Introduction: Interventions that decrease mean glucose have reduced rates of type 1 diabetes (T1D) vascular complications, but the difference in cardiovascular disease (CVD) risk between people with T1D and the general population endures. This suggests that factors beyond hemoglobin A1c (HbA1c) normalization may drive T1D CVD outcomes. HbA1c variability is an established predictor of T1D microvascular disease, but thus far only the FinnDiane Study has implicated it as a risk factor for T1D CVD events. No studies have examined the relationship of HbA1c variability to both CVD risk factors and events in a prospective T1D cohort.

Methods: We used multivariable logistic regression to analyze the Coronary Artery Calcification in Type 1 Diabetes (CACTI) T1D cohort (N=597) . Primary outcomes were square root-transformed coronary artery calcium (CAC) volume and CVD events. CVD events were defined as myocardial infarction, coronary artery bypass grafting, angioplasty, or cardiovascular death. HbA1c variability was defined as a 1-standard deviation increment in HbA1c and calculated as standard deviation of all HbA1c values for each subject.

Results: After adjustment for age, sex, and T1D duration, HbA1c variability predicted both CVD events (HR: 1.562, 95% CI: 1.052-2.318, P=0.0269) and CAC volume (rpartial= 0.3346, P<0.001) , while mean HbA1c predicted CVD events (HR: 1.399, 95% CI: 1.079-1.816, P=0.0114) but not CAC volume (rpartial= 0.0934, P=0.2886) . Further investigation revealed that the relationship between HbA1c variability and CVD events was strongest in those with good glycemic control (HR: 6.330 at mean HbA1c of 6.0%, HR: 3.920 at mean HbA1c of 7.0%, HR: 2.428 at mean HbA1c of 8.0%, HR: 1.5at mean HbA1c of 9.0%, and HR: 0.931 at mean HbA1c of 10.0%) .

Conclusion: HbA1c variability may be a risk factor for both coronary atherosclerosis and CVD events in T1D, and the appropriate care strategy for this population may include maintaining an HbA1c value over time that is both at-target and stable.


W.B.Horton: None. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc.


National Institutes of Health (R01DK116731) National Institutes of Health (R01HL113029)

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