written by Rahul Nawander, MD, FALU, FLMI 

Introduction

Overweight and obesity-related medical costs are estimated at more than $92 billion annually in the U.S. Adults with obesity are associated with an additional $2,505 in annual medical costs that is largely associated with cardiovascular disease (CVD)-related morbidity and mortality. Obesity disproportionately affects minorities with the highest rates among non-Hispanic black and Hispanic adults.

Daniel Drucker, a scientist and endocrinologist at the University of Toronto, Canada spent 10 years researching and experimenting with the venom of Gila monster lizard at his lab in Utah which laid the foundation for discovery of GLP-1 receptor agonist. Later, a biochemist from the United States Dr. John Eng harnessed and synthesized Exendin-4 (hormone) from the venom of Gila monster lizard which had similar structure to GLP-1RA.

GLP-1 receptor agonist are essentially hormones (messengers) called ‘Incretins’ which are physiologically secreted from intestine that gives a sense of ‘stomach is full/satiety.’ When given artificially as medications, they carry that message and help in reduction of food intake and thereby weight loss and increased insulin secretion (see figure 1). Role of incretins in the body.

A synthetic version of this GLP-1RA incretin invented by Jesper Lau of Novo Nordisk that could bind with albumin and used in human beings was named ‘semaglutide’. Semaglutide became the first medicine of its kind to regulate blood sugar and curb appetite. In 2021, semaglutide was approved by the US Food and Drug Administration (US FDA) for control of obesity.

Tirzepatide a newer medication developed recently, also called as ‘twincretin therapy’ or a dual agonist is a synergistic combination of GLP-1 receptor agonist and gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide (GIP). GIP’s stimulate glucose-dependent insulin secretion when an individual consumes fat or glucose meals and amplifies the GLP-1 receptor agonist effects resulting in improved fat metabolism and better glucose control.

Trends in Use of GLP-1 and combination agonists:

Based on the IQVIA U.S. National Prescription Audit report of 2025 and CMS Medicare trends, the prescription growth of GLP-1 agonists increased significantly in the U.S. from 5 million in 2020 to 30-35 million (7x) in 2025, with Ozempic (semaglutide) being the top-prescribed drug at 34% followed by Mounjaro (tirzepatide) at 28% in 2024. Based on the prescription data, 65% females were prescribed GLP-1 and combination agonists. The GLP-1 and combination agonists market in the U.S. is projected to exceed $30 billion by 2026 and the weight loss prescriptions will outpace diabetes as main use of GLP-1 and combination agonists in 2026 (see figure 2).

The US FDA approvals of multiple GLP-1 receptor agonist linked to substantial weight loss have generated interest in underwriters to assess if the benefits outweigh any long-term side effects.

Below is the list of U.S. FDA approved GLP-1 receptor agonist and its combination agonists:

Drug	Active Ingredient	Agonist Type	Details
Adlyxin	Lixisenatide	GLP-1	Short-acting GLP-1 receptor agonist
Byetta	Exenatide (BID)	GLP-1	First approved GLP-1 receptor agonist
Ozempic	Semaglutide (injectable)	GLP-1	Weekly; strong glucose & weight effects
Rybelsus	Semaglutide (oral)	GLP-1	First oral GLP-1 receptor agonist
Saxenda	Liraglutide	GLP-1	Approved for weight loss
Trulicity	Dulaglutide	GLP-1	Weekly; popular in diabetes care
Victoza	Liraglutide	GLP-1	Daily injection for diabetes
Wegovy	Semaglutide (high dose)	GLP-1	For obesity, higher dose than Ozempic
Mounjaro	Tirzepatide	GLP-1 + GIP	FDA approval for diabetes case
Zepbound	Tirzepatide	GLP-1+ GIP	FDA approval for chronic weight managements

 

The U.S. FDA is also looking to expand the use of GLP-1 receptor agonist drugs for pediatric obesity, heart failure, and sleep apnea. The upcoming GLP-1 and combination drugs are listed in the below table:

Drug Name	Agonist Type	Trial Phase	Details
Retatrutide	GLP-1 + GIP + Glucagon	Phase 3	Weight loss
LY3437943	GLP-1 + GIP	Phase 2	“Next-gen” Tirzepatide
SAR441255	GLP-1 + GIP + Glucagon	Early Stage	Experimental triple agonist
HM15211	GLP-1 + GIP + Glucagon	Phase 2	Targeting non-alcoholic steatohepatitis
Twincretin	GLP-1 + GIP	R&D Concept	Generic label for this class

 

Efficacy of GLP-1 receptor agonist and combination agonists in diabetics

The development of GLP-1 receptor agonist novel drugs is a rapidly evolving area, and many new drugs have emerged in the past few years including oforglipron, retatrutide, and CagriSema (semaglutide with cagrilintide). A systematic review and network meta-analysis evaluated and compared GLP-1 receptor agonists and its combination agonists efficacy in glycemic control, weight management, and lipid profile in individuals with type 2 diabetes. It noted that tirzepatide induced the most significant HbA1c reduction (-2.10%) followed by mazdutide (-2.09%) and CagriSema (-1.8%).  In terms of body weight reduction, CagriSema was identified to be the most effective drug in lowering body weight by -14.03 kg (95% CI, -17.05 to -11) followed by tirzepatide -8.47 kg (95% CI, -9.68 to -7.26) and retatrutide -7.87 (95% CI, -9.95 to -5.79).  (See Figure 3).

Efficacy of GLP-1 receptor agonist and combination agonists in overweight non-diabetics

GLP-1 receptor agonist (semaglutide) and weight loss:

Until the advent of tirzepatide, semaglutide demonstrated the most substantial weight loss among all available obesity medications, with average reductions of approximately 15% of baseline body weight at 68 weeks. The Semaglutide Treatment Effect in People with Obesity (STEP) program – one of the largest and longest clinical trial series evaluated a once-weekly 2.4 mg subcutaneous dose of semaglutide in overweight and obese adults. Over two years of follow-up, 52.1% of participants achieved greater than 15% weight loss, while 38.5% achieved reductions exceeding 20%. These findings set a new benchmark for pharmacologic obesity treatment, a standard that has only recently been surpassed by tirzepatide in subsequent clinical trials.

GLP-1 combination receptor agonist (tirzepatide) in weight loss:

A randomized clinical trial of tirzepatide to evaluate the effectiveness of continued treatment for maintenance of weight reduction in non-diabetic individuals with a BMI of >30 and had at least one weight related complication noted that 70% of participants achieved a weight reduction of at least 20% from week 0 to week 88 in comparison to placebo. The trial also noted a 22.5 cm reduction in waist circumference.

Adverse effects and tolerability

Almost 75-80% of individuals taking GLP-1 receptor agonist and combination agonists have reported adverse events with gastrointestinal complaints being the most common – nausea (34-36%), diarrhea (20-22%), constipation (20-22%), and vomiting (15-17%). Approximately, 8-10% individuals may discontinue treatment due to these adverse events. However, no deaths have been reported related to GLP-1RA and combination agonists.

Studies have also noted weight is substantially regained after cessation of GLP-1RA and combination agonists.

GLP-1 and combination agonists have been primarily used to achieve optimal blood glucose control and body weight. However, the later effects of both reducing cardiovascular mortality and all-cause mortality are now being evidenced in several studies.

 

References & Additional Reading:

1. Katie Dangerfiled, “How a Canadian Scientist and a venomous lizard helped pave the way for Ozempic.” Updated on June 29, 2023. Accessed on October 30, 2023.
2. Semaglutide: An Medical Expert’s Guide. Accessed on October 30, 2023.
3. Knudsen, Lotte Bjerre, and Jesper Lau. “The discovery and development of liraglutide and semaglutide.” Frontiers in endocrinology 10 (2019): 155.
4. Becky McCall, “Weight Loss With Semaglutide Maintained for up to 3 Years.” Accessed on October 30, 2023.
5. Chao, Ariana M., et al. “Semaglutide for the treatment of obesity.” Trends in cardiovascular medicine (2021).
6. Bergmann, Natasha Chidekel, et al. “Semaglutide for the treatment of overweight and obesity: A review.” Diabetes, Obesity and Metabolism 25.1 (2023): 18-35.
7. Garvey, W. Timothy, et al. “Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial.” Nature medicine 28.10 (2022): 2083-2091.
8. Wharton, Sean, et al. “Gastrointestinal tolerability of once‐weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss.” Diabetes, Obesity and Metabolism 24.1 (2022): 94-105.
9. Smits, Mark M., and Daniël H. Van Raalte. “Safety of semaglutide.” Frontiers in endocrinology 12 (2021): 645563.
10. Ryan, Donna H., et al. “Semaglutide effects on cardiovascular outcomes in people with overweight or obesity (SELECT) rationale and design.” American heart journal 229 (2020): 61-69.
11. Yao, Haiqiang, et al. “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.” bmj384 (2024).
12. Jastreboff, Ania M., et al. “Tirzepatide once weekly for the treatment of obesity.” New England Journal of Medicine3 (2022): 205-216.
13. Garvey, W. Timothy. “Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, phase 3 trial.”
14. Aronne, Louis J., et al. “Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial.” Jama1 (2024): 38-48.

Rahul provides Medical Director consultations and expert reviews for Fasano Associates Life & Health Insurance and Life Settlement clients. In addition to this, he is involved in the development of underwriting philosophy, training, and digital underwriting.

Rahul began his career with Prudential Process Management Services India Pvt. Ltd. and later moved into managing positions with Kotak Old Mutual India, Max New York Life India, IDBI Fortis India, and RGA International in Toronto, Canada.

Rahul received his Bachelor of Medicine and Surgery from Babasaheb Ambedkar Marathwada University, India. He is a Fellow, Academy of Life Underwriting (FALU) and a Fellow of the Life Management Institute (FLMI). Rahul is also an Executive of the Canadian Life Insurance Medical Officers Association (CLIMOA).