Specialty Corner: Pharmacotherapy in Obesity: Not Just for Three Months

Overweight and obesity rates continue to climb worldwide, contributing to significant morbidity and mortality, despite several effective pharmacotherapy treatments that are grossly underutilized. Obesity is a major health problem with a US prevalence of 42.4% in adults and 19.3% in children.¹ It was first recognized as a disease in 1948 by the World Health Organization.² The National Institute of Health recognized obesity as a disease³ in 1998, and in 2004, the Centers for Medicare and Medicaid Services (CMS) removed the language stating that “obesity is not an illness” from its Coverage Issues Manual⁴, eliminating a significant obstacle to further progress and provide coverage for obesity-related medical services paving the way in 2006 for CMS coverage for bariatric surgery⁵, but unfortunately, not yet for anti-obesity medications (AOMs).

Biology of Weight Regulation

Obesity is defined as a chronic, often progressive, and treatable multifactorial disease, “wherein an increase in body fat promotes adipose tissue dysfunction⁶ . . . resulting in adverse metabolic, biomechanical, and psychosocial health consequences.” Historically, obesity was viewed as a “willpower” disorder or worse, a lifestyle choice, impacting voluntary behaviors that led to increased body weight.⁷ On the contrary, weight regulation is a homeostatic process, much like blood pressure regulation, that primarily operates outside of our conscious control impacting biologically driven behaviors in response to signals of hunger and satiety.⁸ Analogous to its role in other vital body homeostatic systems, including free water balance, body temperature, and endocrinologic systems, the hypothalamus primarily regulates body fat mass. Similar to thirst, hunger and satiety are mediated in the hypothalamus and hindbrain by neurohormonal circuitry in response to gut hormones that sense caloric intake and adipose secretions and thus, changes in energy storage.⁷ Our behaviors around food intake, including hunger and satiety, are based on a primary and homeostatically driven mechanism mediating body weight which are not under conscious control. In the situation of increased thirst occurring in a dehydrated athlete due to activated osmoreceptors, we would not disparage those who seek liquid replenishment until normal osmolarity is restored. Nor should we do this for an individual who succumbs to symptoms of hyperphagia.⁸ Other factors that play a role in weight regulation include energy utilization, inflammatory signaling, the sensory-reward pathways, and genetics.

Weight Related Comorbidities

Obesity correlates with over 200 other medical conditions⁹, including hypertension^10,11, type 2 diabetes, dyslipidemia, fatty liver, sleep apnea, heart failure, and higher risk of incident coronary artery disease (CAD).¹² The degree and duration of obesity, as measured by total exposure to excess overall abdominal adiposity and expressed as excess body mass index-years (BMI-years) and waist circumference-years (WC-years), have been shown to be a stronger predictor of CAD events beyond BMI or WC alone.¹³ Large population studies have shown that obesity is associated with increased cardiovascular disease (CVD) mortality^14-18, and in those with BMI ≥ 35 kg/m² there was a 2 to 3x increased risk of CVD mortality19 compared to persons with normal BMI (18.5-24.9kg/m²). Obesity also increases the risk of stroke. A nearly linear relationship of approximately 5% increase in ischemic stroke has been observed^20-22 for every 1 unit increase in BMI from a normal BMI of approximately 20 kg/m². For every 5-unit increase in BMI, there is 30% higher rate of CVD mortality.²³ Studies have shown that obesity decreases lifespan by up to 8 years.²⁴

Overweight and Obesity Treatment

Weight loss is a key factor in the prevention and control of coronary heart disease, hyperlipidemia, hypertension, inflammation, insulin resistance, type 2 diabetes, cardiorespiratory failure, and a 5% weight loss can reduce, eliminate, or prevent these and many other medical conditions.^3,25,26 Moderate weight loss of 5-10% can produce these benefits even when the BMI remains in the obesity range.^27-30 Given these health benefits, current guidelines recommend a starting weight loss goal of 5-10% as a means of getting the health benefits of weight loss³¹, and the Food and Drug Administration (FDA) uses a benchmark of at least 5% weight loss or more in evaluating potential obesity medicines.³² 

The mainstay of weight management are therapeutic lifestyle changes (TLC) that create a negative energy balance, including sustainable behavioral interventions around nutrition and physical activity. For the > 90% of patients who are unable to achieve clinically significant weight loss following 6 months of TLC33, professional organizations including American Association of Clinical Endocrinologists, the Endocrine Society, The Obesity Society, and the American Heart Association/American College of Cardiology, recommend initiation of anti-obesity medications (AOMs) for those with a body mass index (BMI) of 27 kg/m² with at least one obesity-related comorbidity or those with BMI of > 30 kg/m² with or without obesity-related comorbid conditions.^31,34-36 Thirty years ago the standard of care for treating hyperlipidemia included a 3-month period of TLC prior to starting pharmacotherapy³⁷, whereas, now lifestyle and pharmacotherapy are initiated simultaneously for hyperlipidemia, diabetes, hypertension, and most other chronic diseases other than overweight and obesity.

Anti-obesity Medications for Long-Term Use

There are currently four AOMs that produce an average of 5-15% total body weight loss and are FDA approved for long-term use: phentermine-topiramate, naltrexone-bupropion, liraglutide, and semaglutide (Table 1). Orlistat, which is also FDA approved for long-term use produces less then clinically significant weight loss and setmelanotide is only indicated for specific monogenic obesity mutations (Table 1).³⁸ Each AOM that produces clinically significant weight loss affects different neuronal pathways in the hypothalamic and brainstem weight control centers to help reduce appetite and improve satiety. In clinical trials, in addition to significantly greater weight loss than placebo, each of these medications showed significant improvements in lipids, glycemic control, hypertension, and waist circumference.^39-43 Additionally, cardiovascular outcome trials (CVOTs) showed up to a 26% decrease in composite cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke on lower doses of liraglutide and semaglutide for diabetes^44,45, and another CVOT with semaglutide 2.4 mg is ongoing.³⁸

While some believe they only need AOM to jumpstart the weight loss process with a plan for continued reduction through sheer will power, in the absence of therapy to alter the neurocircuitry, the body will defend the maximum weight even when it is not healthy to do so.⁵⁶ Others believe that an AOM is no longer effective when active weight loss ceases, even if they achieved their target weight; however, lipid lowering medications, antihypertensive agents, and diabetes therapies are not typically viewed in this way. As seen with all AOMs, the STEP 1 trial extension included an additional 52 weeks after treatment withdrawal from semaglutide resulting in regain of two-thirds of prior weight loss.⁵⁵ Hence, for clinical effectiveness, these medications are continued long-term, similarly to how we manage other chronic diseases.

Clinical trials of emerging therapies in obesity management show promising results including tirzepatide, a GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist already on the market for diabetes, but not yet approved for overweight and obesity. In the Surmonut-1 trial, overweight or obese patients without diabetes taking tirzepatide 15 mg averaged 20.1% placebo-subtracted weight loss, with 96.3% achieving ≥ 5% weight loss compared to 27.9% on placebo.⁵⁷ Similar to studies in patients with diabetes, trizepatide lowered cholesterol, triglycerides, glucose, and blood pressure, while results of a CVOT with trizepitide58,59 are expected in 2024. Ongoing research may lead to expanded use of setmelanotide and other agents targeting the melanocortin system and other pathways under investigation with some suggestion that pharmacotherapy options may approach efficacy comparable with surgical weight loss.
Conclusion

As a chronic disease, obesity needs to be managed as such, just as we do for any other disease. Given the prevalence of overweight and obesity and the known contribution to cardiometabolic complications, including increased disability, and higher mortality, treatment should be considered sooner and longer than is currently done. Effective pharmacotherapy for obesity is currently available and should be considered lifelong. Similar therapies are frequently used in individuals with diabetes to prevent mortality in those with established cardiovascular disease, but not in the same population with overweight or obesity. More work needs to be done to remove barriers to pharmacotherapy treatment for overweight and obesity, such as implicit bias, clinical inertia, lack of provider knowledge in treating obesity, and limited insurance coverage of AOMs. 

Ms. Osborn has no financial relationships to disclose. Dr. Nwizu has no financial relationships to disclose.

References

1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of Obesity and Severe Obesity Among Adults: United States, 2017-2018. NCHS Data Brief. Feb 2020;(360):1-8. 
2. James WP. WHO recognition of the global obesity epidemic. Int J Obes (Lond). Dec 2008;32 Suppl 7:S120-6. doi:10.1038/ijo.2008.247
3. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am J Clin Nutr. Oct 1998;68(4):899-917. doi:10.1093/ajcn/68.4.899
4. Services CfMM. Obesity as an Illness. Accessed November 11, 2022, https://www.cms.gov/medicare-coverage-database/view/ncacal-tracking-sheet.aspx
5. Services CfMM. Bariatric Surgery for the Treatment of Morbid Obesity. Accessed November 11, 2022, https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&NCAId=160&ver=32&NcaName=Bariatric+Surgery+for+the+Treatment+of+Morbid+Obesity
6. Association OM. Obesity Algorithm 2019. 2022. https://obesitymedicine.org/wp-content/uploads/2019/05/Obesity-Algorithm-2019.pdf
7. Affinati AH, Myers MG, Jr. Neuroendocrine Control of Body Energy Homeostasis. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext. MDText.com, Inc.
8. Purnell JQ. Management of chronic diseases in preventive cardiology: Revisiting “the Problem of Obesity.”. Am J Prev Cardiol. Mar 2020;1:100005. doi:10.1016/j.ajpc.2020.100005
9. Association OM. What Is Obesity? Accessed November 11, 2022, https://obesitymedicine.org/what-is-obesity/
10. Aronow WS. Association of obesity with hypertension. Ann Transl Med. Sep 2017;5(17):350. doi:10.21037/atm.2017.06.69
11. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. May 31 2011;123(21):2434-506. doi:10.1161/CIR.0b013e31821daaf6
12. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. May 1983;67(5):968-77. doi:10.1161/01.cir.67.5.968
13. Reis JP, Allen N, Gunderson EP, et al. Excess body mass index- and waist circumference-years and incident cardiovascular disease: the CARDIA study. Obesity (Silver Spring). Apr 2015;23(4):879-85. doi:10.1002/oby.21023
14. Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB. Annual deaths attributable to obesity in the United States. Jama. Oct 27 1999;282(16):1530-8. doi:10.1001/jama.282.16.1530
15. Lee IM, Blair SN, Allison DB, et al. Epidemiologic data on the relationships of caloric intake, energy balance, and weight gain over the life span with longevity and morbidity. J Gerontol A Biol Sci Med Sci. Mar 2001;56 Spec No 1:7-19. doi:10.1093/gerona/56.suppl_1.7
16. Troiano RP, Frongillo EA, Jr., Sobal J, Levitsky DA. The relationship between body weight and mortality: a quantitative analysis of combined information from existing studies. Int J Obes Relat Metab Disord. Jan 1996;20(1):63-75. 
17. Albert CM, Chae CU, Grodstein F, et al. Prospective study of sudden cardiac death among women in the United States. Circulation. Apr 29 2003;107(16):2096-101. doi:10.1161/01.Cir.0000065223.21530.11
18. Stevens J, Cai J, Evenson KR, Thomas R. Fitness and fatness as predictors of mortality from all causes and from cardiovascular disease in men and women in the lipid research clinics study. Am J Epidemiol. Nov 1 2002;156(9):832-41. doi:10.1093/aje/kwf114
19. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW, Jr. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. Oct 7 1999;341(15):1097-105. doi:10.1056/nejm199910073411501
20. Kurth T, Gaziano JM, Rexrode KM, et al. Prospective study of body mass index and risk of stroke in apparently healthy women. Circulation. Apr 19 2005;111(15):1992-8. doi:10.1161/01.Cir.0000161822.83163.B6
21. Ni Mhurchu C, Rodgers A, Pan WH, Gu DF, Woodward M. Body mass index and cardiovascular disease in the Asia-Pacific Region: an overview of 33 cohorts involving 310 000 participants. Int J Epidemiol. Aug 2004;33(4):751-8. doi:10.1093/ije/dyh163
22. Kurth T, Gaziano JM, Berger K, et al. Body mass index and the risk of stroke in men. Arch Intern Med. Dec 9-23 2002;162(22):2557-62. doi:10.1001/archinte.162.22.2557
23. Selmer R, Tverdal A. Body mass index and cardiovascular mortality at different levels of blood pressure: a prospective study of Norwegian men and women. J Epidemiol Community Health. Jun 1995;49(3):265-70. doi:10.1136/jech.49.3.265
24. Whitlock G, Lewington S, Sherliker P, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. Mar 28 2009;373(9669):1083-96. doi:10.1016/s0140-6736(09)60318-4
25. Pasanisi F, Contaldo F, de Simone G, Mancini M. Benefits of sustained moderate weight loss in obesity. Nutr Metab Cardiovasc Dis. Dec 2001;11(6):401-6. 
26. Brown JD, Buscemi J, Milsom V, Malcolm R, O’Neil PM. Effects on cardiovascular risk factors of weight losses limited to 5-10. Transl Behav Med. Sep 2016;6(3):339-46. doi:10.1007/s13142-015-0353-9
27. Wing RR. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med. Sep 27 2010;170(17):1566-75. doi:10.1001/archinternmed.2010.334
28. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord. Jun 1992;16(6):397-415. 
29. Vidal J. Updated review on the benefits of weight loss. Int J Obes Relat Metab Disord. Dec 2002;26 Suppl 4:S25-8. doi:10.1038/sj.ijo.0802215
30. Alpert MA, Terry BE, Kelly DL. Effect of weight loss on cardiac chamber size, wall thickness and left ventricular function in morbid obesity. Am J Cardiol. Mar 1 1985;55(6):783-6. doi:10.1016/0002-9149(85)90156-0
31. Klein S, Burke LE, Bray GA, et al. Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation. Nov 2 2004;110(18):2952-67. doi:10.1161/01.Cir.0000145546.97738.1e
32. Guidance for Industry Developing Products for Weight Management 19 
33. Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. Nov 14 2009;374(9702):1677-86. doi:10.1016/s0140-6736(09)61457-4
34. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. Jun 24 2014;129(25 Suppl 2):S102-38. doi:10.1161/01.cir.0000437739.71477.ee
35. Garvey WT, Mechanick JI, Brett EM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr Pract. Jul 2016;22 Suppl 3:1-203. doi:10.4158/ep161365.Gl
36. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. Feb 2015;100(2):342-62. doi:10.1210/jc.2014-3415
37. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Jama. Jun 16 1993;269(23):3015-23. 
38. Tchang BG, Aras M, Kumar RB, Aronne LJ. Pharmacologic Treatment of Overweight and Obesity in Adults. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext. MDText.com, Inc.
39. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. Apr 16 2011;377(9774):1341-52. doi:10.1016/s0140-6736(11)60205-5
40. Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Aug 21 2010;376(9741):595-605. doi:10.1016/s0140-6736(10)60888-4
41. Hendricks EJ, Greenway FL, Westman EC, Gupta AK. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring). Dec 2011;19(12):2351-60. doi:10.1038/oby.2011.94
42. Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N Engl J Med. Jul 2 2015;373(1):11-22. doi:10.1056/NEJMoa1411892
43. Verhaegen AA, Van Gaal LF. Drugs That Affect Body Weight, Body Fat Distribution, and Metabolism. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext. MDText.com, Inc.
44. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. Nov 10 2016;375(19):1834-1844. doi:10.1056/NEJMoa1607141
45. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. Jul 28 2016;375(4):311-22. doi:10.1056/NEJMoa1603827
46. Hauptman J, Lucas C, Boldrin MN, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med. Feb 2000;9(2):160-7. doi:10.1001/archfami.9.2.160
47. Sjöström L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet. Jul 18 1998;352(9123):167-72. doi:10.1016/s0140-6736(97)11509-4
48. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. Feb 2012;95(2):297-308. doi:10.3945/ajcn.111.024927
49. Ritchey ME, Harding A, Hunter S, et al. Cardiovascular Safety During and After Use of Phentermine and Topiramate. J Clin Endocrinol Metab. Feb 1 2019;104(2):513-522. doi:10.1210/jc.2018-01010
50. Munro JF, MacCuish AC, Wilson EM, Duncan LJ. Comparison of continuous and intermittent anorectic therapy in obesity. Br Med J. Feb 10 1968;1(5588):352-4. doi:10.1136/bmj.1.5588.352
51. Hendricks EJ, Srisurapanont M, Schmidt SL, et al. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes (Lond). Feb 2014;38(2):292-8. doi:10.1038/ijo.2013.74
52. Nissen SE, Wolski KE, Prcela L, et al. Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial. Jama. Mar 8 2016;315(10):990-1004. doi:10.1001/jama.2016.1558
53. Clément K, van den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. Dec 2020;8(12):960-970. doi:10.1016/s2213-8587(20)30364-8
54. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. Mar 18 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
55. Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. Aug 2022;24(8):1553-1564. doi:10.1111/dom.14725
56. Association OM. Obesity Medications. Accessed November 11, 2022, https://obesitymedicine.org/obesity-medications/
57. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. Jul 21 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
58. Rosenstock J, Wysham C, Frias JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomized, phase 3 trial. Lancet. Jun 26 2021; 398:143-55. Doi:10.1016/50140-6736(21)01324-6
59. Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. Aug 5 2021; 385:503-515. Doi:10.1056/NEJMoa2107519