Semaglutide made major news this year for displaying an excellent safety and efficacy profile, enabling greater HbA1c reduction, better glycaemic control, and reducing body weight in type 2 diabetes patients. Here is a look back at 3 major trials which proved this.

Semaglutide vs Liraglutide and Placebo

Study: 

Patients with type 2 diabetes, having a HbA1c of 7.0 to 10.0% (53 to 86 mmol/mol) and being managed with diet and exercise, with or without metformin were involved in the 26-week, multicentre, double-blind study to ascertain the efficacy and safety of once-daily semaglutide in comparison with once-daily liraglutide and placebo.

The change in HbA1c from baseline to week 26 was the primary endpoint. Randomisation of patients was done to once-daily semaglutide, liraglutide, or placebo as 2:2:1 in one of four volume-matched doses (Both semaglutide 0.05, 0.1, 0.2, or 0.3 mg and liraglutide 0.3, 0.6, 1.2, or 1.8 mg, within each volume-matched dose group were compared). Trial products were given to a total of 705 patients.

Chief findings:

• A dose-dependent change in HbA1c was observed with semaglutide from -1.1% (0.05 mg) to -1.9% (0.3 mg) at week 26
• With liraglutide, a dose-dependent change in HbA1c was observed from -0.5% (0.3 mg) to -1.3% (1.8 mg) at week 26 (all P < 0.001 in favour of volume-matched semaglutide dose)
• -0.02% change was seen with pooled placebo (P < 0.0001 vs. semaglutide)

The most common adverse events (AEs) were gastrointestinal (GI) disorders which occurred in 32.8 to 54.0% and 21.9 to 41.5% of patients on semaglutide and liraglutide, respectively. Albeit with a higher frequency of gastrointestinal AEs, greater reductions in HbA1c was seen with once-daily semaglutide at doses up to 0.3 mg/day as compared to liraglutide or placebo.

Source: Lingvay I, Desouza CV, Lalic KS et al. Semaglutide Versus Liraglutide and Placebo in Type 2 DM Controlled on Diet and Exercise with or Without Metformin. Diabetes Care. 2018 Sep;41(9):1926-1937.

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Semaglutide vs Exenatide ER

Study:

Once-weekly semaglutide 1.0 mg s.c. was compared for its efficacy and safety versus exenatide extended release (ER) 2.0 mg s.c. in subjects with type 2 diabetes. A phase 3a, open-label, parallel-group, randomised controlled trial was done with 813 subjects with type 2 diabetes that were taking oral antidiabetic drugs for 56 weeks. They were randomized (1:1) to semaglutide 1.0 mg or exenatide ER 2.0 mg. HbA1c change from baseline at week 56 was the primary endpoint.

Chief findings:

• With semaglutide, the mean HbA1c (8.3% [67.7 mmol/mol] at baseline) reduction was by 1.5% (16.8 mmol/mol) whereas the mean HbA1c reduction was 0.9% (10.0 mmol/mol) with exenatide ER (estimated treatment difference vs. exenatide ER [ETD] -0.62% [95% CI -0.80, -0.44] [-6.78 mmol/mol (95% CI -8.70, -4.86)]; P < 0.0001 for noninferiority and superiority)
• With semaglutide, the mean body weight (95.8 kg at baseline) reduction was by 5.6 kg whereas with exenatide ER the mean body weight reduction was 1.9 kg (ETD -3.78 kg [95% CI -4.58, -2.98]; P < 0.0001)
• Subjects treated with semaglutide (67%) achieved HbA1c <7.0% (<53 mmol/mol) significantly more times than those taking exenatide ER (40%)
• Gastrointestinal adverse events were more frequently seen in semaglutide-treated subjects (41.8%) as compared to exenatide ER-treated subjects (33.3%) even though both treatments had similar safety profiles
• Exenatide ER (22.0%) more commonly resulted in injection-site reactions as compared to semaglutide (1.2%)

Source: Ahmann AJ, Capehorn M, Charpentier G et al. Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects with Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, RCT. Diabetes Care. 2018 Feb;41(2):258-266.

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Semaglutide vs Dulaglutide

Study:

Glucagon-like peptide-1 receptor agonists are different in their structure, pharmacokinetic profiles, and clinical effects despite having a common mechanism of action. Semaglutide was compared with dulaglutide in patients with inadequately controlled type 2 diabetes in this open-label, parallel-group, phase 3b head-to-head trial.

Eligible patients aged 18 years or older with type 2 diabetes and HbA1c levels of 7.0 to10.5% (53.0 to 91.0 mmol/mol) on metformin monotherapy from 194 hospitals, clinical institutions or private practices in 16 countries were enrolled. Patients were randomized (1:1:1:1) by using an interactive web-response system to once a week treatment with either semaglutide 0.5 mg, dulaglutide 0.75 mg, semaglutide 1.0 mg, or dulaglutide 1.5 mg subcutaneously.

The primary and confirmatory secondary endpoint at 40 weeks were changes from baseline in percentage of HbA1c, and changes in body weight respectively. Randomly assigned patients exposed to a minimum of one dose of trial product while on treatment and before the onset of rescue medication were included in the primary analysis population.

All randomly assigned patients that were exposed to a minimum of one dose of trial product obtained while on treatment for the safety population. HbA1c non-inferiority (margin 0.4%) and bodyweight superiority were assessed by this trial.

A total of 1201 patients were randomly assigned to treatment between Jan 6, 2016, and June 22, 2016. Semaglutide 0.5 mg was given to 301 patients, dulaglutide 0.75 mg was given to 299 patients, semaglutide 1.0 mg was given to 300 patients, and dulaglutide 1.5 mg was given to 299 patients.

Chief findings:

• The trial withdrawal rate was 6% (n=72) with 22 receiving semaglutide 0.5 mg withdrawing, 13 receiving dulaglutide 0.75 mg withdrawing, 21 receiving semaglutide 1.0 mg withdrawing, and 16 receiving dulaglutide 1.5 mg withdrawing)
• The mean percentage HbA1c reduction from the mean overall baseline was by 1.5 (SE 0.06) percentage points with semaglutide 0.5 mg versus 1.1 (0.05) percentage points with dulaglutide 0.75 mg (estimated treatment difference [ETD] -0.40 percentage points [95% CI -0.55 to -0.25]; p<0.0001) and by 1.8 (0.06) percentage points with semaglutide 1.0 mg versus 1.4 (0.06) percentage points with dulaglutide 1.5 mg (ETD -0.41 percentage points [-0.57 to -0.25]; p<0.0001)
• The mean bodyweight reduction from overall baseline mean was by 4.6 kg (SE 0.28) with semaglutide 0.5 mg compared to 2.3 kg (0.27) with dulaglutide 0.75 mg (ETD -2.26 kg [-3.02 to -1.51]; p<0.0001) and by 6.5 kg (0.28) with semaglutide 1.0 mg compared to 3.0 kg (0.27) with dulaglutide 1.5 mg (ETD -3.55 kg [-4.32 to -2.78]; p<0.0001)

The most frequently reported adverse events were gastrointestinal disorders which were seen in 129 (43%) of 301 patients on semaglutide 0.5 mg, 133 (44%) of 300 patients on semaglutide 1.0 mg, 100 (33%) of 299 patients on dulaglutide 0.75 mg, and in 143 (48%) of 299 patients on dulaglutide 1.5 mg.

The most frequent reason for discontinuing semaglutide and dulaglutide treatment was due to gastrointestinal disorders. In all, there was one fatality in each semaglutide group and two fatalities in each dulaglutide group making the total fatalities to be six.

Source: Pratley RE, Aroda VR, Lingvay I et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018 Apr;6(4):275-286.

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