Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial

Aim To evaluate the impact of relevant patient‐level characteristics on the efficacy and safety of subcutaneous, once‐weekly semaglutide in subjects with type 2 diabetes. Materials and Methods Exploratory post hoc analyses of pooled SUSTAIN 1‐5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c < 7.0% [53 mmol/mol]), without weight gain or severe/blood glucose‐confirmed symptomatic hypoglycaemia at week 30 with semaglutide (0.5/1.0 mg) across clinically relevant patient subgroups: baseline HbA1c (≤7.5%, >7.5%‐8.0%, >8.0%‐8.5%, >8.5%‐9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta‐cell function. Results Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (−0.9%, −1.2%,‐1.5%, −1.7% and −2.3% [effect of subgroup within treatment: P = 0.247] for semaglutide 0.5 mg, and −1.1%, −1.4%, −1.9%, −2.1% and −2.7% [P = 0.045] for semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%‐7.3% and 6.1%‐6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (−4.4, −3.9, −3.9, −3.3 and −2.9 kg [P = 0.004], and −6.4, −5.9, −5.2, −4.5 and −4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta‐cell function subgroups. Adverse events with semaglutide were consistent with the glucagon‐like peptide‐1 receptor agonist class, with gastrointestinal events the most common. Conclusions Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.

Section: Discussionsupporting

confidence: 89%

Impact of baseline characteristics and beta‐cell function on the efficacy and safety of subcutaneous once‐weekly semaglutide: A patient‐level, pooled analysis of the SUSTAIN 1‐5 trials

Aroda

Capehorn

Chaykin

et al. 2019

“…The observed reduction in postprandial insulin and C‐peptide in this trial may be explained, in part, by the reduction in glucose concentrations observed after 12 weeks of treatment. It is conceivable that semaglutide may produce a greater response in subjects with T2D with higher glycaemia . In another 12‐week study with semaglutide in subjects with T2D, a pronounced improvement of beta‐cell function was shown, and the impact on 24‐hour glucose, insulin and C‐peptide responses during a test day with 3 standardized meals was similar to observations in the current study .…”

Section: Discussionsupporting

confidence: 87%

“…It is conceivable that semaglutide may produce a greater response in subjects with T2D with higher glycaemia. 15,35,36 In another 12-week study with semaglutide in subjects with T2D, a pronounced improvement of beta-cell function was shown, and the impact on 24-hour glucose, insulin and C-peptide responses during a test day with 3 standardized meals was similar to observations in the current study. 36 The effects of semaglutide on insulin and glucose are interdependent.…”

Section: Discussionsupporting

confidence: 85%

Semaglutide improves postprandial glucose and lipid metabolism, and delays first‐hour gastric emptying in subjects with obesity

Hjerpsted

Flint

Brooks

et al. 2017

Self Cite

118

140

AimTo investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying.Materials and methodsThis was a randomized, double‐blind, placebo‐controlled, 2‐period, crossover trial. Subjects with obesity (N = 30) received once‐weekly subcutaneous semaglutide, dose‐escalated to 1.0 mg, or placebo. After each 12‐week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed.ResultsSemaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC0‐5h]; estimated treatment difference: glucose −1.34 mmol h/L [−2.42, −0.27]; insulin −921 pmol h/L [−1461, −381]; C‐peptide −1.42 nmol h/L [−2.33, −0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First‐hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC0‐1h; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide‐treated subjects. Overall gastric emptying (AUC0‐5h) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively).ConclusionSemaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first‐hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.

“…Results of the study selection process are depicted in Figure S1. A total of 12 studies, with 9501 patients, were included in our systematic review and meta‐analysis, including a trial published during the preparation of this manuscript that was added post‐hoc . The characteristics of studies included in the meta‐analysis are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

“…The characteristics of studies included in the meta‐analysis are summarized in Table . Subcutaneous semaglutide was compared with placebo or with another antidiabetic agent in 6 studies and 7 studies, respectively, while 1 trial compared both subcutaneous and oral semaglutide with placebo . As we did not identify any other trial that reported results for oral semaglutide, we performed meta‐analyses for only subcutaneous semaglutide.…”

Section: Resultsmentioning

confidence: 99%

Semaglutide for type 2 diabetes mellitus: A systematic review and meta‐analysis

Andréadis

Karagiannis

Malandris

et al. 2018