Could a medication make obesity healthier?

Diabetes and obesity medication
At Lilly Research Labs, researchers are conducting early trials with an experimental drug that might improve the metabolic function and overall health prospects of the obese. Lilly already makes and markets the diabetes drug Byetta, shown here.
(Tom Strattman)

With 78 million American adults in the obese column and showing slim chances of permanently dieting their way out of it, one way of mitigating the public health disaster to come would be to unhook the wagonload of obesity-related ills -- most notably Type 2 diabetes and cardiovascular disease -- from obesity itself. In this scenario, a person could remain heavy, but take a medication or follow some regimen that drives down his or her risk of developing the metabolic dysfunction, the high blood pressure, worrisome cholesterol readings, fatty liver and inflammation that so often come with obesity.

Some would say a therapy capable of such wonders already exists: regular, intensive exercise. But many obese Americans aren’t very inclined to do that. So a medication would be welcome.

In the journal Cell Metabolism, a group of researchers from Lilly Research Center in Indianapolis is reporting some early success with humans taking LY2405319, or LY for short. LY is a variant of fibroblast growth factor 21, a circulating protein present in all humans that helps regulate insulin sensitivity and the metabolism of energy and fatty acids. In obese rhesus monkeys, boosting FGF-21 levels prompted weight loss and improved metabolic function and lipid profiles. In rodents, it activated brown fat to rev up the burning of calories and improved metabolic function in a number of ways.



In a Phase 2 trial of LY, the Lilly researchers recruited 46 obese adults with Type 2 diabetes, and gave 36 of them daily subcutaneous injections of the synthesized protein, in three different doses. Over the next 28 days, they looked for LY’s effects on subjects’ weight, lipids, and metabolic function, and for evidence of how the potential medication works.

As early as Day 2, the triglyceride levels of all three groups of subjects getting LY began to show improvement. That improvement reached its peak and sustained level by Day 7. By Day 7, subjects getting the two higher doses of LY -- 10 mg and 20 mg, respectively -- began showing improvements in their lipid profiles. LDL, or “bad” cholesterol levels, started going down, and HDL, or “good” cholesterol readings, went up.

By the end of the study, participants on the 10 mg and 20 mg doses of LY had significant positive changes in their lipid and triglyceride levels -- both markers for cardiovascular disease -- compared with those on a placebo.

Despite orders to maintain exercise-and-diet habits, participants in the LY arms of the trial also lost weight during the 28 days -- close to 4 pounds for those getting 10 mg doses and a bit over 3 pounds among those getting the 20 mg dose. But so did participants in the placebo arm, so a significant weight loss benefit for LY was not shown in this trial.


The trial also failed to find evidence that LY improved participants’ fasting glucose levels. But researchers found two suggestive changes in those taking LY: They had “robust” reductions, on average, in their fasting insulin levels. And those getting high doses of LY had higher levels of circulating adiponectin than did those on a placebo by the end of the trial. Together, these changes suggest that, given for a longer time, LY might increase insulin sensitivity and possibly boost the effects of existing diabetes medications.

Among participants taking the experimental drug, one in the high-dose group had a severe drop in blood pressure along with rash and hives, and three subjects dropped out of the trial with complaints including hives, sensitivity at the injection site, headache and elevated liver enzymes. 

It will take longer and larger trials to determine whether LY in some form could benefit obese patients who are diabetic or pre-diabetic. But this early trial suggests therapies based on fibroblast growth factor 21 “may be effective for the treatment of selected metabolic disorders,” the authors concluded.


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