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
BMJ2024;385doi:
https://doi.org/10.1136/bmj-2023-078242
(Published 25 April 2024)Cite this as: BMJ2024;385:e078242
- Nikita Simms-Williams, research associate1,
- Nir Treves, doctoral student2,
- Hui Yin, statistician1,
- Sally Lu, research associate3,
- Oriana Yu, endocrinologist and associate professor3 4,
- Richeek Pradhan, postdoctoral fellow5,
- Christel Renoux, neurologist and associate professor3 6 7,
- Samy Suissa, professor3 6,
- Laurent Azoulay, professor3 6 8
Abstract
Objective
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 v10.3 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 v4.6 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 v10.7 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 v2.0 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.
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From the article
Introduction
Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are second to third line antihyperglycaemic drugs commonly prescribed for the treatment of type 2 diabetes.12Individually, these drugs have been shown to reduce the risk of cardiorenal events and mortality in large cardiovascular outcome trials.3456789However, the combined effect of these drug classes on these outcomes has not been extensively studied.
GLP-1 receptor agonists and SGLT-2 inhibitors are often combined in clinical settings when monotherapy fails to maintain glycaemic targets.1011Given their different mechanisms of action, the combination of the drugs may improve clinical outcomes through additive effects.
Observational studies among patients with type 2 diabetes have shown that the GLP-1 receptor agonist-SGLT-2 inhibitor combination results in more significant improvements in haemoglobin A1cand blood pressure while lowering body weight than either drug class alone.121314151617
However, these represent surrogate outcomes, and whether this combination is associated with a reduced risk of macrovascular and microvascular complications remains unclear. To date, observational studies investigating the cardiovascular effectiveness of the combination have either been underpowered or had important methodological limitations, such as immortal time bias.1215181920I
mportantly, none compared the combination with either drug class alone or investigated serious renal events, which are clinically relevant outcomes in this patient population.1215181920
The primary objective of this study was to determine whether the combined use of GLP-1 receptor agonists and SGLT-2 inhibitors is associated with a decreased risk of two co-primary outcomes, major adverse cardiovascular events and serious renal events, compared with the use of either drug class alone among patients with type 2 diabetes. The secondary outcomes included the association with the individual components of major adverse cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular mortality), heart failure, and all cause mortality.
Conclusion
In summary, the results of this population based study, designed to closely emulate a randomised controlled trial, suggest that the use of the GLP-1 receptor agonist-SGLT-2 inhibitor combination is associated with a lower risk of major adverse cardiovascular events and serious renal events among patients with type 2 diabetes compared with each drug class alone. Additional studies, including randomised controlled trials, will be needed to corroborate our findings and to explore the full therapeutic potential of the GLP-1 receptor agonist-SGLT-2 inhibitor combination among patients with type 2 diabetes.