New Avenues for Diagnosing and Treating Diabetic Gastroparesis

A new surgical procedure, a promising minimally invasive, endoscopic device, and new uses for established drugs offer relief from gastrointestinal symptoms of this common complication of diabetes.

with Mahdusudan Grover, MD, and Michael Camilleri, MD

Gastroparesis is more likely to develop in individuals who have had diabetes—either type 1 or type 2—for years. Symptoms, such as abdominal pain, early satiety, prolonged fullness, and nausea, arising oftentimes in response to delayed gastric emptying, occur in up to 55% of patients with type 1 diabetes, and in about one-third of patients with type 2 diabetes, by some accounts.1,2 It appears to arise more often in women than men, possibly due to estrogen regulation of stomach motility.3,4

Diabetics who experience abdominal pain, nausea and vomiting, and feeling full quickly after eating may have gastroparesis.

Other than good glucose management and diet, there have been few resources available to manage this painful, challenging diabetes complication. However, researchers seem optimistic that there will are new pathways in clinical trials aiming to treat the disease and its symptoms. In addition, employing off-label uses for several existing drugs are proving effective in provide symptom relief to patients.

Examining the Drivers of Diabetic Gastroparesis  

Why do so many individuals with diabetes develop this diabetic complication? It appears that the loss of the heme isoform may lead to neuropathy (ie, nerve damage involving the stomach), which effects the impulse directing the stomach to empty.5 According to a study of individuals who have been hospitalized for issues related to diabetic gastroparesis, 36% had poor glycemic control.6

Another theory focuses on the prevalence of obesity as a driver of gastroparesis. In one study, for example, patients with obesity were 10 times more likely to report having symptoms related to diabetic gastroparesis.7

However, there doesn’t seem to be any difference in the presentation of gastroparesis whether it arises in someone with type 1 diabetes or type 2 diabetes, and there is no differentiation in morphology between those with idiopathic disease and those who develop it as a complication of diabetes.

Diagnostics and Treatments Are Expanding—Providing Hope  

The newest treatment is a surgical intervention—Gastro Peroral Endoscopic Myotomy, (G-POEM), which works by helping to relax a dysfunctional pylorus, said Mahdusudan Grover, MBBS, assistant professor of medicine and a gastroenterologist at the Mayo Clinic in Rochester, Minnesota; he is also a member of the Gastroparesis Consortium.

“The procedure entails making an incision in the stomach to relax the muscle that has, in some smaller studies,8,9 provided relief up to 12 months,” says Dr. Grover. However, a poorly functioning pylorus is not a problem for everyone with diabetic gastroparesis so surgery may only be viable in certain patients.

There are efforts underway to assess patient motility by a more diagnostically comprehensive method of internally viewing the function of the pyloric sphincter by, for example, a minimally invasive device—an endoluminal functional lumen imaging probe (EndoFLIP).

“We are still trying to find out what subset of patients have the problem,” he said. “We estimate maybe 30 to 40%, but no one has done that study,” Dr. Grover says. There are a few large multicenter studies underway in Europe to determine who has defective pylori, and these researchers are also assessing long-term outcomes of patients who opt for the G-POEM; no similar trials have been initiated in the United State, at present.

Michael Camilleri, MD, MPhil, professor of medicine, pharmacology, and physiology, who specializes in gastroenterology at the Mayo Clinic in Rochester, indicates that this treatment has not been validated through a sham treatment, paired trial. Right now, the surgery is based on systematic reviews and a meta-analysis that supports improvement of patient symptoms.

“The G-POEM looks promising as it can be done very safely while avoiding perforations or large complications,” he says. However, researchers have not determined why some patients have impaired emptying while others do not, or whether a patient who undergoes this procedure will maintain improvement in symptoms over the long-term. As such, more research on this surgery should be anticipated to inform clinicians appropriate patient profiles and confirmation of efficacy.

Pharmacotherapy Options Expand with Established, New Drugs 

With regard to pharmacologic options, there are existing drugs that proport to benefit patients albeit as an off-label application. One drug of note—aprepitant, a neurokinin receptor antagonist—is approved for cancer chemotherapy-induced nausea and vomiting, says Dr. Grover.

Researchers in the Gastroparesis Consortium, including Dr. Grover, studied whether aprepitant might resolve nausea as its primary endpoint in patients with diabetic gastroparesis, as well as secondary endpoints including bloating, abdominal pain, and postprandial fullness.10 While the primary endpoint was not achieved, the secondary endpoints were met. “That tells us that our choice of a primary endpoint wasn’t the best,” he says.

Off-label use of prucalopride may also prove helpful in these patients, says Dr. Grover. While this drug has been marketed for constipation, it seems to increase motility, thereby accelerating gastric emptying, which is a distinct advantage for patients with diabetes gastroparesis. While the data are limited to a small study of about 20 patients, larger trials are underway that would be used, if successful, to file an application with the Food and Drug Administration for this specific indication.

Dr. Camilleri tells EndocrineWeb about another medication that works on the same pathway as prucalopride, called Velusetrag, which is in phase 2 trials and favorable results based on preliminary data on a fourth drug—TAK-906, a dopamine receptor antagonist, which he presented at the American Neurogastroenterology and Motility Society annual scientific meeting in August.11

The authors indicated that this drug promoted better satiety and less nausea, permitting patients to consume a greater volume of food before feeling “full, bloated, and uncomfortable, and was well-tolerated” but doesn’t appear to improve stomach emptying. The next phase of study will assess for suitable dosing.

Tradipitant, a neurokinin-1 receptor antagonist, which blocks substance P, a signaling molecule, is also being studied, according to Dr. Camilleri. This ghrelin receptor agonist—relamorelin, which in early trials appears to stimulate gastric and antral contractions as well as to accelerate gastric emptying—is currently being studies in a phase 3 trial for efficacy in reducing common gastroparesis symptoms, such as bloating, abdominal pain, early satiety, and nausea.

More than Glucose Management Needed to Improve Diabetes Gastroparesis  

“A year ago, there was no clinical activity regarding therapies for diabetic gastroparesis,” Dr Grover says, “so for patients, it looked bleak but now there are three or four agents in the pipeline.”

As new options are approved, doctors will be able to individualize treatments, Dr. Camilleri says, so patients whose main issue is stomach emptying may benefit from one treatment plan, while those who struggle mostly with nausea and vomiting will find a different drug works best. And, it’s important for health practitioners to become more aware of breakthroughs in this area citing the need to more fully appreciate the issues these patients face beyond those related to stomach emptying.

“Diabetes can affect the nerves in the walls of the stomach, causing neuropathy of the vagus nerve. Consider that the nerves in the stomach are like a filament in a light bulb; when there’s a problem, it could be that the filament is broken, or the switch may have been turned off. Both would prevent the light from illuminating,” Dr. Camilleri.

He goes further to caution clinicians against touting glycemic control as the best way to resolve diabetic gastroparesis. “There are treatments that in and of themselves delay stomach emptying,” Dr. Camilleri said.

When he gets a patient referral, often just changing their diabetes medications to add gliptin to provide improve diabetes symptoms without causing delayed stomach emptying, such as  dipeptidyl peptidase 4 (DPP-4) inhibitors but they don’t have as favorable an impact on gastric symptoms as glucagon-like peptide-1 receptor agonists (GLP-1) [ie, exenatide].

“While good diabetes management isn’t a panacea, erratic blood sugar does have an adverse impact on the stomach. “When the patient’s glucose control is better, she will have better gastric functioning. An insulin pump may help manage blood sugars more precisely for many of these patients diabetic gastroparesis,”12  Dr. Grover says.

Physicians should emphasize stomach emptying by encouraging a changed diet and blending food. “Liquids and blended solids seem to be more tolerable for most patients,” said Dr. Camilleri. This can be a difficult change for patients to make, but it allows them to get the flavor of the food without the nausea and bloating, said Dr. Grover. “It’s a much better option than a feeding tube,” he added.

Dr. Camilleri said as much as 80% of patients can live without that drastic option, and while it is a chronic condition that is likely to remain an issue for life, “there is little evidence that it will get worse. Working with doctors and dieticians, we can keep patients as asymptomatic as possible.”

Encourage patients to look at the many clinical trials, said Dr. Grover, whether they are testing a drug or determining which patients have pyloric dysfunction and may benefit from the G-POEM. “And tell them next year is looking better.”

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