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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
Open accessAbstract
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 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.
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“The addition of a GLP-1 RA on top of SGLT2 inhibitor treatment was associated with a 30% lower risk of major adverse cardiovascular events and 57% lower risk of serious kidney events compared with GLP-1 RA therapy alone after a median follow-up of 9 months.”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [146]
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“The addition of an SGLT2 inhibitor on top of GLP-1 RA was associated with a 29% lower risk of major adverse cardiovascular events compared with SGLT2 inhibitor alone.”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [146]
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“When stratified based on history of kidney disease, the use of combination treatment by individuals with a history of kidney disease was associated with a lower risk of major adverse cardiovascular events compared with those without kidney disease (146).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [146]
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“The authors concluded that the combination of both drug classes was associated with a lower risk of MACE and serious kidney disease events compared with either drug class alone.”
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Metadata
- Authors
- Simms-Williams, N., Treves, N., Yin, H., Lu, S., Yu, O., Pradhan, R., Renoux, C., Suissa, S., & Azoulay, L.
- Affiliations
- University of Birmingham (GB)
- Hebrew University of Jerusalem (IL)
- Jewish General Hospital (CA)
- Brigham and Women's Hospital (US)
- Corresponding author
- Azoulay, Laurent
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2024-04-25
- Volume
- 385
- Pages
- e078242
- ISSN
- 1756-1833 (ISSN-L)
- PMC
- PMC11043905
- OpenAlex
- W4395446333
- Cited by
- 151
- References
- 43
- Citations by year
- 2026: 65 · 2025: 60 · 2024: 26
- FWCI
- 49.73
- Type
- journal article
- Language
- en
- Update notices
- Open access
- hybrid
- doi.org
- Licence
- Locations
- BMJ (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- GLP-1 receptor agonists, SGLT2 inhibitors, combination therapy, type 2 diabetes, major adverse cardiovascular events, heart failure, all-cause mortality, cardiovascular mortality, myocardial infarction, ischemic stroke, drug safety, propensity score matching, new-user cohort, Clinical Practice Research Datalink, Hospital Episode Statistics, Office for National Statistics
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Drug Therapy, Combination, Female, United Kingdom, Humans, Hypoglycemic Agents, Male, Middle Aged, Cohort Studies, Incidence
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