Biomarkers associated with severe hypoglycaemia and death in ACCORD

Abstract

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)

Long‐term efficacy and safety of canagliflozin in combination with insulin in Japanese patients with type 2 diabetes mellitus

“…These results, alongside the fact that all patients received insulin, suggest that lower serum C‐peptide at Week 0 may be a risk factor for hypoglycaemia when patients are treated with insulin. Similarly, in the post‐hoc analysis of the ACCORD trial, a fasting C‐peptide level of ≤0.15 nmol/L (0.45 ng/mL) was identified as a risk factor for severe hypoglycemia …”

“…Similarly, in the post-hoc analysis of the ACCORD trial, a fasting C-peptide level of ≤0.15 nmol/L (0.45 ng/mL) was identified as a risk factor for severe hypoglycemia. 33 In patients with type 1 diabetes or advanced T2DM, absolute β-cell failure results in no decrease in β-cell insulin secretion and, thus, no increase in α-cell glucagon secretion during hypoglycemia. 34,35 Hypoglycaemia may be caused by this lack of response to glucagon among patients who have low fasting C-peptide (ie, low insulin production).…”

Clinical Outcomes of Diabetic Ketoacidosis in Type 2 Diabetes Patients with and without SGLT2 Inhibitor Treatment: A Retrospective Study

“…This is supported by the fact that non-users of SGLT2 inhibitors were more likely to require insulin therapy, which appears to be a marker of more severe insulin deficiency. Progressive insulin deficiency is a recognized risk factor for poor outcomes in T2DM [13]. The presumably higher prevalence of insulin deficiency among non-users of SGLT2 inhibitors suggests a more severe metabolic disturbance, which could have contributed to higher long-term mortality.…”

Frühe oder kurzzeitige Insulintherapie bei Typ-2-Diabetes: Stellenwert und Risiko-Nutzen-Bilanz im Rahmen individualisierter Therapiekonzepte

“…Die C-Peptid-Sekretion nach Glukagonstimulation hatte sich unter Glibenclamid verschlechtert, dagegen unter Insulin signifikant verbessert. Die erhaltene residuale C-Peptid-Sekretion gilt als wichtiger Schutzmechanismus für schwere Hypoglykämien [63,64].…”