•• Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002. This pivotal randomized controlled trial of once-weekly semaglutide (2.4 mg) for overweight/obesity reported a mean 14.9% reduction in baseline weight at 68 weeks (compared with 2.4% for placebo) with generally favorable tolerability and safety findings.

•• Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–16. This pivotal trial of once-weekly tirzepatide (15 mg) for overweight/obesity reported a mean 20.9% reduction in baseline weight at 72 weeks (compared with 3.1% for placebo) with generally favorable tolerability and safety findings.

• Jastreboff AM, Kushner RF. New frontiers in obesity treatment: GLP-1 and nascent nutrient stimulated hormone-based therapeutics. Annu Rev Med. 2023;74:125–39. A variety of new drug targets are being explored for overweight/obesity beyond glucagon like polypeptide-1 (GLP-1) receptor agonists (i.e., semaglutide 2.4 mg) and combined glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists (i.e., tirzepatide 15 mg).

Wegovy (package insert). Plainsboro, NJ: Novo Nordisk, USA;2021.

National Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Obes Res. 1998;6(Suppl.):51S-210S.

Jensen MD, Ryan DH, Donato KA, Apovian CM, Ard JD, Comuzzie AG, et al. Guidelines (2013) for managing overweight and obesity in adults. Obesity. 2014;22(S2):S1–410.

Google Scholar 

Garvey WT. New horizons: a new paradigm for treating to target with second-generation obesity medications. J Clin Endocrinol Metab. 2022;107(4):e1339–47.

Article  PubMed  Google Scholar 

Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of obesity in adults. Am Psychol. 2020;75(2):235–51.

Article  PubMed  PubMed Central  Google Scholar 

The Diabetes Prevention Program Research Group. The Diabetes Prevention Program (DPP). Description of lifestyle intervention Diabetes Care. 2002;25(12):2165–71.

Google Scholar 

Wing RR, Tate DF, Gorin AA, Raynor HA, Fava JL. A self-regulation program for maintenance of weight loss. N Engl J Med. 2006;355(15):1563–71.

Article  CAS  PubMed  Google Scholar 

Look AHEAD Research Group, Wadden TA, West DS, Delahanty L, Jakicic J, Rejeski J, et al. The Look AHEAD study: a description of the lifestyle intervention and the evidence supporting it. Obesity (Silver Spring). 2006;14(5):737–52.

Wadden TA, Tsai AG, Tronieri JS. A protocol to deliver intensive behavioral therapy (IBT) for obesity in primary care settings: the MODEL-IBT program. Obesity (Silver Spring). 2019;27(10):1562–6.

Article  PubMed  PubMed Central  Google Scholar 

Schwartz MW, Seeley RJ, Zeltser LM, Drewnowski A, Ravussin E, Redman LM, et al. Obesity pathogenesis: an Endocrine Society scientific statement. Endocr Rev. 2017;38(4):267–96.

Article  PubMed  PubMed Central  Google Scholar 

Brownell KD, Horgen KB. Food fight: the inside story of the food industry, America’s obesity crisis, and what we can do about it. New York: McGraw-Hill; 2004.

Google Scholar 

Hall KD, Ayuketah A, Brychta R, Cai H, Cassimatis T, Chen KY, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):67-77.e3.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Guyenet SJ. The hungry brain: outsmarting the instincts that make us overeat. New York: Flatiron Books; 2017.

Google Scholar 

U. S. Department of Health and Human Services. Physical activity guidelines for Americans, 2nd edition: US Department of Health and Human Services; 2018. Available from: https://health.gov/sites/default/files/2019-09/Physical_Activity_Guidelines_2nd_edition.pdf. Accessed 29 June 2023.

Donnelly JE, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK. American College of Sports Medicine Position Stand. Appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc. 2009;41(2):459–71.

Centers for Medicare and Medicaid Services. Decision memo for intensive behavioral therapy for obesity (CAG-00423N); 2011. Available from: https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&&NcaName=Intensive%20Behavioral%20Therapy%20for%20Obesity&NCAId=253. Accessed 9 July 2023.

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403.

Article  CAS  PubMed  Google Scholar 

Wadden TA, West DS, Neiberg RH, Wing RR, Ryan DH, Johnson KC, et al. One-year weight losses in the Look AHEAD study: factors associated with success. Obesity (Silver Spring). 2009;17(4):713–22.

Article  PubMed  PubMed Central  Google Scholar 

Haywood C, Sumithran P. Treatment of obesity in older persons—a systematic review. Obes Rev. 2019;20(4):588–98.

Article  PubMed  Google Scholar 

Heymsfield SB, Wadden TA. Mechanisms, pathophysiology, and management of obesity. N Engl J Med. 2017;376(15):1492.

PubMed  Google Scholar 

Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34(7):1481–6.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kolotkin RL, Fujioka K, Wolden ML, Brett JH, Bjorner JB. Improvements in health-related quality of life with liraglutide 3.0 mg compared with placebo in weight management. Clin Obes. 2016;6(4):233–42.

Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, Delahanty L, et al. Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes Care. 2006;29(9):2102–7.

Article  PubMed  Google Scholar 

Foster GD, Wyatt HR, Hill JO, Makris AP, Rosenbaum LD, Brill C, et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial. Ann Intern Med. 2010;153(3):147–57.

Article  PubMed  PubMed Central  Google Scholar 

Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009;360(9):859–73.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tsai AG, Wadden TA. The evolution of very-low-calorie diets: an update and meta-analysis. Obesity (Silver Spring). 2006;14(8):1283–93.

Article  PubMed  Google Scholar 

Butryn ML, Webb V, Wadden TA. Behavioral treatment of obesity. Psychiatr Clin North Am. 2011;34(4):841–59.

Article  PubMed  PubMed Central  Google Scholar 

Perri MG, Limacher MC, Durning PE, Janicke DM, Lutes LD, Bobroff LB, et al. Extended-care programs for weight management in rural communities: the treatment of obesity in underserved rural settings (TOURS) randomized trial. Arch Intern Med. 2008;168(21):2347–54.

Article  PubMed  PubMed Central  Google Scholar 

Klem ML, Wing RR, McGuire MT, Seagle HM, Hill JO. A descriptive study of individuals successful at long-term maintenance of substantial weight loss. Am J Clin Nutr. 1997;66(2):239–46.

Article  CAS  PubMed  Google Scholar 

Rosenbaum M, Leibel RL. Models of energy homeostasis in response to maintenance of reduced body weight. Obesity (Silver Spring). 2016;24(8):1620–9.

Article  PubMed  Google Scholar 

Ravussin E, Smith SR, Ferrante AW. Physiology of energy expenditure in the weight-reduced state. Obesity (Silver Spring). 2021;29(Supp 1):S31–8.

PubMed  Google Scholar 

Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597–604.

Article  CAS  PubMed  Google Scholar 

U. S. Preventive Services Task Force, Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, et al. Behavioral weight loss interventions to prevent obesity-related morbidity and mortality in adults: US preventive services task force recommendation statement. JAMA. 2018;320(11):1163–71.

Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–62.

Article  CAS  PubMed  Google Scholar 

Bessesen DH, Van Gaal LF. Progress and challenges in anti-obesity pharmacotherapy. Lancet Diabetes Endocrinol. 2016;6(3):237–48.

Article  Google Scholar 

Yanovski SZ, Yanovski JA. Progress in pharmacotherapy for obesity. JAMA. 2021;326(2):129–30.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pressley H, Cornelio CK, Adams EN. Setmelanotide: a novel targeted treatment for monogenic obesity. J Pharm Technol. 2022;38(6):368–73.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Front Endocrinol. 2019;10:155.

Article  Google Scholar 

Tan Q, Akindehin SE, Orsso CE, Waldner RC, DiMarchi RD, Müller TD, et al. Recent advances in incretin-based pharmacotherapies for the treatment of obesity and diabetes. Front Endocrinol. 2022;13: 838410.

Article  Google Scholar 

Friedrichsen M, Breitschaft A, Tadayon S, Wizert A, Skovgaard D. The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. Diabetes Obes Metab. 2021;23(3):754–62.

Boer GA, Hay DL, Tups A. Obesity pharmacotherapy: incretin action in the central nervous system. Trends Pharmacol Sci. 2023;44(1):50–63.

Article  CAS  PubMed  Google Scholar 

Heise T, DeVries JH, Urva S, Li J, Pratt EJ, Thomas MK, et al. Tirzepatide reduces appetite, energy intake, and fat mass in people with type 2 diabetes. Diabetes Care. 2023;46(5):998–1004.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Gabery S, Salinas CG, Paulsen SJ, Ahnfelt-Rønne J, Alanentalo T, Baquero AF, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020;5(6): e133429.

Article  PubMed  PubMed Central  Google Scholar 

Wharton S, Batterham RL, Bhatta M, Buscemi S, Christensen LN, Frias JP, et al. Two-year effect of semaglutide 2.4 mg on control of eating in adults with overweight/obesity: STEP 5. Obesity (Silver Spring). 2023;31(3):703–15.

Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. Triple-hormone-receptor agonist retatrutide for obesity - a phase 2 trial. N Engl J Med. 2023. Epub ahead of print.

Enebo LB, Berthelsen KK, Kanam M, Lund MT, Rubino D, Satylganova A, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilinitide with semaglutide 2.4 mg for weight management: a randomized, controlled, phase 1b trial. Lancet. 2021;397(10286):1736–48.

Davies M, Færch L, Jeppesen OK, Pakseresht A, Pedersen SD, Perreault L, et al. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397(10278):971–84.

Article  CAS  PubMed  Google Scholar 

• Wadden TA, Bailey TS, Billings LK, Davies M, Frias JP, Koroleva A, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: the STEP 3 randomized clinical trial. JAMA. 2021;325(14):1403–13. This randomized trial attempted, with limited success, to boost 68-week weight loss with semaglutide 2.4 mg by combining it with an initial 8-week, 1000-kcal/day meal-replacement diet and 30 sessions of intensive behavior therapy (departing from the 17 sessions used in most studies of semaglutide).