Substantial weight loss by dual GIP and GLP-1 receptor agonist in obese individuals
Tirzepatide has an agonistic effect not only on the GLP-1 receptor, but also on the glucose-dependent insulinotropic polypeptide (GIP) receptor. Whether this leads to substantial weight reduction in obese individuals without T2DM was investigated in the SURMOUNT-1 trial.
Tirzepatide Once Weekly for the Treatment of ObesityLiterature - Jastreboff AM, Aronne LJ, Ahmad NN, et al. - N Engl J Med. 2022 Jun 4. doi: 10.1056/NEJMoa2206038
Introduction and methods
Background
Recent evidence shows that lifestyle-based approaches for the treatment of obesity induce counterregulatory mechanisms that limit weight reduction [1]. These central and peripheral mechanisms make it difficult for an obese individual to get to lower weight [2]. Several clinical guidelines now recommend treatment with a long-acting GLP1-RA for people with a BMI ≥30 kg/m2 or a BMI ≥27 kg/m2 and obesity-related complications [3,4]. Tirzepatide is a novel once-weekly subcutaneous injectable peptide that has an agonistic effect not only on the GLP-1 receptor, but also on the glucose-dependent insulinotropic polypeptide (GIP) receptor, which may lead to greater weight reduction than GLP-1RA alone [5]. It has been approved by the FDA for the treatment of T2DM and in a phase 2 study, treatment with tirzepatide in patients with T2DM resulted in clinically relevant weight reduction.
Aim of the study
The aim of this study was to evaluate the efficacy and safety of tirzepatide in adults with obesity or overweight who did not have diabetes.
Methods
The researchers conducted a double-blind, placebo-controlled phase 3 study in 119 sites in 9 countries (SURMOUNT-1 trial). 2539 Patients ≥ 18 years of age with a BMI ≥30 kg/m2 or a BMI 27 kg/m2 and at least 1 weight-related complication, such as hypertension, dyslipidemia, obstructive sleep apnea or CVD, were randomized in a 1:1:1:1 ratio to a weekly subcutaneous injection of tirzepatide (5, 10 or 15 mg ) or placebo for 72 weeks as an adjunct to a lifestyle intervention. To be eligible for participation, patients had to have made 1 or more unsuccessful dietary effort to lose weight. Key exclusion criteria were diabetes, a change in body weight of more than 5 kg in the past 90 days, previous or planned surgical treatment for obesity, and treatment with a drug that promotes weight loss in the past 90 days.
Outcomes
The coprimary end points were the percentage change in body weight from baseline to week 72 and a weight reduction ≥ 5% at week 72. Key secondary end points included: weight reduction ≥10%, ≥15% and ≥20% at week 72; the change in weight from baseline to week 20; and the change from baseline to week 72 in waist circumference, systolic blood pressure, fasting insulin and lipid levels, and the physical function score on the 36-Item Short Form Health Survey (SF-36).
Main results
- The mean percentage change in weight at week 72 was -15.0% (95%CI: -15.9 to -14.2) with 5-mg dose of tirzepatide, -19.5% (95%CI: -20.4 to -18.5) with 10-mg dose, and -20.9% (95%CI: -21.8 to -19.9) with 15-mg dose and -3.1% (95%CI: -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo).
- The percentage of patients with weight reduction ≥ 5% at week 72 was 85% (95%CI: 82-89), 89% (95%CI: 86-92), and 91% (95%CI: 88-94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95%CI: 30-39) with placebo (P<0.001 for all comparisons with placebo).
- More participants in the tirzepatide groups had reductions of 10% or more, 15% or more and 20% or more than participants in the placebo group. For example, weight decreased by 20% or more in 50% (95%CI: 46-54) and 57% (95%CI: 53-61) of patients treated with tirzepatide 10 or 15 mg, respectively, compared with 3% (95%CI: 1-5) of patients in the placebo group (P<0.001 for all comparisons with placebo).
- Treatment with tirzepatide resulted in a statistically significant improvement in all prespecified secondary outcomes, compared with placebo.
- The most common adverse effects of tirzepatide were gastrointestinal symptoms, including nausea, diarrhea, and constipation; these symptoms occurred particularly during dose escalation and were transient and mild to moderate in severity.
- Serious adverse events were reported in similar percentages of participants in tirzepatide and placebo groups.
- Adverse effects necessitated treatment discontinuation in 4.3%, 7.1%, 6.2% of patients treated with 5, 10, or 15 mg of tirzepatide, respectively, and in 2.6% of patients in the placebo group.
Conclusion
In obese individuals, treatment with 5, 10 or 15 mg of tirzepatide resulted in substantial and sustained weight reduction at 72 weeks. Average weight reductions were 19.5% and 20.9% with 10-mg and 15-mg doses of tirzepatide as compared to 3.1% with placebo. The authors wrote: “This is an unusually substantial degree of weight reduction in response to an antiobesity medication as compared with findings of other phase 3 clinical trials.”
The drug was generally well tolerated by participants.
References
1. Aronne LJ, Hall KD, M Jakicic J, et al. Describing the weight-reduced state: physiology, behavior, and interventions. Obesity (Silver Spring) 2021;29:Suppl 1: S9-S24.
2. Schwartz MW, Seeley RJ, Zeltser LM, et al. Obesity pathogenesis: an endocrine society scientific statement. Endocr Rev 2017;38:267-96.
3. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 342-62.
4. Wharton S, Lau DCW, Vallis M, et al. Obesity in adults: a clinical practice guideline. CMAJ 2020; 192(31): E875-E891.
5. Coskun T, Sloop KW, Loghin C, 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.