Class effects of SGLT2 inhibitors on cardiorenal outcomes

Abstract

Background To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA–REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes. Results The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m 2 for DECLARE-TIMI 58, CANVAS, EMPA–REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA–REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30–300, 11.0% UACR > 300 mg/g). Conclusions Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.

Favorable pleiotropic effects of sodium glucose cotransporter 2 inhibitors: head-to-head comparisons with dipeptidyl peptidase-4 inhibitors in type 2 diabetes patients

“…Sixth, this study was based on changes in laboratory data between two drug classes, and thus no inference on cardiovascular events could be made. Nevertheless, we conducted a post hoc analysis and investigated the incidence rate of major cardiovascular events (MACE), including myocardial infarction, ischemic stroke and cardiovascular death, because SGLT2 inhibitors have been proven to reduce MACE in placebo-controlled trials [56][57][58][59]. We found the incidence rate of MACE was 12.6 per 1000 person-years in SGLT2 inhibitors versus 14.5 per 1000 person-years in DPP4 inhibitors.…”

Preventing major adverse cardiovascular events by SGLT-2 inhibition in patients with type 2 diabetes: the role of kidney

“…The risk reduction for MACE ranges from 7% of DECLARE trial (not significant) to 20% of CREDENCE trial (significant), with intermediate and significant reduction (14%) in both EMPA-REG OUTCOME and CANVAS trials. As the cardiorenal protection by SGLT-2 inhibition is considered a class effect [5,6], the reasons for this divergence is not readily apparent, even because the major risk factors for MACE (age, smoking, body weight, blood pressure and lipids) were on average similarly controlled in the four trials, and treatment with RAS inhibitors and statins were comparable (Table 1). It has been suggested that the observed differences are inherent to the population studied; in the DECLARE trial, patients were globally (and relatively) healthier at baseline, which reduced the power to detect differences between the two arms of the study.…”

A Network Meta-Analysis of the Efficacy and Safety of Empagliflozin at Different Doses in Patients with Diabetes Mellitus Based on Randomized Controlled Trials

“…Rosenstock et al reported that 1, 5, 10 and 50 mg (1.4, 5.6, 9.9 and 2.9%) increased the risk of genital infection, but 25 mg and placebo (0%) did not increase the risk. Recent studies have found that the frequent occurrence of urogenital tract infections compared other AEs should be taken seriously and was associated with increases in UGE [47,48] . These ndings suggest that it is important to emphasize monitoring in the clinic for early detection and intervention [49] .…”