Damian McNamara

December 02, 2016

LAS VEGAS — A semisynthetic bile acid analog, obeticholic acid (Ocaliva, Intercept Pharmaceuticals), which improved nonalcoholic steatohepatitis and fibrosis in phase 2 studies, is just one of the therapies on the horizon for the treatment of nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).

There are multiple therapies in the pipeline that could soon improve the outlook of patients with nonalcoholic steatohepatitis, said Manal Abdelmalek, MD, from Duke University in Durham, North Carolina.

In fact, a preclinical trial looks promising for elafibranor (GFT505, Genfit), an agonist of the peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma (Gastroenterology. 2016;150:1147-1159.e5), she said.

Both obeticholic acid and elafibranor are entering phase 3 studies, she reported during a plenary session at the recent American College of Gastroenterology 2016 Annual Scientific Meeting.

The current literature shows various degrees of success with off-label medications, endoscopic interventions, and bariatric surgery. But researchers are working hard to find other treatments; there are an estimated 800 clinical studies of these diseases in the works.

No drugs are specifically approved for the treatment of nonalcoholic steatohepatitis by the US Food and Drug Administration (FDA), but Dr Abdelmalek reviewed the off-label use of metformin, pioglitazone, vitamin E, and statins.

Metformin has no significant effect on liver histology, according to available evidence, she reported. In one study, metformin was no better at sustaining a reduction in alanine aminotransferase (ALT) levels than placebo (JAMA. 2011;305:1659-1668).

In contrast, "pioglitazone may be used to treat steatohepatitis in nondiabetic patients with biopsy-proven nonalcoholic steatohepatitis," although the long-term efficacy is not known, she explained.

One study showed that pioglitazone and vitamin E both improve ALT and aspartate transaminase (AST) levels (New Engl J Med. 2010;362:1675-1685), "but unfortunately, pioglitazone was associated with an increase in weight," she reported.

Jury Still Out on Vitamin E

"Vitamin E can be considered in nondiabetic, noncirrhotic patients, but there is no current indication for long-term use of combination vitamin E and pioglitazone," Dr Abdelmalek said.

"Vitamin E is safe in nondiabetic and noncirrhotic patients, but may not be effective in those with a very high body mass index or a high NAFLD Activity Score."

Many clinicians are concerned about vitamin E in men because of potential elevated risks for prostate cancer and cardiovascular problems, a member of the audience pointed out.

Like you, I am holding out for better alternatives.

"I share your concern," said Dr Abdelmalek. "The data on vitamin E 800 mg daily demonstrated benefit; however, there is concern about the long-term use of vitamin E and associated risks of prostate cancer and cardiovascular outcomes. Like you, I am holding out for better alternatives."

"Statins can be confidently used to improve the lipid profile and cardiovascular risk in our patients," she added. However, "we need randomized controlled trials" because there is insufficient evidence on the effect of statins in patients with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease.

Endoscopic Interventions

Dr Violeta Popov

New endoscopic interventions to treat obesity could also help improve outcomes for patients with nonalcoholic steatohepatitis and nonalcoholic fatty liver disease, said Violeta Popov, MD, PhD, from the NYU Langone Medical Center in New York City.

One technique, approved by the FDA in June, is aspiration therapy (AspireAssist, Aspire Bariatrics), which involves a gastrostomy tube and an external device that are designed to aspirate 30% of calories after each meal. Patients are required to drink a lot of fluid and chew each bite of food 20 times, Dr Popov added.

"When I first heard about it, I thought it was crazy," she said, "however, there is a reason it was approved by FDA."

Research shows that at 1 year, aspiration therapy had slashed about 18% of excess weight (Gastroenterology. 2013;145:1245–52.e1-5). The therapy is indicated for patients with a body mass index (BMI) of 35 to 55 kg/m² and requires nutritionist follow-up.

"It is indicated for heavier patients, often for those who are not candidates for bariatric surgery," Dr Popov explained. "Patients like it. Despite our initial concerns, including psychological concerns, it is here."

When I first heard about it, I thought it was crazy; however, there is a reason it was approved by FDA.

The Revita endoscopic duodenal mucosal resurfacing procedure from Fractyl is another technique showing potential, she said. The technique involves thermal ablation of the duodenal mucosa with a catheter.

Modest weight loss was associated with significant HbA1c decreases in people with diabetes after 6 months in a small study presented at the American Diabetes Association annual meeting in June. "Liver enzymes also significantly decreased in these 28 patients," Dr Popov reported.

"Very Promising Results"

Endoscopic magnets have met with some success, said Dr Popov. The magnets are placed using upper endoscopy and colonoscopy to create a durable jejuno-ileal anastomosis and facilitate weight loss. "The magnets bind together, then the magnets get passed after 1 week, but the bypass is permanent," she explained.

In the first report of their use in humans, participants lost about 11% of their weight, or an average 28 pounds at 6 months (Gastroenterology. 2016:150:S232). Baseline fasting glucose of 177 mg/dL dropped to 110 mg/dL at 6 months, and participants had no dietary restrictions.

These are "very promising results," said Dr Popov.

A member of the audience asked whether the magnets essentially create controlled ischemia, which could be painful. No patient in the study reported pain, Dr Popov explained, and clinicians controlled magnet placement.

"You know you are in the jejunum and ileum and you try to avoid any organs. In that study, they used laparoscopy to confirm that they matched magnets perfectly," she said.

Another endoscopic approach to promote weight loss that could benefit people with nonalcoholic steatohepatitis and nonalcoholic fatty liver disease involves intragastric balloons. The FDA approved two devices in 2015 — the ReShape Dual Balloon (ReShape Medical) and the Orbera Intragastric Balloon System (Apollo Endosurgery) — and just cleared a third — the Obalon System (Obalon Therapeutics) — for marketing in September. The balloons are swallowed and then removed with endoscopy.

Dr Popov and her colleagues performed a meta-analysis of all gastric balloons to assess their effect on liver enzymes (Dig Dis Sci. 2016;61:2477-2487).

"Patients lose quite a bit of weight while they have the balloon in, from 12% to 15% of body weight or 30% to 40% of excess weight at 6 months," they write. The researchers also determined that the intragastric balloons decreased liver enzymes, making them a potentially effective part of a multidisciplinary approach for the short-term treatment of nonalcoholic fatty liver disease.

Endoscopic sleeve gastroplasty can also be effective for weight loss, said Dr Popov. "In experienced hands, it is a very safe device to use."

A multicenter case series of 242 patients showed a total body weight loss of 20% at 18 months (Gastroenterology. 2016;150:S26). Five serious adverse events occurred in the study.

"The data on endoscopic therapies are very promising, but more are needed," Dr Popov pointed out.

Surgical Interventions

With surgery, updates are less about new or upcoming techniques and more about evidence supporting one procedure over another for patients with liver disease.

"We know bariatric surgery is effective for long-term weight loss," said Julie Heimbach, MD, a liver surgeon at the Mayo Clinic in Rochester, Minnesota. Multiple studies have demonstrated that weight loss from bariatric surgery can improve outcomes for overweight and obese people with nonalcoholic steatohepatitis or nonalcoholic fatty liver disease.

Dr Julie Heimbach

"For patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis, or even well-selected patients with compensated cirrhosis, the goal is to achieve a body weight loss greater than 10%," she explained.

Multiple studies point to this value, including a study in which a loss of more than 10% of total body weight effectively reduced fibrosis, she reported (Dig Dis Sci. 2015;60:1024-1030).

"We're not talking about things that are cosmetic. What we are trying to do is save the patient's life," Dr Heimbach said.

Surgical technique can matter. In a study of 1236 people with nonalcoholic fatty liver disease and no cirrhosis, both Roux-en-Y gastric bypass and adjustable gastric banding improved the liver disease, but bypass was better overall (Ann Surg. 2014;260:893-898).

Comorbidities also count. One study showed that hospital stays were longer after bariatric surgery and rates of in-hospital mortality were higher when patients had cirrhosis than when they did not (Clin Gastroenterol Hepatol. 2011;9:897-901).

Two smaller studies evaluated patients with compensated cirrhosis.

In a well-done study, weight loss after laparoscopic sleeve gastrectomy was excellent in patients with and without cirrhosis (Surg Obes Relat Dis. 2014;10:405-410).

Another study suggested that weight loss in patients with compensated cirrhosis who underwent bariatric surgery was good and the complication rate was low (Mayo Clin Proc. 2015;90:209-215).

Laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass should be considered for patients with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or compensated cirrhosis, Dr Heimbach said.

"The gastric band procedure is being performed less often [because of] concerns about efficacy," she added.

There are fewer options for obese people with fatty liver disease and decompensated cirrhosis.

"Bariatric surgery is an option before transplant only in patients with well compensated cirrhosis; you really cannot do this in decompensated cirrhosis patients," Dr Heimbach explained. In those patients, "you can consider bariatric surgery post-transplant or concurrent with transplant."

Despite the effectiveness of bariatric surgery for patients with nonalcoholic fatty liver disease or nonalcoholic steatohepatitis, "surgery alone cannot contain the obesity and [liver disease] epidemics," said Dr Popov.

"About 20 million people qualify for bariatric surgery, and about 200,000 surgeries are performed annually. So it would take about 100 years to cure this population with surgery. It's not sufficient."

For this reason and others, Dr Popov is a proponent of endoscopic therapy. "I do think endoscopic therapies have a role for patients with a BMI too low for bariatric surgery. They are very safe overall, compared with more invasive techniques," she explained.

Lifestyle Modifications

Diet and exercise can improve liver enzymes and hepatic steatosis on liver biopsy, Dr Abdelmalek pointed out.

"Across the majority of studies, there is an improvement in ALT with diet and exercise," she explained.

The benefits of exercise might also extend to decreasing the risk for cancer. In one study, rigorous exercise was associated with a 44% decrease in the relative risk for hepatic carcinoma (Eur J Epidemiol. 2013;28:55-66).

In what Dr Abdelmalek described as an "outstanding study," researchers assessed 293 patients who underwent lifestyle modifications for 1 year (Gastroenterology. 2015;149:367-378). The most positive outcomes — including nonalcoholic steatohepatitis resolution and regression of fibrosis — were seen in patients who lost more than 5% of their body weight, and particularly in those who lost more than 10% of their body weight.

"Lifestyle modification is a must," said Dr Abdelmalek. And "if you have patients with nonalcoholic steatohepatitis, refer them early."

Dr Abdelmalek reports receiving grant or research support from Arisaph Pharmaceuticals, Bristol-Myers Squibb, Galacatin, Galmed, Genfit, Immuron, NGM Pharmaceuticals, TaiwanJ Pharmaceuticals, and Tobira. Dr Popov and Dr Heimbach have disclosed no relevant financial relationships.

American College of Gastroenterology (ACG) 2016 Annual Scientific Meeting.


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