TY - JOUR
T1 - Day-to-day fasting glycaemic variability in DEVOTE
T2 - associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2)
AU - On Behalf Of The Devote Study Group
AU - Zinman, Bernard
AU - Marso, Steven P.
AU - Poulter, Neil R.
AU - Emerson, Scott S.
AU - Pieber, Thomas R.
AU - Pratley, Richard E.
AU - Lange, Martin
AU - Brown-Frandsen, Kirstine
AU - Moses, Alan
AU - Ocampo Francisco, Ann Marie
AU - Barner Lekdorf, Jesper
AU - Kvist, Kajsa
AU - Buse, John B.
N1 - Funding Information:
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.
Funding Information:
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.
Funding Information:
We thank the trial investigators, trial staff and trial participants for their participation, D. K. McGuire (University of Texas Southwestern Medical Center, USA) and P.-M. Haahr (Novo Nordisk A/S, Denmark) for insights that assisted in the development of this article, and F. Hemingway and D. Renshaw from Watermeadow Medical (UK; sponsored by Novo Nordisk) for providing medical writing and editorial support. DEVOTE research activities were supported at numerous US centres by Clinical and Translational Science Awards from the National Institutes of Health?s National Center for Advancing Translational Science. 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.
Funding Information:
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).
Funding Information:
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.
Funding Information:
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.
Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2017, The Author(s).
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Hypoglycaemia
KW - Insulin therapy
KW - Macrovascular disease
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U2 - 10.1007/s00125-017-4423-z
DO - 10.1007/s00125-017-4423-z
M3 - Article
C2 - 28913575
AN - SCOPUS:85029546960
VL - 61
SP - 48
EP - 57
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 1
ER -