CoChat
Sign Up
Cited by 16Cardiac electrophysiology and arrhythmiasDiabetes Treatment and ManagementPharmacogenetics and Drug Metabolism

No QTc Prolongation with Semaglutide: A Thorough QT Study in Healthy Subjects

Open access
Demmel, Valentin, Sandberg-Schaal, Anne, Jacobsen, Jacob B., Golor, Georg, Pettersson, Jonas, Flint, Anne·2018·Diabetes Therapy
DOI 10.1007/s13300-018-0442-0PMC PMC6064589
Open this paper in CoChat — free accountOpen PDF

Abstract

INTRODUCTION: Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for the once-weekly treatment of type 2 diabetes. The objective of this 16-week, double-blind, single-center thorough QT study was to confirm that semaglutide treatment does not prolong cardiac repolarization versus placebo. Prolongation of the QT interval is a biomarker for ventricular tachyarrhythmia. METHODS: . To assess QT assay sensitivity, subjects in the placebo group received a single 400 mg moxifloxacin dose as positive control, and placebo in a crossover fashion. The primary endpoint was the time-matched change from baseline in QT interval corrected individually for heart rate (ΔQTcI), calculated from 11 electrocardiogram recordings from 0 to 48 h after the last 1.5 mg dose. Similar assessments were made for the therapeutic 0.5 and 1.0 mg semaglutide dose levels. RESULTS: No QTcI prolongation occurred with any semaglutide dose; the upper limits of two-sided 90% confidence intervals of the placebo-subtracted ΔQTcI were < 10 ms at all doses and time points. Exposure-response analysis showed no dependence of QTcI on semaglutide concentration. QT assay sensitivity was confirmed. The semaglutide safety profile was similar to that of other GLP-1 receptor agonists. CONCLUSION: Based on investigations of QT/QTc, no concern with regard to ventricular arrhythmias was raised as semaglutide did not prolong the cardiac repolarization duration in healthy subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT 02064348. FUNDING: Novo Nordisk.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s13300-018-0442-0

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Compared with placebo, subcutaneous semaglutide had no effect on the QT interval in healthy volunteers, with doses above what is used in daily practice.

    “Compared with placebo, subcutaneous semaglutide had no effect on this ECG measure in healthy volunteers, with doses above what is used in daily practice”

    From Safety of Semaglutide (2021) · cites this paper as [113]

    The Methods and Conclusions describe subcutaneous semaglutide tested in healthy subjects at doses up to a supratherapeutic 1.5 mg, and the Results report no QT prolongation versus placebo. But “no effect” is broader than the finding: the Results report shorter mean placebo-adjusted QTcI changes with semaglutide. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The observed QTcI interval prolongation may be an effect of glucagon agonism, because QT interval prolongation has not been observed for GLP-1 RAs.

    “The observed QTcI interval prolongation may be an effect of glucagon agonism, because QT interval prolongation has not been observed for GLP-1 RAs [35,36].”

    From Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: Effects on weight loss and safety in adults with overweight or obesity (2023) · cites this paper as [35]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 28

  1. [1]Kapitza C Nosek L Jensen L Hartvig H Jensen CB Flint A Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel J Clin Pharmacol 2015 55 497 504 10.1002/jcph.443 25475122 PMC4418331 · DOI · Paper page
  2. [3]Lau J Bloch P Schaffer L Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide J Med Chem 2015 58 7370 7380 10.1021/acs.jmedchem.5b00726 26308095 · DOI · Paper page
  3. [4]van Noord C Eijgelsheim M Ch. Stricker BH Drug- and non-drug-associated QT interval prolongation Br J Clin Pharmacol 2010 70 16 23 10.1111/j.1365-2125.2010.03660.x 20642543 PMC2909803 · DOI
  4. [5]Straus SMJM Kors JA De Bruin ML Prolonged QTc interval and risk of sudden cardiac death in a population of older adults J Am Coll Cardiol 2006 47 362 367 10.1016/j.jacc.2005.08.067 16412861 · DOI · Paper page
  5. [6]Darpo B Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes Eur Heart J Suppl 2001 3 K70 K80 10.1016/S1520-765X(01)90009-4 · DOI
  6. [7]Nachimuthu S Assar MD Schussler JM Drug-induced QT interval prolongation: mechanisms and clinical management Ther Adv Drug Saf 2012 3 241 253 10.1177/2042098612454283 25083239 PMC4110870 · DOI
  7. [8]International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The clinical evaluation of QT/QTc interval. Prolongation and proarrhythmic potential for non-antiarrhytmic drugs E14. 2005. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf. 16237860
  8. [9]US Food and Drug Administration (FDA). Guidance for industry. E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073153.pdf. 16237860
  9. [10]Smith LL Mosley IJF Parke C Brown J Barris LS Phan LD Dulaglutide (trulicity): the third once-weekly GLP-1 agonist Pharm Ther 2016 41 357 360 PMC4894510 27313432
  10. [11]Darpo B Zhou M Matthews J Albiglutide does not prolong QTc interval in healthy subjects: a thorough ECG study Diabetes Ther 2014 5 141 153 10.1007/s13300-014-0055-1 24510375 PMC4065291 · DOI
  11. [13]Fridericia LS Die Systolendauer im Elektrokardiogramm bei normalen Menchan und bei Herzdranken Acta Med Scand 2002 53 469 486 10.1111/j.0954-6820.1920.tb18266.x · DOI
  12. [16]Yan LK Zhang J Nq MJ Dang Q Statistical characteristics of moxifloxacin-induced QTc effect J Biopharm Stat 2010 20 497 507 10.1080/10543400903581945 20358432 · DOI
  13. [18]Desai M Li L Desta Z Malik M Flockhart D Variability of heart rate correction methods for the QT interval Br J Clin Pharmacol 2003 55 511 517 10.1046/j.1365-2125.2003.01791.x 12814443 PMC1884246 · DOI
  14. [19]Lorenz M Lawson F Owens D Differential effects of glucagon-like peptide-1 receptor agonists on heart rate Cardiovasc Diabetol 2017 28086882 PMC5237337
  15. [20]Mason RE Likar I A new system of multiple-lead exercise electrocardiography Am Heart J 1966 71 196 205 10.1016/0002-8703(66)90182-7 5902099 · DOI
  16. [21]World Medical Association Declaration of Helsinki Ethical principles for medical research involving human subjects JAMA 2000 284 3043 3045 10.1001/jama.284.23.3043 11122593 · DOI · Paper page
  17. [22]International Conference on Harmonisation. ICH Harmonised tripartite guideline. Good Clinical Practice, 1996. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf.
  18. [24]Bloomfield DM Kost JT Ghosh K The effect of moxifloxacin on QTc and implications for the design of thorough QT studies Clin Pharmacol Ther 2008 84 475 480 10.1038/clpt.2008.33 19238652 · DOI
  19. [25]Linnebjerg H Seger M Kothare P Hunt T Wolka AM Mitchell MI A thorough QT study to evaluate the effects of single dose exenatide 10 µg on cardiac repolarization in healthy subjects Int J Clin Pharmacol 2011 49 594 604 10.5414/CP201462 21961484 · DOI
  20. [26]Darpo B Sager P MacConell L Exenatide at therapeutic and supratherapeutic concentrations does not prolong the QTc interval in healthy subjects Br J Clin Pharmacol 2013 75 979 989 10.1111/j.1365-2125.2012.04416.x 22882281 PMC3612716 · DOI
  21. [27]Kapitza C Dahl K Jacobsen JB Axelsen MB Flint A Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial Diabetologia 2017 60 1390 1399 10.1007/s00125-017-4289-0 28526920 PMC5491562 · DOI
  22. [28]Blundell J Finlayson G Axelsen M Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity Diab Obesity Metabol 2017 19 1242 1251 10.1111/dom.12932 PMC5573908 28266779 · DOI · Paper page
  23. [29]Sorli C Harashima S Tsoukas GM Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double-blind, randomised, placebo-controlled, parallel-group, multinational, multicentre phase 3a trial Lancet Diabetes Endocrinol 2017 5 251 260 10.1016/S2213-8587(17)30013-X 28110911 · DOI · Paper page
  24. [34]Miyagawa J Odawara M Takamura T Iwamoto N Takita Y Imaoka T Once-weekly glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once-daily liraglutide and superior to placebo in Japanese patients with type 2 diabetes: a 26-week randomized phase III study Diabetes Obes Metab 2015 17 974 983 10.1111/dom.12534 26179187 PMC5042083 · DOI
  25. [36]Aroda VR Bain SC Cariou B Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine in insulin-naïve subjects with type 2 diabetes (SUSTAIN 4): a randomised open-label clinical trial Lancet Diabetes Endocrinol 2017 5 355 366 10.1016/S2213-8587(17)30085-2 28344112 · DOI · Paper page
  26. [37]Aroda VR Ratner R The safety and tolerability of GLP-1 receptor agonists in the treatment of type 2 diabetes: a review Diabetes Metab Res Rev 2017 27 528 542 10.1002/dmrr.1202 21484979 · DOI
  27. [38]Prasad-Reddy L Isaacs D A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond Drugs in Context 2015 4 212238 10.7573/dic.212283 PMC4509428 26213556 · DOI · Paper page
  28. [39]Trujillo JM Nuffer W Ellis SL GLP-1 receptor agonists: a review of head-to-head clinical studies Ther Adv Endocrinol Metab 2015 6 19 28 10.1177/2042018814559725 25678953 PMC4321870 · DOI · Paper page

Cited by

Sorted by citations

Authors
Demmel, V., Sandberg-Schaal, A., Jacobsen, J. B., Golor, G., Pettersson, J., & Flint, A.
Affiliations
Novo Nordisk (Denmark) (DK)
Corresponding author
Demmel, Valentin
ORCID
Venue
Diabetes Therapy
Publisher
Springer Science and Business Media LLC
Published
2018-05-24
Volume
9
Issue
4
Pages
1441-1456
ISSN
  • 1869-6953 (ISSN-L)
  • 1869-6961
DOI
10.1007/s13300-018-0442-0
PMC
PMC6064589
OpenAlex
W2803700865
Cited by
16
References
8
Citations by year
2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 2
FWCI
1.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes Therapy (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Novo Nordisk
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
semaglutide, QTc prolongation, cardiac repolarization, GLP-1 receptor agonists, type 2 diabetes, ventricular arrhythmias, drug safety, exposure-response relationship, healthy volunteers

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review