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

Chow, Lisa S.; Chen, Haiying; Miller, Michael E.; Marcovina, Santica M.; Seaquist, Elizabeth R.

doi:10.1007/s00125-015-3512-0

Cited by 19 publications

(21 citation statements)

References 27 publications

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“…This assay had a coefficient of variation of 2.89% at a mean level of 54.2 IU/mL, and 0.56% at a mean level of 2.06 IU/mL. C‐peptide was measured in fasting samples using a multiplex assay (Myriad RBM Inc., Austin, Texas) as previously reported …”

Section: Methodssupporting

confidence: 90%

The association of basal insulin treatment versus standard care with outcomes in anti‐GAD positive and negative subjects: A post‐hoc analysis of the ORIGIN trial

Birkeland

Grill

Wium

et al. 2018

Diabetes Obesity Metabolism

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We compared cardiovascular and other outcomes in patients with dysglycaemia with or without anti-glutamic acid dehydrogenase (GAD) antibodies participating in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Of the 12 537 participants, 8162 had anti-GAD measured at baseline and 267 were anti-GAD positive. The effects of insulin glargine versus standard care and of n-3 fatty acids supplements versus placebo were compared by testing the interaction of the treatment effects and anti-GAD status. The effect of glargine on development of new diabetes was assessed in participants without previous diabetes at baseline. The overall incidence of outcomes did not differ between anti-GAD positive and anti-GAD negative subjects. The incidence of the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke did not differ between anti-GAD positive participants randomized to insulin glargine or to standard care, with a hazard ratio (HR) (95% confidence interval [CI]) of 0.80 (0.44-1.44) or in anti-GAD negative participants with a HR of 1.07 (0.96-1.20) (P for interaction = 0.20).

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Section: Methodssupporting

confidence: 90%

The association of basal insulin treatment versus standard care with outcomes in anti‐GAD positive and negative subjects: A post‐hoc analysis of the ORIGIN trial

Birkeland

Grill

Wium

et al. 2018

Diabetes Obesity Metabolism

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“…In our study population, hypoglycaemia occurrence was not a barrier to better control, even though, in short‐term, treat‐to‐target studies, the overall incidence is high. Within each responder group, a higher event rate was associated with lower insulin dose and lower baseline C‐peptide levels, as reported by others, suggesting the existence of sub‐populations with greater insulin deficiency and higher insulin sensitivity . Overall, the contribution of diabetes duration to predicting the achievement of glycaemic outcome is lower than that of HbA1c.…”

Section: Discussionsupporting

confidence: 70%

Commencing insulin glargine 100 U/mL therapy in individuals with type 2 diabetes: Determinants of achievement of HbA1c goal less than 7.0%

Owens

Landgraf

Frier

et al. 2019

Diabetes Obesity Metabolism

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Aims To identify factors associated with achievement of glycated haemoglobin A1c (HbA1c) target at 24 weeks after commencing basal insulin therapy in individuals with type 2 diabetes mellitus (T2DM). Materials and methods Post‐hoc pooled analysis of 16 randomized, treat‐to‐target trials involving individuals with T2DM inadequately controlled with oral anti‐hyperglycaemic drugs (n = 3415) initiated on once‐daily insulin glargine 100 U/mL (Gla‐100). Clinical outcomes were assessed by HbA1c response at 24 weeks and individuals were classified as “good responders” with HbA1c <7.0% (<53 mmol/mol) or as “poor responders” with HbA1c ≥7.0% (≥53 mmol/mol). Univariable and multivariable stepwise logistic regression analyses were performed to identify predictive factors for attaining HbA1c <7.0%. Results Lower levels of baseline HbA1c, fasting plasma glucose (FPG) and post‐prandial plasma glucose (PPG), higher body mass index (BMI), shorter diabetes duration and male sex were associated with a good glycaemic response, but not age or baseline C‐peptide levels. Gla‐100 dose (U/kg) was highest in the poor‐responder group, which had the fewest hypoglycaemia episodes. Univariable analysis for achievement of HbA1c <7.0% confirmed these observations. Multivariable analysis retained baseline HbA1c, body weight, BMI, sex, 2‐hours PPG and diabetes duration as predictors of a good response. Continued use of sulfonylureas, hypoglycaemia and change in body weight were indicative of poor response. Conclusions Baseline HbA1c was the strongest determinant for achieving target HbA1c <7.0% by supplementary Gla‐100 therapy, while sex and BMI were also useful indicators. However, age and C‐peptide levels at baseline did not predict glycaemic response to the introduction of basal insulin.

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“…Given the timing between SH and mortality (median 1.75 years) reported in this study, SH does not seem to be driver for mortality, but rather, in the right clinical substrate, a harbinger for mortality. The current results extend our earlier findings on SH and glycaemic control [20] and suggest that these blood biomarkers may predict SH and mortality. Overall, this work suggest that fasting C-peptide and GAD antibody may serve as potential biomarkers in predicting outcomes in patients with clinically diagnosed Type 2 diabetes.…”

Section: Discussionsupporting

confidence: 90%

Biomarkers associated with severe hypoglycaemia and death in ACCORD

et al. 2015

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Aims and hypothesis In patients with Type 2 diabetes, intensive glycaemic control is associated with hypoglycaemia and possibly increased mortality. However, no blood biomarkers exist to predict these outcomes. Using participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, we hypothesized that insulin deficiency and islet autoantibodies in patients with clinically diagnosed Type 2 diabetes would be associated with severe hypoglycaemia and death. Methods A nested case–control study design was used. A case (n = 86) was a participant who died with at least one episode of severe hypoglycaemia, defined as hypoglycaemia requiring assistance, at any point during ACCORD follow-up. A control (n = 344) was a participant who did not die and did not have severe hypoglycaemia during follow-up. Each case was matched to four controls (glycaemic intervention arm, race, age and BMI). 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 (ZnT8)] were measured. Conditional logistic regression with and without adjustment for age, BMI and diabetes duration was used. Results Death during ACCORD in those who experienced at least one episode of severe hypoglycaemia was associated with insulin deficiency [OR 4.8 (2.1, 11.1): P < 0.0001], GAD antibodies [OR 2.3 (1.1, 5.1): P = 0.04], the presence of IAA or baseline insulin use [OR 6.1 (3.5,10.7): P < 0.0001], which remained significant after adjusting for age, BMI, and diabetes duration. There was no significant association with IA2 or ZnT8 antibodies. Conclusions In patients with Type 2 diabetes, C-peptide or GAD antibodies may serve as blood biomarkers predicting higher odds of subsequent severe hypoglycaemia and death. (Clinical Trial Registry No: NCT00000620, www.clinicaltrials.gov for original ACCORD study)

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

Cited by 19 publications

References 27 publications

The association of basal insulin treatment versus standard care with outcomes in anti‐GAD positive and negative subjects: A post‐hoc analysis of the ORIGIN trial

The association of basal insulin treatment versus standard care with outcomes in anti‐GAD positive and negative subjects: A post‐hoc analysis of the ORIGIN trial

Commencing insulin glargine 100 U/mL therapy in individuals with type 2 diabetes: Determinants of achievement of HbA1c goal less than 7.0%

Biomarkers associated with severe hypoglycaemia and death in ACCORD

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