Once-weekly treatment with the GLP-1–GIP receptor agonist tirzepatide has been shown to significantly reduce body weight and improve important cardiometabolic measures in overweight or obese adults.

The phase 3 SURMOUNT-1 trial, featured at the American Diabetes Association (ADA) 82nd Scientific Sessions and published in the NEJM, comprised 2,539 participants with either obesity or overweight with an additional weight-related complication.

The participants from 119 sites in nine countries were randomised to either 5 mg, 10 mg or 15 mg subcutaneous tirzepatide or placebo weekly for 72 weeks.

Associate Professor Ania Jastreboff, Director of Weight Management & Obesity Prevention at the Yale University School of Medicine, told the ADA that participants in the three tirzepatide groups lost 15%, 19.5% and 20.9% respectively compared to the control group who lost 3.1% of their body weight.

The absolute change in body weight in the treated groups was 16-24 kg with the treatment response apparent as early as four weeks.

She said greater than 90% of individuals on the 15mg dose achieved the ≥ 5% weight reduction target. More than half achieved the ≥20% target and more than a third achieved the ≥25% target.

The study found participants on tirzepatude lost 14-19 cm off their waist circumference compared to 4 cm on placebo.

“Now, we don’t only want to know that our participants and patients are losing weight but we also want to know the quality of that weight loss,” she said.

In a subset of 160 patients who had DEXA at baseline and at 72 weeks, the mean reduction in total body fat mass was 33.9% with tirzepatide (all doses pooled) compared to 8.2% with placebo.

“So as with lifestyle and surgical treatments, participants on tirzepatide had a three times greater percent reduction in fat mass and lean mass, resulting in overall improvement in body composition.”

Glycaemia impact

Associate Professor Jastreboff said most participants had a HbA1c in the normal range at baseline however there was an average decrease in HbA1c by 0.5% with tirzepatide.

“And in terms of the participants with prediabetes, more than 95% of them reverted to normal glycemia in the tirzeptide groups.”

Similarly, despite the fact that there were near normal lipid, fasting glucose and insulin levels at baseline, there were consistent improvements observed with tirzeptide.

Blood pressure also improved overall – systolic by about 8 mm Hg and diastolic by about 5 mm Hg.

She said the improvements in blood pressure did not appear to be dependent on the high magnitude of weight reduction.

Dr Sriram Machineni, Director of the Medical Weight Program at the University of North Carolina told the meeting that the vast majority of adverse event were gastrointestinal including nausea, diarrhoea and constipation.

However most GI events were transient, primarily occurring during the dose escalation period, and of mild to moderate severity.

Other treatment-emergent adverse events included headache, hair loss, dizziness, injection site reactions and decreased appetite which he said was an on-target effect of the drug.

An Editorial in the NEJM said the weight loss observed in the SURMOUNT-1 trial was “astonishing”.

“It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”

However there were unanswered questions including whether tirzepatide could reduce major adverse CV events, whether the GI effects would eventually lead to new health issues or drug discontinuation, and whether drug holidays or interval treatment would be feasible.

“Notwithstanding, the “tides” are shifting, and there are now more options for people with obesity to lose weight and maintain euglycemia,” they concluded.

The study was supported by Eli Lilly.