Glucose as a modifiable cause of atherosclerotic cardiovascular disease: Insights from type 1 diabetes and transplantation. (October 2021) - Senior, Peter A.
Abstract: Diabetes is a major risk factor for cardiovascular (CV) disease. In contrast to the clear benefits from treatments which reduce blood pressure and lipids, clinical trials targeting blood glucose have not shown clear CV benefits. Interventions to intensify glycemic control early in the course of diabetes may have benefits in long term observational studies (DCCT-EDIC/UKPDS), but may not be helpful if introduced late in the course of type 2 diabetes (ACCORD, ADVANCE, VA-DT). More recent CVOT in high risk subjects suggest that the benefits of SGLT2 and GLP1-RA are glucose-independent. Type 1 diabetes provides a "cleaner" model to study the links between glucose and cardiovascular disease. Abnormalities of glucose regulation in type 1 diabetes is not restricted to hyperglycemia, but includes glycemic variability and hypoglycemia. Increasingly the mechanisms linking glycemic variability and hypoglycemia as key mediators of cardiovascular complications are being understood. Furthermore, data from pancreas and islet transplantation showing reduced cardiovascular mortality and regression of intima-media thickness supports a causal role for glucose in the pathogenesis of atherosclerosis, but suggests that restoration of normal glucose regulation may be required to demonstrate substantial impact on CV risk accrued over decades of type 1 diabetes. Considering the limited organ supply and risks of immunosuppression, advances in biology (stem cell derived beta cells) or technology (automated insulin delivery systems) will be required to provide a scalable solution to deliver optimal glucose control and reduce CV risk for people with type 1 diabetes. Graphical abstract: Image 1 Highlights: Early intensive glycemic control can reduce long-term cardiovascular risk (legacy effect), but may not be effective later. Independent of hyperglycemia, glycemic variability and hypoglycemia are key drivers of atherosclerosis in type 1 diabetes. Pancreas and islet transplantation can normalize glucose regulation with abolition of glucose variability and hypoglycemia. Successful pancreas and islet transplantation reduces cardiovascular mortality and progression of intima-media thickening. Restoration of normal glucose regulation may be required to substantially address residual risk in diabetes.