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The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials
Open accessAbstract
Aims/hypothesis Several cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking.Methods We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed.Results A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control.Conclusions/interpretation SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles.Prospero registration number CRD42020206600.
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“However, the comparative effectiveness of the two drug classes has been assessed in three recent network meta-analyses, which found that, in people with type 2 diabetes, SGLT2i were superior to GLP-1 RA in reducing HHF and a composite kidney outcome, while GLP-1 RA seemed more ef fi cacious in reducing the risk of stroke (223,259,260).”
From Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) (2022) · cites this paper as [260]
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Metadata
- Authors
- Lin, D. S.-H., Lee, J.-K., Hung, C.-S., & Chen, W.-J.
- Affiliations
- National Taiwan University Hospital (TW)
- National Taiwan University (TW)
- Corresponding author
- Hung, Chi-Sheng
- Venue
- Diabetologia
- Published
- 2021-09-18
- Volume
- 64
- Issue
- 12
- Pages
- 2676-2686
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W3199651111
- Cited by
- 108
- References
- 37
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 25 · 2023: 25 · 2022: 25 · 2021: 1
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology, Taiwan (MOST 109, 109-2221-E, 2221-E-002, MOST108-2221-E002-163, MOST 108-, MOST109-2221-E002-083, MOST 109-2221)
- National Taiwan University Hospital (109-EDN11, 108‐N4406, 108‐EDN02, 107-EDN11, 109-O20, 109-S4579)
- National Taiwan University
- 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 › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- antidiabetic drugs, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, major adverse cardiovascular events, cardiovascular outcomes, heart failure hospitalization, renal outcomes, chronic kidney disease, atherosclerotic cardiovascular disease, congestive heart failure, subgroup analysis, drug safety, type 2 diabetes
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Network Meta-Analysis, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, Aged, Cardiovascular Diseases, Brain Ischemia, Diabetes Mellitus, Type 2, Glucose, Humans, Hypoglycemic Agents, Stroke, Dipeptidyl-Peptidase IV Inhibitors
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