Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2)

Abstract

Aims/hypothesis: The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes.

Methods: In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA1c.

Results: Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient's day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49).

Conclusions/interpretation: Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality.

Trial registration: ClinicalTrials.gov NCT01959529.

Keywords: Hypoglycaemia; Insulin therapy; Macrovascular disease.

Conflict of interest statement

Data availability

The data generated during and/or analysed during the current trial are available from the corresponding author on reasonable request.

Funding

This trial and secondary analysis was sponsored and funded by Novo Nordisk (Bagsvaerd, Denmark). JBB received support from The National Institutes of Health (UL1TR001111). The trial sponsor was involved in the design of the trial; the collection, and analysis of data; and writing the clinical report.

Duality of interest

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

SPM has received personal fees from Abbott Vascular, Novo Nordisk, University of Oxford, AstraZeneca and Bristol-Myers Squibb; and research support from Novo Nordisk, The Medicines Company and Terumo Medical.

NRP 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 mellitus) from Diabetes UK, National Institute for Health Research Efficacy and Mechanism Evaluation (NIHR EME), Julius Clinical and the British Heart Foundation.

SSE has received personal fees related to Data Monitoring Committees from CTI BioPharma, Arena Pharmaceuticals, SFJ Pharmaceuticals, BioMarin, Medivation, Biom’up, Dynavax, Genentech, GlaxoSmithKline, Janssen Research, Novartis, Novo Nordisk, Pfizer, Roche, Sarepta Therapeutics and Xoma; personal fees related to other statistical consulting from AstraZeneca, Celltrion, Sprout Pharmaceuticals, Sanofi, Collegium Pharmaceutical, Intercept, Coherus BioMedical and Emmaus Life Sciences; and research grant support from National Heart, Lung, and Blood Institute (NHLBI).

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

REP’s services were paid for directly to Florida Hospital, a non-profit organisation. 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, Eisai, Inc.; research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Inc., Eli Lilly, Merck, Sanofi US LLC and Takeda.

ML, KB-F, AM, AMOF, JBL and KK are full-time employees of, and hold stock in, Novo Nordisk A/S.

JBB reports receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly, GI Dynamics, Elcylex, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzen HighTide, Fractyl and Dexcom; grant support from Eli Lilly, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos and Bayer; he also reports receiving fees and holding stock options in PhaseBio and Insulin Algorithms; he also reports serving on the board of the AstraZeneca Healthcare Foundation.

Contribution statement

All authors confirm that they meet the International Committee of Medical Journal Editors uniform requirements for authorship. Specifically, all authors made substantial contributions to the interpretation of data for the manuscript, drafted and critically revised the manuscript, provided final approval of the version to be published and agreed to be accountable for all aspects of the manuscript. All the authors had access to the final results and vouch for the fidelity of the trial to the protocol. Medical writing and editorial support, under the guidance of the authors, was provided by Watermeadow Medical, an Ashfield company, part of UDG Healthcare plc, funded by Novo Nordisk. All authors are responsible for the integrity of the work as a whole.

Figures

Fig. 1

Representative SMBG profiles from three separate DEVOTE participants illustrating the low (a), medium (b) and high (c) variability groups. Day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements

Fig. 2

Day-to-day fasting glycaemic variability and its associations with severe hypoglycaemia, MACE and all-cause mortality. Day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. Adjustment 1: adjusted for the most recent HbA1c measurement on a continuous scale. Adjustment 2: adjusted for baseline HbA1c above or below 8% (64 mmol/mol) and baseline characteristics (investigational product, sex, region, age at baseline, smoking status at baseline, diabetes duration at baseline, cardiovascular risk group inclusion criteria, insulin-naive at baseline and renal function [eGFR] at baseline). Adjustment 3: adjusted for baseline HbA1c on a continuous scale and baseline characteristics as for adjustment 2. Adjustment 4: adjusted for most recent HbA1c measurement on a continuous scale and baseline characteristics as for adjustment 2

Fig. 3

Day-to-day fasting glycaemic variability and its association with cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. For adjustments, see Fig. 2 legend. MI, myocardial infarction