GLP-1 targeted therapy may help diabetes patients

Take-Home

The role of ophthalmologists will become increasingly more vital in the management of type 2 diabetes as the numbers of patients with the disease is projected to double by 2030. Exenatide may prove to be an important adjunct to current oral anti-diabetes drugs.

By Lynda Charters; Reviewed by Susan M. Pepin, MD

Hanover, NH-Given that the numbers of individuals with type 2 diabetes is nearly 300 million worldwide, and likely to double by 2030, ophthalmologists will play an even greater role in the management of the disease.

“Type 2 diabetes and cardiovascular disease are intimately linked,” said Susan M. Pepin, MD, associate professor of surgery and pediatrics, Geisel School of Medicine, Dartmouth College, Hanover, NH,

A glucagon-like peptide-1 (GLP-1) agonist, exenatide (Byetta, Bydureon, Bristol-Myers Squibb), is proving to be an important adjunctive therapy to current oral anti-diabetes drugs by helping to prevent the cardiovascular side effects of type 2 diabetes.

Traditional oral anti-diabetic agents, according to Dr. Pepin, do not specifically address the severity of cardiovascular disease in patients with type 2 diabetes.

New therapeutic agents should be identified that involve GLP-1, a potent incretin. Also, the agents should be classified based on the GLP-1 effects to consider potential cardiovascular safety profiles, as well as potential increased risk of pancreatitis or cancer in patients undergoing treatment with these drugs.

Underscoring the importance of GLP-1, Dr. Pepin described the case of a 59-year-old obese (body mass index, 33) male with a 12-year history of diabetes and who presented with sudden-onset binocular horizontal diplopia.

The patient was treated with metformin 1,000 mg injected subcutaneously and atorvastatin (Lipitor, Pfizer) and denied having cardiovascular disease or diabetic retinopathy. The hemoglobin A1c was in the 8s, and blood pressure was 144/97 mm Hg. Clinical examination showed that the left eye did not adduct and the patient had a left sixth-nerve palsy.

Ophthalmologists are important in the care of such patients, she stressed, noting the intimate link between type 2 diabetes and cardiovascular disease.

Cardiovascular disease is the leading cause of more than 60% of deaths in patients with diabetes. High glucose levels are believed to increase the risk of coronary artery disease and myocardial infarction, she noted.

“Most of the standard oral anti-diabetes drugs do not reduce the incidence rates of myocardial infarction, stroke, or cardiovascular death in patients with diabetes,” Dr. Pepin added.

The case for GLP-1

After a meal, L-cells in the gut release GLP-1, which results in increased insulin secretion in the pancreas, glucose uptake in muscles, glucagon formation in the liver, improved satiety, and delayed gastric emptying, Dr. Pepin explained.

Inhibitors of the activity of dipeptidyl peptidase 4 (DDP-4)-a protein that rapidly degrades GLP-1-and GLP-1 receptor agonists-which resist the activity of DDP-4-are important potential therapeutic agents to augment the standard oral therapies, because in patients with type 2 diabetes, GLP-1 secretion is greatly reduced.

Currently, the DPP-4 inhibitors-sitagliptin (Januvia, Merck), saxagliptin (Onglyza, Bristol-Myers Squibb), and vildagliptin (Galvus, Novartis Pharmaceuticals)-are in clinical trials. GLP-1R agonists include exenatide, which received FDA approval in 2006, and liraglutide (Victoza, Novo-Nordisk), which is similar to exenatide.

Cardioprotective effect

Exenatide affects the GLP-1 receptor and through a series of different mechanisms is thought to have a cardioprotective effect. Dr. Pepin cited a recent study by Mundil and associates (Diabetesand Vascular Disease Research. 2012;9:95-108) that combined data from six studies investigating treatment of hyperglycemia and the cardiovascular risk factors associated with GLP-1 receptor agonists in more than 2,000 patients.

“The study showed a substantial and significant reduction of hyperglycemia in these patients who were already receiving oral hyperglycemic agents and exenatide,” she said.

Investigators found that GLP-1R agonists reduced body weight and systolic blood pressure and improved patients’ lipid profiles. The proposed mechanisms by which these effects occurred were appetite suppression, reduced body fat stores, natriuresis and diuresis, and improved endothelial function.

The caveat associated with GLP-1 drugs is a potential risk for development of chronic pancreatitis as reported in cases submitted to the FDA.

However, this risk is questionable, Dr. Pepin noted, because patients who are obese and have type 2 diabetes already are at an increased risk of pancreatitis and pancreatic cancer. In a 3-year period from 2005 to 2007, more than 7 million exenatide prescriptions were written, but only 78 cases of kidney dysfunction were reported, she said.

“Because type 2 diabetes causes significant end-organ complications-primarily cardiovascular disease-anti-diabetic treatment should favor cardiovascular safety profiles and not result in weight gain,” Dr. Pepin said. “Exogenous GLP-1 analogues are proving to be powerful adjunctive therapy for hyperglycemic control with these safety profiles.”

There are inadequate data to assess the true pancreatitis and cancer risks in patients at this time, she noted. A large clinical trial of GLP-1 agents is under way, but the results are not expected for 3 years.

Susan M. Pepin, MD

E: susan.m.pepin@dartmouth.edu

Dr. Pepin has no financial interest in any aspect of this report.

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