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HbA1c Associated with Aortic Stiffness

Progression of arterial stiffness directly linked to diabetes.

Arterial stiffening is a hallmark of the aging, and classic cardiovascular risk factors play a role in accelerating this process (Sethi et al.). Progression of arterial stiffness has been directly linked to diabetes; however, a recent study has shown that conflicting glucometabolic status in nondiabetic patients may also increase arterial stiffness.

The purpose of the study was to test the hypothesis that the impaired glucometabolic status is associated with accelerated aortic stiffening in individuals without diabetes, independently of known risk factors for arterial stiffening. In a recent longitudinal observational study, 4,386 nondiabetic participants were drawn from the Whitehall II cohort study to assess the response of glycated hemoglobin (HbA1c) on aortic stiffening. The baseline subjects included civil servants at the mean age of 60 years with 74% male and 94% white ethnic origin. Less than 5% of subjects had chronic disease, ~30% were on antihypertensive drugs, and ~27% were on lipid-lowering drugs. Every 4-5 years participants were followed up for detailed clinical examinations and self-administered questionnaires.

The glucometabolic status and cardiovascular risk factors were measured at baseline (2008-2009) and aortic stiffness was assessed by carotid femoral pulse wave velocity (cfPWV) at baseline and during follow-up (2012-2013). Heart rate, blood pressure before cfPWV, and mean arterial pressure were also recorded. Standard protocols were used to measure anthropometric and other covariates including weight, height, waist and hip circumferences, fluoride plasma, total and HDL cholesterol, triglycerides, plasma glucose, and HbA1c. The covariates analyzed were the mean values of risk factors assessed in 2003-2004 (prebaseline) and baseline to provide reliable estimates of exposure in the five years before the first cfPWV measurement. Linear mixed models estimated the glucometabolic index on cfPWV at baseline (2008-2009) by the coefficient and the progression of cfPWV until 2012-2013 was estimated with time per five years by quintile of each glucometabolic index distribution and per 1 SD increment in each index. This was done to study the relations with cfPWV across the distribution of each glucometabolic index and whether the coefficients increased linearly across quintiles. Sensitivity analysis compared participants’ characteristics and the glucometabolic measures from baseline or prebaseline.

The study found no association of the glucometabolic indices with cfPWV and its progression of cfPWV after adjustment for confounding factors and other cardiovascular risk factors between men and women. Assessment of all participants with and without cfPWV revealed that those who did not have cfPWV measured were mainly female with generally poorer health. The study showed significant positive association between fasting glucose, 2h glucose, HbA1c, and homeostatic model assessment of insulin resistance (HOMA-IR). During the four years of follow-up, cfPWV increased from (mean ± SE) 8.30 ± 0.03 to 8.98 ± 0.04 m/s. After adjustment for physiological confounders and cardiovascular risk factors, HbA1c and HOMA-IR correlated with progression of cfPWV. Greater increases in cfPWV were associated with 1 SD higher HbA1c (0.11 m/s per 5 years; P = 0.003) and HOMA-IR (0.09 m/s per 5 years; P = 0.03), but, in the fully adjusted model, only HbA1c was associated with progression in cfPWV. The addition of BMI to the models resulted in no association with HOMA-IR, and adjustment of treatments and risk factors did not attenuate these associations. To exclude selection bias, the relationship between HbA1c and blood pressure was explored at baseline and follow up with ~3% higher HbA1c in hypertensive participants with or without assessing cfPWV.

In conclusion, increased aortic stiffening is associated with higher HbA1c and HOMA-IR without diabetes and independent of other cardiovascular risk factors. BMI did not weaken the association between HbA1c and aortic stiffness. There was no association between FBG and 2 h after a standard glucose tolerance test with progression of aortic stiffness. The study was restricted to four years follow up, however, longer period of time would have added relative strength and consistency to the data. Improvement in vascular health was suggested to improve glucometabolic status because the data highlighted that higher glucose levels increased vascular aging through long-term changes in the arterial wall. Overall, further studies on glucometabolic status with longer term and interventions would help influence public health strategies against vascular aging.

Practice Pearls:

  • Diabetes is associated with increased aortic stiffness, but the importance of nondiabetic glucometabolic status for accelerated aortic stiffening is unclear.
  • HbA1c is independently associated with accelerated progression of aortic stiffness in individuals without diabetes.
  • Whitehall II is a large cohort study with prospective data on cfPWV and other risk factors, which makes it ideal to assess the relation between glycemic and aortic stiffening in non-diabetic individuals.

References:

McEniery CM, Wilkinson IB, Johansen NB, et al. Nondiabetic glucometabolic status and progression of aortic stiffness: The whitehall II study. Diabetes Care. 2017 Jan 25.

Sethi S, Rivera O, Oliveros R, and Chilton R. Aortic stiffness: pathophysiology, clinical implications, and approach to treatment. Integr Blood Press Control. 2014, May 23; 7: 29-34.