Tirzepatide is a once-weekly GIP and GLP-1 receptor agonist with a once-weekly dosing regimen that has previously been FDA-approved for treating type 2 diabetes mellitus (T2DM). Its effectiveness in reducing body weight in obese T2D patients has been demonstrated in the SURMOUNT-1 trial. However, its effect on maintaining weight reduction as a long-term intervention has been unknown. In the European Association for the Study of Diabetes (EASD) Congress 2023, Professor Louis Aronne from the Comprehensive Weight Control Center, New York, USA, presented the latest results of the SURMOUNT-4 trial, a phase 3 randomized maintenance trial which examined the effects of continued tirzepatide therapy on the maintenance of weight reduction and other benefits in obese patients.¹ According to Professor Aronne, the results of this study were very encouraging with many advancements in the treatment of obesity and cardiometabolic diseases with semaglutide now being observed with tirzepatide as well.

In this trial, patients were given open-label tirzepatide at the maximum tolerated dose (MTD) of 10mg or 15mg for 36 weeks which was followed by a double-blinded 52-week period where patients were randomized to continue tirzepatide treatment or to switch to a placebo.¹ Endpoints included the change in weight which was described both over the open-label lead-in period over 36 weeks as well as the double-blinded period for up to 88 weeks.¹ Other key endpoints included the proportion of patients achieving the weight-reduction threshold, and change in waist circumference and body mass index (BMI).¹

At 36 weeks of treatment, there was a 20.9% weight reduction from baseline with a reduction in mean body weight from 107.3kg to 85.2kg. Over 88 weeks, those who received tirzapatide in both the open-label and randomized phase had a weight loss of 27.6kg (-25.8% from baseline) while those who were randomized to receive placebo from week 36 onwards only had an aggregated weight loss of 10.0kg (-9.5% from baseline) (p<0.001). When looking at weight change after randomization at week 36, there was a 14.8% (11.9kg) increase in the placebo group compared with a 6.7% (5.7kg) weight loss in the tirzepatide group (p<0.001). Additionally, patients in the tirzepatide group were more likely to achieve a weight reduction of ≥5%, ≥20%, and ≥25% than patients on placebo (p<0.001).¹ This is an important clinical outcome since a weight reduction of ≥5% is believed to reduce the risk of developing T2DM by 50%.¹ At week 88, more than 90% of patients in the tirzepatide group maintained ≥80% of the weight loss compared with 13.5% in the placebo group (p<0.001).¹

Waist circumference also decreased by 17.8cm at week 36 from a baseline of 115.2cm and was further reduced by 4.6cm in the tirzepatide group compared with an increase of 8.3cm in the placebo group at week 88 (p<0.001).¹ Similarly, there was an 8kg/m² decrease in BMI at week 36 from a baseline of 38.4kg/m². Those who continued tirzepatide had a further reduction to 28.2kg/m² at 88 weeks, which was significantly lower than those who received placebo (34.8kg/m²) (p<0.001) and was 2 category shifts lower than the baseline.¹ Although an improvement from baseline occurred in both groups, a much greater reduction in waist circumference and BMI was observed in the tirzepatide group.¹

In terms of safety, most patients (81%) who received tirzepatide during the first 36 weeks had a treatment-emergent adverse event (TEAE), of which 68.2% were related to the study drug but only 2% were serious adverse events (SAE).¹ Seven percent of discontinuations were related to tirzepatide, which is similar to that seen in the SURMOUNT-1 trial.¹ After randomization, the TEAEs were slightly higher in the tirzepatide group (60.3%) than in the placebo group (55.8%) with a similar rate of SAEs and death reported in both groups.¹ The most common TEAEs (≥5%) with tirzepatide were mild to moderate nausea, diarrhea, constipation, vomiting, reflux, dyspepsia, and abdominal pain.¹ Gastrointestinal AEs were more common in those continuing tirzepatide than those on placebo and were the primary reason for drug discontinuation during the first 36 weeks.¹ No difference was observed in the incidences of cholecystitis and cholelithiasis between the two groups.¹

In conclusion, tirzepatide was associated with a significant weight reduction from baseline to week 36.¹ This benefit was maintained over 88 weeks to a greater extent in patients who continued tirzepatide but was not nullified in patients who switched to placebo.¹ Beyond 36 weeks, patients receiving tirzepatide had significantly greater improvements in body weight, waist circumference, BMI, and cardiometabolic improvements than those in the placebo group.¹ Generally, tirzepatide had a tolerable safety profile, consistent with other GLP-1 receptor agonists in people with obesity.¹