SMART-C Meta-Analysis: SGLT2 Inhibitors Reduce Cardiovascular Events

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Meta-analysis of 11 phase 3 trials shows SGLT2 inhibitors reduce cardiovascular event risk by 9% across diverse patient populations.

Insights from a meta-analysis of nearly a dozen phase 3 trials of SGLT2 inhibitors is providing a comprehensive overview of the effects of the class on cardiovascular event risk and mortality across a multitude of patient populations.

provideAn analysis of 11 phase 3 trials encompassing more than 75,000 individuals, results of the study underline the safety and efficacy of SGLT2 inhibitors in patients with diabetes at high risk for atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (CKD), suggesting use reduced the risk of major adverse cardiovascular events by 9% relative to placebo therapy, with this effect consistent across all 3 patient populations and all key subgroups.1

“Despite the various benefits of SGLT2 inhibitors on cardiovascular-kidney-metabolic diseases, this class of medicine remains under-prescribed,” said lead investigator Brendon Neuen, MBBS, PhD, senior Research Fellow at The George Institute for Global Health.2

Beyond the revelations of weight loss and cardiovascular benefits of GLP-1 receptor agonist and other incretin-based therapies, few classes had garnered the same attention from across a breadth of specialties in the last decade in the same manner as the SGLT2 inhibitor class. Once considered an agent with modest anti-hyperglycemic effects, the SGLT2 inhibitor class has thrust itself to the forefront of treatment algorithms for patients with CKD and heart failure, regardless of diabetes status.3

Despite the class’s benefit in type 2 diabetes, chronic kidney disease, and heart failure demonstrated in multiple clinical trial programs and further evidenced, less is certain as it pertains to effects on major adverse cardiovascular events among these patient populations. To better elucidate this risk, Neuen and colleagues from the SGLT2 Meta-Analysis Cardio-Renal Trialists' Consortium designed the current study as a meta-analysis of phase 3 trials of SGLT2 inhibitors.1,2

Investigators included phase 3 placebo-controlled, double-blind, randomized trials of SGLT2 inhibitor therapy, which enrolled at least 1000 participants in each arm, with median follow-up of at least 6 months published from January 1, 2012 through December 28, 2023 in their meta-analysis. A total of 11 trials were identified for inclusion.1

Of the 78,607 patients from the 11 randomized trials, 42,568 (54.2%), 20,725 (26.4%), and 15,314 (19.5%) included from trials that focused on patients with diabetes at high risk for ASCVD, patients with established heart failure, or patients with chronic kidney disease, respectively.1

The primary outcome of interest for the meta-analysis was a 3-point MACE composite of cardiovascular death, myocardial infarction, and stroke. Secondary outcomes of interest included individual components of the composite endpoint, all-cause mortality, and subtypes of death. Risk of the aforementioned outcomes was assessed among the entire meta-analysis cohort and stratified by the 3 primary patient populations as well as predefined subgroups, including ASCVD history, diabetes status at baseline, prior myocardial infarction, albuminuria at baseline, and KDIGO risk groups defined by a combination of eGFR and albuminuria.1

Results of the meta-analysis suggested use of SGLT2 inhibitors were associated with a 9% reduction in risk of major adverse cardiovascular disease relative to placebo therapy (Hazard Ratio [HR], 0.91; 95% Confidence Interval [CI], 0.87 to 0.96; P < .0001). Further analysis indicated this effect was consistent across all 3 patient populations and key subgroups.1

Analysis of individual MACE components suggested the benefit seen in the primary endpoint analysis was driven by, with no significant effect for myocardial infarction in the overall population (HR, 0.95; 95 % CI, 0.87 to 1.04; P =.29) and no effect observed on stroke (HR, 0.99; 95% CI, 0.91 to 1.07; P = .77). Additionally, the effect on cardiovascular death observed in the meta-analysis was driven by reductions in heart failure death (HR, 0.68; 95% CI, 0.46-1.02) and sudden cardiac death (HR, 0.86; 95% CI, 0.78-0.95), with this effect consistent across subgroups except for being more apparent in those with albuminuria (P for interaction = .02).1

“We hope that our findings inform more tailored prescription of SGLT2 inhibitors, particularly in patients with comorbid presentation of diabetes and heart failure or chronic kidney disease, who may experience multiple treatment benefits,” Neuen added.2

For more insights from Neuen into evolving landscape of chronic kidney disease management: check out this recent episode of Diabetes Dialogue. In the episode, Neuen joins hosts to discuss FLOW and the concept of a 4-pillared approach to managing kidney risk in type 2 diabetes.


  1. Patel SM, Kang YM, Im K, et al. Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis. Circulation. Published online April 7, 2024. doi:10.1161/CIRCULATIONAHA.124.069568
  2. The George Institute for Global Health. Diabetes drug improves cardiovascular outcomes across a range of heart and kidney conditions. The George Institute for Global Health. April 8, 2024. Accessed April 18, 2024.
  3. Campbell P, Iapoce C. 10 years of SGLT2 inhibitors: A Decade of Redefining Cardiometabolic Care. HCP Live. March 29, 2023. Accessed April 18, 2024.