Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials

Ellen M Apperloo; Brendon L Neuen; Robert A Fletcher; Niels Jongs; Stefan D Anker; Deepak L Bhatt; Javed Butler; David Z I Cherney; William G Herrington; Silvio E Inzucchi; Meg J Jardine; Chih-Chin Liu; Kenneth W Mahaffey; Darren K McGuire; John J V McMurray; Bruce Neal; Milton Packer; Vlado Perkovic; Marc S Sabatine; Scott D Solomon; Natalie Staplin; Michael Szarek; Muthiah Vaduganathan; Christoph Wanner; David C Wheeler; Stephen D Wiviott; Faiez Zannad; Hiddo J L Heerspink

doi:10.1016/S2213-8587(24)00155-4

Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials

Lancet Diabetes Endocrinol. 2024 Aug;12(8):545-557. doi: 10.1016/S2213-8587(24)00155-4. Epub 2024 Jul 8.

Authors

Ellen M Apperloo¹, Brendon L Neuen², Robert A Fletcher³, Niels Jongs¹, Stefan D Anker⁴, Deepak L Bhatt⁵, Javed Butler⁶, David Z I Cherney⁷, William G Herrington⁸, Silvio E Inzucchi⁹, Meg J Jardine¹⁰, Chih-Chin Liu¹¹, Kenneth W Mahaffey¹², Darren K McGuire¹³, John J V McMurray¹⁴, Bruce Neal¹⁵, Milton Packer¹⁶, Vlado Perkovic³, Marc S Sabatine¹⁷, Scott D Solomon¹⁸, Natalie Staplin⁸, Michael Szarek¹⁹, Muthiah Vaduganathan¹⁸, Christoph Wanner²⁰, David C Wheeler²¹, Stephen D Wiviott¹⁷, Faiez Zannad²², Hiddo J L Heerspink²³

Affiliations

¹ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.
² The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia; Department of Renal Medicine, Royal North Shore Hospital, Sydney, NSW, Australia.
³ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁴ Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, German Center for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany.
⁵ Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Baylor Scott and White Research Institute, Dallas, TX, USA; Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA.
⁷ Department of Medicine, Division of Nephrology, Toronto General Hospital, ON, Canada.
⁸ Renal Studies Group, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁹ Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA.
¹⁰ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia; NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Renal Medicine, Concord Repatriation General Hospital, Sydney, NSW, Australia.
¹¹ Merck, Rahway, NJ, USA.
¹² Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ University of Texas Southwestern Medical Center and Parkland Health, Dallas, TX, USA.
¹⁴ British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
¹⁵ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
¹⁶ Baylor University Medical Center, Dallas TX, USA; Imperial College, London, UK.
¹⁷ TIMI Study Group, Boston, MA, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁸ Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁹ Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA; Colorado Prevention Center Clinical Research, Aurora, CO, USA; State University of New York, Downstate Health Sciences University, Brooklyn, NY, USA.
²⁰ Department of Clinical Research and Epidemiology, Comprehensive Heart Failure Centre, University Hospital, Würzburg, Germany.
²¹ Department of Renal Medicine, University College London, London, UK.
²² Université de Lorraine, Inserm, Center d'Investigations Cliniques, Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
²³ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands; The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia. Electronic address: h.j.lambers.heerspink@umcg.nl.

PMID: 38991584
DOI: 10.1016/S2213-8587(24)00155-4

Abstract

Background: SGLT2 inhibitors and GLP-1 receptor agonists both improve cardiovascular and kidney outcomes in patients with type 2 diabetes. We sought to evaluate whether the benefits of SGLT2 inhibitors are consistent in patients receiving and not receiving GLP-1 receptor agonists.

Methods: We conducted a collaborative meta-analysis of trials included in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium, restricted to participants with diabetes. Treatment effects from individual trials were obtained from Cox regression models and pooled using inverse variance weighted meta-analysis. The two main cardiovascular outcomes assessed included major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), and hospitalisation for heart failure or cardiovascular death. The main kidney outcomes assessed were chronic kidney disease progression (≥40% decline in estimated glomerular filtration rate [eGFR], kidney failure [eGFR <15 mL/min/1·73 m², chronic dialysis, or kidney transplantation], or death due to kidney failure), and the rate of change in eGFR over time. Safety outcomes were also assessed.

Findings: Across 12 randomised, double-blind, placebo-controlled trials, 3065 (4·2%) of 73 238 participants with diabetes were using GLP-1 receptor agonists at baseline. SGLT2 inhibitors reduced the risk of major adverse cardiovascular events in participants both receiving and not receiving GLP-1 receptor agonists (hazard ratio [HR] 0·81, 95% CI 0·63-1·03 vs 0·90, 0·86-0·94; p-heterogeneity=0·31). Effects on hospitalisation for heart failure or cardiovascular death (0·76, 0·57-1·01 vs 0·78, 0·74-0·82; p-heterogeneity=0·90) and chronic kidney disease progression (0·65, 0·46-0·94 vs 0·67, 0·62-0·72; p-heterogeneity=0·81) were also consistent regardless of GLP-1 receptor agonist use, as was the effect on the chronic rate of change in eGFR over time (heterogeneity=0·92). Fewer serious adverse events occurred with SGLT2 inhibitors compared with placebo, irrespective of GLP-1 receptor agonist use (relative risk 0·87, 95% CI 0·79-0·96 vs 0·91, 0·89-0·93; p-heterogeneity=0·41).

Interpretation: The effects of SGLT2 inhibitors on cardiovascular and kidney outcomes are consistent regardless of the background use of GLP-1 receptor agonists. These findings suggest independent effects of these evidence-based therapies and support clinical practice guidelines recommending the use of these agents in combination to improve cardiovascular and kidney metabolic outcomes.

Funding: National Health and Medical Research Council of Australia and the Ramaciotti Foundation.

Publication types

Meta-Analysis

MeSH terms

Cardiovascular Diseases / epidemiology
Cardiovascular Diseases / prevention & control
Diabetes Mellitus, Type 2* / drug therapy
Glomerular Filtration Rate / drug effects
Glucagon-Like Peptide-1 Receptor* / agonists
Humans
Hypoglycemic Agents / adverse effects
Hypoglycemic Agents / therapeutic use
Randomized Controlled Trials as Topic*
Renal Insufficiency, Chronic / drug therapy
Sodium-Glucose Transporter 2 Inhibitors* / adverse effects
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
Treatment Outcome

Substances

Sodium-Glucose Transporter 2 Inhibitors
Glucagon-Like Peptide-1 Receptor
Hypoglycemic Agents