Treating Diabetes Without Breaking Your Heart

Figures from the World Health Organization show that cardiovascular diseases (CVDs), a spectrum of conditions that include coronary artery disease and cerebrovascular disease, are the leading cause of death worldwide.

Dig a little deeper and you will discover the group most impacted by CVD. Adults with diabetes are two to four times more likely to suffer a heart attack or stroke than those without the disease. All of the traditional risk factors for developing heart disease—hyperlipidemia, hypertension, smoking, and obesity—are amplified in diabetics.

The good news here is that aggressive management of hyperglycemia, blood pressure and dyslipidemia (abnormal amount of lipids in the blood) can significantly cut the risk of any CVD by nearly 50%! The bad news is that less than 10% of diabetics have achieved the American Diabetes Association’s recommended goals for control of blood glucose, blood pressure and cholesterol. Nonetheless, progress has been made over the past 20 years in reducing these diabetes complications, as evidenced in a recent study in the New England Journal of Medicine study. At least some of the rate reduction can be attributed to better management of major risk factors using novel therapies.

For instance, the PPARγ agonists, such as rosiglitazone and pioglitazone, are insulin- sensitizing agents that allow that hormone to act more efficiently. Exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, acts in a number of ways to stimulate insulin secretion, decrease appetite and suppress glucagon secretion to lower blood glucose. Sitagliptin and other members of the “gliptin” family are inhibitors of dipeptidyl peptidase-4, an enzyme that degrades GLP-1. Treatment with these agents prolongs the lifetime of GLP-1 in the bloodstream and enhances its anti-diabetic activities. A relative newcomer to the armamentarium of diabetes therapies are the sodium-glucose co-transporter-2 inhibitors. These therapies inhibit the re-absorption of glucose from blood filtered by the kidney, causing glucose to be excreted in the urine.

In vivo testing of candidate therapies has played a large part in the discovery and development of these groundbreaking medicines used in the treatment of diabetes and its complications. As with any drug discovery effort, translatable disease models are extremely important, and the medical research community strives to select those systems that best recapitulate the disease pathophysiology, guided by clinical observations.

Traditionally, rodent models have been used as the proving ground for assessing glycemic control with novel agents. Several mouse and rat strains have been discovered that present with diabetes. Some strains fail to synthesize insulin (Akita mouse), while others develop diabetes driven by excessive obesity (ob/ob, db/db, Zucker fatty rat and Zucker diabetic fatty rat). These strains are all deficient in some key aspect of metabolic regulation. The use of diet-induced obesity in normal animals has also been used to study the development of diabetes driven purely by consumption of high fat diets. A variety of chemical and surgical approaches have also been used to impair the secretion of insulin from the pancreas. Many of these strains, given enough time, will develop complications of diabetes similar to what is observed in humans.

Under the auspices of the US National Institutes of Health, the Diabetic Complications Consortium was created to foster communication and collaboration between researchers engaged in diabetes research. The group provides data on the phenotype of mouse models of diabetes, and other resources for the research community. Eight sites engage in mouse engineering and phenotyping and one site is dedicated to coordinating the accrued bioinformatics. The primary goal of all nine sites is the creation of mouse models for studying the complications of diabetes.

The importance of this effort is underscored by the clinical experience with rosiglitazone (Avandia), a potent regulator of insulin sensitivity that ran into some rough waters about five years ago. Population studies published in 2009 showed that there appears to be an increase in cardiovascular events in patients treated with the drug, despite good glycemic control. Pioglitazone, another popular insulin-sensitizing agent in the same chemical class which is sold under the tradename Actos, didn’t. Studies in standard rodent models failed to uncover this potential liability, perhaps because of differences between mice and humans in the density of the receptor that binds rosiglitazone in the heart. Or it could also have been due to some unknown ancillary activity that is specific to this drug. The data led the FDA to issue restrictions and warning labels for rosiglitazone while Europe simply pulled the drug off market, but in an about-face, the FDA withdrew the restrictions last November after determining that Avandia presented no greater heart risk than the most commonly used diabetes drugs.

Whatever the case, it’s clear that there is a need to de-risk these kinds of agents before they reach the clinic. To do this effectively, we need to better understand how well our models and test systems translate to the human clinical situation. The work being conducted and coordinated by the Diabetic Complications Consortium is going to be an important driver in this process. That effort will help guide the selection of appropriate models not only for efficacy studies, but for the assessment of potential adverse events.

The end game should be clear, though: Achieve tight glycemic control without breaking someone’s heart!