Discover How Tirzepatide Maintenance Dose Transforms Weight Loss: Insights from the SURMOUNT-4 Trial

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a promising therapeutic option for individuals struggling with obesity or overweight. The SURMOUNT-4 trial, a phase 3 randomized withdrawal study, delved into the efficacy of continued tirzepatide treatment for the maintenance of weight reduction in adults with obesity. This article provides a comprehensive summary of the trial's design, results, and implications, offering valuable insights for healthcare professionals and individuals seeking effective weight management strategies.

Background

Obesity, defined as a body mass index (BMI) ≥30, or overweight, defined as a BMI ≥27 with at least one weight-related complication, is a chronic disease affecting a significant portion of the global population. Weight-related complications include, but are not limited to, obstructive sleep apnea, hypertension, dyslipidemia, and cardiovascular disease. The rising prevalence of obesity has fueled the demand for effective interventions that not only promote weight loss but also sustain long-term weight management. GLP-1 receptor agonists, such as semaglutide, and GIP and GLP-1 receptor agonists, like tirzepatide, have gained traction in recent years due to their ability to induce substantial weight loss.

Study Design and Methodology

The SURMOUNT-4 trial was a meticulously designed study conducted across 70 sites in Argentina, Brazil, Taiwan, and the US. The trial, which started on March 29, 2021, and finished on May 18, 2023, comprised two distinct phases: a 36-week open-label lead-in period followed by a 52-week double-blind, placebo-controlled period.

Participants

Eligible participants were adults aged 18 years or older with obesity (BMI ≥30) or overweight (BMI ≥27) and at least one weight-related complication. Key exclusion criteria included diabetes, prior or planned surgical treatment for obesity, and treatment with a medication that promotes weight loss within 3 months prior to enrollment. A total of 952 patients were screened and 783 were enrolled in the 36-week open-label tirzepatide lead-in treatment period.

Intervention

During the 36-week open-label lead-in period, participants received once-weekly subcutaneous injections of tirzepatide. The starting dose was 2.5 mg, which was increased by 2.5 mg every 4 weeks until a maximum tolerated dose of 10 or 15 mg was achieved. Participants also received lifestyle counseling by a qualified health care professional throughout the study to encourage adherence to a healthy 500 kcal/d deficit diet and at least 150 minutes of physical activity per week. Throughout the study, gastrointestinal symptoms were managed by dietary counseling, symptomatic medications per the investigator’s discretion, or skipping of a single dose of treatment as described in the protocol. During the lead-in period, if these mitigations were not successful, a cycle of tirzepatide dose deescalation and reescalation (in 2.5-mg increments) was allowed. At the end of the lead-in period, participants who attained the maximum tolerated dose of tirzepatide (10 or 15 mg) were randomized in a 1:1 ratio to either continue receiving the maximum tolerated dose of tirzepatide or switch to matching placebo for an additional 52 weeks. Randomization was stratified by country, sex, maximum tolerated dose of tirzepatide, and percent weight reduction at week 36 (<10% vs ≥10%).

Outcome Measures

The primary outcome was the percent change in body weight from randomization (week 36) to week 88. Key secondary end points capturing weight maintenance and regain, respectively, were the proportion of participants at week 88 maintaining at least 80% of the body weight loss during the 36-week open-label period and time during the 52-week double-blind treatment period to first occurrence of participants returning to greater than 95% baseline body weight for those who lost at least 5% during the open-label lead-in period. Safety assessments included treatment-emergent adverse events, serious adverse events, and early discontinuation of study drug due to adverse events during the tirzepatide lead-in treatment period (weeks 0-36), the double-blind period (weeks 36-88), and safety follow-up period.

Statistical Analysis

Efficacy end points were analyzed using the full analysis set (data obtained during the double-blind period, regardless of adherence to study drug) and the efficacy analysis set (data obtained during the double-blind period, excluding data after discontinuation of study drug). Assessment of adverse events and laboratory parameters used the safety analysis set (data obtained during the double-blind period and safety follow-up period, regardless of adherence to study drug). Two estimands (treatment regimen estimand and efficacy estimand) were used to assess efficacy from different perspectives and accounted for intercurrent events and missing data. The treatment regimen estimand was conducted on the full analysis set representing the mean treatment effect of tirzepatide relative to placebo for all participants who had undergone randomization, regardless of treatment adherence. The efficacy estimand was conducted on the efficacy analysis set representing the mean treatment effect of tirzepatide relative to placebo for all participants who had undergone randomization if the treatment was administered as intended (ie, excluding the data collected after study drug discontinuation).

Key Findings

After 36 weeks of open-label maximum tolerated dose of tirzepatide (10 or 15 mg), adults (n = 670) with obesity or overweight (without diabetes) experienced a mean weight reduction of 20.9%. Among enrolled participants, 113 discontinued the study drug during the lead-in period, most commonly due to an adverse event or participant withdrawal. A total of 670 participants (92.7% achieved a maximum tolerated dose of 15 mg and 7.3% achieved a maximum tolerated dose of 10 mg) were randomized to continue receiving the maximum tolerated dose of tirzepatide (n = 335) or switch to receiving placebo (n = 335). Of the randomized participants, 600 (89.6%) completed the study and 575 (85.8%) completed the study while receiving the study drug.

Weight Change

The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide vs 14.0% with placebo (difference, −19.4% [95% CI, −21.2% to −17.7%]; P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo.

During the 52-week, randomized withdrawal period (week 36 through week 88), study patients who continued on tirzepatide had an additional mean weight loss of 5.5%, or approximately 6kg/13 pounds. However, study patients randomized to placebo subq injections regained 14.0% of body weight, or approximately 15kg/33 pounds.

Maintenance of Weight Loss

At week 88, a significantly greater percentage of participants who continued receiving tirzepatide vs placebo maintained at least 80% of the body weight loss during the 36-week open-label tirzepatide lead-in treatment period (89.5% vs 16.6%; P < .001). Time-to-event analysis showed that continued tirzepatide treatment during the double-blind period reduced the risk of returning to greater than 95% baseline body weight for those who had already lost at least 5% since week 0 by approximately 98% compared with placebo (hazard ratio, 0.02 [95% CI, 0.01 to 0.06]; P < .001).

Cardiometabolic Risk Factors

Relative to placebo, tirzepatide was associated with significant improvements from randomization at week 36 to week 88 in BMI, hemoglobin A1c, fasting glucose, insulin, lipid levels, and systolic and diastolic blood pressure (P < .001 for all except P = .014 for high-density lipoprotein cholesterol and P = .008 for free fatty acids). A significantly greater percentage of participants continuing tirzepatide vs placebo met the weight reduction thresholds of at least 5% (97.3% vs 70.3%), at least 10% (92.1% vs 46.2%), at least 15% (84.1% vs 25.9%), and at least 20% (69.5% vs 12.6%) from week 0 to week 88 (P < .001 for all).

Adverse Events

A total of 81.0% of participants reported at least 1 treatment-emergent adverse event during the tirzepatide lead-in treatment period, with the most frequent events being gastrointestinal (nausea [35.5%], diarrhea, [21.1%], constipation [20.7%], and vomiting [16.3%]). During the double-blind period, 60.3% of participants continuing tirzepatide reported at least 1 treatment-emergent adverse event compared with 55.8% of participants who switched to placebo. The most frequent treatment-emergent adverse events during the double-blind period were COVID-19 and gastrointestinal disorders. Gastrointestinal events were more common in the tirzepatide group than in the placebo group (diarrhea, 10.7% vs 4.8%; nausea, 8.1% vs 2.7%; and vomiting, 5.7% vs 1.2%). Treatment discontinuation due to an adverse event occurred in 7.0% of enrolled participants during the tirzepatide lead-in treatment period, mainly due to gastrointestinal events. Overall, 16 participants (2.0%) reported serious adverse events during the lead-in period and 10 (3.0%) during the double-blind period, with similar percentages across treatment groups. There was 1 death reported during the tirzepatide lead-in treatment period due to COVID-19 pneumonia and 2 deaths reported during the double-blind period (1 in the tirzepatide group due to congestive heart failure and 1 in the placebo group due to adenocarcinoma of the colon. There were no adjudication-confirmed cases of pancreatitis reported during the study. Cholelithiasis was reported in 7 participants (0.9%) during the tirzepatide lead-in treatment period and in 1 participant (0.3%) in both the tirzepatide group and placebo group during the double-blind period. Acute cholecystitis was reported in 4 participants (0.5%) during the tirzepatide lead-in treatment period and in 3 (0.9%) in the placebo group during the double-blind period.

Implications and Considerations

The SURMOUNT-4 trial provides compelling evidence that continued treatment with tirzepatide is crucial for maintaining weight loss in adults with obesity or overweight. Participants who switched to placebo after an initial 36-week period of tirzepatide treatment experienced a significant regain in body weight, highlighting the importance of sustained therapy.

These findings have several important implications for clinical practice:

Long-Term Treatment

The SURMOUNT-4 trial underscores the need for long-term treatment strategies for obesity. While initial weight loss can be achieved with tirzepatide, maintaining this weight loss requires continued therapy. This reinforces the notion that obesity is a chronic disease that necessitates ongoing management. When patients initiate treatment with GLP-1 receptor agonists, like semaglutide, or GIP and GLP-1 receptor agonists, like tirzepatide, they frequently ask physicians if they will need to continue the medication indefinitely in order to maintain weight loss.

Individualized Approach

The optimal duration of tirzepatide treatment should be determined on an individual basis, taking into account factors such as patient preferences, tolerability, and overall health goals. Some patients may require indefinite treatment to maintain weight loss, while others may be able to transition to alternative strategies after a period of sustained weight management.

Lifestyle Modifications

While tirzepatide is an effective pharmacological intervention, it should be used in conjunction with lifestyle modifications, including a healthy diet and regular physical activity. Lifestyle counseling, such as adhering to a healthy 500 kcal/day diet and lifestyle counseling to achieve >150 minutes (2.5 hours) of physical activity per week, plays a crucial role in supporting long-term weight management.

Adverse Event Management

Gastrointestinal side effects, such as nausea, diarrhea, constipation, and vomiting, are common during tirzepatide treatment. These side effects can be managed through dietary counseling, symptomatic medications, or dose adjustments. When prescribing GLP-1 receptor agonists, the dose should be gradually increased in 2.5 mg increments every 4 weeks based on tolerability. Treatment should be reverted to a lower dose if clinically important nausea develops. If patients develop mild constipation, treatment with an osmotic laxative without lowering the dose is acceptable.

Risk of Pancreatitis and Gallstone Development

There does appear to be a small risk of developing pancreatitis based on all available data, so do not use in patients with a history of pancreatitis. Significant weight loss does increase the risk of gallstone development and also may increase the risk of cholecystitis and choledocholithiasis.

Anesthesia Considerations

Whether or not GLP-1 receptor agonists need to be discontinued prior to endoscopic procedures to minimize aspiration risk during monitored anesthesia care remains controversial. Although the American Society for Anesthesiology updated their pre-operative fasting guidelines in 2023 and recommended that subq injections of GLP-1 receptor agonists should be held for 1 week, there is insufficient research data to support this recommendation and position statements from our GI societies do not support this. Nevertheless, many endoscopists and patients will be required by their anesthesiology team to hold subq injections of GLP-1 receptor agonists for one week if deep sedation with propafol is used.

Strengths and Limitations

The strengths of this study include its large sample size and the randomized withdrawal design. The duration of the open-label lead-in period allowed the study to assess the maintenance of body weight reduction. This study has limitations. First, the design of this study did not allow dose adjustments after randomization and did not evaluate the effects of intensive behavioral therapy on the maintenance of body weight reduction. Also, the study was not designed to represent the racial diversity of each of the participating countries.

Notable finding

A notable finding in the SURMOUNT-4 trial is that after switching to placebo for 1 year, participants ended the study with substantial body weight reduction (9.9%). However, much of their initial improvement in cardiometabolic risk factors had been reversed.

tags: #tirzepatide #maintenance #dose #weight #loss #studies