Case Study: Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obesity

Background

Incretins are hormones secreted by intestinal cells in response to the ingestion of glucose and other nutrients. These hormones stimulate pancreatic β cells to secrete insulin and are essential to maintaining normal glucose homeostasis. The insulinotropic effect of incretins is greater than that induced by intravenous glucose infusion.¹ The discovery of incretins (INtestine seCRETion INsulin) dates back more than 100 years, with the finding that ingestion of extracts of ground intestines could produce a lowering of blood glucose. With the advent of modern protein purification techniques and gene sequencing over the last 40 years, several specific incretins have been identified. The 2 primary incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), both of which act on their own specific cell membrane receptors.  In addition to their insulinotropic effects on the pancreas, these proteins have been found to affect multiple other tissues including the gastrointestinal tract, heart, bone, kidney, adipose tissue, liver, and brain.² We now have clinical data that supports the notion that activation of GLP-1 receptors with GLP-1 receptor agonist (GLP-1 RA) in these non-pancreatic tissues very likely accounts for the cardioprotective and anti-obesity properties of some of these agents, as well as potential benefits in non-alcoholic fatty liver disease.³

Current GLP-1RA Available

Multiple GLP-1 RA drugs have been approved for the treatment of diabetes and presently include exenatide, dulaglutide, liraglutide, and semaglutide. GLP-1 RA exhibit significant differences in their properties and have complex profiles, making comparisons difficult. A class effect should not be assumed. However, clinical trials comparing agents head-to-head highlight the differences. The long-acting agents tend to produce more significant weight loss compared with the short-acting agents. In regard to weight loss, the agents could be ranked (from least to most) as follows: lixisenatide = exenatide (twice daily) = exenatide XR＜dulaglutide＜liraglutide＜semaglutide when studied in diabetic patients.⁴

Due to the discovery of significant weight loss in diabetes trials, GLP-1 RA have been studied for weight loss, independent of diabetes status. To date, only liraglutide 3.0 mg daily and semaglutide 2.4 mg weekly have FDA approval for the treatment of obesity. In the Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals (SCALE) trial,⁵ a 56-week, double-blinded trial with 3,731 patients without type-2 diabetes but with a body-mass index (BMI) of at least 30 or 27 with a history of treated or untreated dyslipidemia or hypertension (mean body weight 106.2 kg), patients in the 3.0 mg daily liraglutide group, compared to placebo, had a mean weight loss difference of −5.4%; [95% confidence interval, −5.8 to −5.0]; P<0.001. Also, in the Satiety and Clinical Adiposity — Liraglutide Evidence in Nondiabetic and Diabetic Individuals (STEP-1) trial, ⁶ a 68 week, double-blinded trial with 1,961 patients with BMI of 30 or ≥ to 27 with ≥1 weight-related coexisting condition, non-diabetic patients (mean body weight 105.3 kg) in the 2.4 mg weekly semaglutide group compared to placebo had a mean estimated treatment difference of −12.4%; [95% confidence interval, −13.4 to −11.5]; P<0.001. Both trials included lifestyle modification and counseling.^5,6 Liraglutide at the 3.0 mg daily dosing is approved in adolescents aged 12-17 years for the treatment of obesity,^7,8 and semaglutide clinical trials in adolescents are ongoing.^8,9

A head-to-head randomized clinical trial, STEP-8, compared semaglutide 2.4 mg weekly vs liraglutide 3.0 mg daily in adults with obesity. This study included 338 participants for 68 weeks (mean body weight 104.5 kg at baseline) and showed a statistically significant difference favoring semaglutide (–9.4% [95% CI, –12.0 to –6.8]; P < .001), when added to diet and physical activity.¹⁰ Similar findings were observed comparing these two medications in a Phase II trial in obesity.¹¹

Case Study:

Kelli is a 53-year-old Black Female with a known history of mixed hyperlipidemia, hypertension, and nicotine dependence. She has a very strong family history of CAD (mother died of MI at 60, brother died of MI at 58).

Initial parameters and bloodwork results:

Current 10-year ASCVD risk: 8.6%. Lifetime ASCVD risk: 50%.

Current medications: Amlodipine 10 mg, Valsartan/HCT 320/25 mg, Spironolactone 25 mg, Rosuvastatin 40 mg, Aspirin 81 mg.

Current Exercise and Diet Regimen: 150 minutes of exercise per week. Dietary Approaches to Stop Hypertension (DASH) diet along with a high glycemic index restricted diet recommended by the local dietician.

Plan: Recommend smoking cessation. Add Ezetimibe (Zetia®) 10 mg daily.

She is agreeable to try a weight loss medication and Semaglutide (Wegovy®) is recommended. A prior authorization denial is received stating the patient must try Phentermine, Naltrexone/Bupropion (Contrave®) or Liraglutide (Saxenda®) instead. Due to the patient’s history of uncontrolled hypertension in the past and the cardiovascular favorable profile of Liraglutide, authorization for this medication was submitted and approved.

3 month follow-up:

She is no longer smoking. Current 10-year ASCVD risk: 2.9%. Lifetime ASCVD risk: 39%

Mechanism of Action of GLP-1 RA in Obesity

In regard to the mechanisms of weight reduction, GLP-1 RA treatment has multiple physiological actions affecting appetite and energy intake. Delayed gastric emptying does occur but is limited to the first post-prandial hour and the overall gastric emptying time is not affected, thus suggesting that other mechanisms are involved.¹² Stimulating GLP-1 receptors in the hypothalamus exerts multiple effects which are thought to correlate with weight loss. These mechanisms include reducing hunger, energy intake and food cravings, as well as increasing satiety via both the stimulation of pro-opiomelanocortin and cocaine-and amphetamine-regulated transcript (POMC/CART) neurons and the inhibition of neuropeptide Y (NPY) and agouti-related peptide (AgRP).³ In addition, the stomach derived hormone ghrelin and the adipocyte derived hormone leptin, which have appetite stimulating and suppressing effects respectively, appear to be influenced by GLP-1. The exact role of GLP-1 receptor stimulation and interactions with ghrelin and leptin is complex and still being elucidated.¹⁴ Overall, GLP-1 RA treatment appears to reduce appetite, decrease the desire for energy dense foods, alter food reward pathways and decrease food cravings.^15-18

Side Effects and Costs of GLP-1 RA

Tolerability and access due to cost are some of the challenges in clinical practice with using GLP-1 RA in obesity treatment. Nausea, vomiting, and diarrhea are common side effects and are more frequent with the short-acting GLP-1 RAs compared to the longer-acting formulations.^4,19 Injection site reactions are also common. In a meta-analysis, there was no increase in pancreatitis, pancreatic cancer, or thyroid cancer.¹⁹ However, a black-boxed warning still exists for the risk of thyroid C-cell tumors found in rodents given supratherapeutic doses of the drug.^19,20 Caution should also be taken when using GLP-1 RA in pregnancy and those who have hypersensitivity to the ingredients.²⁰ The cost for GLP-1RA at $1000-1500 per month is also significantly higher than other weight loss medications.²¹ Yet, a recent cost analysis study comparing four GLP-1 RA showed semaglutide as a cost effective medication, especially when other medications may be contraindicated or the cardioprotective nature of GLP-1 RA is preferred.²² Currently, some insurers cover these medications for obesity. Saving cards are available for cash and non-governmental insurers. Most insurers will cover these medications for a Type 2 diabetes diagnosis. 

Future Treatments of Obesity:

A first in class medication, which acts on both GLP-1 and GIP receptors, tirzepatide, has also been approved for the treatment of diabetes. Up until recently, GLP-1 alone had been thought to be the main incretin target for diabetes and obesity treatment. This was based on multiple knock-out mice studies, however with recent human data from several tirzepetide studies showing robust hemoglobin A1C and weight reductions, there is renewed interest in the GIP/GLP-1 complex interaction.²³ In the Efficacy and Safety of Tirzepatide Once Weekly in Participants Without Type 2 Diabetes Who Have Obesity or Are Overweight With Weight- Related Comorbidities (SURMOUNT-1) phase 3 double-blind, randomized, controlled trial of 2,539 non-diabetic adults with a body-mass index of 30 or more, or 27 or more and at least one weight-related complication, the mean percentage change in weight at the maximum 15 mg dose, compared to placebo, at week 72 was −20.9% [95% confidence interval , −21.8 to -19.9], initial body weight was 104.8 kg. Participants had to have failed at least one trial of unaided dietary effort to lose weight.²⁴ Though not currently approved for obesity; this study may pave the way for this indication. In fact, the future of anti-obesity medications looks promising with many new mechanisms of action on the horizon.²⁵

Clinicians are challenged with treating obesity more frequently in practice. As our case, and this review shows, GLP-1 RA are an option for the management of obesity, with limited side effects and good efficacy. 

References

1. Drucker, Daniel J., et al. “Discovery, Characterization, and Clinical Development of the Glucagon-like Peptides.” Journal of Clinical Investigation, vol. 127, no. 12, 2017, pp. 4217–4227., https://doi.org/10.1172/jci97233.
2. Seino, Yutaka, et al. “GIP and GLP-1, the Two Incretin Hormones: Similarities and Differences.” Journal of Diabetes Investigation, vol. 1, no. 1-2, 2010, pp. 8–23., https://doi.org/10.1111/j.2040-1124.2010.00022.x.
3. Wong, Chloe, et al. “Glucagon-like Peptide-1 Receptor Agonists for Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: A Meta-Analysis.” Frontiers in Endocrinology, vol. 12, 2021, https://doi.org/10.3389/fendo.2021.609110.
4. Trujillo, Jennifer M., et al. “GLP-1 Receptor Agonists: An Updated Review of Head-to-Head Clinical Studies.” Therapeutic Advances in Endocrinology and Metabolism, vol. 12, 2021, p. 204201882199732., https://doi.org/10.1177/2042018821997320.
5. Pi-Sunyer, Xavier, et al. “A Randomized, Controlled Trial of 3.0 Mg of Liraglutide in Weight Management.” New England Journal of Medicine, vol. 373, no. 1, 2015, pp. 11–22., https://doi.org/10.1056/nejmoa1411892.
6. Wilding, John, et al. “Once-Weekly Semaglutide in Adults with Overweight or Obesity.” New England Journal of Medicine, vol. 384, no. 11, 2021, pp. 989–1002., https://doi.org/10.1056/nejmoa2032183.
7. Kelly, Aaron S., et al. “A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity.” New England Journal of Medicine, vol. 382, no. 22, 2020, pp. 2117–2128., https://doi.org/10.1056/nejmoa1916038.
8. Jensterle M, et al. “Glucagon like Peptide 1 Receptor Agonists in the Treatment of Obesity.” Hormone Research in Paediatrics, U.S. National Library of Medicine, 1 Dec. 2021, https://pubmed.ncbi.nlm.nih.gov/34852347/.
9. “A Research Study on How Well SEMAGLUTIDE Works in Adolescents with Overweight or Obesity.” Full Text View - ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT04102189. Accessed 8.2.2022
10. Rubino, Domenica M., et al. “Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults with Overweight or Obesity without Diabetes.” JAMA, vol. 327, no. 2, 2022, p. 138., https://doi.org/10.1001/jama.2021.23619.
11. O'Neil, Patrick M, et al. “Efficacy and Safety of Semaglutide Compared with Liraglutide and Placebo for Weight Loss in Patients with Obesity: A Randomised, Double-Blind, Placebo and Active Controlled, Dose-Ranging, Phase 2 Trial.” The Lancet, vol. 392, no. 10148, 25 Aug. 2018, pp. 637–649., https://doi.org/10.1016/s0140-6736(18)31773-2.
12. Ard, Jamy, et al. “Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-like Peptide 1 Receptor Agonists.” Advances in Therapy, vol. 38, no. 6, 2021, pp. 2821–2839., https://doi.org/10.1007/s12325-021-01710-0.
13. Secher, Anna, et al. “The Arcuate Nucleus Mediates GLP-1 Receptor Agonist Liraglutide-Dependent Weight Loss.” Journal of Clinical Investigation, vol. 124, no. 10, 2014, pp. 4473–4488., https://doi.org/10.1172/jci75276.
14. Ronveaux, Charlotte C, et al. “Glucagon-like Peptide 1 Interacts with Ghrelin and Leptin to Regulate Glucose Metabolism and Food Intake through Vagal Afferent Neuron Signaling.” The Journal of Nutrition, vol. 145, no. 4, 2015, pp. 672–680., https://doi.org/10.3945/jn.114.206029. 
15. Van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond) 2014;38(6):784–793. doi: 10.1038/ijo.2013.162
16. Blundell, John, et al. “Effects of Once‐Weekly Semaglutide on Appetite, Energy Intake, Control of Eating, Food Preference and Body Weight in Subjects with Obesity.” Diabetes, Obesity and Metabolism, vol. 19, no. 9, 2017, pp. 1242–1251., https://doi.org/10.1111/dom.12932.
17. Friedrichsen, Martin, et al. “The Effect of Semaglutide 2.4 Mg Once Weekly on Energy Intake, Appetite, Control of Eating, and Gastric Emptying in Adults with Obesity.” Diabetes, Obesity and Metabolism, vol. 23, no. 3, 2021, pp. 754–762., https://doi.org/10.1111/dom.14280.
18. Van Bloemendaal, L., et al. “Brain Reward-System Activation in Response to Anticipation and Consumption of Palatable Food Is Altered by Glucagon-like Peptide-1 Receptor Activation in Humans.” Diabetes, Obesity and Metabolism, vol. 17, no. 9, 2015, pp. 878–886., https://doi.org/10.1111/dom.12506.
19. Filippatos, Theodosios D., et al. “Adverse Effects of GLP-1 Receptor Agonists.” The Review of Diabetic Studies, vol. 11, no. 3-4, 2014, pp. 202–230., https://doi.org/10.1900/rds.2014.11.202.
20. Collins, L, and RA Costello. “Glucagon-like Peptide-1 Receptor Agonists - NCBI BOOKSHELF.” StatPearls, Jan. 2022, https://www.ncbi.nlm.nih.gov/books/NBK551568/.
21. “GLP-1 Agonists - Prices and Information - Goodrx.” GLP-1 Agonists - Prices and Information , https://www.goodrx.com/glp-1-agonists. Accessed 8.2.2022
22. Hu, Ying, et al. “Cost-Effectiveness Analysis of 4 GLP-1RAS in the Treatment of Obesity in a US Setting.” Annals of Translational Medicine, vol. 10, no. 3, Feb. 2022, pp. 152–152., https://doi.org/10.21037/atm-22-200.
23. Frías, Juan P., et al. “Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.” New England Journal of Medicine, vol. 385, no. 6, 2021, pp. 503–515., https://doi.org/10.1056/nejmoa2107519.
24. Jastreboff, Ania M., et al. “Tirzepatide Once Weekly for the Treatment of Obesity.” New England Journal of Medicine, vol. 387, no. 3, 2022, pp. 205–216., https://doi.org/10.1056/nejmoa2206038.
25. Srivastava, Gitanjali, and Caroline Apovian. “Future Pharmacotherapy for Obesity: New Anti-Obesity Drugs on the Horizon.” Current Obesity Reports, vol. 7, no. 2, 2018, pp. 147–161., https://doi.org/10.1007/s13679-018-0300-4. 

Disclosures:

Dr. Alisa Nance has no financial relationships to disclose. 

Dr. George Chaconas has earned honoraria from Amgen.