Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis
Authors: Patel Siddharth M. , Kang Yu Mi , Im KyungAh , Neuen Brendon L. , Anker Stefan D. , Bhatt Deepak L. , Butler Javed , Cherney David Z.I. , Claggett Brian L. , Fletcher Robert A. , Herrington William G. , Inzucchi Silvio E. , Jardine Meg J. , Mahaffey Kenneth W. , McGuire Darren K. , McMurray John J.V. , Neal Bruce , Packer Milton , Perkovic Vlado , Solomon Scott D. , Staplin Natalie , Vaduganathan Muthiah , Wanner Christoph , Wheeler David C. , Zannad Faiez , Zhao Yujie , Heerspink Hiddo J.L. , Sabatine Marc S. , Wiviott Stephen D. 
Published: April 2024

BACKGROUND:
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear.

METHODS:
This was a collaborative trial-level meta-analysis from the SGLT2i Meta-analysis Cardio-Renal Trialists Consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across 3 patient populations (patients with diabetes at high risk for atherosclerotic cardiovascular disease, heart failure [HF], or chronic kidney disease). The outcomes of interest were MACE (composite of cardiovascular death, myocardial infarction , or stroke), individual components of MACE (inclusive of fatal and nonfatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i versus placebo were meta-analyzed across trials and examined across key subgroups (established atherosclerotic cardiovascular disease, previous myocardial infarction, diabetes, previous HF, albuminuria, chronic kidney disease stages, and risk groups).

RESULTS:

A total of 78 607 patients across 11 trials were included: 42 568 (54.2%), 20 725 (26.4%), and 15 314 (19.5%) were included from trials of patients with diabetes at high risk for atherosclerotic cardiovascular disease, HF, or chronic kidney disease, respectively. SGLT2i reduced the rate of MACE by 9% (hazard ration [HR], 0.91 [95% CI, 0.87–0.96],
P
<0.0001) with a consistent effect across all 3 patient populations (
I
2
=0%) and across all key subgroups. This effect was primarily driven by a reduction in cardiovascular death (HR, 0.86 [95% CI, 0.81–0.92],
P
<0.0001), with no significant effect for myocardial infarction in the overall population (HR, 0.95 [95% CI, 0.87–1.04],
P
=0.29), and no effect on stroke (HR, 0.99 [95% CI, 0.91–1.07],
P
=0.77). The benefit for cardiovascular death was driven primarily by reductions in HF death and sudden cardiac death (HR, 0.68 [95% CI, 0.46–1.02] and HR, 0.86 [95% CI, 0.78–0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (
P
interaction
=0.02).

CONCLUSIONS:
SGLT2i reduce the risk of MACE across a broad range of patients irrespective of atherosclerotic cardiovascular disease, diabetes, kidney function, or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of cardiovascular death, particularly HF death and sudden cardiac death, without a significant effect on myocardial infarction in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.