In this study, we demonstrated that most FLP-CGM–derived metrics are significantly associated with arterial stiffness, even after adjusting for various risk factors including HbA1c levels in 445 outpatients with type 2 diabetes and no history of apparent CVD. Notably, some FLP-CGM–derived metrics related to inter-day glucose variability and hyperglycemia identified subjects with high arterial stiffness who were at high risk for developing CVD.
In patients with type 2 diabetes, the main cause of arterial stiffness is damage to vascular walls caused by prolonged hyperglycemia. In fact, previous cross-sectional studies have indicated that higher HbA1c levels are associated with increased arterial stiffness in patients with type 2 diabetes [22, 23]. In contrast, HbA1c was not associated with arterial stiffness in this study, a finding that was consistent with a different previous study . On the other hand, this study found significant associations between FLP-CGM derived metrics related to hyperglycemia such as TAR> 13.9 mmol/L and HBGI. Unlike HbA1c, these parameters reflect remarkable hyperglycemia and were not affected by hypoglycemia. Thus, our data do not contradict the fact that the main cause of arterial stiffness is damage to vascular walls caused by prolonged hyperglycemia in patients with type 2 diabetes.
Previous cross-sectional studies demonstrated that CGM-derived metrics related to intra-day glucose variability are associated with carotid atherosclerosis, coronary atherosclerosis, or endothelial dysfunction in patients with type 2 diabetes [7–10]. This study also found that SD, CV, and MAGE are significantly associated with arterial stiffness; these variables reflect another aspect of atherosclerosis in patients with type 2 diabetes. Various factors are involved in the progression of arterial stiffness in patients with type 2 diabetes. Indeed, previous cross-sectional studies have demonstrated that conventional atherosclerotic risk factors such as age, BMI, duration of type 2 diabetes, glycemic control, dyslipidemia, systolic BP, eGFR, elevated uric acid levels, and albuminuria [25–27] are associated with arterial stiffness in patients with type 2 diabetes. Intriguingly, in this study FLP-CGM–derived metrics related to intra-day glucose variability were significantly associated with degree of arterial stiffness, even after adjusting for those possible conventional atherosclerotic risk factors. Taken together, this study highlighted the importance of intra-day glucose variability in terms of assessing the risk of arterial stiffness.
A recent study demonstrated that the incremental glucose peak, an indicator of glucose variability, during an oral glucose tolerance test is associated with arterial stiffness in patients with type 2 diabetes . However, whether oral glucose tolerance test-derived incremental glucose peak reflects the pattern of glucose variability during usual living conditions has not yet been clarified. In this regard, this is the first study to provide evidence that FLP-CGM–derived metrics related to intra-day glucose variability evaluated during usual living conditions are significantly associated with arterial stiffness. Although the exact mechanism of how glucose variability contributes to arterial stiffness remains unclear, we propose the following possible scenarios. Previous studies have shown that glucose variability induces inflammation and overproduction of oxidative stress to a greater extent than chronic persistent hyperglycemia [29, 30], leading to advanced AGE formation. The formation of AGEs is considered to be involved in arterial stiffness through cross-linking of collagen molecules and a subsequent loss of collagen elasticity . Accordingly, vascular walls may be damaged by glucose variability more than by chronic persistent hyperglycemia.
In this study, FLP-CGM–derived metrics related to hypoglycemia were associated with arterial stiffness. Similarly, some recent studies have demonstrated that the acute effects of hypoglycemia include inflammation and endothelial injury in patients with type 1 diabetes [32, 33]. In addition, a cross-sectional study demonstrated that repeated episodes of hypoglycemia are associated with preclinical atherosclerosis as evaluated by carotid and femoral ultrasonography and measurement of flow-mediated brachial dilatation in patients with type 1 diabetes . Furthermore, we previously reported that a higher frequency of hypoglycemic episodes is associated with progression of carotid atherosclerosis in patients with type 2 diabetes . Accordingly, physicians need to help prevent hypoglycemic episodes through assessing the risks of hypoglycemia with CGM in order to minimize arterial stiffness, especially in patients who have difficulty detecting or who are completely unaware of hypoglycemia.
As discussed above, this study demonstrated that FLP-CGM–derived metrics are significantly associated with arterial stiffness. On the other hand, it is more important to screen for patients with a high potential of developing CVD in order to reduce the incidence of CVD. To achieve this goal, the Japanese Circulation Society proposed baPWV of 1,800 cm/sec as the cutoff value to identify subjects who are at high risk for developing CVD based on the results of several studies . Based on this cutoff value, approximately 33% of study participants were defined as being at high risk for CVD. Subjects with high arterial stiffness were older, had longer duration of diabetes, lower BMI, higher systolic BP, higher UAE, higher prevalence of diabetic retinopathy, and lower eGFR. They were more frequently treated with insulin and calcium channel blockers. Even after adjusting for these confounding factors, FLP-CGM–derived metrics related to intra-day glucose variability such as SD, CV, MAGE, and metrics related to hyperglycemia such as TAR> 13.9 mmol/L and HBGI were significantly associated with high arterial stiffness. Given that FLP-CGM–derived metrics related to hypoglycemia, such as TIR3.9–10 mmol/L and TAR> 10 mmol/L were not associated with high arterial stiffness, high postprandial glucose excursion amplitude may be a major contributor to increased arterial stiffness. Thus, based on FLP-CGM–derived metrics, focusing on reducing the amplitude of postprandial glucose excursion may be important to reducing the risk of both arterial stiffness and CVD development.
One strength of this study is its multicenter study design. Our study had certain limitations. First, the study was an exploratory study with a relatively small sample size. Second, the cross-sectional study design made it impossible to evaluate whether there was a causal relationship between FLP-CGM–derived metrics and arterial stiffness. We only used arterial stiffness as a marker for the risk of CVD development. In this regard, we are currently conducting a long-term follow-up study in the same cohort that focuses on FLP-CGM–derived metrics and onset of primary CVD or changes in arterial stiffness. Third, FLP-CGM–derived metrics were evaluated based on FLP-CGM measurements during a limited time. Due to this limitation, FLP-CGM–derived metrics related to inter-day glucose variability may be not associated with arterial stiffness after adjusting for various atherosclerotic risk factors. Repeated FLP-CGM measurements may be required to clarify the relationship between inter-day glucose variability and arterial stiffness. Fourth, we only recruited Japanese patients with type 2 diabetes. These constraints may limit the generalizability of our results.