The "twincretin" tirzepatide (Mounjaro) kept on producing "highly significant weight loss" when the drug was continued in a 1-year follow-up trial, and those who discontinued the drug regained some weight but not all.

In Eli Lilly's SURMOUNT-4 trial of 783 adults with obesity or overweight but not diabetes who all took the drug for 36 weeks, those randomized to continue taking it for another 52 weeks had a mean 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. There were no unexpected adverse effects.

"The weight loss we saw in the SURMOUNT-4 trial was, as expected, very, very good. It's really incredible where we are now in the treatment of obesity compared to where we were as recently as 5 or 10 years ago. We're in the middle of a revolution, in case you haven't noticed, in the treatment of cardiometabolic disease," said study investigator Louis J. Aronne, MD, during his presentation of the data at the annual meeting of the European Association for the Study of Diabetes (EASD). Aronne is the director of the Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York, NY.

Lilly had announced topline results for SURMOUNT-4 and another weight loss trial SURMOUNT-3 in July 2023. Detailed results from the latter will be presented at Obesity Week, to be held October 14-17 in Dallas, Texas. Results from two other trials, SURMOUNT-1 and SURMOUNT-2, were reported previously. 

The US Food and Drug Administration approved tirzepatide for treating type 2 diabetes in May 2022 and is expected to announce a decision later in 2023 for use of the drug to treat weight loss in people with or without diabetes.

At EASD, independent commentator Jens Juul Holst, of the Department of Biomedical Sciences at the University of Copenhagen, Denmark, said that
- SURMOUNT-4 "is a fantastic result. It's a huge weight loss, and it's absolutely true that we're approaching that of bariatric surgery."

However, Holst questioned whether addition of a glucose-dependent insulinotropic polypeptide (GIP) agonist to the glucagon-like peptide 1 (GLP-1) receptor agonist in tirzepatide really adds much compared with single-agonist GLP-1 receptor agonists such as semaglutide. He noted that the apparent higher weight loss with the dual-agonist agent may be due to dosing differences and that the same result could be achieved with equivalent dosing of semaglutide in people with obesity but not diabetes. And, he added, the side effect profile is similar.

He also questioned whether SURMOUNT-4 was really a "maintenance" trial, compared with at least 2 years in liraglutide trials and more than 20 years now with bariatric surgery. "That's maintenance. This isn't maintenance at all. It's just a nice study."

And, Holst said, "The real problem is that the important questions in GLP-1 therapy are not answered in this trial. What do you do after stopping the trial? That's when we're really talking about maintenance. Should you reduce the dose? Change to another compound? Send people home and say goodbye? This is going to be really, really important."

Moreover, "Will people stop taking the drug and if they do, why? That's an unanswered question right now. That's something we haven't talked about. People stop eating because they've lost their appetite. They've lost the pleasure of eating. They've lost the pleasure and reward of having a beautiful meal. How long can you stand that? That's a real, real question."

At 1 Year, Continued Benefit On and Even Off Tirzepatide

Regarding the topline result, Aronne noted, there was weight regain among people who discontinued the drug but "interestingly, they had not returned back to baseline. The slope continues to rise and given enough time would probably get back to baseline eventually, but they still hadn't gotten there at 52 weeks."

Compared with a mean weight of 107.3 kg (236 lb) at baseline, participants' mean weight was 85.2 kg (187.8 lb) after 36 weeks. Those who discontinued tirzepatide regained weight to a mean of 97.0 kg (213.8 lb), whereas those who continued to take the drug got down to a mean of 79.1 kg (174.4 lb).

Among participants who continued tirzepatide, 95% achieved at least 5% weight loss compared with 69% in the placebo group. In addition, 72.6% vs 11.6% of tirzepatide vs placebo recipients, respectively, achieved at least 20% weight loss, and 56.6% vs 4.0% achieved at least 25% weight loss.

"What we see here is weight loss on par with that achieved with sleeve gastrectomy, the most commonly performed bariatric procedure. This has been a goal of many people in the field of medical treatment of obesity, to achieve the same magnitude of weight loss as achieved by our surgical colleagues. This suggests that we are getting there," Aronne said.

Cardiometabolic outcomes followed similar patterns. 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. That result was "a good improvement in both groups and better than I would have expected from stopping medication for 1 year. If you do the math, 22.5 cm is equivalent to nine loops on an American belt, while [a 9.3 cm drop] is about three to four belt loops, also a very good result," Aronne said.  

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. 

A1c, for example, dropped by a mean of 0.5 percentage point at 36 weeks, and at 52 weeks, the reductions were 0.2 vs 0.6 percentage point in the placebo and tirzepatide continuation groups, respectively. "This is a very interesting finding when you think about the possibility of diabetes prevention. This will be the subject, I'm sure, of further trials," Aronne commented.

Adverse Events Similar to Those in Other GLP-1 Trials

Adverse events were common, as with previous tirzepatide trials and those of the incretin class generally. During the 36-week lead-in with 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.

During the 52-week randomized period, treatment-emergent events related to study drug were reported by 26.3% of those who continued tirzepatide vs 10.4% receiving placebo. However, serious adverse events did not differ between the groups. As in the past, most of the adverse events were gastrointestinal and were characterized as mild to moderate.

During the 52-week randomized period, diarrhea (10.7% vs 4.8%), nausea (8.1% vs 2.7%), and vomiting (5.7% vs 1.2%) were all more common in the group continuing tirzepatide.

Pancreatic enzymes increased with tirzepatide but remained within the normal range. During the lead-in period, there was no difference between the groups in reported cholelithiasis, a known complication of weight loss, but this condition was more common in the placebo group after the follow-up period. Hepatic enzymes decreased with tirzepatide during the lead-in period and were increased at 52 weeks but remained within the normal range in both study groups.

Heart rate peaked during dose escalation and declined over the rest of the study period, with differences of +3.3 beats/min with tirzepatide vs -2.1 with placebo at week 88, "consistent with earlier observations with injectable, incretin-based therapies of obesity," Aronne noted. 

Regarding that finding, Holst commented,
- "Was the heart rate increase as expected, or more? It was quite a pronounced increase. Could there be a cardiovascular effect of the GIP? There are effects of GIP on the heart. This is something we will have to look at much more closely in the future."

Nonetheless, Holst ended his talk by saying, "But my conclusion is, congratulations on a great study with a great drug and great results!"



www red DiabetologNytt