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Randomized Controlled Trial
. 2019 Jul;21(7):1625-1633.
doi: 10.1111/dom.13699. Epub 2019 Apr 15.

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7)

Richard E Pratley  1 , Scott S Emerson  2 , Edward Franek  3 , Matthew P Gilbert  4 , Steven P Marso  5 , Darren K McGuire  6 , Thomas R Pieber  7 , Bernard Zinman  8 , Charlotte T Hansen  9 , Melissa V Hansen  9 , Thomas Mark  9 , Alan C Moses  9 , John B Buse  10 ; DEVOTE Study Group
Affiliations
Randomized Controlled Trial

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7)

Richard E Pratley et al. Diabetes Obes Metab. 2019 Jul.

Abstract

Aims: The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older.

Materials and methods: A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs).

Results: Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes.

Conclusions: There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age.

Keywords: basal insulin; cardiovascular disease; hypoglycaemia; type 2 diabetes.

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Conflict of interest statement

R. E. P. has received consultancy and speaker fees from AstraZeneca, Takeda and Novo Nordisk; has received 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 has received research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Inc., Eli Lilly, Merck, Sanofi US LLC and Takeda, all of which were paid directly to Florida Hospital, a non‐profit organization.

S. S. E. has received personal fees related to Data Monitoring Committees from CTI BioPharma, Arena Pharmaceuticals, SFJ Pharmaceuticals, BioMarin, Medivation, Biom'up, Bristol‐Myers Squibb, Dynavax, Genentech, GlaxoSmithKline, Janssen Research, Novartis, Pfizer, Roche, Sarepta Therapeutics and Xoma; has received personal fees related to other statistical consulting from Amgen, AstraZeneca, Celltrion, Daiichi Sankyo, Nektar Pharmaceuticals, Novo Nordisk, Sage Therapeutics, Shire, Sprout Pharmaceuticals, Sanofi, Takeda Pharmaceutical Company, Collegium Pharmaceutical, Intercept, Coherus BioMedical and Emmaus Life Sciences; and has received research grant support from the National Heart, Lung, and Blood Institute (NHLBI).

E. F. has received personal fees related to advisory board activities from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme Corp. and Novo Nordisk; and has received speaker's fees from AstraZeneca, Bristol‐Myers Squibb, Boehringer Ingelheim, Eli Lily, Merck, Merck Sharp & Dohme Corp., Novo Nordisk and Servier.

M. P. G. has received personal fees as a consultant from Sanofi US and Novo Nordisk.

S. P. M. has received personal fees from Abbott Vascular, Novo Nordisk, University of Oxford and Bristol‐Myers Squibb; and has received research support from Novo Nordisk, the Medicines Company and Terumo Medical.

D. K. M. has received personal fees for clinical trial leadership from Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi US, Merck Sharp and Dohme Corp., Pfizer, Lilly USA, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon Pharmaceuticals, Eisai and Esperion; and has received fees for consultancy from AstraZeneca, Sanofi Aventis, Lilly US, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Applied Therapeutics and Metavant.

T. R. P. has received research support from Novo Nordisk and AstraZeneca, paid directly to the Medical University of Graz; has received personal fees for consulting from AstraZeneca, Bristol‐Myers Squibb, Eli Lilly, Novo Nordisk and Roche Diabetes Care; and is the Chief Scientific Officer of CBmed (Center for Biomarker Research in Medicine), a public‐funded biomarker research company.

B. Z. has received grant support from Boehringer Ingelheim, AstraZeneca and Novo Nordisk; and has received consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Sanofi.

C. T. H., M. V. H. and T. M. are full‐time employees of, and hold stock in, Novo Nordisk A/S.

A. C. M. was a full‐time employee of Novo Nordisk A/S at the time of the study and remains a consultant to Novo Nordisk, and holds stock in the company.

J. B. B. has received contracted consulting fees, paid to the University of North Carolina, from Adocia, AstraZeneca, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, and vTv Therapeutics; has received grant support from Novo Nordisk, Sanofi and vTv Therapeutics; is a consultant to Neurimmune AG; is supported by a grant from the National Institutes of Health (UL1TR002489); and holds stock options in Mellitus Health, PhaseBio and Stability Health.

Figures

Figure 1
Figure 1
Age group comparisons concerning time to first MACE and its components (CV death, non‐fatal MI and non‐fatal stroke), time to all‐cause mortality, number of severe and nocturnal severe hypoglycaemic events and SAEs (pooled treatments; adjusted for baseline covariates). All comparisons accounted for age group, treatment, interactions between age group and treatment, sex, region, diabetes duration, CV risk, insulin‐naïve status, smoking status and kidney function at baseline. Severe hypoglycaemia was defined, according to the American Diabetes Association, as an episode requiring the assistance of another person to actively administer carbohydrate or glucagon, or to take other corrective actions.8 Nocturnal severe hypoglycaemia was defined as an episode with an investigator‐reported onset between 00:01 am and 5:59 am. Abbreviations: CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular event; MI, myocardial infarction; SAE, serious adverse event
Figure 2
Figure 2
Treatment group comparisons (degludec vs glargine U100) concerning time to first MACE and its components (CV death, non‐fatal MI and non‐fatal stroke), time to all‐cause mortality, number of severe and nocturnal severe hypoglycaemic events and SAEs adjusted for baseline covariates. All comparisons accounted for age group, treatment, interactions between age group and treatment, sex, region, diabetes duration, CV risk, insulin‐naïve status, smoking status and kidney function at baseline. Severe hypoglycaemia was defined, according to the American Diabetes Association, as an episode requiring the assistance of another person to actively administer carbohydrate or glucagon, or to take other corrective actions.8 Nocturnal severe hypoglycaemia was defined as an episode with an investigator‐reported onset between 00:01 am and 5:59 am. Abbreviations: %, proportion of patients experiencing events; CI, confidence interval; CV, cardiovascular; E, number of events; glargine U100, insulin glargine 100 units/mL; MACE, major adverse cardiovascular event; MI, myocardial infarction; N, number of patients experiencing events; R, number of events per 100 patient‐years of observation; SAE, serious adverse event
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