This systematic review with meta-analyses found that treatment that treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus. GLP-1 is a hormone in the gut that is secreted from the intestine in response to meal ingestion. Treatment with GLP-1 increases the endogenous secretion of insulin induced by meal ingestion and inhibits glucagon secretion, thereby improving glucose homoeostasis. GLP-1 based therapy was recently introduced as a new treatment for patients with type 2 diabetes mellitus. There are currently 2 GLP-1R agonists licensed in the UK – exenatide (twice daily and once weekly formulations) and liraglutide.
The researchers conducted the systematic review with meta-analysis to provide an up to date overview of the beneficial and harmful effects of GLP-1R agonists in patients who are overweight or obese. They searched the literature up until May 2011 for randomised controlled trials (RCTs) of adult participants with a body mass index of 25 or higher. Trial participants were either with or without type 2 diabetes mellitus and received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically appropriate doses for at least 20 weeks. Control interventions assessed as part of the review were placebo, oral antidiabetic drugs, or insulin. Overall, 25 trials were included in the analysis.
The primary objective was to assess the effect of GLP-1R agonists versus placebo, no intervention, or other antidiabetic interventions for weight loss in overweight patients with or without type 2 diabetes mellitus. Secondary outcome measures included changes in systolic and diastolic blood pressure, plasma concentrations of liver enzymes, total cholesterol, and adverse events. The researchers additionally evaluated markers of glycaemic control for patients with type 2 diabetes. A random effects model was used for the primary meta-analyses and further statistical methods were employed to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors. The following results are reported (from source):
• GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference −2.9 kg, 95% confidence interval –3.6 to –2.2; 21 trials, 6411 participants).
• The researchers found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses.
• They recorded weight loss in the GLP-1R agonist groups for patients without diabetes (–3.2 kg, –4.3 to –2.1; three trials) as well as patients with diabetes (–2.8 kg, –3.4 to –2.3; 18 trials).
• In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes.
• GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.
The authors conclude that their meta-analysis, “Provides convincing evidence that GLP-1R agonists, when given to obese patients with or without diabetes, results in clinically relevant beneficial effects on body weight. Additional beneficial effects on blood pressure and total cholesterol might also be achieved. The intervention should be considered in patients with diabetes who are obese or overweight. Further studies are needed to elucidate the effects of GLP-1R agonists in the treatment of obese patients without diabetes.”
A related editorial discusses the results of this paper and concludes that GLP-1agonists cannot be recommended strictly for weight reduction until their benefits and risks are clarified. The author of the editorial notes that bodyweight was a secondary, not primary, end point in 18 of 21 trials. He adds that there are several unanswered questions, including around the safety of these agents, and writes:
“Modification of diet and lifestyle remains the cornerstone of the treatment of type 2 diabetes. Treatment with statins and antihypertensive drugs to achieve guideline concordant reductions in cardiovascular risk factors is vital. Metformin should be the first line drug for glycaemic control and HbA1c targets should be individualised. If indicated, glycaemic control can be further improved by the addition of other agents, including GLP-1 agonists, with the expectation that microvascular but not necessarily macrovascular complications will be reduced.
On the basis of current evidence, off label use of GLP-1-agonists for weight loss in people without diabetes cannot be recommended at this time. Studies evaluating the weight reducing efficacy of GLP-1 agonists in obese people without diabetes and those with pre-diabetes are ongoing.”
Nb: NICE has made recommendations on the use of twice daily exenatide and once daily liraglutide in patients with type 2 diabetes mellitus. NICE guidance on the use of once weekly exenatide is under development and expected in February 2012.