DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality
On Behalf Of The Devote Study Group
Aims/hypothesis: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. Methods: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. Results: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. Conclusions/interpretation: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. Trial registration: ClinicalTrials.gov NCT01959529.
Hypoglycaemia
Insulin therapy
Macrovascular disease
Dive into the research topics of 'DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality'. Together they form a unique fingerprint.
Hypoglycemia Medicine & Life Sciences 100%
insulin degludec Medicine & Life Sciences 30%
Insulin Glargine Medicine & Life Sciences 16%
Type 2 Diabetes Mellitus Medicine & Life Sciences 9%
Safety Medicine & Life Sciences 7%
Hypoglycemic Agents Medicine & Life Sciences 5%
Sex Characteristics Medicine & Life Sciences 5%
On Behalf Of The Devote Study Group (2018). DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia, 61(1), 58-65. https://doi.org/10.1007/s00125-017-4422-0
DEVOTE 3 : temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. / On Behalf Of The Devote Study Group.
In: Diabetologia, Vol. 61, No. 1, 01.01.2018, p. 58-65.
On Behalf Of The Devote Study Group 2018, 'DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality', Diabetologia, vol. 61, no. 1, pp. 58-65. https://doi.org/10.1007/s00125-017-4422-0
On Behalf Of The Devote Study Group. DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. Diabetologia. 2018 Jan 1;61(1):58-65. https://doi.org/10.1007/s00125-017-4422-0
On Behalf Of The Devote Study Group. / DEVOTE 3 : temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality. In: Diabetologia. 2018 ; Vol. 61, No. 1. pp. 58-65.
@article{2d74746a6f48492db87845836eb0a275,
title = "DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality",
abstract = "Aims/hypothesis: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. Methods: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. Results: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. Conclusions/interpretation: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. Trial registration: ClinicalTrials.gov NCT01959529.",
keywords = "Hypoglycaemia, Insulin therapy, Macrovascular disease",
author = "{On Behalf Of The Devote Study Group} and Pieber, {Thomas R.} and Marso, {Steven P} and McGuire, {Darren K} and Bernard Zinman and Poulter, {Neil R.} and Emerson, {Scott S.} and Pratley, {Richard E.} and Vincent Woo and Simon Heller and Martin Lange and Kirstine Brown-Frandsen and Alan Moses and {Barner Lekdorf}, Jesper and Lucine Lehmann and Kajsa Kvist and Buse, {John B.}",
note = "Funding Information: Open access funding provided by Medical University of Graz. We thank the trial investigators, trial staff and trial participants for their participation, P.-M. Haahr (Novo Nordisk A/S, Denmark) for insights that assisted in the development of this article, and F. Hemingway and R. McDonald 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: 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 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{\textquoteright} 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: 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. Funding Information: Acknowledgements Open access funding provided by Medical University of Graz. We thank the trial investigators, trial staff and trial participants for their participation, P.-M. Haahr (Novo Nordisk A/S, Denmark) for insights that assisted in the development of this article, and F. Hemingway and R. McDonald 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{\textquoteright}s National Center for Advancing Translational Science. Funding Information: SSE has received personal fees related to Data Monitoring Committees from CTI BioPharma, Arena Pharmaceuticals, SFJ Pharmaceuticals, BioMarin, Medivation, Biom{\textquoteright}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: 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: REP{\textquoteright}s services were paid 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 grant from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Inc., Eli Lilly, Merck, Sanofi US LLC and Takeda. 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. Publisher Copyright: {\textcopyright} 2017, The Author(s).",
journal = "Diabetologia",
T1 - DEVOTE 3
T2 - temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality
AU - On Behalf Of The Devote Study Group
AU - Pieber, Thomas R.
AU - Marso, Steven P
AU - McGuire, Darren K
AU - Poulter, Neil R.
AU - Emerson, Scott S.
AU - Pratley, Richard E.
AU - Woo, Vincent
AU - Heller, Simon
AU - Lange, Martin
AU - Brown-Frandsen, Kirstine
AU - Moses, Alan
AU - Barner Lekdorf, Jesper
AU - Lehmann, Lucine
AU - Kvist, Kajsa
AU - Buse, John B.
N1 - Funding Information: Open access funding provided by Medical University of Graz. We thank the trial investigators, trial staff and trial participants for their participation, P.-M. Haahr (Novo Nordisk A/S, Denmark) for insights that assisted in the development of this article, and F. Hemingway and R. McDonald 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: 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 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: 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. Funding Information: Acknowledgements Open access funding provided by Medical University of Graz. We thank the trial investigators, trial staff and trial participants for their participation, P.-M. Haahr (Novo Nordisk A/S, Denmark) for insights that assisted in the development of this article, and F. Hemingway and R. McDonald 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. 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: 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: REP's services were paid 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 grant from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Inc., Eli Lilly, Merck, Sanofi US LLC and Takeda. 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. Publisher Copyright: © 2017, The Author(s).
N2 - Aims/hypothesis: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. Methods: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. Results: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. Conclusions/interpretation: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. Trial registration: ClinicalTrials.gov NCT01959529.
AB - Aims/hypothesis: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. Methods: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. Results: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. Conclusions/interpretation: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. Trial registration: ClinicalTrials.gov NCT01959529.
KW - Hypoglycaemia
KW - Insulin therapy
KW - Macrovascular disease
JO - Diabetologia
JF - Diabetologia