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Successful weight loss with GLP-1 agonists

Summary Insights

  • GLP-1 agonists are effective in weight loss as they delay gastric emptying, induce satiety, and decrease food
  • These agents have been successfully studied in obese, non-diabetic patients
  • Weight loss results seen as early as two weeks into treatment
  • Liraglutide especially is shown to be effective for long-term (2 year) weight loss
  • Liraglutide even produces greater weight loss results than orlistat
  • More favorable effects on HbA1c and blood pressure seen with liraglutide vs. exenatide
  • The enhanced satiety is a dose-dependent effect
  • Combining soluble fiber with GLP-1 agonists increase weight loss results 

GLP-1 induces satiety, decreases food intake

Glucagon-like peptide-1 (GLP-1), a naturally occurring incretin, is released subsequent to food intake and stimulates the secretion of insulin, inhibits the release of glucagon, delays gastric emptying, and decreases food intake through increased satiety. Gut hormones play an important role in appetite regulation, and GLP-1 is one of the significant gut hormones studied in both diabetes and weight management. In addition to suppressing glucagon secretion and delaying gastric emptying, its positive effects on weight loss stem from its actions in the brain, where it induces satiety, thereby reducing food intake.1 Early studies investigated this relationship, showing infusion of the GLP-1 hormone resulted in prolonged periods of decreased desire to eat and lessened sensations of hunger.2

The hormone is secreted from L cells in the intestine following nutrient ingestion but has an extremely short half-life of one to two minutes. Due to swift inactivation by the enzyme dipeptidyl peptidase IV (DPP-4), the natural peptide itself lacks efficacy as a tool for therapy. Synthetically produced GLP-1 agonists such as exenatide and liraglutide are instead approved for treatment in type 2 diabetes and have been used successfully as adjunct or monotherapy to lower HbA1c in diabetes for many years now; recent research has focused on their effect on weight loss even in non-diabetic patients.

GLP-1 agonists studied in obese, non-diabetic patients

Overweight or obese patients are more likely to develop diabetes, putting these patients at even higher risk for cardiovascular events. Current approved treatments for weight loss have high rates of adverse events and large rates of attrition, and therefore show little success in long-term sustained weight loss. But recent research shows promising results: a systematic review and meta-analysis of 25 randomized controlled trials investigated weight loss results in both diabetic and non-diabetic patients treated with the FDA-approved glucagon-like peptide-1 receptor agonists liraglutide or exenatide. Published January 2012 in BMJ, the study results revealed that patients treated with GLP-1 agonists experienced greater weight loss, as well as lower levels of cholesterol and blood pressure, versus patients who received treatment with placebo, insulin, or other antidiabetic drugs.3

Weight loss results as early as two weeks into treatment

Another recent study, to be published early 2012 in Diabetes Care, demonstrated that GLP-1 agonists have been used successfully in non-diabetic obese women for weight loss. Short-term treatment with twice-daily exenatide was associated with modest weight loss at as early as two weeks into treatment. During this 35-week study, comprised of two 16-week treatment periods and one 3-week crossover period, over two-thirds of the study population experienced weight loss and decreased waist circumference. Approximately 39% of study subjects lost less than 5% body weight, while at least 30% of study subjects lost more than 5% of body weight compared to baseline weight. Study subjects increased their doses from 5μg to 10μg exenatide or placebo twice daily after two weeks of treatment, and all women in the study reported similar rates of nausea, hunger, and satiety.4

Even treatment with once-weekly exenatide showed success in sustaining weight loss after two years. In its follow-up assessment, the DURATION-1 trial reported that after two years of treatment, 66% of patients treated with exenatide QW experienced weight loss and 61% achieved reductions in both HbA1c and body weight.5

Liraglutide shown to be effective for long-term weight loss

The SCALE study (Satiety and Clinical Adiposity – Liraglutide Evidence in Non-Diabetic and Diabetic Subjects) investigated liraglutide’s efficacy for weight loss in a particularly obese population. Baseline BMI of the SCALE patients averaged 38 kg/m2, while approximately one third of SCALE patients had a BMI of over 40 kg/m2. The SCALE study consisted of two phases. The first period was a 4-to-12 week “run-in” in which a 5% weight loss was achieved with a low-calorie diet (1200-1600 calories/day) for all subjects. Randomization into either placebo or active treatment with liraglutide followed (doses were titrated to a final dose of 3mg per week). While the usual treatment dose in diabetes is 1.8mg, the supra-therapeutic 3mg dose demonstrates greater efficacy for weight loss.6

Average weight loss in the first phase (the run-in period) remained a steady 6% loss from baseline weight. Eighty-one percent of the liraglutide patients versus 49% of the placebo patients maintained this weight loss 56 weeks out. Furthermore, treatment with liraglutide showed an added benefit of additional weight loss of at least 5% (average additional loss was 6.1%). Roughly half of the patients treated with liraglutide reported nausea as a side effect; this resolved itself after the first few weeks of treatment. 7

Liraglutide shows greater weight loss results than orlistat; lowers blood pressure

In a different two-year, randomized, double-blind, placebo-controlled study, liraglutide for weight loss in non-diabetic patients showed positive results as well. The results of this 20-week study, published 2009 in the Lancet, determined that patients randomized to receive one of four different doses of liraglutide (1.2mg, 1.8mg, 2.4mg, or 3.0mg) experienced greater weight loss compared to placebo (p = 0.003 for 1.2mg, p<0.0001 for liraglutide 1.8-3.0mg). Patients who received one of the two highest doses of liraglutide also experienced greater weight loss than patients who were randomized to receive the FDA-approved weight loss drug orlistat (p=0.003 for liraglutide 2.4mg; p<0.0001 for liraglutide 3.0mg).

The extended trial switched all liraglutide or placebo patients to liraglutide 2.4mg after 52 weeks; all patients were then titrated up to the 3mg efficacious dose. Results after two years showed that for patients who completed the study, 69% percent experienced greater than a 5% weight loss compared to 49% of patients treated with orlistat. Side effects noted with liraglutide treatment were nausea and vomiting. Treatment with liraglutide also had favorable results on blood pressure, where patients in the liraglutide treatment group experienced a systolic decrease of 12.5mmHg compared to 9.9mmgHg in the orlistat group (diastolic blood pressure decreased by 7mmHg in each group).8

More favorable effects on HbA1c with liraglutide vs exenatide

While both the GLP-1 agonists exenatide and liraglutide are approved for treatment of type 2 diabetes, a head-to-head study comparing the two found more favorable results with liraglutide. The LEAD-6 study failed to show that once-weekly exenatide injections were equal to daily injections of liraglutide in reducing HbA1c in patients suffering from type 2 diabetes. Patients being treated with liraglutide reported an average of 1.48% reduction in HbA1c, while patients treated with exenatide once-weekly dosing reported an average of 1.26% reduction in HbA1c. However, patients treated with exenatide reported less frequent nausea and vomiting.9

Enhanced satiety is a dose-dependent effect

The enhanced satiety experienced with GLP-1 agonists is a dose-dependent effect. Higher doses of GLP-1 agonist produce greater nausea and vomiting, which may be due to a transient effect on delayed gastric emptying. While there was some thought that the greater amount of nausea and vomiting may contribute to greater weight loss, a post-hoc analysis of patients treated with liraglutide who experienced at least one episode of nausea and vomiting did not show significantly greater weight loss than patients who experienced none.10

Combining soluble fiber with GLP-1 agonists increase weight loss results

The unique drug properties of GLP-1 agonists provide a safe and effective tool for both glucose control and weight loss in obese patients. However, these agents are more likely to be efficacious in those obese patients with visceral fat with high chances of progression to diabetes versus other types of obesity.11 Futhermore, combining GLP-1 agonist therapy with increased consumption of dietary fiber has shown positive effects in diabetes and weight reduction, with water-soluble viscous fibers showing better efficacy compared to insoluble fiber. Intake of soluble fiber helps to slow gastric emptying time due to its bulk-forming and carbohydrate- binding characteristics; research shows it also increases levels of GLP-1 due to increased expression of its precursor, proglucagon.12,13

  1. Suzuki K, Jayasena CN, Bloom SR. The gut hormones in appetite regulation. J Obes. 2011;2011:528401. Epub 2011 Sep 22.
  2. Näslund E, Gutniak M, Skogar S, Rössner S, Hellström PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am J Clin Nutr. 1998 Sep;68(3):525-30.
  3. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 2012;344:d7771
  4. Dushay J, Gao C, Gopalakrishnan GS, Crawley M, Mitten EK, Wilker E, Mullington J, Maratos-Flier E. Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes. Diabetes Care. 2012 Jan;35(1):4-11. Epub 2011 Oct 31.
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  7. American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 1859-P. Presented June 25, 2011.
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  9. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009 Jul 4;374(9683):39-47. Epub 2009 Jun 8.
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  11. American Diabetes Association (ADA) 71st Scientific Sessions: Abstract 1859-P. Presented June 25, 2011.
  12. Wang, Z. Q., Zuberi, A. R., Zhang, X. H., Macgowan, J., Qin, J., Ye, X., Son, L., Wu, Q., Lian, K., and Cefalu, W. T. Effects of dietary fibers on weight gain, carbohydrate metabolism and gastric ghrelin gene expression in mice fed a high fat diet. Metab. Clin. Exp. 2007(56): 1635–1642.
  13. Reimer, R. A.,andMcBurney,M. Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats. Endocrinology 1996 (137): 3948–3956.