Efficacy and safety of SGLT2 inhibitors with and without ...

Summary

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.

Introduction

SGLT2 inhibitors reduce the risk of kidney failure, cardiovascular events, and death in patients with type 2 diabetes and those with heart failure or chronic kidney disease, regardless of diabetes status.1 Consequently, consensus statements from professional diabetes, kidney, and cardiovascular organisations recommend that SGLT2 inhibitors be routinely offered to patients with type 2 diabetes with or at a high risk of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease.2, 3, 4 Results from multiple large-scale randomised trials have also shown that GLP-1 receptor agonists reduce the risk of cardiovascular events in people with type 2 diabetes.5 Therefore, prevailing type 2 diabetes treatment guidelines and society recommendations endorse the use of SGLT2 inhibitors or GLP-1 receptor agonists, or both, for individuals with type 2 diabetes with or at a high risk of atherosclerotic cardiovascular disease.6

The distinct mechanisms of action of these two classes of agents, their myriad effects on intermediate markers of cardiometabolic risk that differ between the classes, and the different types of events prevented have led to considerable interest in using SGLT2 inhibitors and GLP-1 receptor agonists in combination to further reduce cardiorenal event risk. For example, although SGLT2 inhibitors have substantial benefits on the incidence or worsening of heart failure and chronic kidney disease progression, GLP-1 receptor agonists might yield greater reductions in myocardial infarction and stroke.7 Guidelines therefore recognise the potential benefits of the combined use of both classes of agents.8

Research in context

Evidence before this study

Multiple large-scale randomised trials have shown that SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of cardiovascular events and improve chronic kidney disease outcomes in patients with type 2 dabetes. Given the different mechanisms of action of these two classes of agents as well as key differences in their effects on a myriad of intermediates of cardiovascular and kidney risk (eg, substantially greater effects on glycaemia and bodyweight with GLP-1 receptor agonists compared with SGLT2 inhibitors), there has been considerable interest in using SGLT2 inhibitors and GLP-1 receptor agonists in combination to reduce cardio-kidney-metabolic risk. We searched Medline and Embase from database inception to Jan 1, 2024, for randomised trials evaluating the effects of combination treatment with SGLT2 inhibitors and GLP-1 receptor agonists in people with type 2 diabetes, using the search terms “sodium glucose cotransporter 2 inhibitor”, “glucagon-like peptide-1 receptor agonists” “type 2 diabetes mellitus”, “clinical trial”, random allocation” and “double-blind method”. We identified small, randomised trials of relatively short duration indicating that the combined use of SGLT2 inhibitors and GLP-1 receptor agonists improves cardiometabolic risk factors to a greater extent than either alone. However, there are few data on clinical outcomes. Because the event-driven randomised trials of each class of agent were conducted before the benefit of either was confirmed, the background use of GLP-1 receptor agonists in SGLT2 inhibitors trials was too infrequent in any single trial to evaluate the effects of SGLT2 inhibitors in patients receiving and not receiving GLP-1 receptor agonists. To address this evidence gap, we conducted a collaborative meta-analysis of randomised, double-blind, placebo-controlled, event-driven outcome trials within the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. We aimed to assess the effects of SGLT2 inhibitors on cardiovascular, kidney, and safety outcomes in patients with diabetes receiving and not receiving GLP-1 receptor agonists at baseline.

Added value of this study

With 73 238 participants with diabetes from 12 large-scale randomised trials, including 3065 receiving GLP-1 receptor agonists at baseline, to the best of our knowledge, this collaborative meta-analysis represents the largest and most comprehensive assessment of the effects of SGLT2 inhibitors on cardiovascular, kidney, and safety outcomes in people with diabetes receiving and not receiving GLP-1 receptor agonists. Compared with placebo, SGLT2 inhibitors reduced the risk of major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death) by 11% and hospitalisation for heart failure or cardiovascular death by 23%, with consistent effects regardless of GLP-1 receptor agonist use at baseline. SGLT2 inhibitors also reduced the risk of chronic kidney disease progression (defined as a ≥40% decline in estimated glomerular filtration rate, kidney failure, or death due to kidney failure) by 33% and attenuated the annual rate of decline in kidney function, irrespective of GLP-1 receptor agonist use at baseline. The effect of SGLT2 inhibitors on key safety outcomes, including serious adverse events, hypoglycaemia, and volume depletion, did not differ by baseline use of GLP-1 receptor agonists (all p-heterogeneity>0·10).

Implications of all the available evidence

Pooled subgroup data from the totality of the worldwide large-scale placebo-controlled SGLT2 inhibitors trials suggest that the effects of SGLT2 inhibitors on cardiovascular, kidney, and safety outcomes are likely to be similar in patients prescribed a GLP-1 receptor agonist and those not, irrespective of indication for the use of SGLT2 inhibitors. These data suggest that the benefits of SGLT2 inhibitors are independent of GLP-1 receptor agonists, and provide support for the combined use of both classes of agent to optimise cardiovascular and kidney outcomes for patients with type 2 diabetes.

Since clinical trials of SGLT2 inhibitors and GLP-1 receptor agonists were conducted during approximately the same time period before the benefits of either therapy had been established, few participants in SGLT2 inhibitors outcome trials were receiving a GLP-1 receptor agonist. As a result, individual trials did not have sufficient power to examine the effects of SGLT2 inhibitors on clinical outcomes in patients receiving or not receiving GLP-1 receptor agonists. Accordingly, we conducted a meta-analysis of 12 completed trials enrolling patients with diabetes with or at a high risk of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease to examine and compare the efficacy and safety of SGLT2 inhibitors with and without the use of GLP-1 receptor agonists at baseline in patients with diabetes.

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Section snippets

Overview

The SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium (SMART-C) comprises completed, randomised, double-blind, placebo-controlled, event-driven trials that have assessed the effects of an SGLT2 inhibitor (including SGLT1 and SGLT2 inhibitors) on a primary clinical outcome in adults (aged ≥18 years), restricted to trials with more than 500 participants in each group and with a follow-up of at least 6 months. SMART-C is led by an academic steering committee featuring key

Results

We included participants from 12 randomised trials, of whom 73 238 (82·1%) of 89 183 had diabetes. Details of these 12 trials are summarised in the appendix (p 2). Among the 73 238 participants with diabetes, 3065 (4·2%) were using GLP-1 receptor agonists at baseline. GLP-1 receptor agonist use varied across all trials, with a range of 2·8–4·4% in the atherosclerotic cardiovascular disease trials, 4·2–11·1% in the chronic kidney disease progression trials, and 1·0–2·2% in the heart failure

Discussion

This collaborative meta-analysis of 12 large placebo-controlled outcome trials of SGLT2 inhibitors involving more than 70 000 participants with diabetes, of whom more than 3000 were receiving a GLP-1 receptor agonist at baseline, represents the largest and most comprehensive evaluation of the effects of SGLT2 inhibitors on clinical outcomes, with and without GLP-1 receptor agonist use. The smaller proportion of participants receiving GLP-1 receptor agonists at baseline is reflected in the wider

Declaration of interests

BLN reports fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Alexion, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Cornerstone Medical Education, Janssen, the limbic, Medscape, Novo Nordisk, and Travere Therapeutics with all honoraria paid to The George Institute for Global Health. RAF has received studentship awards from the HDR-UK-Turing Wellcome Programme in Health Data Science. SDA reports grants and

Acknowledgments

The EMPA-REG Outcome, EMPEROR-Reduced, EMPEROR-Preserved, and EMPA-KIDNEY trials were funded by Boehringer Ingelheim. The CANVAS Program and CREDENCE trials were funded by Janssen Research & Development. The DECLARE-TIMI 58, DAPA-HF, DAPA-CKD, and DELIVER trials were funded by AstraZeneca. The SCORED trial was funded initially by Sanofi and then by Lexicon Pharmaceuticals. The VERTIS CV trial was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co, in collaboration with Pfizer. SMART-C is

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