Experimental molecule may reduce side effects of controversial diabetes drug

Experimental molecule may redu...
The new molecule is hoped to reduce the side effects of rosiglitazone, offering diabetics a novel and safe therapy
The new molecule is hoped to reduce the side effects of rosiglitazone, offering diabetics a novel and safe therapy
View 1 Image
The new molecule is hoped to reduce the side effects of rosiglitazone, offering diabetics a novel and safe therapy
The new molecule is hoped to reduce the side effects of rosiglitazone, offering diabetics a novel and safe therapy

A newly developed experimental drug could help mitigate some of the dangerous side effects caused by a once-promising diabetes medication. Early animal tests suggest the novel combination treatment is both safe and effective at helping regulate blood sugar levels in type 2 diabetes.

Rosiglitazone was first approved for human uses by the FDA in 1999. It was certainly effective as a treatment for type 2 diabetics, however concerns quickly began to arise as reports grew citing a number of adverse effects. Heart failure, osteoporosis, weight gain and fluid retention were all problematic side effects that some research linked to rosiglitazone.

By 2010 it was clear rosiglitazone was in trouble. Drug-maker GlaxoSmithKline faced a number of civil lawsuits, and ultimately was found guilty by the US government of withholding study data that suggested the drug could increase risk of heart attack. Since then, the drug has been withdrawn from several international markets, although it is still available for use in the United States.

A recently published study from the Yale School of Public Health delivered the largest systemic review to date investigating rosiglitazone’s association with heart problems. That research confirmed the drug does indeed raise a person’s risk of cardiovascular problems.

“For a long time, rosiglitazone has been used for treating Type 2 diabetes and insulin resistance,” explains Da Young Oh, from UT Southwestern and senior author on the new study. “… this drug is very good – very effective. But at the same time, there are still serious side effects, including weight gain, fluid retention, and more.”

The new research tested rosiglitazone in combination with a new experimental small molecule dubbed Compound A. The new molecule is designed to activate a receptor called GPR120. Activating this receptor in fat cells, and some immune cells, has been seen to improve insulin sensitivity and lower inflammation. Omega-3 fatty acids, found in fish oils, is a natural GPR120 activator.

Animal tests revealed rosiglitazone and Compound A worked in tandem to reduce insulin sensitivity in diabetic mouse models. Most importantly, the combination treatment allowed for low doses of rosiglitazone to produce efficacious results similar to what would be seen in more problematic high doses.

“The very low dose we used in this study showed no side effects – no weight gain, no fluid retention – in mouse models,” says Oh. “The hope is that we will be able to use rosiglitazone at lower doses to treat Type 2 diabetes patients in a more effective way without side effects.”

At this stage the animal studies do not specifically demonstrate this combination therapy directly mitigating the bone loss and heart problems seen in human rosiglitazone experiences. While the study does hypothesize the lower rosiglitazone dose could potentially avoid the dangerous adverse effects seen in higher doses, that will need to be verified in future research.

Compound A has been developed by Merck, one of the largest pharmaceutical companies in the world. At this stage it's still an early investigational drug so there is a long road ahead before we see this new rosiglitazone combination therapy in clinical use.

The new study was published in the journal Cell Metabolism.

Source: UT Southwestern

Hmm. Very effective at treating the original disease, but causes other diseases instead. Which are then treated with another drug...
Awesome. When rosiglitazone was first available, it seemed to check all the boxes and made us wonder how much longer adult onset DM was going to be a problem. The research was toying out individual receptors close to the source of hormonal switched - the mythical "turn on insulin resistance and turn off normal blood glucose feedback mechanisms" theories of the day. Nothing like that has come to fruition - just another drug company that touted the benefit and ignored the comorbidity that accompanied the new drug. If my patients can't get the picture that what they do to their body for twenty years results in the body they have today, then I give them the options.....compound A may make rosiglitazone a more efficacious therapy, but once again polypharmacology rules and reason wanes. Glad for the breakthrough, and I hope that mythical trigger compound is finally found so we can turn the hormonal system back to normal feedback levels instead of treat the broken system.