GLP-1s Are At the Forefront, but Other Obesity Treatments Exist

A greater proportion of the US population is diagnosed with obesity every day, defined as a BMI above 30. An estimated 41.9% of adult Americans are obese today, with that rate expected to reach 48.9% by 2030.^1,2

As the science behind preventive diseases continues to grow (i.e., vaccinations and smoking cessation), researchers have established that obesity is a risk factor for many conditions that can be managed and/or eliminated. Conditions that obesity is a risk factor for include cardiovascular diseases (CVD), type 2 diabetes, musculoskeletal disorders, fatty liver disease, and several cancers.³

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It is not fully understood exactly how obesity plays a role in so many disease states, but it may be linked with the increased level of adipokines released by the increased level of adipocytes present.4 Adipokines are types of cytokines that have a variety of metabolic and inflammatory mechanisms, depending on the type of adipocyte that releases it (i.e. white, brown, or beige), size, volume, and location. Through many different mechanisms, these adipokines (i.e., leptin, adiponectin, resistin, etc.) generate multiple negative pathophysiological changes.⁴

Such negative physiological changes amplified by adipokines include atherosclerosis, diabetes, fatty liver disease, hypertension, and cancer.^4,5

The current obesity guidelines recommend intervening for anyone with a BMI >30 or have a BMI >27 with 1 or more weight-related complications, targeting a weight loss goal of 5% to 10% within 6 months.⁶ A comprehensive weight loss approach should be implemented, including aerobic exercise and resistance training, alongside a decreased caloric diet.⁶

Education on healthy eating strategies includes the Healthy Eating Plate concept, diets (i.e. Mediterranean and the Dietary Approaches to Stop Hypertension diet), understanding nutritional fact labels, and/or intermittent fasting techniques. Additionally, referral to a nutritionist or dietician is beneficial to help educate and reinforce healthy eating habits.^7-9 If lifestyle modifications are not sufficient alone, surgical and/or anti-obesity medications (AOMs) can be considered.⁷

Several bariatric surgery options for weight loss exist (i.e., Rou-en-Y gastric bypass, sleeve gastrectomy, gastric banding, and duodenal switch).¹⁰ The Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial used the Roux-en-Y gastric bypass and sleeve gastrectomy techniques to evaluate weight loss surgery vs intensive medication therapy alone. The surgical patients were shown to have a significant reduction in many medication classes (i.e., diabetes, blood pressure, antithrombotic agents, and lipid-lowering agents), even eliminating the need for diabetes medications in some patients entirely and substantially reducing the need for lipid-lowering and antihypertensive drugs.¹¹

Without the risks or long-term complications of surgery, there are several AOMs approved for weight loss, including the following^3,12-15:

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

• Clinical trials of semaglutide (Wegovy; Novo Nordisk) show a weight loss of 10.6 kg to 12.7 kg at 52 weeks and a clinically significant all-cause mortality decrease in non-diabetes patients (6.5% treatment group vs 8% placebo group with a number needed to treat of 67). The weight loss version of semaglutide is initiated at 0.25 mg injected subcutaneously (SQ) once weekly and gradually increased to a target dose of 2.4 mg weekly.
• The first GLP-1 receptor agonist approved for chronic weight management, liraglutide (Saxenda; Novo Nordisk) has been shown to have a weight loss of 3.7 kg to 5.2 kg at 56 weeks. The weight loss version of liraglutide starts at 0.6 mg SQ daily and is increased to a daily dose of 3 mg.

Dual GLP-1 and Gastric Inhibitory Polypeptide (GIP) Receptor Agonist

• Currently, a mortality trial with tirzepatide (Zepbound; Lilly) is ongoing, but results are not expected to be published until 2027. This novel twincretin demonstrated an 18.8 kg weight loss at 72 weeks. It is initiated at 2.5 mg SQ weekly and titrated up every 4 weeks, as tolerated, to a maximum dose of 15 mg weekly.

Intestinal Lipase Inhibitor

• Orlistat (Xenical; Chepla Pharm, H2-Pharma) is an overall very safe medication, but it does have bothersome gastrointestinal adverse effects and can interfere with drug and vitamin absorption. The prescription formula shows a weight loss of 3.45 kg at 1 year whereas the OTC formula (Alli; Halleon) shows 2 kg at 24 weeks.

Sympathomimetics

• Phentermine (Lomaira; KVK Tech) is by far the most frequently prescribed sympathomimetic in the US. However, it is only approved for short-term use and guidelines suggest continuing an approved weight loss medication that has a weight loss of at least 5% at 12 weeks.
• Other sympathomimetics include diethylpropion, benzphetamine, and phendimetrazine. Like phentermine, these are controlled substances and share similar adverse reactions and contraindications.

Combination Medications

• Phentermine/Topiramate ER (Qsymia; Vivus) adds topiramate, a carbonic anhydrase inhibitor, to phentermine to create a weight loss of 9 kg in 1 year. It also has a high discontinuation rate of about 1 in 6 patients, due to adverse reactions. It has a Risk Evaluation and Mitigation Strategies program and needs to be monitored and avoided in pregnancy due to birth defects.
• Bupropion ER/Naltrexone (Contrave; Currax) is believed to be beneficial in patients with underlying mood disorders and/or eating disorders. It can produce < 4.1 kg weight loss at 56 weeks and has a discontinuation rate of 1 in 4 patients due to adverse effects.

Remember, obesity is a chronic condition, and it should be treated as such. Medications implemented should be intended for lifelong use and in conjunction with lifestyle modifications.³ Clinical decision making needs to be made on a case-by-case basis, considering patient affordability and availability of products.

REFERENCES

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2. Ward ZJ, Bleich SN, Cradock AL, et al. Projects US state-level prevalence of adult obesity and severe obesity. N Eng J Med. 2019;381:2440-2450. doi:10.1056/NEJMsa1909301

3. Tchang BG, Aras M, Kumar RB, et al. Pharmacologic treatment of overweight and obesity in adults. In: Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc. 2000. August 20, 2024.

4. Clemente-Suarez VJ, Redondo-Florez L, Beltran-Velasco AI, et al. The role of adipokines in health and disease. Biomedicines. 2023;11(5):1290. doi:10.3390/biomedicines11051290

5. El Meouchy P, Wahoud M, Allam S, Chedid R, Karam W, Karam S. Hypertension related to obesity: pathogenesis, characteristics and factors for control. Int J Mol Sci. 2022;23(20):12305. doi:10.3390/ijms232012305

6. Cornier MA. A Review of Current Guidelines for the Treatment of Obesity. Am J Manag Care. 2022;28(15).

7. Mchiza ZJR. Diet therapy and public health. Int J Environ Res Public Health. 2022;19(14):8312. doi:10.3390/ijerph19148312

8. Healthy Eating Plate. The Nutrition Source. Updated January 2023. Accessed November 7, 2024. https://nutritionsource.hsph.harvard.edu/healthy-eating-plate/

9. Patikorn C, Roubal K, Veettil SK, et al. Intermittent fasting and obesity-related health outcomes. JAMA Netw Open. 2021;4(12):e2139558. doi:10.1001/jamanetworkopen.2021.39558

10. Wharton S, Lau DCW, Vallis M, et al. Obesity in adults: a clinical practice guideline. CMAJ. 2020;192(31):E875-E891. doi:10.1503/cmaj.191707

11. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567-1576. doi:10.1056/NEJMoa1200225

12. Weight Loss Products. Prescriber Insights. Updated May 2024. Accessed November 7, 2024. https://naturaldatabase.therapeuticresearch.com/Content/Segments/PRL/2017/Jan/Weight-Loss-Products-10572

13. Lincoff AM, Brown-Fransen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563

14. A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With Obesity (SURMOUNT-MMO). ClinicalTrials.gov. Updated October 1, 2024. Accessed November 7, 2024. https://clinicaltrials.gov/study/NCT05556512

15. Plodkowski RA, McGarvey ME, Reisinger-Kindle K, et al. Obesity management: clinical review and update of the pharmacologic treatment options. Fed Pract. 2016;33(1):6-16.

16. Greenway FL, Aronne LJ, Raben A, et al. A randomized, double-blind, placebo-controlled study of Gelesis100: a novel nonsystemic oral hydrogel for weight loss. Obesity (Silver Spring). 2019;27(2):205-216. doi:10.1002/oby.22347