Introduction

Lifestyle management has a pivotal role in obesity management. Nevertheless, sustaining weight reduction achieved through lifestyle intervention is challenging. Guidelines therefore recommend adjunctive anti-obesity medication to promote weight loss and facilitate weight maintenance, while improving the health outcomes. The impact of continued treatment with tirzepatide [a single molecule that combines glucose dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist] on maintaining initial weight reduction has not been established well.

Aim

The SURMOUNT-4 trial determined the impact of continued treatment with the maximum tolerated dose (i.e., 10 or 15 mg) of once-weekly tirzepatide, compared with placebo, on the maintenance of weight reduction following an initial open-label lead-in treatment period in participants with obesity or overweight.

Patient Profile

Methods

Study Design

Treatment Strategy

• Study participants enrolled in the open-label lead-in period received maximum tolerated dose of once-weekly subcutaneous tirzepatide (10 or 15mg) for 36 weeks. 
• At the end of the lead-in period (week 36), a total of 670 participants (who attained the maximum tolerated dose of tirzepatide) were randomized (1:1) to either continue treatment with tirzepatide (n = 335) or to receive placebo (n = 335) for 52 weeks.

Outcomes

Primary Outcome

Secondary Outcomes

• The proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period (week 36).
• Time to first occurrence of participants regaining more than 95% of baseline body weight during the 52‑week double‑blind treatment period, among those who had lost at least 5% in the open‑label lead‑in phase.
• Change in absolute body weight and waist circumference during the double-blind period (week 36 to 88) and the proportion of participants achieving weight reduction thresholds of ≥5%, ≥10%, ≥15%, and ≥20% since enrolment (week 0 to 88)

Exploratory Outcome 

Additional Secondary Outcomes

Results

• A total of 670 participants were randomized to continue receiving the maximum tolerated dose of tirzepatide or placebo [mean age, 48 years; mean weight, 107.3 kg; mean weight reduction of 20.9%]. 
• Patients who continued tirzepatide treatment achieved further weight loss as compared to those treated with placebo who in contrast, gained weight from week 36 to week 88. The corresponding changes for the efficacy estimand were −6.7% with tirzepatide vs. +14.8% with placebo (difference, −21.4%; P < 0.001) (Fig. 1). The overall change in weight during the period 0 to week 88 as per the efficacy estimand was greater with tirzepatide vs. placebo (Fig. 1). 

Fig. 1: Change in weight from week 0 to 88

 

• As per the efficacy estimand analysis, at 88 weeks, 93.4% of the patients receiving tirzepatide maintained ≥80% of the weight loss during the lead-in period, as compared to 13.5% of the patients receiving placebo (P < 0.001). 
• As per a time-to-event analysis, continued tirzepatide treatment during the double-blind period decreased the risk of returning to greater than 95% baseline body weight in patients who had already lost at least 5% since week 0 by approximately 99%, as compared to placebo [hazard ratio (HR): 0.013; P < 0.001) for the treatment regimen estimand. 
• The overall mean weight reduction from week 0 to 88 was higher in the patients treated with tirzepatide vs. placebo (-26% vs. -9.5%). 
• The mean change from week 36 to week 88 in body weight and waist circumference as per the efficacy estimand were better with tirzepatide vs. placebo (Table 1).
• A greater proportion of patients treated with tirzepatide achieved weight reduction thresholds of ≥ 5%, ≥ 10%, ≥ 15%, and ≥ 20% during weeks 0 to 88 (Table 1).
• A higher proportion of patients treated with tirzepatide vs. placebo achieved ≥25% of the body weight reduction (Table 1).
• The patients treated with tirzepatide vs. placebo had greater improvement in various additional secondary outcomes including cardiometabolic risk factors including glycemic parameters, fasting insulin, lipids, blood pressure during enrolment (week 0) to week 88 and during week 36 to week 88 (Table 1).  

Table1: Secondary outcomes (efficacy estimand)

Parameter	Estimate (95% CI)		Absolute difference* (95% CI)	P value
	Tirzepatide (N=335)	Placebo (N=335)
Change in body weight (week 36 to 88), kg	-5.7 (-6.5 to -4.9)	11.9 (11.1 to 12.7)	-17.6 (-18.8 to -16.4)	<0.001
Change in waist circumference (week 36 to 88), cm	-4.6 (-5.4 to -3.8)	8.3 (7.4 to 9.2)	-12.9 (-14.1 to -11.7)	<0.001
Participants achieving body weight reduction (week 0 to 88) (%)
≥5%	98.5%	69.0%	47.3 (18.3 to 122.0)	<0.001
≥10%	94.0%	44.4%	71.5 (34.5 to 148.4)	<0.001
≥15%	87.1%	24%	80.0 (42.1 to 152.1)	<0.001
≥20%	72.6%	11.6%	140.8 (66.1 to 300.3)	<0.001
Additional secondary outcomes (week 36 to 88)
Change in fasting glucose, mg/dL	-0.9 (-1.9 to 0.1)	7.7 (6.6 to 8.8)	-8.6 (-10.1 to -7.2)	<0.001
Percent change in fasting insulin, %	-15.4 (-21.0 to -9.8)	23.3 (14.7 to 31.9)	-31.4 (-37.7 to -24.4)	<0.001
Exploratory end point (week 0 to 88)
Participants achieving ≥25% body weight reduction. (%)	56.6%	4.0%	172.2 (71.0 to 417.6)	<0.001

*Data are absolute differences between mean changes unless stated otherwise. The differences between mean percent changes in body weight, fasting insulin, and lipid levels are expressed in percentage points. Data for participants maintaining or achieving certain criteria are proportions of participants and estimated odds ratio (95% CI).

• Significant improvements were observed in the SF-36 v2 acute form and in the IWQOL-Lite-CT form amongst patients treated with tirzepatide vs placebo.
• Mild to moderate gastrointestinal events were the most frequent adverse events, occurring more often with tirzepatide than with placebo

Conclusions

• Amongst individuals with obesity or overweight, withdrawing tirzepatide after achieving clinically meaningful weight reduction, resulted in substantial regain of lost weight. 
• On the contrary, continued treatment with tirzepatide maintained and further enhanced the initial weight reduction.

JAMA. 2024;331(1):38-48. doi:10.1001/jama.2023.24945.