Cardiovascular Risk in Diabetes Mellitus: Complication of the Disease or of Antihyperglycemic Medications

Abstract

Cardiovascular disease is the principal complication and the leading cause of death for patients with diabetes (DM). The efficacy of antihyperglycemic treatments on cardiovascular disease risk remains uncertain. Cardiovascular risk factors are affected by antihyperglycemic medications, as are many intermediate markers of cardiovascular disease. Here we summarize the evidence assessing the cardiovascular effects of antihyperglycemic medications with regard to risk factors, intermediate markers of disease, and clinical outcomes.

Figure 1. Proposed conceptual model of demonstrating the relationship between diabetes mellitus and cardiovascular disease

Figure 2. Sodium–glucose co-transporter 2 mechanism of action and glucose handling in the kidney

Na+/K+ ATPase creates a gradient that allows for the transport of sodium and glucose across the luminal border via SGLT2. Glucose is returned to the bloodstream via GLUT2. Ninety-seven percent of filtered glucose is reabsorbed through this mechanism. SGLT2 inhibitors block the action of SGLT2 allowing glucose to be eliminated by the kidneys. The remaining 3% of glucose that travels to the late proximal tubule is reabsorbed by SGLT1. Legend: Na+/K+ ATPase: sodium potassium adenosine triphosphatase active transporter; SGLT: sodium-glucose transporter; GLUT: facilitative glucose transporter; KCNE1: potassium voltage-gated channel Isk-related family member 1; KCNQ1: potassium voltage-gated channel KQT-like subfamily member 1.

Figure 3. Effect of thiazolidinediones on renal sodium reabsorption

Legend: Thiazolidinediones (TZDs) enhance sodium reabsorption through the promotion of translocation of the epithelial sodium channel (ENaC) in the renal collecting ducts. TZDs promote 1) ENaC mRNA transcription in the nucleus, 2) ENaC translocation to the luminal surface, 3) phosphorylation of SGK1 which enhances ENaC translocation.

Figure 4. Sulfonylurea effect on ischemic preconditioning

Legend: Potassium ATP (K_ATP) channel is a heterodimer composed of sulfonylurea receptor (SUR) and Kir6.2, a pore forming subunit, that assemble in the plasma membrane. SUR1 found in the pancreas (A) shares 68% identity to the SUR2A isoform found in cardiac tissue (B). Sulfonylureas (S) inhibit channel activity responsible for potassium influx. This inhibition is thought to effect ischemic preconditioning in cardiac myocytes.