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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

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Korsatko, Stefan, Jensen, Lene, Brunner, Martina, Sach‐Friedl, Stefanie, Tarp, Maja D., Holst, Anders G., Heller, Simon R., Pieber, Thomas R.·2018·Diabetes, Obesity and Metabolism
DOI 10.1111/dom.13422PMC PMC6221089
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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: , 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.

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  • GLP-1RA mainly lower blood glucose by stimulating glucose-dependent insulin secretion, so hypoglycemia is an infrequent problem.

    “However, since GLP-1RA mainly lower blood glucose by stimulating glucose-dependent insulin secretion, hypoglycemia is an infrequent problem. In addition, the inhibition of glucagon release does not occur under hypoglycemic conditions (35).”

    From Safety of Semaglutide (2021) · cites this paper as [35]

    The Introduction states that GLP-1 stimulates insulin secretion in a glucose-dependent manner, and the Discussion describes semaglutide as providing glycaemic control with a low risk of hypoglycaemia (page numbers unavailable). The paper does not establish that insulin secretion is the main glucose-lowering mechanism or that hypoglycaemia is infrequent across all GLP-1 receptor agonists. (LLM, conf=0.84)

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  • In other phase 3 trials, no increase in hypoglycemia risk was observed versus comparator groups, including other GLP-1RAs.

    “In other phase 3 trials, no increase in hypoglycemia risk was observed versus comparator groups, including other GLP-1RAs (18–21, 23, 33–36).”

    From Safety of Semaglutide (2021) · cites this paper as [35]

    The Discussion (page unavailable) reports that studies of semaglutide conducted to date had noted no increase in hypoglycaemia rates, consistent with the broad claim about other trials. It does not establish the specific comparison with other GLP-1 receptor agonists; it also cautions that those studies were not powered to assess differences in severe hypoglycaemia. (LLM, conf=0.84)

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Authors
Korsatko, S., Jensen, L., Brunner, M., Sach‐Friedl, S., Tarp, M. D., Holst, A. G., Heller, S. R., & Pieber, T. R.
Affiliations
  • Medical University of Graz (AT)
  • Novo Nordisk (Denmark) (DK)
  • University of Sheffield (GB)
Corresponding author
Pieber, Thomas R.
ORCID
Venue
Diabetes, Obesity and Metabolism
Publisher
Wiley
Published
2018-07-16
Volume
20
Issue
11
Pages
2565-2573
ISSN
  • 1462-8902 (ISSN-L)
  • 1463-1326
DOI
10.1111/dom.13422
PMC
PMC6221089
OpenAlex
W2807974398
Cited by
29
References
10
Citations by year
2026: 4 · 2025: 8 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3
FWCI
1.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes Obesity and Metabolism (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Novo Nordisk (NN9535‐3684)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
semaglutide, type 2 diabetes, hypoglycemia, counterregulatory response, glucagon, norepinephrine, cortisol, GLP-1 receptor agonists, hypoglycaemic symptoms, metformin
MeSH terms
Semaglutide, Adult, Blood Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Administration Schedule, Glucagon-Like Peptides, Female, Humans, Hypoglycemia, Male, Middle Aged, Placebos, Cross-Over Studies

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