Conference Coverage

Semaglutide aids T2DM weight loss over 2 years


Key clinical point: Semaglutide added to standard of care was associated with significant weight loss independent of any gastrointestinal side effects.

Major finding: There was a -2.87 kg to -4.35 kg change in body weight comparing two doses of semaglutide with matching placebos (both P less than .0001).

Data source: SUSTAIN-6: A long-term outcomes study in 3,297 patients with type 2 diabetes treated with once-weekly semaglutide or placebo for 104 weeks.

Disclosures: Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.


AT EASD 2017


– The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.

Dr. Agostino Consoli, endocrinologist and professor at the University of Chieti-Pescara, Italy Sara Freeman/Frontline Medical News
Dr. Agostino Consoli
“A dose-response effect was observed on weight loss with semaglutide treatment,” study investigator Agostino Consoli, MD, reported at the annual meeting of the European Association for the Study of Diabetes.

Semaglutide is under development by Novo Nordisk and is currently under review by regulatory agencies in the United States, Europe, and Japan. It has 94% homology to human GLP-1 and modifications have been made to help it avoid degradation and which give it a half-life that allows it to be given once a week.

SUSTAIN 6 is part of an ongoing phase 3 program and is a long-term outcome study with the primary objective of evaluating the cardiovascular safety of semaglutide. Effects on macro- and microvascular complications, glycemic control, body weight, body mass index and weight circumference are key secondary endpoints, together with assessment of its overall safety and tolerability.

Other trials in the program, have evaluated treatment with semaglutide as monotherapy (SUSTAIN 1; Lancet Diabetes Endocrinol. 2017;5:251-60) or versus other treatments including sitagliptin (Januvia, Merck; SUSTAIN 2; Lancet Diabetes Endocrinol. 2017;5:341-54), exenatide extended release (Bydureon, AstraZeneca; SUSTAIN 3), or insulin glargine (SUSTAIN 4), as add-on to basal insulin with or without metformin (SUSTAIN 5), and most recently, versus dulaglutide (Trulicity, Eli Lilly; SUSTAIN 7).

SUSTAIN 6 involved 3,297 people with T2DM with established cardiovascular disease or chronic kidney disease or otherwise identified as being at increased cardiovascular risk, according to Dr. Consoli, who is an endocrinologist and professor at the University of Chieti-Pescara, Italy. The results of the primary endpoint have been reported (N Engl J Med. 2016; 375:1834-44) and showed that the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The hazard ratio for the reduction in the composite endpoint was 0.74 (95% CI, 0.58-.95; P less than .001 for noninferiority).

Results of the secondary analyses reported by Dr. Consoli at EASD 2017 showed that semaglutide could help more patients than placebo achieve significant weight loss, which could help further reduce their cardiovascular risk. He reported that a 5% or greater weight loss at 2 years was achieved by 36% and 47% of patients treated with semaglutide 0.5 mg and 1 mg groups, respectively, and by 18% and 19% of patients in the matching placebo groups (P less than .0001 for both comparisons). A 10% or greater weight loss was achieved by 13% and 21% of the semaglutide-treated patients and by 6% and 7% of those given placebo.

“The effect of weight was not dependent on BMI [body mass index] at baseline,” Dr. Consoli said, emphasizing that there was a consistent reduction in the weight in all BMI categories. Importantly, Dr. Consoli observed, the effects of semaglutide on weight seen were not driven by just a few patients losing weight, and around 80% of patients in the study experienced some degree of weight loss.

“As expected, the subjects treated with the GLP-1a had more GI [gastrointestinal] effects,” Dr. Consoli reported. Nausea or vomiting were reported in twice as many patients treated with semaglutide 0.5 mg (21.9%) and 1 mg (27.3%) as their placebo-matched counterparts (10.8% and 10.6%).

A post-hoc analysis found that the effect of semaglutide on weight loss was not likely to be down to these side effects, however, with a similar weight reductions seen in those who did and did not experience nausea or vomiting. The “estimated natural direct effect of treatment” was -2.75 kg for the 0.5 mg dose and -4.32 for the 1 mg dose of semaglutide versus their placebos Dr. Consoli said. GI drove the weigjht loss to a small degree; -0.12 kg and -0.04 kg of weight loss seen in the 0.5 mg and 1 mg semaglutide groups versus their placebos could be ascribed to nausea or vomiting.

In a poster presentation at the meeting, data on another post-hoc analysis from the SUSTAIN phase 3 program were reported. In a responder analysis of T2DM patients achieving glycemic and weight loss thresholds, a greater proportion of those treated with semaglutide achieved clinically meaningful reductions in both glycated hemoglobin (HbA1c) and body weight than those given comparator treatments.

The composite endpoint of at least a 1% reduction in HbA1c and a 5% or greater decrease in body weight was achieved by 25%–35% of patients treated with the 0.5 mg dose of semaglutide, by 38%–56% of those given the higher dose, and by 2%–13% or all comparators (P less than .0001). The higher dose of semaglutide also allowed more people to achieve this endpoint than the lower dose.

Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
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