Type 2 diabetes and cardiovascular disease
Nonglycemic effects of diabetes medications
Managing one to prevent the other
The prevalence of type 2 diabetes mellitus (T2DM) is increasing inexorably in Western countries and developing nations. Epidemiological studies indicate that one-half to three-quarters of people with T2DM are destined to die of cardiovascular events and their sequelae. Considerable controversy exists, however, concerning the mediators of this increased risk and whether treatment can reduce the risk.
John M. Miles, M.D., of the Division of Endocrinology at Mayo Clinic in Rochester, Minn., says: "Although early scientists assumed that hyperglycemia was the mediator of all of the complications of diabetes, many studies undertaken over the past half-century have cast doubt on this notion. This research indicates that many factors, including hypertension, dyslipidemia and a prothrombotic state, contribute to the increased cardiovascular risk of type 2 diabetes."
The nonischemic cardiomyopathy that occurs in T2DM is an area of increasing interest to investigators. Ananda Basu, MBBS, M.D., of the Division of Endocrinology at Mayo Clinic in Rochester, explains: "The notion that fatty heart (the accumulation of lipid in the heart muscle, analogous to fatty liver) is a common occurrence in obesity and type 2 diabetes and mediates diastolic dysfunction leading, in some cases, to overt heart failure has gained credence in recent years on the basis of results from animal and human studies. There is virtually no information on the effect of diabetes pharmacotherapy on this phenomenon."
Before 1995, pharmacological treatment of T2DM in the United States was limited to insulin and sulfonylurea agents. Dr. Miles notes: "Since that time, numerous new agents with unique and disparate mechanisms of action have become available. It is now clear that there are marked differences among agents in their nonglycemic effects, with potential implications regarding cardiovascular risk reduction."
UK Prospective Diabetes Study
The U.K. Prospective Diabetes Study demonstrated that insulin provision therapy in the form of either insulin or sulfonylureas produced a statistically significant (P=.01), but somewhat disappointing (~15%), reduction in the incidence of myocardial infarction, durable over 20 years of follow-up.
Dr. Miles explains: "The same study showed a one-third reduction in myocardial infarction with metformin over 20 years. The differences between the modest benefit of insulin provision and the more robust effect of metformin could not be explained by differences in glycemic control. What, then, is the explanation?
- "Metformin produces modest weight loss, whereas insulin provision therapy is associated with weight gain.
- "A number of studies have shown favorable effects of metformin on high-density lipoprotein cholesterol and triglycerides; in contrast, the effects of sulfonylureas on lipids are modest to negligible.
- "Metformin is associated with lowering of the plasminogen activator inhibitor-1 (PAI-1) level. Insulin and sulfonylureas, on the other hand, produce no change (in some instances, they have been shown to result in an increase in PAI-1).
- "Metformin does not appear to be associated with an increase in blood pressure, whereas several studies have shown an increase in blood pressure during insulin treatment that appears to be related to weight gain.
- "In addition, insulin is an underrated regulator of renal tubular sodium metabolism, promoting sodium retention.
"These observations explain, in part, why the American Diabetes Association recommends metformin as first line therapy for type 2 diabetes."
Dr. Basu says: "Other classes of diabetes agents, such as thiazolidinediones (TZDs) and a-glucosidase inhibitors, have been shown to have favorable effects on cardiovascular outcomes in some clinical trials, although results are inconsistent:
- "TZDs (specifically, pioglitazone) lower blood pressure and decrease PAI-1, improve dyslipidemia and endothelial function, and induce a favorable redistribution of body fat.
- "a-Glucosidase inhibitors lower blood pressure and decrease low-density lipoprotein cholesterol (and in some studies also lower triglyceride levels), improve endothelial function, and promote modest weight loss.
"Although improvements in forearm endothelial function have been shown with acute administration of glucagon-like peptide 1 (GLP-1) and GLP-1 agonists, hard outcome data are not yet available with long-term exposure to these agents. In addition, GLP-1 agonists lower blood pressure and triglycerides levels, raise high-density lipoprotein cholesterol levels, and produce significant weight loss. This result stands in contrast to sulfonylureas, which are associated with weight gain and do not have favorable effects on blood pressure, lipid levels or endothelial function."
Dr. Miles concludes: "Thus, there are many roads to Rome and it matters how you get there. It should be acknowledged that insulin and sulfonylureas remain important and necessary tools for the treatment of hyperglycemia in type 2 diabetes. In the presence of difficult-to-manage dyslipidemia, hypertension and a generally increased risk profile, however, the nonglycemic effects of diabetes agents should be taken into consideration when selecting therapy. Metformin should be prescribed as monotherapy or in combination with other agents, including insulin and sulfonylureas, for most overweight and obese patients unless there is a specific contraindication to its use."