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Effect of Combination Treatment With GLP-1 Receptor Agonists and SGLT-2 Inhibitors on Incidence of Cardiovascular and Serious Renal Events
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
To determine whether the combined use of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious renal events compared with either drug class alone among patients with type 2 diabetes, and to assess the effect of the combination on the individual components of major adverse cardiovascular events, heart failure, and all cause mortality.
DESIGN
Population based cohort study using a prevalent new-user design, emulating a trial.
SETTING
UK Clinical Practice Research Datalink linked to Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases.
PARTICIPANTS
Two prevalent new-user cohorts were assembled between January 2013 and December 2020, with follow-up until the end of March 2021. The first cohort included 6696 patients who started GLP-1 receptor agonists and added on SGLT-2 inhibitors, and the second included 8942 patients who started SGLT-2 inhibitors and added on GLP-1 receptor agonists. Combination users were matched, in a 1:1 ratio, to patients prescribed the same background drug, duration of background drug, and time conditional propensity score.
MAIN OUTCOME MEASURES
Cox proportional hazards models were fitted to estimate the hazard ratios and 95% confidence intervals of major adverse cardiovascular events and serious renal events, separately, comparing the GLP-1 receptor agonist-SGLT-2 inhibitor combination with the background drug, either GLP-1 receptor agonists or SGLT-2 inhibitors, depending on the cohort. Secondary outcomes included associations with the individual components of major adverse cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular mortality), heart failure, and all cause mortality.
RESULTS
Compared with GLP-1 receptor agonists, the SGLT-2 inhibitor-GLP-1 receptor agonist combination was associated with a 30% lower risk of major adverse cardiovascular events (7.0 v 10.3 events per 1000 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and a 57% lower risk of serious renal events (2.0 v 4.6 events per 1000 person years; hazard ratio 0.43, 0.23 to 0.80). Compared with SGLT-2 inhibitors, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 29% lower risk of major adverse cardiovascular events (7.6 v 10.7 events per 1000 person years; hazard ratio 0.71, 0.52 to 0.98), whereas serious renal events generated a wide confidence interval (1.4 v 2.0 events per 1000 person years; hazard ratio 0.67, 0.32 to 1.41). Secondary outcomes generated similar results but with wider confidence intervals.
CONCLUSIONS
In this cohort study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse cardiovascular events and serious renal events compared with either drug class alone.
Additional Info
Disclosure statements are available on the authors' profiles:
Effect of combination treatment with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on incidence of cardiovascular and serious renal events: population based cohort study
BMJ 2024 Apr 25;[EPub Ahead of Print], N Simms-Williams, N Treves, H Yin, S Lu, O Yu, R Pradhan, C Renoux, S Suissa, L AzoulayFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Benefits of GLP-1 agonists and SGLT-2 inhibitors
Two papers reviewed this week support the benefits of both GLP-1 agonists and SGLT-2 inhibitors. The first paper is the American College of Physicians guidelines regarding the treatment of adults with type 2 diabetes.1 The guidelines report strong evidence with high certainty for adding either a GLP-1 agonist or an SGLT2 antagonist to lifestyle interventions and metformin if needed.
GLP-1 agonists reduce the risk for all-cause mortality, major adverse cardiovascular events, and stroke. SGLT2 inhibitors reduce the risk for all-cause mortality, major adverse cardiovascular events, progression of chronic kidney disease, and hospitalization due to congestive heart failure.
The second paper concerns a population-based cohort study of patients with diabetes in the UK who were followed for 5 years.2 The researchers were able to compare the outcomes of patients receiving a GLP-1 agonist or an SGLT2 inhibitor alone with those of patients receiving both medications. Compared with patients receiving either medication alone, those receiving both medications had improved outcomes. Specifically, the combination was associated with a 30% reduced risk of major adverse cardiovascular events (MACE) and a 57% reduction of serious renal events when compared with using either drug alone. The confidence interval for renal events was broad (CI, 0.32–1.41).
In summary, these two studies provide evidence to support the use of an SGLT2 inhibitor or a GLP-1 agonist after initiating lifestyle modifications and metformin therapy in patients with type 2 diabetes, and the use of a combination of both medications reduces the risk of major adverse cardiovascular events and renal events compared with using either alone.
References
This rigorous pharmacoepidemiology study conducted by Simms-Williams et al suggests cardiac and kidney benefits of the combination SGLT2 inhibitor and GLP-1 receptor agonist therapy compared with the use of either class alone in people with type 2 diabetes. Despite the new user design, the lack of an active comparator, specifically the addition of another second glucose-lowering medication, may leave conclusions open to significant residual confounding. The effect sizes of the comparisons for cardiovascular outcomes are also much higher than would be suggested by randomized controlled trials using either agent alone, also raising the concern for residual confounding. Still, given the lack of randomized controlled trials evaluating combination therapy, real-world evidence suggesting safety and benefit, regardless of the accuracy of the effect estimate, is valuable information.