Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis

Abstract

Objective: To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes.

Design: Systematic review and network meta-analysis.

Data sources: PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023.

Eligibility criteria for selecting studies: Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible.

Results: 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A_1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A_1c concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration.

Conclusions: GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A_1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events.

Systematic review registration: PROSPERO CRD42022342845.

Fig 1

Flow diagram of preferred reporting items identified, included, and excluded for systematic reviews and meta-analyses (PRISMA)

Fig 2

Network of available comparisons of GLP-1RAs and placebo for HbA_1c. The size of the nodes is proportional to the number of trial participants, and the thickness of the line connecting the nodes is proportional to the randomised number of trial participants directly comparing the two treatments. Numbers represent the number of trials contributing to each treatment comparison. GLP-1RA=glucagon-like peptide 1 receptor agonist; PEG-loxenatide=polyethylene glycol loxenatide; ITCA 650=a combination of drug and device containing exenatide in osmotic mini pump

Fig 3

Forest plot of network effect sizes between GLP-1RAs and placebo for HbA_1c measured in percentage. According to the network confidence meta-analysis (CINeMA) framework, the certainty of evidence is visually represented in the forest map, with varying colours indicating different confidence levels. The complete CINeMA assessments are shown in appendix 9. GLP-1RA=glucagon-like peptide-1 receptor agonist; PEG-loxenatide=polyethylene glycol loxenatide; ITCA 650=a combination of drug and device containing exenatide in osmotic mini pump

Fig 4

Network of available comparisons between GLP-1RAs and placebo for fasting blood glucose. The size of the nodes is proportional to the number of trial participants, and the thickness of the line connecting the nodes is proportional to the randomised number of trial participants directly comparing the two treatments. Numbers represent the number of trials contributing to each treatment comparison. GLP-1RA=glucagon-like peptide 1 receptor agonist; PEG-loxenatide=polyethylene glycol loxenatide

Fig 5

Forest plot of network effect sizes between GLP-1RAs and placebo for fasting blood glucose. Certainty of evidence is visually represented in the forest map, with varying colours indicating different confidence levels. The complete CINeMA assessments are shown in appendix 9. GLP-1RA=glucagon-like peptide 1 receptor agonist; PEG-loxenatide=polyethylene glycol loxenatide

Fig 6

Network of available comparisons between GLP-1RAs and placebo for weight loss. The size of the nodes is proportional to the number of trial participants, and the thickness of the line connecting the nodes is proportional to the randomised number of trial participants directly comparing the two treatments. Numbers represent the number of trials contributing to each treatment comparison. GLP-1RA=glucagon-like peptide-1 receptor agonist; PEG-loxenatide=polyethylene glycol loxenatide; ITCA 650=a combination of drug and device containing exenatide in osmotic mini pump

Fig 7

Forest plot of network effect sizes between GLP-1RAs and placebo for weight loss. Certainty of evidence is visually represented in the forest map, with varying colours indicating different confidence levels. The complete CINeMA assessments are shown in appendix 9. GLP-1RA=glucagon-like peptide-1 receptor agonist; PEG-loxenatide=polyethylene glycol loxenatide; ITCA 650=a combination of drug and device containing exenatide in osmotic mini pump

Fig 8

Estimates in network meta-analysis for common adverse events of glucagon-like peptide-1 receptor agonist compared with placebo. (A) discontinuation; (B) diarrhoea; (C) nausea; (D) vomiting. Effect sizes are presented as odds ratios with 95% confidence intervals (CIs). PEG=polyethylene glycol