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Biomarkers related to severe hypoglycaemia and lack of good glycaemic control in ACCORD.

ABSTRACT: In patients with diabetes, intensive glycaemic control reduces microvascular complications. However, severe hypoglycaemia frequently complicates intensive glycaemic control. Blood biomarkers that predict successful intensification of glycaemic control in patients with type 2 diabetes without the development of severe hypoglycaemia would advance patient care. In patients who received intensive treatment for type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesised that insulin deficiency and islet autoantibodies would be associated with severe hypoglycaemia and failure to achieve near-normal glycaemia (HbA1c <6.0% [42 mmol/mol]).A nested case-control design was used. Cases (n?=?326) were defined as participants having severe hypoglycaemia and failure to achieve an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death. Controls (n?=?1,075) were those who achieved an HbA1c level of <6.0% (42 mmol/mol) prior to the ACCORD transition or death without severe hypoglycaemia. Each case was matched (for race, age and BMI) by up to four controls. Baseline insulin deficiency (fasting C-peptide ?0.15 nmol/l) and islet autoantibodies (glutamic acid decarboxylase [GAD], tyrosine phosphatase-related islet antigen 2 [IA2], insulin [IAA] and zinc transporter 8 [ZnT8]) were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used on the full cohort and after removal of patients who died and their respective controls.Severe hypoglycaemia accompanied by an inability to achieve an HbA1c level of <6.0% (42 mmol/mol) was associated with insulin deficiency (adjusted OR 23.2 [95% CI 9.0, 59.5], p?

SUBMITTER: Chow LS

PROVIDER: S-EPMC4416999 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Biomarkers related to severe hypoglycaemia and lack of good glycaemic control in ACCORD.

Chow Lisa S LS Chen Haiying H Miller Michael E ME Marcovina Santica M SM Seaquist Elizabeth R ER

Diabetologia 20150205 6

<h4>Aims/hypothesis</h4>In patients with diabetes, intensive glycaemic control reduces microvascular complications. However, severe hypoglycaemia frequently complicates intensive glycaemic control. Blood biomarkers that predict successful intensification of glycaemic control in patients with type 2 diabetes without the development of severe hypoglycaemia would advance patient care. In patients who received intensive treatment for type 2 diabetes from the Action to Control Cardiovascular Risk in ...[more]

PMID: 25652389

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Project description:ObjectiveTo determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.DesignRetrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics.ParticipantsPatients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A(1C)) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A(1C) <6.0%) or standard (haemoglobin A(1C) 7.0-7.9%) glucose control.Outcome measuresSymptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.Results10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia.ConclusionSymptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued.Trial registrationNCT00000620.

Project description:Aims/hypothesisThe 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.MethodsIn 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.ResultsDay-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/interpretationHigher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality.Trial registrationClinicalTrials.gov NCT01959529.

Project description:AimsTo examine maternal fear of hypoglycaemia, glycaemia and pregnancy outcomes in women with impaired and normal awareness of hypoglycaemia.MethodsA pre-planned sub-study of 214 pregnant women with type 1 diabetes who participated in the CONCEPTT trial. Participants completed hypoglycaemia fear surveys (HFS-II) at baseline. Logistic regression and Poisson regression analyses were used to obtain an adjusted estimate for the rate ratio relating awareness to the number of severe hypoglycaemic episodes, and for several neonatal outcomes in relation to the total HFS-II score. The role of continuous glucose monitoring (CGM) use was examined.ResultsOverall, 30% of participants reported impaired awareness of hypoglycaemia (n = 64). Women with impaired awareness of hypoglycaemia had more episodes of severe hypoglycaemia (mean 0.44 vs. 0.08, p < 0.001) (12-34 weeks gestation) and scored higher on the HFS-II scale (43.7 vs. 36.0, p 0.008), indicating more fear of hypoglycaemia. They spent more time below range (CGM <3.5 mmol/L) and exhibited more glycaemic variability at 12 weeks gestation. Higher overall HFS-II scores were associated with a higher risk of maternal severe hypoglycaemia episodes (Rate Ratio 1.78, 95% CI 1.39-2.27). Women with impaired awareness of hypoglycaemia had less maternal weight gain but there were no differences in neonatal outcomes between women with impaired awareness of hypoglycaemia and normal hypoglycaemia awareness. Higher HFS-II scores were associated with more nephropathy (Odds Ratio 1.91, 95% CI 1.06-3.4). CGM use after 12 weeks was not associated with the number of episodes of severe hypoglycaemia (RR 0.75, 95% CI 0.49-1.15; p = 0.18).ConclusionsIn pregnant women with type 1 diabetes, impaired awareness of hypoglycaemia is associated with more maternal severe hypoglycaemia episodes and more fear of hypoglycaemia. Having impaired awareness of hypoglycaemia and/or fear of hypoglycaemia should alert clinicians to this increased risk. Reassuringly, there was no increase in adverse neonatal outcomes.

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Biomarkers related to severe hypoglycaemia and lack of good glycaemic control in ACCORD.

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Biomarkers related to severe hypoglycaemia and lack of good glycaemic control in ACCORD.

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