Understanding the type 2 diabetes mellitus and cardiovascular disease risk paradox

Patients with diabetes have approximately a 2-fold increase in the risk for coronary heart disease, stroke, and death from vascular causes compared with patients who do not have diabetes. Interventions targeted at modifiable risk factors, such as smoking cessation and management of hypertension and dyslipidemia, reduce the risk of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). Paradoxically, large randomized studies have failed to conclusively show that intensively lowering glucose reduces CVD event rates in patients with T2DM, despite pathophysiologic and epidemiologic evidence suggesting that hyperglycemia contributes to CVD. Although initiation of intensive glycemic control early in the disease course may be associated with a reduction in the long-term risk of cardiovascular (CV) events, this approach in those with long-standing or complicated T2DM is not of clear benefit and may even be harmful in some. Failure to mitigate risk with antihyperglycemic therapy and the potential for some treatments to increase CVD risk underlies a treatment paradox. New glucose-lowering therapies are now subject to close scrutiny for CV safety before and after drug approval. Results from the first trials designed to meet the recent CV regulatory requirements have shown no increased risk of major adverse CV events but also no CV benefit from dipeptidyl peptidase-4 inhibitor therapy, as well as a potentially increased risk of hospitalization for heart failure. Conclusive evidence of CV risk reduction with glucose-lowering therapy is still lacking and scrutiny of additional agents is necessary. Type 2 diabetes mellitus is a heterogeneous disease, for which patient-centered, individualized care, and goal-setting is appropriate. Interventions that focus on the management of CV risk factors and glucose lowering with medications that are not cardiotoxic represent an optimal and attainable treatment approach.