Bariatric surgery in a pill takes a step forward

A three-hormone treatment shows promise as an alternative to bariatric surgery

It's more of a glimmer of hope on the horizon than it is an actual drug right now. But an Indiana University lab has synthesized and fused a trio of gut hormones into a single agent and shown that obese rodents treated with the resulting molecule experience dramatic weight loss and a reversal of obesity-related ills such as Type 2 diabetes and fatty liver disease.

Reporting their latest findings this week in the journal Nature Medicine, the authors of the new study described a cascade of synergistic effects in lab animals in response to the three-hormone agent the researchers devised.

The researchers likened the results in lab animals to the subtle and far-reaching changes brought about in human patients following bariatric surgery, who not only experience weight loss in response to gastric bypass surgery, but often an abrupt reversal of Type 2 diabetes, high blood pressure, inflammation and worrisome cholesterol readings.

The strategy of targeting several of obesity's causes with a single multipronged treatment, the authors of the latest research wrote, "has the potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders."

In obese mice, the agent brought about a weight reduction approaching 30% and reversing some of the hallmarks of Type 2 diabetes. Early clinical trials in humans already are underway to test prototype molecules based on the principles explored in the latest study. Those are sponsored by the Swiss pharmaceutical giant Roche, which owns Marcadia Biotech, the Indiana-based biotech company founded by Richard DiMarchi, one of the latest study's senior authors.

"We have a global epidemic of obesity and related diseases, and gastric bypass is not going to be available or appropriate for everyone," DiMarchi said in an interview with The Times. "It’s expensive, it involves surgical risks, and quite frankly, it’s primitive.

"If we’re going to find a breakthrough that meets the needs of this population, it's going to take bold thinking," he added. "This is one possible way forward. Let’s hope the clinical data supports it."

The history of weight-loss drug development is littered with failures, not least because most drug developers tend to fasten on to a single physiological goal--to reduce fat deposition, to improve insulin sensitivity, or to blunt appetite, for instance--and design a drug to influence that one contributor to obesity and its related ills.

The problem is that healthy humans and other mammals appear to be programmed by evolution to hold on to weight gained at all costs--even if it brings disease. Signals from the gut, brain, fat stores and visceral organs all contribute to consumption and energy usage in complex, interconnected ways. Even if a medication succeeds in harnessing one of those components to the task of weight loss, others are likely to step in to thwart the effort.

In the process, metabolic processes are disturbed and stomach distress is a common side effect. One isolated measure of good health--insulin sensitivity or weight--may be improved. But body composition may change for the worse, or blood sugar levels may continue to waver, and the larger goal of better health remains unrealized.

DiMarchi's lab, which reengineers proteins to make more powerful or targeted medicines, set out to beat the system by attacking three targets at once. They engineered a single new peptide by integrating three gastrointestinal hormones at the molecular level (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors). Those act on three key hormone receptors that govern metabolism and digestion, nudging them to work cooperatively to support weight loss, enhance glycemic control and reverse the accumulation of damaging fat in the liver.

In obese mice, a very low dose of the prototype therapy brought a 15% weight loss in 20 days (a higher dose produced a nearly 27% weight loss), reducing food intake and lowering circulating glucose without driving it so low as to induce hypoglycemia. Insulin sensitivity improved, body composition took a turn for the leaner, and evidence of fatty liver decreased.

Though testing of such an approach is in the very early stages, these improvements are on a par with those seen in patients after bariatric surgery, DiMarchi said. And that is promising.

It remains to be seen whether the same widespread effects can be replicated in humans, he added. Given the expectation that such a medication--should it pan out--would need to be used "for a sustained period," he cautioned, its safety and continued effectiveness over the long term would also need to be demonstrated.

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