Long‐Term Visit‐to‐Visit Glycemic Variability as a Predictor of Major Adverse Limb and Cardiovascular Events in Patients With Diabetes

Abstract

Background Peripheral arterial disease (PAD) is a severe complication in patients with type 2 diabetes. Glycemic variability (GV) is associated with increased risks of developing microvascular and macrovascular diseases. However, few studies have focused on the association between GV and PAD. Methods and Results This cohort study used a database maintained by the National Taiwan University Hospital, a tertiary medical center in Taiwan. For each individual, GV parameters were calculated, including fasting glucose coefficient of variability (FGCV) and hemoglobin A1c variability score (HVS). Multivariate Cox regression models were constructed to estimate the relationships between GV parameters and composite scores for major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs). Between 2014 and 2019, a total of 45 436 adult patients with prevalent type 2 diabetes were enrolled for analysis, and GV was assessed during a median follow‐up of 64.4 months. The average number of visits and time periods were 13.38 and 157.87 days for the HVS group and 14.27 and 146.59 days for the FGCV group, respectively. The incidence rates for cardiac mortality, PAD, and critical limb ischemia (CLI) were 5.38, 20.11, and 2.41 per 1000 person‐years in the FGCV group and 5.35, 20.32, and 2.50 per 1000 person‐years in HVS group, respectively. In the Cox regression model with full adjustment, the highest FGCV quartile was associated with significantly increased risks of MALEs (hazard ratio [HR], 1.57 [95% CI, 1.40–1.76]; P <0.001) and MACEs (HR, 1.40 [95% CI, 1.25–1.56]; P <0.001). Similarly, the highest HVS quartile was associated with significantly increased risks of MALEs (HR, 1.44 [95% CI, 1.28–1.62]; P <0.001) and MACEs (HR, 1.28 [95% CI, 1.14–1.43]; P <0.001). The highest FGCV and HVS quartiles were both associated with the development of PAD and CLI (FGCV: PAD [HR, 1.57; P <0.001], CLI [HR, 2.19; P <0.001]; HVS: PAD [HR, 1.44; P <0.001], CLI [HR, 1.67; P =0.003]). The Kaplan‐Meier analysis showed significantly higher risks of MALEs and MACEs with increasing GV magnitude (log‐rank P <0.001). Conclusions Among individuals with diabetes, increased GV is independently associated with the development of MALEs, including PAD and CLI, and MACEs. The benefit of maintaining stable glycemic levels for improving clinical outcomes warrants further studies.

Glycated hemoglobin variability and the risk of cardiovascular events in patients with prediabetes and type 2 diabetes mellitus: A post‐hoc analysis of a prospective and multicenter study

“…The present results were in line with those from previous observational studies, which reported the association of high HbA1c variability and increased cardiovascular complications, including coronary events, heart failure, microvascular diseases, stroke, major adverse limb events, cardiovascular mortality, non-cardiovascular mortality and all-cause mortality 7,8,21 .…”

“…However, the present study showed a very high magnitude of increased risk of developing myocardial infarction by 6.9-fold, increased risk of all-cause death by 3.1fold and increased risk of heart failure by 3.3-fold in the highest quartile compared with the lowest quartile of HbA1c variability, which is greater than other studies that found only 1.2-2-fold the increased risk 7,8,21 . This difference could be explained by the fact that the two studies by Hsu et al 8 and Ceriello et al 21 excluded all diabetes patients with established ASCVD from the cohort, whereas in the present study, all diabetes participants, with or without established ASCVD, were included 8,21 . It is possible that patients who have previously had ASCVD might be at a higher risk of developing new events of cardiovascular disease compared with those without previous ASCVD.…”

“…Multiple observational studies and post‐hoc analyses have shown that high long‐term HbA1c variability is associated with an increase in MACE, major adverse limb events and all‐cause mortality in type 2 diabetes patients 5 , 6 , 7 , 8 . Furthermore, one study found this association to be significant in non‐diabetes patients 9 .…”

“…Few studies of the consequences of HbA1c variability have been carried out in Asian populations 8 , 11 , 12 , 13 . A recent large Asian cohort study showed that HbA1c variability was associated with an increased risk of long‐term MACE 8 .…”

Chronic Limb-Threatening Ischemia and the Need for Revascularization

“…Glycemic fluctuation and chronic hyperglycemia can trigger an inflammatory response, and GV has adverse effects on autonomic function and increases thrombogenicity, leading to the development of macrovascular disease. A cohort study [ 18 ] on 45 436 patients with prevalent type 2 diabetes investigated the relationship between GV and the occurrence of major adverse limb events (MALEs), and the impacts of GV on major adverse cardiovascular events (MACEs) in patients with diabetes. The study concluded that in patients with diabetes, higher GV led to a significantly increased risk of MALEs compared with lower GV, largely driven by the increased development of PAD and CLI.…”