozin in all groups. Although not significant by interaction testing, the absolute risk reduction for the primary and kidney-specific outcomes was greatest in patients with glomerulonephritis, most of whom had IgA nephropathy.

It is exciting to have a new class of medication, in addition to ACE inhibitors and ARBs, that can slow down the progression of kidney disease. We need further studies on use of these agents in nonproteinuric kidney diseases and in patients with even lower eGFR. The EMPA-kidney trial, which is currently under way, may fill some of these gaps. The mechanisms by which SGLT2 inhibitors achieve CV and renal benefits need further elucidation.

When considering use of SGLT2 inhibitors in patients with nondiabetic kidney disease, one must keep in mind the exclusion criteria used in DAPA-CKD (e.g., patients with immunosuppression or polycystic kidney disease were excluded) and the nonsignificant results in some subgroups. Clinicians need to familiarize themselves with potential adverse events from SGLT2 inhibitors, such as diabetic ketoacidosis and hypoglycemia in patients with T2DM, and risk for genitourinary infections. Patient education about prevention and mitigation strategies is essential.