Cardiovascular, mortality and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials

Kristensen, S. L., Rorth, R., Jhund, P. S. , Docherty, K. , Sattar, N. , Preiss, D. , Kober, L., Petrie, M. C. and McMurray, J. J.V. (2019) Cardiovascular, mortality and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes and Endocrinology, 7(10), pp. 776-785. (doi: 10.1016/S2213-8587(19)30249-9) (PMID:31422062)

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Background: Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs. Methods: We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology. Findings: Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82–0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81–0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76–0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84–1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83–0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83–0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78–0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer. Interpretation: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.

Item Type:Articles
Additional Information:DP is supported by a University of Oxford BHF Centre of Research Excellence Senior Transition Fellowship (RE/13/1/30181).
Glasgow Author(s) Enlighten ID:Preiss, Dr David and Docherty, Dr Kieran and Jhund, Professor Pardeep and Petrie, Professor Mark and Kober, Professor Lars and Kristensen, Mr Soren Lund and Sattar, Professor Naveed and McMurray, Professor John
Authors: Kristensen, S. L., Rorth, R., Jhund, P. S., Docherty, K., Sattar, N., Preiss, D., Kober, L., Petrie, M. C., and McMurray, J. J.V.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Lancet Diabetes and Endocrinology
ISSN (Online):2213-8595
Published Online:14 August 2019
Copyright Holders:Copyright © 2019 Elsevier Ltd.
First Published:First published in Lancet Diabetes and Endocrinology 7(10):776-785
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
3039440BHF Centre of ExcellenceRhian TouyzBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science