A Reassessment of the Causal Effects of Dysglycemia on Atherosclerotic and Thrombotic Events

The links between dysglycemia and cardiovascular disease have been known for over a century (1). Early autopsy studies provided evidence of accelerated coronary and aortic atherosclerosis among people with diabetes (2). More recent longitudinal studies consistently demonstrated that people with diabetes are at a two- to threefold higher risk of cardiovascular complications, leading to the consideration of dysglycemia as a critical player in developing cardiovascular complications (3). However, diabetes is a complex and heterogeneous condition in which distinct concomitant metabolic alterations such as hypertension, dyslipidemia, or abdominal obesity are present in people (4). Therefore, it is difficult to disentangle the contribution of hyperglycemia in the development of cardiovascular complications.

Understanding the role of hyperglycemia in intermediary processes such as atherosclerosis and thrombosis is necessary to elucidate the contribution of hyperglycemia to the development of cardiovascular complications. Atherosclerosis is a pathological process that involves structural and functional changes in the intima and media of arterial vessels and the subsequent development of atherosclerotic plaques (5). Atherosclerotic plaques are prone to rupture, local platelet activation and aggregation, and atherothrombotic events. Venous thrombosis results from the interplay between coagulation and inflammation. Activation of the coagulation cascade triggers innate immune cells to contribute to thrombus formation and subsequent vessel occlusion (6). Although atherosclerosis and venous thrombosis are separate disease entities with distinct pathophysiological features (7), both processes involve the activation of platelets and the coagulation cascade and increased cardiovascular pathology.

Experimental studies prove that hyperglycemia contributes to many cellular alterations in vascular tissue that potentially accelerate atherosclerosis and thrombosis (8,9). Supporting these observations, clinical and genetic epidemiology studies indicated that glucose-lowering therapies reduce the risk of cardiovascular complications (10–13), primarily because of a reduction in the risk of microvascular complications. Despite this evidence, several questions remain unanswered, including regarding the contribution of different glycemic traits in developing cardiovascular complications and whether glycemic traits impact atherosclerotic or thrombotic outcomes differently.

In this issue of Diabetes, Yuan et al. (14) report on investigation of the associations of glycemic traits with a broad range of atherosclerotic and thrombotic conditions in a Mendelian randomization study. Mendelian randomization is a statistical technique that uses genetic variants as instrumental variables to infer causal associations of modifiable exposures with outcomes (15). In leveraging publicly available genetic data for four glycemic traits from the Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), including fasting glucose, fasting insulin, 2-h glucose, and HbA_1c, and outcome data for 12 atherosclerotic and 4 thrombotic outcomes from the UK Biobank and FinnGen studies and large-scale genetic consortia, the study provides evidence that dysglycemia increases the risk of atherosclerotic outcomes but not thrombotic events (Fig. 1).

A novel contribution from this study is the observation that genetically driven 2-h glucose is causally associated with a wide range of atherosclerotic events, including increased risk of coronary artery disease, peripheral artery disease, and stroke subtypes. The results of the study also corroborated that hyperglycemia and hyperinsulinemia are causally associated with atherosclerotic outcomes. Sensitivity analyses to account for unbalanced pleiotropy or potential collider bias were overall consistent, reinforcing the notion that dysglycemia is causally related to the development of atherosclerotic cardiovascular events. Further, a sensitivity analysis to mutually account for glycemic traits showed that findings for 2-h glucose were highly consistent with results of the primary analysis, indicating that the mechanism by which 2-h glucose is increased influences atherosclerosis independently of the mechanism that increases fasting glucose and insulin. These observations are aligned with clinical studies showing that variable and prolonged postprandial glycemia could have detrimental cardiovascular effects due to increased oxidative stress and inflammation (16,17). These findings provide a new perspective on the importance of monitoring dynamic glycemic fluctuations among people with and without dysglycemia.

As the authors noted, some reported associations have been noted in previous clinical and epidemiology studies. A significant strength of the current study is the inclusion of a broad range of atherosclerotic and thrombotic outcomes, some rarely studied in large-scale studies, such as peripheral artery disease or venous thromboembolism. In addition, the inclusion of independent data sets could strengthen conflicting evidence from other smaller genetic epidemiology studies. However, the study has several limitations, as acknowledged by Yuan et al. First, distinguishing between atherosclerotic and thrombotic outcomes is challenging. For example, unstable angina and ischemic stroke are often associated with thrombosis at the sites of atherosclerotic lesions. This problem is likely more relevant when outcome ascertainment is based on billing diagnoses codes and electronic medical records. Previous studies have shown that billing codes are relatively inaccurate in cardiovascular event case classification (18). This misclassification could explain null findings for thrombotic outcomes. Second, the small variance explained by genetic instruments could inflate the rate of false-negative results. However, genetic instruments were selected from the most recent genetic study for glycemic traits, and there was no presence of weak genetic instruments. Third, unbalanced pleiotropy,reverse causation, or the presence of competing risks of the outcome could bias estimates. Finally, the study was restricted to participants of European ancestry, and therefore, the results may not be generalizable to other populations.

Overall, these results are valuable in understanding the role of dysglycemia on atherosclerosis, thrombosis, and subsequent cardiovascular complications. Evidence from this study may foster new investigation lines to gain insights into the etiology of atherosclerosis and how hyperglycemia induces initial changes in the structure and function of the artery. From a clinical perspective, this study could also inform new studies to assess the effect of glycemic control or glycemic variability on subclinical atherosclerosis. Further studies using noninvasive atherosclerosis imaging techniques and continuous glucose monitoring could provide a unique perspective on cardiovascular risk stratification. Still, current guidelines for cardiovascular risk prevention do not recommend the systematic use of such tools and technologies (19). There is an unmet medical need to enhance cardiovascular risk prevention and management, and findings from this study constitute a critical milestone in cardiovascular risk stratification among people with dysglycemia.