Physicians' Academy for Cardiovascular Education

Substantial weight loss by dual GIP and GLP-1 receptor agonist in obese individuals

Tirzepatide Once Weekly for the Treatment of Obesity

Literature - Jastreboff AM, Aronne LJ, Ahmad NN, et al. - N Engl J Med. 2022 Jun 4. doi: 10.1056/NEJMoa2206038

Introduction and methods


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.


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.


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


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.


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