Obesity is a chronic, multifactorial disease characterized by excessive or abnormal adiposity that adversely affects health and is associated with increased morbidity, impaired quality of life, and premature mortality.¹ The increasing prevalence of obesity worldwide has created a substantial need for effective and sustainable treatment strategies. More than 890 million adults worldwide are living with obesity, while approximately 43% of adults are classified as overweight.² Although lifestyle modification remains the foundation of obesity management, the difficulty of achieving and maintaining substantial weight loss has increased the need for effective pharmacological therapies.
Among the newer anti-obesity medications, tirzepatide has emerged as an important therapeutic option because of its dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. This distinct mechanism targets multiple pathways involved in appetite regulation, food intake, glucose metabolism, and energy homeostasis. Clinical evidence has demonstrated substantial weight reduction with tirzepatide, together with improvements in several metabolic parameters, positioning the drug as an important development in contemporary obesity management.
Tirzepatide: a dual incretin-based approach
Tirzepatide is a once-weekly injectable peptide that combines GIP and GLP-1 receptor agonism in a single molecule.³ Both GIP and GLP-1 are incretin hormones involved in postprandial glucose regulation, insulin secretion, and energy metabolism. Tirzepatide activates these complementary pathways to produce glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, modulation of gastric emptying, and reduction in appetite and food intake.³,⁴ The integrated effects of these pathways contribute to reductions in body weight and improvements in glycaemic control.
The dual incretin activity of tirzepatide distinguishes it from GLP-1 receptor agonists that act predominantly through a single incretin pathway. GIP receptor activation may complement GLP-1 receptor-mediated effects on appetite and glucose metabolism and may contribute to the magnitude of weight loss observed with tirzepatide.⁴ This pharmacological profile has provided the basis for its evaluation across a broad range of individuals with obesity or overweight, including those with and without type 2 diabetes.
Evidence from the SURMOUNT programme
The efficacy of tirzepatide for weight management has been extensively evaluated in the SURMOUNT clinical development programme. In SURMOUNT-1, adults with obesity or overweight without diabetes received once-weekly tirzepatide at doses of 5, 10, or 15 mg or placebo for 72 weeks, alongside lifestyle intervention.⁵ Tirzepatide produced dose-dependent reductions in body weight, with mean reductions of approximately 15% with the 5-mg dose and approximately 20% or more with the higher doses. A substantial proportion of participants receiving the 10- and 15-mg doses achieved at least 20% weight loss.⁵
The efficacy of tirzepatide has also been demonstrated in individuals with obesity and type 2 diabetes. SURMOUNT-2 showed significantly greater weight reduction with tirzepatide than with placebo over 72 weeks, together with clinically meaningful improvements in glycaemic control.⁶ Although weight reduction was somewhat lower than that observed in people without diabetes, the findings demonstrate that tirzepatide can simultaneously address excess adiposity and metabolic dysfunction.
Effects on body composition
The effects of tirzepatide extend beyond reductions in total body weight. Body-composition analyses provide important information regarding the nature of the weight lost and the relative changes in fat and lean tissue. In a body-composition substudy of SURMOUNT-1, tirzepatide treatment resulted in substantial reductions in total fat mass, including visceral adipose tissue, together with reductions in lean mass.⁷ The majority of weight loss was attributable to a reduction in fat mass.
The reduction in visceral adiposity is particularly relevant because visceral fat is associated with insulin resistance, chronic inflammation, dyslipidaemia, and increased cardiometabolic risk.⁷ Therefore, the favourable changes in body composition observed with tirzepatide may provide additional insight into its metabolic effects beyond conventional measures such as body weight and body mass index.
Cardiometabolic effects
Tirzepatide produces metabolic benefits in addition to its effects on body weight. Treatment has been associated with improvements in glycemic control, insulin sensitivity, blood pressure, and lipid parameters in clinical trials.⁵,⁶ These effects are particularly relevant because obesity frequently coexists with type 2 diabetes, hypertension, dyslipidaemia, and other cardiometabolic disorders.
The clinical benefits of tirzepatide may also extend to obesity-related complications. In individuals with obesity and heart failure with preserved ejection fraction, tirzepatide has been associated with improvements in symptoms, physical limitations, and quality of life, together with substantial weight reduction.⁸ These findings suggest that the therapeutic effects of tirzepatide may extend beyond weight reduction to clinically meaningful improvements in obesity-related disease burden.
Safety and tolerability
Tirzepatide is generally well tolerated, with gastrointestinal adverse events representing the most frequently reported adverse effects. Nausea, diarrhoea, vomiting, and constipation are commonly reported, particularly during dose escalation.⁵,⁶ These events are generally mild to moderate, and gradual dose escalation is used to improve tolerability.
Because tirzepatide is intended for chronic weight management, treatment decisions should consider both efficacy and long-term tolerability. Individual factors, including comorbidities, concomitant medications, treatment response, and adverse effects, should be considered when determining the appropriate maintenance dose and duration of therapy.
Tirzepatide within the evolving obesity treatment landscape
Tirzepatide has substantially expanded the potential magnitude of weight loss achievable with pharmacological treatment. The reductions observed in clinical trials, with weight loss approaching or exceeding 20% in some treatment groups, represent a considerable advance compared with many earlier anti-obesity medications.⁵ This degree of weight reduction may have important implications for obesity-related metabolic complications and overall health outcomes.
The durability of treatment response is also an important consideration. In SURMOUNT-4, participants who continued tirzepatide after an initial period of weight loss maintained and further increased their weight reduction, whereas discontinuation and switching to placebo resulted in substantial weight regain.9 These findings support the concept of obesity as a chronic disease and indicate that continued pharmacological treatment may be necessary to maintain the benefits achieved with tirzepatide.
Tirzepatide should therefore be considered as part of a comprehensive long-term obesity management strategy rather than as a short-term treatment used only until a target weight is achieved. Lifestyle intervention remains an important component of treatment, while pharmacotherapy can provide additional support for individuals who require greater or sustained weight reduction.
Conclusion
Tirzepatide represents a significant development in pharmacological weight management through its dual GIP and GLP-1 receptor agonist activity. Its effects extend from appetite and food-intake regulation to substantial reductions in body weight and adiposity, together with improvements in glycaemic and cardiometabolic parameters. Evidence from the SURMOUNT programme demonstrates clinically meaningful weight loss across individuals with and without type 2 diabetes, while body-composition analyses indicate that the majority of weight lost is attributable to reductions in fat mass. The observed weight regain following treatment discontinuation further emphasizes the need to consider tirzepatide within a long-term approach to obesity management. Its substantial efficacy, metabolic benefits, and once-weekly administration position tirzepatide as an important therapeutic option in the evolving treatment landscape of obesity.
References
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- Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist K, et al.LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018;18:3-14.
- Rizvi AA, Rizzo M. The emerging role of dual GLP-1 and GIP receptor agonists in glycemic management and cardiovascular risk reduction. Diabetes Metab Syndr Obes. 2022;15:1023-1030.
- Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Ket al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216.
- Garvey WT, Frias JP, Jastreboff AM, Kravitz BG, Marshall J, Aronne LJ, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a randomised, double-blind, multicentre, placebo-controlled trial. Lancet. 2023;402:613-626.
- Look M, Dunn JP, Kushner RF, Cao D, Harris C, Gibble TH, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab. 2025 May;27(5):2720-2729.
- Packer M, Zile MR, Kramer CM, Kamolz K, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med. 2025;392:120-132.
- Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331:38-48.