![]() ![]() To further support this hypothesis, postprandial blood glucose (PBG) levels are more predictive for CVD than HbA1c levels. These episodes of high glucose levels increase oxidative stress, which in turn has several detrimental downstream effects, activating immune cells, and keeping the vasculature in a persistent state of elevated risk of cardiovascular events ( Figure 1). ![]() Epidemiological studies have also suggested that postprandial spikes of high glucose levels may be a more robust determinant of CVD risk than average glucose levels ( 11– 15). Studies investigating the long-term benefits of glucose lowering treatment have revealed a modest benefit of glucose-lowering treatment in both type 1 ( 9) and type 2 diabetes ( 10), and suggest that prolonged reductions are required to achieve this benefit. The fact that glucose lowering treatment in people with diabetes has not convincingly reduced the high risk of CVD does not rule out the possibility that high glucose levels are causally involved in the development of CVD. The phenomenon that diabetes is characterized by high glucose levels and an increased risk of CVD, but glucose lowering treatment fails to effectively reduce this risk, is often referred to as the glucose paradox ( 8). However, statins are less effective in people with diabetes, even if cholesterol levels are lowered equally ( 7), suggesting there is still a large unmet medical need for optimized cardiovascular risk-management in diabetes. ![]() In reality, controlling traditional CVD risk factors including blood pressure and plasma lipids still remains the most successful strategy to reduce CVD mortality in diabetes ( 6). The reasons for this are not completely understood, but it is thought that benefits of glucose-lowering treatments may be partly counterweighed by an increased occurrence of severe hypoglycemic episodes associated with intensive insulin therapy. Although others have found a modest reduction of coronary heart disease by glucose-lowering treatment in large meta-analyses ( 4, 5), the effects are somewhat disappointing with no reduction of all-cause mortality being identified. Therefore, the extent to which a reduction of hyperglycemia in diabetes directly reduces cardiovascular disease (CVD) remains controversial. Even though new glucose-lowering treatments, such as glucagon-like peptide 1 (GLP1) agonists and sodium glucose receptor 2 uptake inhibitors (SGLT2i) reduce major adverse cardiovascular events (MACE), it is already evident that most of the therapeutic benefit is achieved independently of their reduction in HbA1c ( 3). Despite the fact that benefits from intensive glucose-lowering treatment were obvious in reducing microvascular complications in initial trials such as the Diabetes Control and Complications Trial (DCCT) (type 1 diabetes), the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trials (type 2 diabetes) showed no obvious benefit from glucose lowering treatment in the short term ( 2). In this review, we summarize the potential mechanisms through which hyperglycemic spikes may increase atherosclerosis and how new and emerging interventions may combat this.Īlthough the pathophysiological mechanisms through which individuals develop type 1 and type 2 diabetes are different, both conditions are characterized by elevated blood glucose levels and share a similar elevated risk of cardiovascular mortality ( 1). It is proposed that these short, intermittent bursts of hyperglycemia may have detrimental effects on several organ systems including the vasculature and the hematopoietic system collectively contributing to the state of elevated CVD risk in diabetes. In fact, lowering glucose appears to promote some beneficial long-term effects, and continuous glucose monitoring devices have revealed that postprandial spikes of hyperglycemia occur frequently, and may be an important determinant of CVD risk. However, this doesn't rule out the possibility of hyperglycemia playing a major causal role in promoting CVD or elevating CVD risk.
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