Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

Siddharth M Patel; Yu Mi Kang; KyungAh Im; Brendon L Neuen; Stefan D Anker; Deepak L Bhatt; Javed Butler; David Z I Cherney; Brian L Claggett; Robert A Fletcher; William G Herrington; Silvio E Inzucchi; Meg J Jardine; Kenneth W Mahaffey; Darren K McGuire; John J V McMurray; Bruce Neal; Milton Packer; Vlado Perkovic; Scott D Solomon; Natalie Staplin; Muthiah Vaduganathan; Christoph Wanner; David C Wheeler; Faiez Zannad; Yujie Zhao; Hiddo J L Heerspink; Marc S Sabatine; Stephen D Wiviott

doi:10.1161/CIRCULATIONAHA.124.069568

Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis

Circulation. 2024 Apr 7. doi: 10.1161/CIRCULATIONAHA.124.069568. Online ahead of print.

Authors

Siddharth M Patel¹, Yu Mi Kang², KyungAh Im¹, Brendon L Neuen³, Stefan D Anker⁴, Deepak L Bhatt⁵, Javed Butler⁶, David Z I Cherney⁷, Brian L Claggett⁸, Robert A Fletcher⁹, William G Herrington¹⁰, Silvio E Inzucchi¹¹, Meg J Jardine⁹, Kenneth W Mahaffey¹², Darren K McGuire¹³, John J V McMurray¹⁴, Bruce Neal⁹, Milton Packer¹⁵, Vlado Perkovic⁹, Scott D Solomon⁸, Natalie Staplin¹⁰, Muthiah Vaduganathan⁸, Christoph Wanner¹⁶, David C Wheeler¹⁷, Faiez Zannad¹⁸, Yujie Zhao¹⁹, Hiddo J L Heerspink²⁰, Marc S Sabatine¹, Stephen D Wiviott¹

Affiliations

¹ TIMI Study Group, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
² TIMI Study Group, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
³ Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Department of Renal Medicine, Royal North Shore Hospital, Sydney, Australia.
⁴ Berlin Institute of Health Center for Regenerative Therapies (BCRT); German Centre for Cardiovascular Research (DZHK) partner site Berlin; Charité Universitätsmedizin Berlin, Germany.
⁵ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY.
⁶ Baylor Scott and White Research Institute, Dallas, TX; Department of Medicine, University of Mississippi School of Medicine, Jackson, MS.
⁷ Department of Medicine, Division of Nephrology, Toronto General Hospital, Ontario, Canada.
⁸ Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
⁹ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
¹⁰ Renal Studies Group, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
¹¹ Section of Endocrinology, Yale School of Medicine, New Haven, CT.
¹² Stanford Center for Clinical Research (SCCR), Department of Medicine, Stanford University School of Medicine, Stanford, CA.
¹³ University of Texas Southwestern Medical Center, Parkland Health, Dallas, TX.
¹⁴ British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
¹⁵ Baylor University Medical Center, Dallas, TX and Imperial College, London United Kingdom.
¹⁶ Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Center (CHFC), University Hospital, Würzburg, Germany.
¹⁷ Department of Renal Medicine, University College London, London, United Kingdom.
¹⁸ Université de Lorraine, Inserm Centre d'Investigations Cliniques Plurithématique 1433, and CHRU, Nancy, France.
¹⁹ Merck & Co., Inc., Rahway, NJ.
²⁰ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

PMID: 38583093
DOI: 10.1161/CIRCULATIONAHA.124.069568

Abstract

Background: Sodium glucose co-transporter 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 three patient populations (diabetes at high risk for atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. placebo were meta-analyzed across trials and examined across key subgroups (established ASCVD, prior MI, diabetes, prior HF, albuminuria, CKD 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 ASCVD, HF, or CKD, respectively. SGLT2i reduced the rate of MACE by 9% (HR 0.91 [95% CI 0.87-0.96], p<0.0001) with a consistent effect across all three patient populations (I²=0%) and across all key subgroups. This effect was primarily driven by a reduction in CV death (HR 0.86 [0.81-0.92], p<0.0001), with no significant effect for MI in the overall population (HR 0.95 [0.87-1.04], p=0.29), and no effect on stroke (HR 0.99 [0.91-1.07], p=0.77). The benefit for CV death was driven primarily by reductions in HF death and sudden cardiac death (HR 0.68 [0.46-1.02] and HR 0.86 [0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (P_int=0.02).

Conclusions: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of ASCVD, diabetes, kidney function or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of CV death, particularly HF and sudden cardiac death, without a significant effect on MI 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.