Wednesday, June 22, 2016

Endoscopic Approaches Emerging For Diabetes

By Christina Frangou

"Promising, but most experts agree 'Prime Time' still a ways off.

Las Vegas - A treatment gap exists in diabetes care, and millions of Americans with poorly controlled diabetes fall into it.

Treatment options for the nearly 30 million Americans with type 2 diabetes start with diet and exercise. If those fail, and they often do, patients move on to pharmacotherapy and them polypharmacy. Even so, only about one-third of patients achieve the recommended glycemic target set by the American Diabetes Association.

The next option is bariatric surgery, associated with the greatest likelihood of diabetes reversal and improvement. However, very few patients are referred for surgery as a treatment for diabetes because it is invasive, has a higher risk and until recently was not broadly endorsed by disciplines outside of surgery.

Now, some physicians are looking to endoscopic treatments to fill the gap between lifestyle interventions, which have low risk but are rarely successful, and bariatric surgery, which has a beneficial effect on diabetes but poses more risk to patients.

"I think in the next five or 10 years, endoscopic treatments for type 2 diabetes will allow us to treat more patients," said Shelby Sullivan, MD, assistant professor of medicine and director of bariatric endoscopy at Washington University School of Medicine, in St. Louis. "What these therapies offer is another option for patients. In the long term, hopefully, they will offer better treatment options for a wider and larger number of patients."

Device Innovation
Dr. Sullivan and other specialists in bariatric endoscopy acknowledge that this field is still in "its infancy." But it is changing quickly. Two intragastric balloons for obesity were approved by the FDA last year, the first endoscopicaly implantable devices for diabetes that are on the market. Several more endoscopic devices are expected to come up for FDA approval in the next two years, including gastric aspiration and transpyloric shuttle.

Gastric aspiration therapy with the AspireAssist device (Aspire Bariatrics) involves placement of a gastrostomy tube that allows people to aspirate contents of their stomach 20 minutes after meal consumption. The first pilot study with 11 patients who had the therapy reported an 18.6% loss of body weight after the first year. Dr. Sullivan, who was the lead investigator on that tril, said the device is expected to be approved soon.

Dr. Sullivan was also the first physician in the United States to place a transpyloric shuttle device in a human patient. The shuttle consists of a large spherical bulb connected by a flexible tether to a smaller cylindrical bulb. Once placed endoscopicaly, the bulbs create an intermittent seal intended to reduce the rate of gastric outflow, resulting in decreased caloric intake and increased weight loss. An open-label, nonrandomized study of 20 patients treated with the transpyloric shuttle was reported at a meeting of the Society of American Gastrointestinal and Endoscopic Surgeons in 2013. After six months, patients achieved a mean excess weight loss of 50%±26.4% and a mean weight loss of 15.6±5.7 kg. Two patients required device removal because of persistent gastric ulceration. Experts said it could be approved in the latter half of 2017.

Today, there are eight endoscopic devices and techniques for diabetes that may come into clinical use before 2020, said Lee M. Kaplan, MD, PhD, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital, in Boston.

"The hope is because these various treatments and endoscopic devices target the GI tract, which is of course where bariatric surgery works, we will get to the point where some of these endoscopic treatments fall in the space between drugs and bariatric surgery. Maybe one day they will, but they are not quite there yet."

Excluding the Duodenum
Endoscopic therapies take one of two approaches to diabetes treatment: Some target diabetes solely via weight loss, which others aim to both induce weight loss and provide an additional antidiabetic effect. Those in the latter category would ideally work much like the Roux-en-Y gastric bypass, which has been shown to have a marked impact on diabetes beyond its weight loss effect. It is unclear precisely why this happens. There is speculation that the rearranged anatomy leads to a suppression of the GLP-1 hormone that is involved in high blood glucose, or the change may be driven by other changes in the physiology of the digestive tract.

The ultimate goal of endoscopic therapies is to replicate the weight loss-independent effect of gastric bypass, said Vivek Kumbhari, MD, assistant professor of medicine and director of bariatric endoscopy at John Hopkins School of Medicine, in Baltimore. "What the endoscopist is trying to do is find the critical component of bariatric surgery that leads to the positive metabolic changes of the Roux-en-Y gastric bypass."

So far, "no one could say ... that any of the endoscopic therapies are equivalent to the Roux-en-Y gastric bypass. However, we have now established methods of excluding the duodenum from being in contact with food," he said.

One of these methods, the EndoBarrier Gastrointestinal Liner System (GI Dynamics), has been shown to result in significant metabolic benefits in studies. But, importantly, that has not come without adverse events. Currently limited to investigational use in the United States, the liner is a thing flexible tube that is placed inside the intestine for up to 12 months, making it a fully reversible duodenal-jejunal bypass sleeve (DJBS). An observational study of 39 patients implanted with the liner for a year showed excess weight loss in the same range as that reported for gastric bypass. In another multicenter trial in which 38 patients were randomized to six months with EndoBarrier treatment and dietary intervention and 39 additional patients to dietary intervention alone, glycated hemoglobin A1c (HbA1c) levels improved to 7.0% (6.4%-7.5%) in the DJBS group and 7.9% (6.6%-8.3%) in the control group (P<0.05), and the effects persisted six months after explantation.

Despite these successes, the bulk of the evidence so far suggests changes in HbA1c, fasting blood glucose and changes in antidiabetic medications among obese patients with type 2 diabetes who underwent EndoBarrier treatment are "insignificant" compared with diet and/or lifestyle modifications alone, said the authors of a recent systematic review and meta-analysis. They found the mean differences in HbA1c, and fasting plasma glucose among patients with type 2 diabetes were not statistically significant. Patients treated with the EndoBarrier liner had higher rates of nonfatal adverse events than patients in bariatric surgical trials, according to the report. The most common events reported were bleeding, migration or obstruction, with 19% of patients requiring early explantation.

In March, GI Dynamics announced results from a randomized, sham-controlled trial of this device in U.S. patients (the ENDO trial). The effectiveness of the therapy fell short of the efficacy end point criterion, reaching 92.8% rather than 96.5%. But the results were considered encouraging given that the trial only enrolled two-thirds of the intended subjects. The trial was halted when the device was found to be associated with a small but significant risk for hepatic abscess, the cause of which is being studied.

The EndoBarrier is an implanted device, and such devices often perform poorly in the GI tract because of mobility and high cell turnover, said Dr. Kumbhari, who heads a major research effort to look at novel metabolic endoscopic therapies. "So we see pain, bleeding and infection associated with this device. At the same time, the research with EndoBarrier did show is that excluding the duodenum is technically possible and leads to an improvement in metabolic profile."

Therapies on the Horizon

Experts have been working on other methods that might achieve the same metabolic outcomes but without requiring implantation. Duodenal mucosal resurfacing (DMR) is a technique being explored in a European multicenter study. Developed by Fractyl Laboratories, the procedure is performed by a physician who endoscopically inserts a precision-controlled heated balloon at the end of a catheter to superficially modify the lining of the duodenum, thereby decreasing its absorptive capacity. In a proof-of-concept study reported last fall during the 3rd World Congress on Inverventional Therapies for Type 2 Diabetes and 2nd Diabetes Surgery Summit, in London, 39 patients with poorly controlled type 2 diabetes received DMR on a long segment (>9 cm) or short segment (<6 cm) of the duodenum. In patients who had a baseline HbA1c of 7.5% to 10% and were taking concomitant antidiabetic medications, long-segment DMR resulted in a reduction in HbA1c from 8.5% to 7.1% (P<0.05) at six months, accompanied by a weight loss of 2.3 kg. Mean HbA1c was reduced more with long- than short-segment DMR at three months after the procedure, suggesting a dose-dependent effect, the investigators reported.

Another novel therapy on the horizon: self-assembling magnets. The technology has only been published in animal studies to date with reports in five animals, although it is now being studied in humans. The magnets are endoscopically delivered through the mouth and rectum, and advanced toward the stomach under fluoroscopic guidance. The sets of magnets come together, causing tissue necrosis and leading to formation of a fistula.

"It's essentially a jejunoileal bypass except that you're not completely bypassing the native loop," said Dr. Sullivan. "The question is what will happen in a human population? Will we see the same effects in humans?"

The hope is that endoscopic therapies will help extend diabetes and weight loss treatment to more patients. The American Diabetes Association currently recommends consideration of bariatric surgery for patients with type 2 diabetes and a body mass index greater than 35 kg/m2. However, less than 1% of the eligible patient population underwent bariatric surgery in 2014. Of those who do undergo bariatric surgery, approximately 80% are self-referred, according to Dr. Kaplan.

The need is there, but so far the research is not, Dr. Kaplan noted. He does not regularly offer endoscopic treatment for weight loss or diabetes control because the current treatments do not work well and are not covered by insurance.

"We are no way close to maturity in this field and we won't be for at least a decade. We need more research, we need more creative inventors, more clinical trials, etc. We're at the very earliest stages, so whatever we see today is only a toe in the water."

Francesco Rubino, MD, chair of metabolic and bariatric surgery at King's College London, is one of the surgical leaders looking at the antidiabetic effects of certain bariatric procedures. His own work suggests a strong role of the GI tract in the pathophysiology of diabetes and obesity. Based on his research findings, Dr. Rubino has worked closely with multidisciplinary societies around the world to raise awareness of the value of surgery as a diabetes treatment. He has also served as a consultant to Fractyl Laboratories, the maker of the DMR balloon.

Dr. Rubino believes endoscopic treatment for diabetes is "very promising." He said, "There's a huge potential for endoscopic interventions that might be in between surgery and medical treatments."

He predicts surgery will become a more common type of intervention but will never be a mass treatment. "It's a treatment that should be used for patients who fail other therapies."

Endoscopic therapies one day could serve as an adjuvant treatment for diabetes, he said. "It might be an extra mechanism of action, especially for patients who don't necessarily qualify for bariatric surgery, patients with poorly controlled diabetes perhaps without obesity. There is, at the moment, no alternatives to escalate therapy in these patients."

But even if these devices are approved by the FDA, they will need to be cost-effective for patients and third-party payers, if they are to fill a treatment gap.

"My hope is that third-party payers and insurance companies will see the value in these other therapies and start covering them," said Dr. Sullivan."

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