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Manuscript Sample (Review Article)

Glucagon-Like Peptide 1 Receptor Agonists for Treatment of Overweight and Obesity

By Sarah DeParis, MD

Introduction

Obesity is a significant global health issue that has been increasing substantially in scale. Worldwide, there has been a nearly 3-fold increase in the prevalence of obesity since 1975 and a more than 4-fold increase among children and adolescents.1 The World Health Organization defines obesity as a body mass index (BMI) of 30 kg/m2 or greater and overweight as a BMI of 25 kg/m2 or greater.1 In 2020, 2.6 billion people worldwide had overweight or obesity, and this is expected to increase to 4 billion by 2035.2

Overweight and obesity increase the risk for numerous other medical conditions, including cardiovascular disease and type 2 diabetes.3,4 From 1980 to 2015, 4 million deaths worldwide were attributed to high BMI.5 In the United States in 2019, the annual cost of medical care related to obesity was estimated at $173 billion.6 Worldwide, the cost of overweight and obesity is expected to increase to $4.32 trillion per year by 2035.2 Clearly, more effective treatments for overweight and obesity are needed.

The glucagon-like peptide 1 (GLP-1) receptor agonists are medications that were initially used for treatment of type 2 diabetes. Several of these agents have more recently been FDA approved for treatment of overweight and obesity and show promise for greater reductions in body weight than with older treatment methods.7,8 This review will examine the GLP-1 receptor agonists that are currently available for treatment of patients with overweight and obesity and explore some other agents that are currently in development.

Treatment Overview

Treatment of overweight and obesity is recommended to prevent additional medical complications. A reduction in body weight by 5% or more with treatment is generally considered to be a clinically meaningful improvement.9 Typical first-line treatments include lifestyle modification with reduced-calorie diets, exercise, and behavioral counseling.1,10 With intensive lifestyle treatment, a decrease in body weight by 3% to 5% can often be achieved.11 Bariatric surgery is an option for patients with BMI greater than or equal to 35 kg/m2 who have failed conservative treatment.10

Pharmacotherapy has been recommended as an adjunct to lifestyle treatment for patients with BMI of 30 kg/m2 or greater or BMI of 27 kg/m2 or greater with at least one weight-related comorbidity.11 These BMI levels are used as standard inclusion criteria in clinical trials for obesity and overweight treatments.12 Several older Food and Drug Administration (FDA)-approved medications for treatment of overweight and obesity are available, with resulting mean reductions in body weight in treated patients ranging from 4.7% to 9.8%.13

GLP-1 is a peptide secreted by the gastrointestinal tract and pancreas. Its actions include increasing insulin secretion and inhibiting glucagon secretion in response to oral glucose, delaying gastric emptying, and inhibiting gastric and duodenal peristalsis.14,15 GLP-1 receptor agonists increase satiety and decrease appetite, leading to clinically significant weight loss.16,17

Liraglutide and semaglutide are the 2 GLP-1 receptor agonists that are currently FDA approved for treatment of overweight and obesity.7,8 Research and development within this drug class is rapidly evolving, with several newer combination agents with multiple mechanisms of action in various stages of clinical trials.

Liraglutide

Liraglutide is a GLP-1 receptor agonist that was previously FDA approved for treatment of type 2 diabetes. In 2014, it became the first FDA-approved GLP-1 receptor agonist for treatment of patients with obesity or overweight (using the above criteria of BMI ≥27 kg/m2 with at least 1 weight-related comorbidity).8

A phase 3 clinical trial of liraglutide included 3731 patients with BMI of 30 kg/m2 or greater or with BMI of 27 kg/m2 or greater with at least one comorbidity (dyslipidemia or hypertension). Patients received either liraglutide (3.0 mg subcutaneous daily) combined with lifestyle intervention or placebo plus lifestyle intervention for 56 weeks.18 In the liraglutide group, 63.2% of the patients lost 5% or more of their baseline body weight compared with 27.1% of the patients in the placebo group (P < .001). The mean body weight lost in the liraglutide group was 8.0% compared with 2.6% in the placebo group (treatment difference, −5.4%; 95% CI, −5.8 to −5.0; P < .001).18 The most common adverse events were mild to moderate gastrointestinal symptoms occurring early in the treatment course, including nausea and diarrhea.18 In the liraglutide group, 6.4% of patients withdrew from the study due to gastrointestinal symptoms (compared with 0.7% of patients in the placebo group), which was the most common withdrawal reason.18

The combination of exercise and liraglutide treatment was later demonstrated to improve metabolic syndrome, abdominal obesity, and inflammation (measured by high-sensitivity C-reactive protein).19 The same combination was shown to improve weight loss maintenance more than either exercise or liraglutide alone.20

Semaglutide

Semaglutide is a GLP-1 receptor agonist with a longer half-life that can thus be administered weekly. 21 It was FDA approved for treatment of patients with obesity or overweight with weight-related comorbidities in 2021.7 Like liraglutide, this medication had already been in use for treatment of type 2 diabetes, with prior approval for that indication in 2017.22

A seminal phase 3 clinical trial of semaglutide included 1961 patients with BMI of 30 kg/m2 or greater or BMI of 27 kg/m2 or greater with 1 or more obesity-related comorbidity. Patients were randomized to receive either semaglutide 2.4 mg subcutaneous weekly or placebo for 68 weeks.23 The mean decrease in body weight for the semaglutide group was 14.9% compared with 2.4% in the placebo group (treatment difference, −12.4%; 95% CI, −13.4 to −11.5; P < .001). In the semaglutide group, 86.4% of patients reached a reduction in body weight of at least 5% compared with 31.5% of patients in the placebo group (P < .001). As with liraglutide, the most common adverse events with semaglutide were mild to moderate nausea and diarrhea that improved over time. In the semaglutide group, 4.5% of patients withdrew from the study due to these symptoms (compared with 0.8% in the placebo group).23 

A follow-up study of semaglutide demonstrated similar benefits after 2 years of treatment, with a mean body weight loss of 15.2% in the treatment group compared with 2.6% in in the placebo group (treatment difference, −12.6%; 95% CI, −15.3 to −9.8; P < .0001).24 However, in several subsequent studies, it was demonstrated that weight loss was not maintained if the semaglutide treatment was stopped.25,26

Additionally, a subsequent study compared daily liraglutide 3.0 mg and weekly semaglutide 2.4 mg in patients with overweight or obesity over 68 weeks.21 Patients in the semaglutide group had greater mean weight loss than patients in the liraglutide group (−15.8% body weight vs −6.4% body weight, respectively; treatment difference, –9.4%; 95% CI, –12.0 to –6.8; P < .001).21

Finally, a phase 3 clinical trial of oral semaglutide for treatment of patients with overweight or obesity is currently underway.27 This may expand treatment options for patients with barriers to administering subcutaneous injections.

Agents With Multiple Mechanisms

Several therapeutics with multiple mechanisms of action are in the pipeline for treatment of obesity. Most notably, tirzepatide is a combined glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and GLP-1 receptor agonist that was FDA approved for treatment of type 2 diabetes in 2022.28 GIP receptor activation is thought to have additive effects for appetite suppression when combined with GLP-1 receptor activation.29

. . .

Conclusion

Overweight and obesity are increasing in prevalence and new therapeutic options are needed to address this widespread global health issue. With the introduction of the GLP-1 receptor agonists as a treatment option in recent years, greater reductions in body weight can be achieved than with lifestyle interventions alone. In particular, semaglutide has demonstrated greater reductions in body weight than are typically achieved with lifestyle interventions or the older available pharmaceutical agents. As the development of additional GLP-1 receptor agonists with combined mechanisms of action continues, more promising treatment options are likely to become available in the future. Knowledge of the most recent trial results will be vital to physicians in providing the most current therapies for patients going forward.

References

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