medwireNews: The STEP 2 trial shows that overweight or obese people with type 2 diabetes achieve greater weight loss and larger improvements in cardiometabolic risk factors when given a higher semaglutide dose than is currently approved.
Improvements in glycemic control were relatively small, with glycated hemoglobin (HbA1c) levels falling by an average of 1.6% (17.5 mmol/mol) among people randomly assigned to receive weekly semaglutide 2.4 mg for 68 weeks and 1.5% (15.9 mmol/mol) among those given the standard 1.0 mg dose. People given placebo had an average HbA1c reduction of 0.4% (4.1 mmol/mol).
Trial participants taking semaglutide 2.4 mg were also the most likely to reduce concomitant glucose-lowering medications, at 28.6%, but again this rate was only slightly more than the 25.1% of people taking the standard dose. Just 7.1% of people taking placebo reduced other diabetes medications.
“The benefits of the higher dose of semaglutide can be clearly seen in the context of weight loss,” write Ildiko Lingvay (University of Texas Southwestern Medical Center, Dallas, USA) and study co-authors in The Lancet.
Ildiko Lingvay discusses the STEP 2 findings, and why a higher semaglutide dose may be optimal for most people with type 2 diabetes.
The average reduction in bodyweight by week 68 was 9.64% in the 404 trial participants taking semaglutide 2.4 mg, which was significantly greater than the 6.99% reduction achieved by the 403 people taking the standard dose and the 3.42% reduction in the 403 taking placebo.
There was a similar pattern for the co-primary endpoint of at least 5% weight loss, with this achieved by 68.8% and 57.1% of those taking semaglutide 2.4 and 1.0 mg, respectively, compared with 28.5% of the placebo group.
The corresponding rates for at least 10% bodyweight loss were 45.6%, 28.7%, and 8.2%, and for at least 15% bodyweight loss they were 25.8%, 13.7%, and 3.2%.
In addition to taking their randomized medications, all study participants undertook a lifestyle intervention focused on diet and physical activity, supported by counselling sessions every 4 weeks.
The participants’ average age was 55 years, average diabetes duration was 8 years, and BMI was 35.7 kg/m2. Slightly more than half (50.9%) were women, and the majority were White (62.1%), followed by Asian (26.2%), Hispanic or Latino (11.6%), and Black or African American (8.3%).
Most weight loss with semaglutide occurred within approximately the first 36 weeks, after which it plateaued.
“The observed plateau of weight loss towards the end of the current study is consistent with metabolic adaptation and physiological response to the weight loss, and is typical of any weight loss intervention,” say the researchers.
They highlight that, in addition to the weight loss and modest reduction in HbA1c, people given semaglutide 2.4 mg also had significant improvements in cardiometabolic risk factors and physical functioning.
These included a numerically larger reduction in systolic blood pressure than that achieved with semaglutide 1.0 mg, and numerically larger reductions in triglycerides and C-reactive protein, although these two endpoints were exploratory and did not undergo statistical testing.
Also, the researchers caution that “the patient population in the present study was at relatively low cardiovascular risk, as they were well controlled for existing comorbidities, and further studies are therefore needed.”
Cardiovascular efficacy will be addressed in the SELECT cardiovascular outcomes trial, involving people with obesity without diabetes.
Finally, gastrointestinal adverse events were slightly more common in people taking semaglutide 2.4 mg versus the standard dose, and accounted for the majority of discontinuations, but discontinuations because of gastrointestinal adverse events were generally low, at 4.2% and 3.5% with semaglutide 2.4 mg and 1.0 mg, respectively, versus 1.0% in the placebo group.
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