Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial

Stefan Korsatko, Lene Jensen, Martina Brunner, Stefanie Sach-Friedl, Maja D Tarp, Anders G Holst, Simon R Heller, Thomas R Pieber, Stefan Korsatko, Lene Jensen, Martina Brunner, Stefanie Sach-Friedl, Maja D Tarp, Anders G Holst, Simon R Heller, Thomas R Pieber

Abstract

Aims: To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D).

Methods: In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L).

Results: The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m2 , glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide.

Conclusions: Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

Keywords: GLP-1; GLP-1 analogue; hypoglycaemia; type 2 diabetes.

Conflict of interest statement

No potential conflicts of interest relevant to this article are reported by S.K., M.B. or S.S. S.R.H. has served on speaker panels for AstraZeneca, Eli Lilly, Novo Nordisk, Sanofi Aventis and Takeda, for which he has received personal remuneration. He has consulted for Boeringher Ingelheim, Eli Lilly, Novo Nordisk and Takeda, for which his institution has received remuneration. T.R.P. declares Board membership for Adocia, AstraZeneca, Eli Lilly, Novo Nordisk and Sanofi, and institutional grants from AstraZeneca and Novo Nordisk, and payment for lectures/speakers bureaus from Novo Nordisk. L.J., M.D.T. and A.G.H. are employed by and hold stock in Novo Nordisk.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
A, Trial design. Semaglutide was self‐injected once weekly with the starting dose of 0.25 mg for 4 weeks (starting at week 0), increasing to 0.5 mg for the next 4 weeks and subsequently to 1.0 mg for 5 weeks. Assessments were made after the 5th dose of 1.0 mg semaglutide. Placebo was given in doses volume‐matched to semaglutide. B, Hypoglycaemic clamp design. Response assessments included counterregulatory hormones, C‐peptide, hypoglycaemic symptoms, hypoglycaemic recognition, cognitive function tests, and vital signs. GIR, glucose infusion rate; PG, plasma glucose; PK, pharmacokinetics
Figure 2
Figure 2
Counterregulatory responses to hypoglycaemic clamp: A, glucagon; B, adrenaline; C, noradrenaline; D, cortisol; E, growth hormone and F, C‐peptide. Graphs show geometric means and standard error bars. Of the 37 participants included in the full analysis set, 35 completed both treatment periods and are included in the analysis. Mean (SD) fasting plasma glucose concentrations (prior to the clamp) were 6.6 (1.3) mmol/L for semaglutide and 8.8 (2.6) mmol/L for placebo. For glucagon SI units (ng/L), please use the conversion factor 1.0. For adrenaline SI units (pmol/L), please use the conversion factor 5.459. For noradrenaline SI units (pmol/L), please use the conversion factor 5.911. For cortisol SI units (nmol/L), SI units (pmol/L), please use the conversion factor 27.588. For growth hormone SI units (μg/L), please use the conversion factor 1.0. *P < 0.05 for semaglutide vs placebo from analysis of covariance. NA, not analysed; NS, not significant
Figure 3
Figure 3
Hypoglycaemic symptom score. The score was based on responses to 11 questions, providing a total score of between 11 and 77, with a lower score indicating fewer symptoms. Graph shows geometric means and standard error bars. *P < 0.05 for semaglutide vs placebo from analysis of covariance. NS, not significant

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