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

Diabetologia, Sep 2017

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

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

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2) Bernard Zinman 0 1 2 3 4 5 6 7 8 9 Steven P. Marso 0 1 2 3 4 5 6 7 8 9 Neil R. Poulter 0 1 2 3 4 5 6 7 8 9 Scott S. Emerson 0 1 2 3 4 5 6 7 8 9 Thomas R. Pieber 0 1 2 3 4 5 6 7 8 9 Richard E. Pratley 0 1 2 3 4 5 6 7 8 9 Martin Lange 0 1 2 3 4 5 6 7 8 9 Kirstine Brown-Frandsen 0 1 2 3 4 5 6 7 8 9 Alan Moses 0 1 2 3 4 5 6 7 8 9 Ann Marie Ocampo Francisco 0 1 2 3 4 5 6 7 8 9 Jesper Barner Lekdorf 0 1 2 3 4 5 6 7 8 9 Kajsa Kvist 0 1 2 3 4 5 6 7 8 9 John B. Buse 0 1 2 3 4 5 6 7 8 9 on behalf of the DEVOTE Study Group 0 1 2 3 4 5 6 7 8 9 0 Research Medical Center , Kansas City, MO , USA 1 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , 60 Murray St, Box 17 , University of Toronto , Toronto, ON M5T 3L9 , Canada 2 Bernard Zinman 3 University of North Carolina School of Medicine , Chapel Hill, NC , USA 4 Novo Nordisk A/S , Søborg , Denmark 5 Sanford Burnham Prebys Medical Discovery Institute , Orlando, FL , USA 6 Florida Hospital Translational Research Institute for Metabolism and Diabetes , Orlando, FL , USA 7 Medical University of Graz , Graz , Austria 8 University of Washington , Seattle, WA , USA 9 Imperial Clinical Trials Unit, Imperial College London , London , UK 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 (prebreakfast 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 prespecified 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 prebreakfast 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 dayto-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 allcause 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 Abbreviations DEVOTE Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events EAC Event Adjudication Committee FPG Fasting plasma glucose MACE Major adverse cardiovascular event SMBG Self-measured blood glucose Introduction The main goal of glucose-lowering therapy in type 2 diabetes is to reduce the incidence and progression of both microvascular and macrovascular complications [ 1 ]. However, while insulin is traditionally considered to be the most effective glucose-lowering therapy, and often becomes necessary as type 2 diabetes progresses, it is (...truncated)


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Bernard Zinman, Steven P. Marso, Neil R. Poulter, Scott S. Emerson, Thomas R. Pieber, Richard E. Pratley, Martin Lange, Kirstine Brown-Frandsen, Alan Moses, Ann Marie Ocampo Francisco, Jesper Barner Lekdorf, Kajsa Kvist, John B. Buse, on behalf of the DEVOTE Study Group. Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2), Diabetologia, 2017, pp. 1-10, DOI: 10.1007/s00125-017-4423-z