Clinical Context

According to the World Health Organization Fact Sheet on obesity and overweight, 1.5 billion adults are overweight, and 500 million adults are obese. Glucagon-like peptide-1 (GLP-1), which is secreted from the intestine, enhances endogenous insulin secretion after meal ingestion, inhibits glucagon secretion, suppresses food intake, and suppresses appetite.

This systematic review and meta-analysis by Visbøll and colleagues assesses the effects of treatment with GLP-1 receptor (GLP-1R) agonists in overweight or obese adults with or without type 2 diabetes mellitus.

Study Synopsis and Perspective

Patients treated with GLP-1R agonists exhibited greater weight loss and improved blood pressure and cholesterol levels irrespective of the presence of type 2 diabetes, according to the findings of a systematic review and meta-analysis.

Tina Visbøll, MD, DMSc, and colleagues from the University of Copenhagen in Denmark, published their findings online January 11, 2012, in BMJ.

The authors mention the difficulties people have in achieving and maintaining weight loss, suggesting that new treatments are required. "Meta-analyses of clinical trials on non-pharmacological strategies for weight reduction have reported 1-6 kg losses that have been difficult to maintain," the authors write. "Meta-analyses of sibutramine and orlistat trials report average weight reductions of 3 kg to 5 kg, but some of the included trials had attrition rates of up to 50% that were possibly due to adverse events, suggesting that the interventions could be less effective in clinical practice."

In the random effects meta-analysis, patients who received GLP-1R agonists exhibited greater weight loss (weighted mean change in body weight, −2.9 kg; 95% confidence interval [CI], −3.6 to −2.2) than patients who received placebo, oral antidiabetic drugs, or insulin, with the greatest weight loss associated with higher doses of GLP-1R agonists.

In this study, the authors searched the Cochrane Library, Medline, Embase, and Web of Science databases for studies that included GLP-1R agonists. The authors included 25 randomized controlled trials (10,560 total participants) in which patients were administered GLP-1R agonists (liraglutide or exenatide) for a minimum of 20 weeks.

Evidence of intertrial heterogeneity was found in the analysis (τ2, 2.4; < .01). Weight reduction was observed in patients both without (weighted mean difference, −3.2 kg; 95% CI, −4.3 to −2.1) and with (weighted mean difference, −2.8 kg; 95% CI, −3.4 to −2.3) diabetes.

In the fixed-effects meta-analysis, no clear evidence of bias or small study effects were observed (> .01 for all analyses). In the subgroup analysis, patients receiving exenatide twice daily (−2.8 kg; 95% CI, −2.9 to −2.7 kg), exenatide once weekly (−2.8 kg; 95% CI, −5.2 to −0.3 kg), or liraglutide (−2.2 kg; 95% CI, −3.5 to −0.9 kg) exhibited weight reduction. Additional analysis indicated that GLP-1R agonists improved systolic and diastolic blood pressure, plasma cholesterol levels, and glycemic control.

The authors suggest that their findings indicate the clinical utility of GLP-1R agonists in treating obesity. "The present 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," the authors write. "Additional beneficial effects on blood pressure and total cholesterol might also be achieved."

In a linked commentary, Raj Padwal, MD, from the Walter C. Mackenzie Health Sciences Centre in Edmonton, Canada, notes that despite the findings of the present study, current clinical practice should not be changed. "Modification of diet and lifestyle remains the cornerstone of the treatment of type 2 diabetes," Dr. Padwal writes. "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."

The authors and commentator have disclosed no relevant financial relationships.

BMJ. Published online January 11, 2012. Full textcommentary

Related Link 
An accredited program entitled Successful Use of GLP-1 Receptor Agonists in Clinical Practice: A Nurse Practitioner's Approach is available from Medscape.

STUDY HIGHLIGHTS

 

  • The investigators identified 25 randomized controlled trials from a search of the Cochrane Library, Medline, Embase, Web of Science, and reference lists through May 2011.
  • Eligibility criteria were randomized controlled trials of adults with a body mass index of 25 kg/m2 or higher, with or without type 2 diabetes; treatment with a GLP-1R agonist for at least 20 weeks; and control comparison.
  • Exclusion criteria were duplicate studies, irrelevant references, subgroup analyses, nonrandomized follow-up studies, treatment dose less than the clinically relevant dose, or treatment for less than 20 weeks.
  • GLP-1R agonists included exenatide twice a day (at least 10 µg total/day), exenatide once a week (2 mg extended release), or liraglutide once a day (at least 1.2 mg/day).
  • The control measures were placebo, no intervention, or antidiabetic drugs (third-generation sulphonylurea compounds, insulin, dipeptidyl peptidase 4 inhibitors, thiazolidinediones, or metformin).
  • The trials were multicentered and multinational.
  • Duration of the trials ranged from 20 to 52 weeks.
  • 3 trials included patients without diabetes, and 22 trials included only patients with type 2 diabetes.
  • Mean body mass index ranged from 29 to 41 kg/m2.
  • Mean hemoglobin A1c level ranged from 7.6% to 10.4% in the GLP-1R agonist groups and 7.4% to 10.3% in the control groups.
  • 13 trials assessed exenatide twice daily, 8 trials assessed liraglutide, and 4 trials assessed exenatide once weekly.
  • Weight loss was greater in the GLP-1R agonist groups (3395 participants) vs control groups (3016 participants) (difference, −2.9 kg), based on 21 trials of 6411 participants.
  • Mean weight loss ranged from 0.2 kg to 7.2 kg for patients treated with the highest GLP-1R agonist doses.
  • In patients without diabetes, weight loss was greater in the GLP-1R agonist groups vs the control groups (difference, −3.2 kg), based on 3 trials.
  • In patients with diabetes, weight loss was greater in the GLP-1R agonist groups vs the control groups (difference, −2.8 kg), based on 18 trials.
  • Intertrial heterogeneity was noted.
  • Regression analysis showed no bias or small-study effects.
  • 3 trials comparing exenatide twice daily vs liraglutide or exenatide once weekly showed no significant differences in weight loss.
  • Baseline body mass index or duration of study did not predict the size of the intervention or explain heterogeneity.
  • Use of GLP-1R agonists resulted in improved systolic blood pressure, diastolic blood pressure, and plasma total cholesterol levels.
  • However, use of GLP-1R agonists did not clearly affect plasma liver enzymes, based on 12 studies.
  • Alanine aminotransferase levels were significantly decreased in fixed-effects meta-analysis and with liraglutide treatment, but not in random-effects analysis or with exenatide treatment.
  • Alkaline phosphatase levels were not clearly affected overall or by exenatide or liraglutide use.
  • In patients with type 2 diabetes, use of GLP-1R agonists improved glycemic control:
    • Fasting blood glucose levels improved in the GLP-1R groups vs the control groups in the fixed-effects model but not in the random-effects model.
    • Hemoglobin A1c levels decreased more with the highest vs the lowest doses of GLP-1R agonists (−0.10%).
    • More participants achieved target hemoglobin A1c levels of less than 7% in the GLP-1R groups vs the control groups (relative risk, 1.98).
  • The most common adverse effects reported with use of GLP-1R agonists were hypoglycemia, nausea, diarrhea, and vomiting.
  • The number of patients who withdrew from the study was not increased with GLP-1R agonist use.
  • Increased doses of GLP-1R agonists were linked with more frequent adverse events.
  • Serious adverse events were not common.
  • Study limitations included intertrial heterogeneity and inability to perform subgroup analysis according to study funding.

 

Clinical Implications

 

  • In overweight or obese adults, treatment with GLP-1R agonists for at least 20 weeks results in a 2.9-kg weight reduction overall, a 3.2-kg weight reduction in adults without diabetes, and a 2.8-kg weight reduction in adults with type 2 diabetes.
  • In overweight or obese adults with or without type 2 diabetes mellitus, treatment with GLP-1R agonists improves systolic and diastolic blood pressure and cholesterol levels but does not clearly affect liver enzymes.
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