Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes : A Meta-analysis

Abstract

This meta-analysis uses data from patients with type 2 diabetes from 6 outcomes trials to investigate the association of sodium-glucose cotransporter 2 inhibitors with cardiovascular- and kidney disease–related outcomes.

Key Points

Question

Is the effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular- and kidney-related outcomes similar across the class of medications overall and by the presence or absence of prevalent cardiovascular and chronic kidney disease?

Findings

Results from a meta-analysis of 6 outcomes trials of 4 SGLT2 inhibitors suggest an associated reduction in risk of major adverse cardiovascular events and heterogeneity of cardiovascular death. The greatest magnitude of benefit was for reduction in risk for hospitalization for heart failure (HHF) and kidney disease progression, with estimates of HHF risk outcome the most consistent observation across the trials.

Meaning

These findings suggest that SGLT2 inhibitors have some heterogeneity of associations with outcomes for cardiovascular death, with consistency of favorable HHF and kidney disease outcomes across the class.

Abstract

Importance

Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain.

Objective

To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes.

Data Sources

A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020.

Study Selection

One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials.

Data Extraction and Synthesis

Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model.

Main Outcomes and Measures

Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials.

Results

Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I ² = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I ²  = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death ( P = .62 for interaction), HHF ( P = .26 for interaction), or kidney outcomes ( P = .73 for interaction).

Conclusions and Relevance

In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.