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Efficacy and Safety of SGLT2 Inhibitors With and Without GLP-1 Receptor Agonists
TAKE-HOME MESSAGE
- This meta-analysis of 12 randomised controlled trials evaluated whether the benefits of SGLT2 inhibitors are consistent in patients receiving and not receiving GLP-1 receptor agonists (GLP-1 RAs). SGLT2 inhibitors reduced the risk of major adverse cardiovascular events in participants receiving GLP-1 RAs as well as in those not receiving GLP-1 RAs. The effects on hospitalisation for heart failure or cardiovascular death and chronic kidney disease progression were also consistent regardless of GLP-1 RA use.
- The effects of SGLT2 inhibitors on cardiovascular and kidney outcomes are consistent regardless of background use of GLP-1 RAs. The findings support other guidelines by professional societies recommending the use of these agents in combination with GLP-1 RAs for additional cardiovascular and metabolic benefits.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
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.
Additional Info
Disclosure statements are available on the authors' profiles:
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 Jul 08;[EPub Ahead of Print], EM Apperloo, BL Neuen, RA Fletcher, N Jongs, SD Anker, DL Bhatt, J Butler, DZI Cherney, WG Herrington, SE Inzucchi, MJ Jardine, CC Liu, KW Mahaffey, DK McGuire, JJV McMurray, B Neal, M Packer, V Perkovic, MS Sabatine, SD Solomon, N Staplin, M Szarek, M Vaduganathan, C Wanner, DC Wheeler, SD Wiviott, F Zannad, HJL HeerspinkFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP-1 RAs) have rapidly emerged as effective cardiovascular and kidney therapies in patients with type 2 diabetes (T2D).1-3 However, background rates of SGLT2i use in trials evaluating GLP-1 RAs and of GLP-1 RAs in trials evaluating SGLT2is have both been low. This meta-analysis from the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium sought to address these limited numbers by pooling data from 12 cardiovascular and kidney outcomes trials of SGLT2is in patients with T2D with or at high risk of atherosclerotic disease, heart failure, and/or kidney disease, comparing the impact of randomization to SGLT2i in those with versus without GLP-1 RA use at baseline.
The authors found that the benefits of randomization to an SGLT2i were sustained regardless of GLP-1 RA use, including the risk of major adverse cardiovascular events, risk of hospitalization for heart failure or cardiovascular death, and progression of chronic kidney disease. Furthermore, they noted that SGLT2is were well-tolerated, with fewer adverse events when compared with placebo, regardless of background GLP-1 RA use.
These findings were not necessarily unexpected: SGLT2is and GLP-1 RAs have fundamentally different mechanisms of action, and neither class of drug solely exerts its effects via glucose-lowering.4,5 However, given the low uptake of both of these therapies, even in patients with T2D,6 these results should both 1) reassure clinicians that combination therapy with drugs from both classes is safe, and 2) support the use of an SGLT2i in patients with T2D with or at high risk of atherosclerotic disease, with heart failure, and/or with chronic kidney disease, regardless of background GLP-1 RA use. The high cost of each of these drug classes may ultimately reduce the feasibility of this approach for clinicians and patients, and the impact of dual therapy with these drugs on healthcare resource utilization and cost is not yet known. However, the clinical benefit seen from each therapy supports the use of simultaneous treatment with both classes of drugs.
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