The following are 10 points to remember from a clinical update on the impact of glucose-lowering drugs on cardiovascular disease (CVD) in type 2 diabetes:

1. Although beta-cell failure and insulin resistance are the core pathophysiologic mechanisms in type 2 diabetes, there are multiple other abnormalities, including: adipocyte insulin resistance, impaired incretin effect, increased glucagon secretion (leading to increased rate of hepatic and renal glucose production), increased renal glucose absorption, and brain insulin resistance/altered neurotransmitter function (leading to dysregulation of appetite and weight gain). Given this myriad of abnormalities, multiple drugs (with varying mechanisms of action) may be necessary for normalization of glucose homeostasis.
2. Macrovascular complications are the primary cause of mortality in diabetes mellitus. Myocardial infarction (MI) and stroke account for 80% of deaths in patients with type 2 diabetes.
3. Although metformin is the most commonly prescribed oral glucose-lowering agent worldwide, there is not conclusive evidence that it reduces CVD morbidity and mortality. It does not appear to exert adverse effects on CVD in patients with type 2 diabetes mellitus.
4. While it is unclear whether sulfonylureas are associated with an increased CVD risk, the ongoing CAROLINA (Cardiovascular Outcome Study of Linaglitin vs. Glimepiride in Patients with Type 2 Diabetes) study may offer more definitive insight.
5. Thiazolidinediones (TZDs) are the only true insulin-sensitizing agents. TZDs can cause heart failure (through enhanced sodium and water absorption), especially in patients with diastolic dysfunction. Although the Food and Drug Administration (FDA) restricted the use of rosiglitazone in the United States in 2011 (following concern about increased CVD risk, especially MI), the FDA recently re-examined the RECORD study and concluded that there was no increase in overall CV risk. The FDA has lifted its restriction on rosiglitazone; however, the drug has been slow to gain traction again.
6. Select analyses of the dipeptidyl peptidase-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin) have demonstrated a significant reduction in CV events. That said, the SAVOR-TIMI trial did demonstrate an unexpected finding of an increased incidence of hospitalization for congestive heart failure for those randomized to saxagliptin, versus those patients receiving placebo.
7. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert beneficial effects on multiple CV risk factors and the metabolic syndrome. All GLP-1RAs are associated with weight loss. Long-term prospective studies (LEADER, EXSCEL, ELIXA, SUSTAIN 6, and REWIND) will clarify how these agents modify CV outcome in high-risk individuals.
8. Sodium glucose co-transporter-2 inhibitors (SGLT2i) represent the newest class of oral agents approved for the treatment of diabetes mellitus. These agents lead to increased urinary glucose excretion, contributing to weight loss and modest reduction in blood pressure.
9. Insulin may be associated with an unpredictable and variable impact on CVD outcome. This may be related to background CVD risk, insulin dose, strategy of administration, and/or associated weight gain.
10. The authors opine: “The last word on the prevention of CVD by glucose-lowering agents must await large, long-term clinical trials in patients at low risk.”

Keywords: Adipocytes, Blood Pressure, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Dipeptidyl-Peptidase IV Inhibitors, Glucose, Heart Failure, Homeostasis, Hospitalization, Incretins, Insulin, Insulin Resistance, Metabolic Syndrome, Metformin, Myocardial Infarction, Neurotransmitter Agents, Outcome Assessment, Health Care, Pharmaceutical Preparations, Primary Prevention, Prospective Studies, Risk Factors, Stroke, Sulfonylurea Compounds, Thiazolidinediones, Weight Gain, Weight Loss

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