Trial finds weekly semaglutide lowers blood sugar and weight more than exenatide ER

In a 56-week phase 3 trial, once-weekly semaglutide 1.0 mg lowered average blood sugar and body weight more than once-weekly exenatide extended release (ER) 2.0 mg in adults with type 2 diabetes whose blood sugar was not controlled on oral diabetes drugs ^[1]. The findings were published in December 2017 by the American Diabetes Association ^[1].

The study, called SUSTAIN 3, was an open-label, randomized, multicenter trial. It enrolled 813 participants with type 2 diabetes who were taking oral antidiabetic drugs and assigned them 1:1 to semaglutide or exenatide ER, both given as injections under the skin once a week, for 56 weeks ^[1]. The primary goal was the change in HbA1c — a measure of average blood sugar over roughly the previous two to three months — from the start of the trial to week 56 ^[1].

Baseline HbA1c averaged 8.3% (67.7 mmol/mol). It fell by 1.5 percentage points (16.8 mmol/mol) with semaglutide and 0.9 points (10.0 mmol/mol) with exenatide ER ^[1]. The estimated difference between the two groups was -0.62 points (95% confidence interval -0.80 to -0.44), and the trial reported statistical significance for both noninferiority and superiority ^[1].

Body weight started at an average of 95.8 kg. It dropped by 5.6 kg with semaglutide and 1.9 kg with exenatide ER, an estimated difference of -3.78 kg (95% CI -4.58 to -2.98; P < 0.0001) ^[1]. In other words, the average weight loss on semaglutide was close to three times that seen with exenatide ER ^[1].

More participants on semaglutide reached an HbA1c below 7.0% (below 53 mmol/mol) — 67%, compared with 40% on exenatide ER ^[1].

The abstract reports comparable overall safety profiles but different patterns of side effects. Gastrointestinal adverse events were more common with semaglutide (41.8%) than with exenatide ER (33.3%), while injection-site reactions were more frequent with exenatide ER (22.0%) than with semaglutide (1.2%) ^[1]. The authors concluded that semaglutide 1.0 mg was "superior to exenatide ER 2.0 mg in improving glycemic control and reducing body weight after 56 weeks of treatment; the drugs had comparable safety profiles" ^[1].

The trial was open-label, meaning participants and investigators knew which drug was being given. That design can affect how side effects are reported and how people respond ^[1]. The abstract does not report cardiovascular outcomes, kidney outcomes, or how either drug compared with placebo, and it does not name the trial's sponsor. The study enrolled only people with type 2 diabetes who were already taking oral antidiabetic drugs, so the results do not address other groups or other doses of semaglutide ^[1].

Why it matters for patients

Both drugs in this trial were once-weekly injections, so the practical difference for a patient was not how often the drug is taken but how large the average effects were ^[1].

These are averages across hundreds of people, not a prediction for any one person. Individual responses to GLP-1 drugs vary, and the abstract does not report how many participants in either group saw little or no change ^[1].

Side-effect patterns matter for staying on treatment. Nearly 42% of people on semaglutide reported gastrointestinal side effects, compared with about a third on exenatide ER, while injection-site reactions were roughly 18 times more common with exenatide ER (22.0% versus 1.2%) ^[1].

An HbA1c below 7.0% is a common treatment target in diabetes care. In this trial, about two-thirds of the semaglutide group reached it, compared with 40% of the exenatide ER group ^[1].

Weight change was a secondary finding, not the main goal of the study. The abstract says nothing about whether the weight lost was regained after the 56 weeks ended, or what happened to blood sugar after treatment stopped ^[1].

What happens next

The trial is registered with ClinicalTrials.gov as NCT01885208 ^[1]. A commentary summarizing the results appeared in Annals of Internal Medicine on April 17, 2018, stating that weekly semaglutide reduced HbA1c and increased weight loss more than weekly exenatide ER ^[1]. No longer-term follow-up from this trial has been reported in the abstract ^[1].