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Cited by 151Diabetes Treatment and ManagementHeart Failure Treatment and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

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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 access
Simms-Williams, Nikita, Treves, Nir, Yin, Hui, Lu, Sally, Yu, Oriana, Pradhan, Richeek, Renoux, Christel, Suissa, Samy, Azoulay, Laurent·2024·BMJ
DOI 10.1136/bmj-2023-078242PMC PMC11043905
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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 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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Crossref · 10.1136/bmj-2023-078242

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Fig 1 Study flowchart for construction of glucagon-like peptide-1 (GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination users versus GLP-1 RA users cohort. An individual can represent multiple matching opportunities at different times during follow-up period; thus, number of possible matches exceeds total number of patients. ESRD=end stage renal disease
Fig 1 Study flowchart for construction of glucagon-like peptide-1 (GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination users versus GLP-1 RA users cohort. An individual can represent multiple matching opportunities at different times during follow-up period; thus, number of possible matches exceeds total number of patients. ESRD=end stage renal diseaseCC BY-NC · PubMed Central
Fig 2 Cumulative incidence curves of major adverse cardiovascular events (MACE) for glucagon-like peptide-1 (GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination versus GLP-1 RAs
Fig 2 Cumulative incidence curves of major adverse cardiovascular events (MACE) for glucagon-like peptide-1 (GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination versus GLP-1 RAsCC BY-NC · PubMed Central
Fig 3 Study flowchart for construction of glucagon-like peptide-1(GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination users versus SGLT-2 inhibitor users cohort. An individual can represent multiple matching opportunities at different times during follow-up period; thus, number of possible matches exceeds total number of patients. ESRD=end stage renal disease
Fig 3 Study flowchart for construction of glucagon-like peptide-1(GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination users versus SGLT-2 inhibitor users cohort. An individual can represent multiple matching opportunities at different times during follow-up period; thus, number of possible matches exceeds total number of patients. ESRD=end stage renal diseaseCC BY-NC · PubMed Central
Fig 4 Cumulative incidence curves of major adverse cardiovascular events (MACE) for glucagon-like peptide-1(GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination versus SGLT-2 inhibitors
Fig 4 Cumulative incidence curves of major adverse cardiovascular events (MACE) for glucagon-like peptide-1(GLP-1) receptor agonist (RA)-sodium-glucose cotransporter-2 (SGLT-2) inhibitor combination versus SGLT-2 inhibitorsCC BY-NC · PubMed Central

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  1. Rubin DB . Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons, 2004.

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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
ORCID
Venue
BMJ
Publisher
BMJ
Published
2024-04-25
Volume
385
Pages
e078242
ISSN
1756-1833 (ISSN-L)
DOI
10.1136/bmj-2023-078242
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
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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