Obesity is widely recognized as a chronic, relapsing, and multifactorial disease that demands long-term treatment. While various pharmacotherapies have shown efficacy in initiating weight loss, maintaining that loss over time has proven far more difficult. The SURMOUNT-4 trial, a phase 3 randomized withdrawal study, investigates the role of tirzepatide, a dual GIP and GLP-1 receptor agonist, in maintaining weight loss after initial success.

Study Design and Objective

The SURMOUNT-4 trial aimed to evaluate whether continued treatment with once-weekly subcutaneous tirzepatide would help sustain weight loss in adults with obesity or overweight with a related comorbidity, excluding those with diabetes. The trial included a 36-week open-label lead-in phase, where all participants received tirzepatide, followed by a 52-week double-blind period, where participants were randomized to either continue tirzepatide or switch to placebo.

Conducted at 70 sites in 4 countries, the trial involved 783 participants during the lead-in phase, with 670 randomized at week 36 (335 in each group) to continue tirzepatide or receive placebo.

Participants and Intervention

Eligible adults had a BMI ≥30, or ≥27 with at least one weight-related condition (e.g., hypertension, dyslipidemia, sleep apnea). Participants began tirzepatide at 2.5 mg, titrated to their maximum tolerated dose (either 10 mg or 15 mg) over the 36-week lead-in.

During both study phases, participants were advised to follow a 500 kcal/day calorie deficit diet and engage in ≥150 minutes of weekly physical activity, supported by regular lifestyle counseling.

Primary Outcome: Weight Maintenance vs. Regain

At the end of the 36-week lead-in period, participants had achieved an impressive average weight loss of 20.9%. The primary outcome evaluated the percent weight change from week 36 to 88.
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- Participants continuing tirzepatide lost an additional 5.5% of their body weight.

- Participants switched to placebo regained 14.0% of their body weight.

- This equated to a difference of 19.4 percentage points between the groups (P < .001).

Thus, discontinuation of tirzepatide led to substantial weight regain, while continued therapy not only preserved but enhanced weight reduction.

Secondary Outcomes: Sustained Benefits with Tirzepatide

Several key secondary endpoints reinforced the benefits of ongoing treatment:

- 89.5% of tirzepatide users maintained ≥80% of their initial weight loss by week 88, compared to just 16.6% in the placebo group.

- Participants continuing tirzepatide had a 54.5% rate of ≥25% weight loss from baseline, vs. only 5.0% for placebo.

- Across the full 88 weeks, the average weight loss was 25.3% for tirzepatide and 9.9% for placebo groups.

Notably, the time to regain weight (defined as reaching >95% of baseline weight) was significantly shorter for those on placebo. Continuing tirzepatide reduced this risk by approximately 98%.

Improvements in Cardiometabolic Health

In addition to weight loss, continued tripeptide led to sustained improvements in several metabolic health markers:

Waist circumference: Further reduced by 4.3 cm (tirzepatide) vs. increased by 7.8 cm (placebo).

BMI: Continued to decline with tirzepatide.

Glycemic control: Hemoglobin A1c and fasting glucose remained significantly lower with tirzepatide.

Lipid profile: Improvements in LDL, VLDL, total cholesterol, and triglycerides were maintained.

Blood pressure: Continued reductions in both systolic and diastolic readings.

These metabolic benefits emphasize the value of tirzepatide not just in weight control, but also in overall cardiometabolic risk reduction.

Quality of Life and Functional Outcomes

Participants reported improved physical and emotional well-being, measured through:

- SF-36 v2: Enhanced scores in physical functioning, role-physical, and mental health domains.

- IWQOL-Lite-CT: Significant improvement in physical function, which correlated with better mobility and reduced limitations.

These findings suggest that beyond physiological markers, continued treatment translates into meaningful improvements in daily life and well-being.

Safety and Adverse Events

Tirzepatide was generally well tolerated. Common side effects during the lead-in and double-blind phases were primarily gastrointestinal, including:

- Nausea: 8.1% (tirzepatide) vs. 2.7% (placebo)

- Diarrhea: 10.7% vs. 4.8%

- Vomiting: 5.7% vs. 1.2%

Most events were mild to moderate, occurring mainly during dose escalation. Serious adverse events occurred in 3.0% of participants in both groups. Only 1.8% discontinued tirzepatide due to side effects during the double-blind phase.

There were no confirmed cases of pancreatitis or medullary thyroid carcinoma, and cardiovascular safety appeared acceptable.

Conclusions and Clinical Implications

The SURMOUNT-4 trial clearly demonstrates that ongoing treatment with tirzepatide is essential for maintaining weight loss and its associated health benefits. The findings emphasize a critical point: obesity is a chronic condition that, like hypertension or diabetes, may require long-term medical management.

Participants who stopped tirzepatide regained much of their lost weight, reversing many of the improvements in cardiometabolic health. Conversely, those who continued therapy maintained their weight loss and experienced further gains in well-being.

Final Thoughts

Tirzepatide is not just a promising therapy for initial weight loss—it’s a vital tool for long-term weight management. Its dual hormone action, once-weekly dosing, and durable results position it as a potential cornerstone of obesity treatment strategies moving forward.

The SURMOUNT-4 study reinforces the importance of continuous pharmacologic intervention for obesity, a disease that deserves the same long-term attention as other chronic conditions.

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