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. 2020 Dec;22(12):2241-2247.
doi: 10.1111/dom.14049. Epub 2020 Jul 9.

Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE

Simon Heller  1 , Ildiko Lingvay  2 , Steven P Marso  3 , Athena Philis-Tsimikas  4 , Thomas R Pieber  5 , Neil R Poulter  6 , Richard E Pratley  7 , Elise Hachmann-Nielsen  8 , Kajsa Kvist  8 , Martin Lange  8 , Alan C Moses  8   9 , Marie Trock Andresen  8 , John B Buse  10 ; DEVOTE Study Group
Affiliations

Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE

Simon Heller et al. Diabetes Obes Metab. 2020 Dec.

Abstract

Aims: To undertake a post-hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk affected the risk of cardiovascular outcomes.

Materials and methods: The DEVOTE population was divided into quartiles according to patients' individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all-cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all-cause mortality. In addition, treatment differences within each risk quartile [insulin degludec (degludec) vs. insulin glargine 100 units/mL (glargine U100)] in terms of severe hypoglycaemia, MACE and all-cause mortality were investigated.

Results: Patients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all-cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 95% confidence interval (CI) 0.56 (0.39; 0.80) (severe hypoglycaemia), 95% CI 0.76 (0.58; 0.99) (MACE) and 95% CI 0.77 (0.55; 1.07) (all-cause mortality).

Conclusions: The risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all-cause mortality and that, in this high-risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.

Trial registration: ClinicalTrials.gov NCT01959529.

Keywords: MACE; all-cause mortality; severe hypoglycaemia; type 2 diabetes.

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Conflict of interest statement

S.H. has served on speaker panels for MSD, Eli Lilly, Takeda, Novo Nordisk and AstraZeneca, for which he has received remuneration. He has served on advisory panels or as a consultant for Zeeland, UNEEG Medical, Boehringer Ingelheim, Novo Nordisk, Eli Lilly and Takeda, for which his institution has received remuneration. I.L. received funds for research, consulting, editorial support and/or travel expenses from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Intarcia, MannKind, TARGETPharma, GI Dynamics and Pfizer. S.P.M. has received personal fees from Abbott Vascular, Novo Nordisk, University of Oxford, AstraZeneca, Bristol‐Myers Squibb, Asahi‐Intec and Boehringer Ingelheim, and research support from Novo Nordisk. DKM has led clinical trials for AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co. Inc., Novo Nordisk and Sanofi Aventis, and has received consultancy fees from AstraZeneca, Boehringer Ingelheim, Lilly, Merck & Co. Inc., Pfizer, Novo Nordisk, Metavant and Sanofi Aventis. A.P.T. has served on advisory panels for Eli Lilly and Co, Dexcom, Inc. and Voluntis, provided consultancy services for Novo Nordisk A/S and Sanofi US, and received research support from Merck & Co., Inc., Novo Nordisk A/S, Sanofi US, Eli Lilly and Co, AstraZeneca, Janssen Pharmaceuticals, Inc. and Genentech, Inc. A.P.T. did not receive any direct or indirect payment for these services. She is supported by grants from the US National Institutes of Health (R01DK112322, R18DK104250, R01NR015754 and 1UL1 TR002550). T.R.P. has received research support from Novo Nordisk and AstraZeneca (paid directly to the Medical University of Graz), and personal fees as a consultant from AstraZeneca, Bristol‐Myers Squibb, Eli Lilly, Novo Nordisk and Roche Diabetes Care. T.R.P. is also the Chief Scientific Officer of CBmed (Center for Biomarker Research in Medicine), a public‐funded biomarker research company. N.R.P. has received personal fees from Servier, Takeda, Novo Nordisk and AstraZeneca in relation to speakers' fees and advisory board activities (concerning diabetes mellitus), and research grants for his research group (relating to type 2 diabetes) from Diabetes UK, the UK National Institute for Health Research Efficacy and Mechanism Evaluation (NIHR EME), Julius Clinical and the British Heart Foundation. R.E.P.'s services were paid directly to Florida Hospital, a non‐profit organization. He has received consultancy and speaker fees from AstraZeneca, Takeda and Novo Nordisk, consultancy fees from Boehringer Ingelheim, GlaxoSmithKline, Hanmi Pharmaceutical Co. Ltd., Janssen Scientific Affairs LLC, Ligand Pharmaceuticals, Inc., Eli Lilly, Merck, Pfizer and Eisai, Inc., and research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Inc., Eli Lilly, Merck, Sanofi US LLC and Takeda. K.K., M.L. and M.T.A. are full‐time employees of, and hold stock in, Novo Nordisk A/S. E.H.N. is a full‐time employee of Novo Nordisk A/S. A.C.M. was an employee of Novo Nordisk during the conduct of DEVOTE. He now serves as an independent consultant, including consulting for Novo Nordisk, and retains shares in Novo Nordisk A/S. J.B.B.'s contracted consulting fees and associated travel support are paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics and Zafgen, and he receives grant support from Novo Nordisk, Sanofi, Tolerion and vTv Therapeutics. He is also a consultant to Cirius Therapeutics Inc., CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics and Stability Health. He holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio and Stability Health. He is supported by grants from the US National Institutes of Health (UL1TR002489, U01DK098246, UC4DK108612, U54DK118612), the Patient‐Centered Outcomes Research Institute and the American Diabetes Association. The trial sponsor was involved in the design of DEVOTE and this secondary analysis, the collection and analysis of data, and writing the clinical report. J.B.B. received support from The US National Institutes of Health (UL1TR002489). All authors interpreted the data and wrote the manuscript together with the sponsor's medical writing services team. The funders of the study had no role in the approval of the manuscript or the decision to submit for publication.

Figures

FIGURE 1
FIGURE 1
Risk of outcomes: A, severe hypoglycaemia, B, MACE and C, all‐cause mortality by severe hypoglycaemia risk quartiles. MACE, major adverse cardiovascular events
FIGURE 2
FIGURE 2
Risk of outcomes: A, severe hypoglycaemia, B, MACE and C, all‐cause mortality with degludec vs. glargine U100 by severe hypoglycaemia risk quartiles. CI, confidence interval; glargine U100, insulin glargine 100 units/mL; MACE, major adverse cardiovascular events; PYO, patient‐years of observation
See this image and copyright information in PMC

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