Greater Long-Term HbA1c Variability Increases Risk of All-Cause, Cardiovascular Death

December 2, 2020
Patrick Campbell

An analysis of the Look AHEAD study by investigators at Johns Hopkins details associations between long-term variability of glycemic markers and increased risk of all-cause and cardiovascular mortality.

New research from an analysis of more 3500 patients with type 2 diabetes is giving clinicians further insight into the relationship between HbA1c variability and risk of all-cause mortality in diabetic patients.

A secondary analysis of the Look AHEAD study, results suggested those in the highest quartile of HbA1c variability were at a 2-times greater risk of all-cause mortality and more than a 3-times greater risk of death from cardiovascular causes when compared to those in the lowest quartile of glycemic variability.

“Our findings underscore the need of a consistent and less variable glycemic control over time and indicate that HbA1C variability is potentially a better marker of long-term glycemic variability than fasting plasma glucose variability,” wrote study investigators. “Our results also suggest that long-term glycemic variability, especially that measured by HbA1C may capture the metabolic memory effect, which has been shown to be detrimental in terms of outcomes in diabetes.”

With the burden of diabetes continuing to grow in the US and throughout the world, a team led by investigators from Johns Hopkins University sought to develop a greater understanding of how long-term variability of glycemic markers might predict negative outcomes in patients with type 2 diabetes. Using the Look AHEAD trial, which was designed to assess the effects of intensive lifestyle intervention versus an education intervention on cardiovascular outcomes, investigators had access to data from more than 5000 participants with a median follow-up of 9.6 years.

From the multicenter, randomized clinical trial, investigators identified a cohort of 3560 participants with data related to HbA1c and fasting plasma glucose (FPG) measurements at baseline, 12 months, 24 months, and 36 months. In addition to participants missing glycemic marker data, investigators also excluded those who had cardiovascular disease, heart failure events or died before the 36-month visit and those with consent restrictions or prevalent CVD at baseline.

The goal of the current analysis was to assess the effects of HbA1c and FPG variability, separately, on all-cause mortality, cardiovascular mortality, incident heart failure, and a composite cardiovascular endpoint of myocardial infarction, hospitalization for angina, stroke, and death from cardiovascular causes.

For the purpose of analysis, age, sex, race/ethnicity, randomization arm, cigarette smoking status, alcohol consumption, body mass index (BMI), use of antihypertensive medication, duration of diabetes, and eGFR were used as covariates in adjusted models. Investigators also noted data obtained from baseline through the 4 study visits were used to calculate average systolic and diastolic blood pressures, average ratio of total to HDL cholesterol, average FPG, and average HbA1c for study participants.

The 3560 participants included in the study had a median follow-up of 6.8 years. Over the follow-up period, 164 deaths from any cause, 33 cardiovascular-related deaths, 91 heart failure events, and 340 events meeting the composite cardiovascular endpoint.

In adjusted analyses comparing those in the highest quartile of standard deviation (SD) of HbA1c, results suggested those in the highest quartile were at increased risk of all-cause mortality (HR, 2.10; 95% CI, 1.26-3.51), cardiovascular mortality (HR, 3.43; 95% CI, 0.95-12.38), heart failure (HR, 1.71; 95% CI, 0.69-4.24), and the composite cardiovascular endpoint (HR, 1.01; 95% CI, 0.69-1.46). Analyses comparing highest to lowest quintiles of SD for FPG revealed equivalent HRs 1.66 (95% CI, 0.96-2.85) for all-cause mortality, 2.20 (95% CI, 0.67-7.25) for cardiovascular mortality, 2.05 (95% CI 0.80 to 5.31) for heart failure, and 0.94 (95% CI, 0.65-1.35) for the composite cardiovascular endpoint.

“Our findings have potential implications, as these add to the growing body of evidence on the prognostic value of glycemic variability,” investigators noted.

Investigators pointed out multiple limitations within their study. These included the observational design of the study, excluding patients who died during the first 36 months of follow-up, and the inability to evaluate 2-hour post oral load glucose level.

This study, “Long-term variability of glycemic markers and risk of all-cause mortality in type 2 diabetes: the Look AHEAD study,” was published in BMJ Open Diabetes Research and Care.