GLP-1 Agonism Holds Promise for Preventing Macrovascular Disease in Type 2 Diabetes

Value-Based Care in Cardiometabolic Health Dec 2012, Vol 1, No 3
Wayne Kuznar

Boston, MA—No glucose-lowering regimen has been shown to reduce macrovascular complications, such as myocardial infarction (MI) or stroke, but glucagon-like peptide (GLP)-1 agonism appears to have favorable effects on many surrogate markers for cardiovascular disease (CVD), according to presenters at the 2012 Cardiometabolic Health Congress.

Although hyperglycemic states increase cardiovascular (CV) risk in a continuous manner, definitive evidence that glucose control decreases the risk of major CV events is missing, said Jorge Plutzky, MD, Director, Vascular Disease Prevention Program, Brigham and Women’s Hospital, Harvard Medical School, Boston.

As many as 80% of patients with type 2 diabetes will develop and possibly die from macrovascular disease. Even impaired glucose tolerance increases the risk for atherosclerosis and death. “By the time that type 2 diabetes is diagnosed, there are already changes that are manifest in the vasculature,” Dr Plutzky said.

Although lower levels of hemoglobin A1c levels were associated with a lower risk of mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, this study also showed that intensive glucose lowering increased 5-year mortality compared with conventional glucose lowering. As for macrovascular disease, “there is conflicting evidence that achievement of glycemic control with antidiabetic therapy is associated with reductions in CV morbidity and mortality,” said Jaime A. Davidson, MD, FACP, FACE, President of Endocrine and Diabetes Associates of Texas, and Clinical Professor of Medicine, University of Texas Southwestern Medical School, Dallas.

Evidence from the United Kingdom Prospective Diabetes Study (UKPDS) suggests, however, that early diagnosis and intensive glucose control from the start are keys to long-term risk reduction in diabetes, said Dr Davidson. Long-term follow-up of the UKPDS cohort demonstrated a significant 15% to 33% reduction in the rate of MI within the intensive glycemic control group compared with the conventionally treated group.

Some common oral therapies for type 2 diabetes have adverse CV effects, said Dr Davidson, including the sulfonylureas and thiazolidinediones. In particular, sulfonylureas that are not selective for KATP channels may have negative CV effects. In addition, sulfonylureas increase the risk for severe hypoglycemia, which is associated with increased risk for death.

Potential for CV Protection, Outcomes Studies in Progress
Recent regulatory obligations for all diabetes medications include excluding excess risk in phase 2/3 clinical trials, especially in high-risk populations, that include predefined CV end points with independent blind adjudication being mandatory, said Benjamin Scirica, MD, MPH, of the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital.

Until now, guideline recommendations have been made in high-risk patients based on CV end points in clinical studies that enrolled less than 1000 patients. “We need better data in more patients and over a longer follow-up to appropriately evaluate the risks and benefits of antidiabetic agents,” he said. “Surrogate end points are not sufficient for such a prevalent and morbid disease.”

The incretin GLP-1 is secreted by enteroendocrine L cells. GLP-1 receptors are expressed at multiple sites in the body. Normal GLP-1 secretion is stimulated by food intake. Activation of GLP-1 receptors in the central nervous system promotes satiety and the reduction of appetite, and their activation in the pancreas enhances insulin secretion and insulin sensitivity. However, the release of GLP-1 is no longer intact in persons with type 2 diabetes, said Dr Plutzky.

GLP-1 receptors are also prominent in cardiac tissues. In animal models of cardiac function, GLP-1 receptor agonism leads to vasodilation, increased myocardial glucose uptake, attenuation of ischemic injury, limitation of infarct size, and improvements in stroke volume, cardiac output, ejection fraction, and systemic resistance.

The half-life of GLP-1 in circulation is less than 2 minutes, because it is rapidly degraded by the dipeptidyl peptidase (DPP)-4 enzyme.

In humans, incretin-based therapies in the form of GLP-1 receptor agonists and DPP-4 inhibitors have improved peripheral blood flow in short-term studies in patients with type 2 diabetes, improved left ventricular function and short-term exercise capacity in patients with class II to III heart failure, and decreased the incidence of arrhythmias and improved glycemic control after coronary artery bypass graft surgery.

The potential for CV protection with the use of DPP-4 inhibitors and GLP-1 agonists is being tested in clinical studies. Incretin modulators and other antidiabetes agents are being studied in studies of CVD outcomes in more than 120,000 patients with type 2 diabetes.

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