The Longer-Term Benefits and Harms of Glucagon-Like Peptide-1 Receptor Agonists: a Systematic Review and Meta-Analysis

• Published in: Journal of general internal medicine : JGIM Vol. 37; no. 2; pp. 415 - 438
• Main Authors: Alexander, Jason T., Staab, Erin M., Wan, Wen, Franco, Melissa, Knitter, Alexandra, Skandari, M. Reza, Bolen, Shari, Maruthur, Nisa M., Huang, Elbert S., Philipson, Louis H., Winn, Aaron N., Thomas, Celeste C., Zeytinoglu, Meltem, Press, Valerie G., Tung, Elizabeth L., Gunter, Kathryn, Bindon, Brittany, Jumani, Sanjay, Laiteerapong, Neda
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2022; Springer Nature B.V
• Subjects: Adverse events; Agonists; Bias; Cardiovascular diseases; Clinical trials; Complications; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - chemically induced; Diabetes Mellitus, Type 2 - drug therapy; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - therapeutic use; Health risks; Humans; Hypoglycemic Agents - adverse effects; Internal Medicine; Medicine; Medicine & Public Health; Meta-analysis; Microvasculature; Mortality; Patients; Peptides; Placebos; Receptors; Risk analysis; Risk factors; Systematic Review; meta-analysis; systematic review; diabetes; glucagon-like peptide-1 receptor agonists
• ISSN: 0884-8734; 1525-1497
• DOI: 10.1007/s11606-021-07105-9

Background
Previous meta-analyses of the benefits and harms of glucagon-like peptide-1 receptor agonists (GLP1RAs) have been limited to specific outcomes and comparisons and often included short-term results. We aimed to estimate the longer-term effects of GLP1RAs on cardiovascular risk factors, microvascular and macrovascular complications, mortality, and adverse events in patients with type 2 diabetes, compared to placebo and other anti-hyperglycemic medications.
Methods
We searched PubMed, Scopus, and
clinicaltrials.gov
(inception–July 2019) for randomized controlled trials ≥ 52 weeks’ duration that compared a GLP1RA to placebo or other anti-hyperglycemic medication and included at least one outcome of interest. Outcomes included cardiovascular risk factors, microvascular and macrovascular complications, all-cause mortality, and treatment-related adverse events. We performed random effects meta-analyses to give summary estimates using weighted mean differences (MD) and pooled relative risks (RR). Risk of bias was assessed using the Cochrane Collaboration risk of bias in randomized trials tool. Quality of evidence was summarized using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The study was registered a priori with PROSPERO (CRD42018090506).
Results
Forty-five trials with a mean duration of 1.7 years comprising 71,517 patients were included. Compared to placebo, GLP1RAs reduced cardiovascular risk factors, microvascular complications (including renal events, RR 0.85, 0.80–0.90), macrovascular complications (including stroke, RR 0.86, 0.78–0.95), and mortality (RR 0.89, 0.84–0.94). Compared to other anti-hyperglycemic medications, GLP1RAs only reduced cardiovascular risk factors. Increased gastrointestinal events causing treatment discontinuation were observed in both comparisons.
Discussion
GLP1RAs reduced cardiovascular risk factors and increased gastrointestinal events compared to placebo and other anti-hyperglycemic medications. GLP1RAs also reduced MACE, stroke, renal events, and mortality in comparisons with placebo; however, analyses were inconclusive for comparisons with other anti-hyperglycemic medications. Given the high costs of GLP1RAs, the lack of long-term evidence comparing GLP1RAs to other anti-hyperglycemic medications has significant policy and clinical practice implications.