Tirzepatide maintained significant weight loss when treatment was continued in a follow-up study

Diabetes, Obesity Metabolism (DOM) NOW—November 2023

The dual GLP-1 and GIP agonist, Tirzepatide has been shown to induce significant weight loss in overweight/obese people with or without type 2 diabetes. Much of its efficacy was derived from The SURMOUNT program which included four global phase 3 trials NCT04184622 (SURMOUNT-1), NCT04657003 (SURMOUNT-2), NCT04657016 (SURMOUNT-3) and NCT04660643 (SURMOUNT-4). In these studies, participants were randomized to once-weekly subcutaneous tirzepatide versus placebo in a double-blind manner. The primary end point in all trials was the percentage change in body weight from randomization to end of treatment. Results for the primary endpoint for SURMOUNT-1¹ (in overweight/obese people without type 2 diabetes) and SURMOUNT 2² (in overweight/obese people with type 2 diabetes) have been published. The magnitude of weight loss with Tirzepatide was generally superior to single GLP-1 agonists, that is, −2.8% and −14.7% weight reduction in people with type 2 diabetes and − 19.5% and − 20.9% weight reduction in people without type 2 diabetes, at 10 and 15 mg doses of Tirzepatide respectively for both studies. Whether weight lost persists with continuation of the therapy or weight regain following discontinuation of the treatment is unclear.

In a presentation at the European Association of the Study of Diabetes (EASD) meeting, results of the SURMOUNT-4 trial was presented. In this study, 783 adults with obesity or overweight but did not have diabetes who all took the drug for 36 weeks were randomized to continue taking it for another 52 weeks or to stop taking treatment. Those who were randomized to continue taking the therapy experienced a mean total weight loss of 26.0%, whereas those randomized to discontinue taking the drug and switch to placebo regained some weight but still maintained a 9.5% weight loss from baseline by 88 weeks. No unexpected adverse effects were reported. The observed weight loss in this latest study at 88 weeks is the largest that has been seen using pharmacotherapy for weight loss and approaching to the amount of weight loss seen with the most common bariatric surgery procedure, sleeve gastrectomy. It is important to note, however, that weight regain was observed among people who discontinued the drug. Compared with a mean weight of 107.3 kg at baseline, participants' mean weight was 85.2 kg after 36 weeks. Those who discontinued tirzepatide regained weight to a mean of 97.0 kg whereas those who continued to take the drug achieved a mean weight of 79.1 kg. Therefore, although mean weight did not return back to baseline, the slope appeared to continue to rise and given enough time would probably get back to baseline eventually. Among participants who continued tirzepatide, 95% achieved at least 5% weight loss compared with 69% in the placebo group. In addition, 72.6% versus 11.6% of tirzepatide versus placebo recipients, respectively, achieved at least 20% weight loss, and 56.6% versus 4.0% achieved at least 25% weight loss. The weight regain pattern observed here was also seen in previous GLP-1 analogue studies and support the importance of long-term prescribing in combination with lifestyle and dietary intervention to maintain weight loss.

Cardiometabolic benefits were also seen. There was an overall waist circumference loss of 17.8 cm at 36 weeks. At 52 weeks, the reduction from baseline was a further 22.5 cm in the continued tirzepatide group vs a reversion to 9.3 cm below baseline in the placebo group. Significant changes at in systolic and diastolic blood pressure, A1c, fasting glucose, fasting insulin, and lipids were similar to previous SURMOUNT trials at 36 weeks and showed similar patterns to the weight loss at 52 weeks, with regression in the discontinuation group but maintenance of some benefit, and continued improvement in the group that continued tirzepatide. The reduction of HbA1c levels was also observed in conjunction with weight loss and raised important speculation of the role of Tirzepatide to prevent type 2 diabetes. As with other GLP-1 and dual GLP-1-GIP agonist studies, adverse events were common. During the 36-week lead-in with an escalation of drug dose, 68.2% of participants experienced treatment-emergent events related to the drug. However, only 7.0% discontinued the drug owing to adverse events. Crucially, serious adverse events did not differ between the groups with most of the adverse events were gastrointestinal (mainly diarrhoea, nausea and vomiting) and characterized as mild to moderate.