Discontinuation of dual GIP and GLP-1 receptor agonist leads to weight regain in people with obesity or overweight

EASD 2023 In the SURMOUNT-4 trial, patients on 36-weeks of treatment with tirzepatide at maximally tolerated doses (10 mg or 15 mg) were randomized to continued therapy or discontinuation of therapy with placebo to assess whether body weight reductions by tirzepatide are maintained in people with obesity or overweight.

Presented at the EASD annual meeting 2023. Naveed Sattar, MD, PhD (Glasgow, UK) presented SURMOUNT-4 background, rationale design and baseline characteristics, and Louis Aronne, MD (New York, NY, USA) presented SURMOUNT-4 study efficacy and safety results.

Introduction and methods

Tirzepatide is a dual GIP and GLP-1 receptor agonist, which is approved for the management of T2D and currently under review for chronic weight management. In SURMOUNT-1 , robust reductions in body weight were seen in patients with obesity without T2D taking tirzepatide. According to obesity management guidelines, pharmacologic interventions should be used long-term to prevent weight regain. It is unknown what the effects of tirzepatide are on the maintenance of weight reductions in people with obesity. The aim of the current study was to determine whether weight reduction by tirzepatide is maintained in patients discontinuing therapy, and determine the benefits of continued therapy.

SURMOUNT-4 was a randomized, double-blind, multicenter, placebo-controlled trial. 783 adults with obesity or overweight (BMI ≥30 kg/m² or ≥27 kg/m² with at least 1 weight-related complication [hypertension, dyslipidemia, obstructive sleep apnea, or CVD]; mean BMI: 38.6 kg/m²; weight: 107 kg; waist circumference: 115.1 cm) without diabetes first entered a 36-week open-label phase with tirzepatide treatment, followed by a 52-week double-blind treatment period (n=670 patients) with tirzepatide at maximally tolerated doses (MTD) of 10 mg or 15 once weekly or matching injectable placebo. In the open-label phase, treatment doses of tirzepatide were gradually escalated to the MTD at week 20 (2.5 mg dose increases in each escalation cycle). At randomization, 49 patients (7.3%) were treated with tirzepatide 10 mg and 621 patients (92.7%) were treated with tirzepatide 15 mg. After the total treatment period, there was a 4-week safety follow-up period. People could participate in the study when they had at least one self-reported unsuccessful dietary effort to lose body weight. 290 patients (86.6%) in the placebo group and 310 patients (92.5%) in the tirzepatide group completed the study.

The primary endpoint was the percent change in body weight from randomization (36 weeks) to end of treatment period (88 weeks).

Main results

//Efficacy outcomes//

• After the open-label phase with tirzepatide, from week 36 to week 88, the mean percent change in body weight was +14.8% in the placebo group, and -6.7% in the tirzepatide MTD group (P<0.001).
• In the first 36 weeks of the study, mean body weight reduction of -20.9% were achieved with tirzepatide MTD. During the remaining 52 weeks of the study, patients randomized to placebo regained weight, whereas patients who continued treatment with tirzepatide MTD achieved additional body weight reductions (percent change in body weight of -9.9% and -25.3% over 88 weeks, respectively).
• In the efficacy analysis set, the absolute weight loss was -10.0 kg in the placebo group and -27.6 kg in the tirzepatide MTD group (P<0.001).
• Over the whole study period, body weight reductions of ≥5% were achieved by 97.3% of participants in the tirzepatide MTD group and by 70.3% of participants in the placebo group.
• Body weight reductions of ≥20% at week 88 were achieved by 69.5% of the participants in the tirzepatide MTD group vs. 12.6% of the participants in the placebo group.
• The proportion of participants who reached ≥25% body weight reductions was 54.5% in the tirzepatide MTD group vs. 5.0% in the placebo group.
• At week 88, the majority of patients who continued treatment with tirzepatide MTD maintained ≥80% of the weight reductions achieved during the lead-in phase, whereas this was only achieved by a small proportion of patients who discontinued treatment (89.5% in the tirzepatide MTD group vs. 16.6% in the placebo group).

Safety outcomes

• 534 patients (68.2%) experienced a treatment emergent adverse events related to study drug during the first 36 weeks of the study. Most of these reported adverse events were related to gastrointestinal system and mostly occurred during the drug escalation period.
• During the randomization period, 88 patients (26.3%) in the tirzepatide MTD group vs. 33 patients (10.4%) in the placebo group experienced a treatment emergent adverse event related to study drug. These were diarrhea (10.7% vs. 4.8%), nausea (8.1% vs. 2.7%), and vomiting (5.7% vs. 1.2%).

Conclusion