Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: The EXAMINE trial

Abstract

AimsTo investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).MethodsThe EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double‐blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events.ResultsPatients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (P interaction = 0.971) or HbA1c category at 1 month. Patients in the combined treatment groups (n = 5380) who experienced serious hypoglycaemia (n = 34) had higher MACE rates than those who did not (35.3% vs 11.4%, adjusted hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.27–4.60; P = .007), although the association was less strong when analysing only events after the hypoglycaemic event (adjusted HR 1.60, 95% CI 0.80, 3.20).ConclusionsThere were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post‐ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

Exposure to hypoglycemia and risk of stroke

“…Similarly, a nonsignificant increase in the risk for nonfatal stroke was observed in individuals those who had (hazard ratio 1.81, P = 0.085) versus those who had not experienced severe hypoglycemia. However, a recently published study using data from the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study observed that the adjusted hazard ratio for MACE risk in patients who experienced serious hypoglycemia events (hazard ratio 2.42, P = 0.007) was significantly higher than those without serious hypoglycemia exposure . However, this study did not report effects on nonfatal stroke separately.…”

Early cardiovascular risk and all‐cause mortality following an incident of severe hypoglycaemia: A population‐based cohort study

“…Our analysis provides robust chronological evidence that death and CV events occur soon after a severe hypoglycaemic event. Few studies have investigated the temporal relationship between severe hypoglycaemia and CV events, as well as death, and most such studies were post‐hoc analyses of randomized controlled trials . Moreover, in these sub‐analyses, the credibility of results was limited by the small number of severe hypoglycaemic events and subsequent CV events.…”

“…Furthermore, there remains considerable controversy regarding the potential temporal relationship between severe hypoglycaemia and adverse cardiovascular events. In the Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care (EXAMINE) trial, it was found that severe hypoglycaemia was associated with higher rates of major adverse cardiovascular events (MACE), but this did not reach a level of statistical significance if only MACE after a hypoglycaemic event was included in the analysis . Results from the Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) showed a greater risk of all‐cause mortality in the short term after a severe hypoglycaemic episode and a decreased risk with long‐term windows, although there was a non‐significant association between severe hypoglycaemia and the risk of MACE .…”

“…Conclusive evidence concerning the exact temporal relationship between hypoglycaemia and subsequent cardiovascular events or death remains lacking. Several recent post‐hoc analyses in randomized clinical trials attempted to clarify these relationships, but the number of events was relatively small and the results were inconsistent . In addition, some of the recruited populations in these clinical trials were at high cardiovascular risk or had established cardiovascular diseases and, therefore, were not representative of the general population.…”

The Fallacy of Average: How Using HbA1c Alone to Assess Glycemic Control Can Be Misleading

“…CGM profiles provide far more information than just the mean glucose concentration by identifying patterns of hyperglycemia and hypoglycemia as well as potentially dangerous high or low glucose concentrations that are often missed with self-monitoring of blood glucose. The results of secondary analyses of two major studies (the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care [EXAMINE] trial and the Atherosclerosis Risk in Communities [ARIC] Study) (25,26) that found an association between hypoglycemia and cardiovascular events emphasize the importance of understanding a patient’s glucose profile with CGM to potentially identify patients who may be at high risk for these events. Thus CGM by providing more clinical insights than HbA 1c or self-monitoring of blood glucose measurements can help optimize and personalize glucose control and diabetes management (27).…”