Pioglitazone reverses nonalcoholic steatohepatitis in diabetes patients

Last Updated: 2016-06-23

By Will Boggs MD

NEW YORK (Reuters Health) - Long-term treatment with pioglitazone reverses nonalcoholic steatohepatitis (NASH) in patients with prediabetes or type 2 diabetes, according to a new trial.

"Physicians should learn more about the health risks associated with NASH and treat it," Dr. Kenneth Cusi from the University of Florida in Gainesville told Reuters Health by email. "NASH is the second cause of liver transplantation in the United States, more than alcohol abuse. The combination of pioglitazone's efficacy, safety, and low cost should put a new awareness on the disease and the potential to prevent cirrhosis in many patients."

Thiazolidinediones target insulin resistance and adipose tissue dysfunction or inflammation that promotes hepatic lipotoxicity in NASH, a prominent feature of type 2 diabetes. So it may be helpful for treating steatohepatitis in this population, Dr. Cusi and colleagues hypothesized.

The team assessed the efficacy and safety of long-term (36 months) pioglitazone treatment in improving liver histologic outcomes in a randomized placebo-controlled study of 101 patients with NASH and prediabetes or type 2 diabetes.

Eighteen patients (nine in each group) did not complete the first 18 months of the study, mostly due to withdrawal of their consent after being informed about a potential risk for bladder cancer with pioglitazone. Another four patients in each group withdrew their consent for the 18- to 36-month open-label phase of the study.

More patients in the pioglitazone group than in the placebo group (58% vs. 17%, p<0.001) achieved at least a two-point reduction in nonalcoholic fatty liver disease activity score (NAS). Among the subgroup of patients with definite NASH at baseline, 67% achieved this same primary outcome with pioglitazone versus 17% with placebo (p<0.001).

More pioglitazone-treated patients than placebo-treated patients achieved resolution of NASH (51% vs. 19%, p<0.001), the researchers reported in Annals of Internal Medicine, online June 21.

Progression of any fibrosis over 18 months occurred in only 12% of pioglitazone-treated patients, compared to 28% of patients receiving placebo (p=0.039).

Pioglitazone treatment was also associated with reduced hepatic triglyceride content, improved insulin action, reduced insulin resistance, and improved adipose tissue function.

Patients treated with pioglitazone gained an average 2.5 kg more in body weight than did patients treated with placebo (p=0.02).

The histologic benefits of pioglitazone treatment were maintained after 36 months of therapy.

"Fear of bladder cancer was removed last year with a 10-year prospective study in a large population," Dr. Cusi said. "However, doctors still fear this class (thiazolidinediones) based on the perception of cardiovascular risk left with the 'rosiglitazone fiasco,' but both drugs are very different. However, in the end, rosiglitazone was not associated with increased cardiovascular disease, as per the (Food and Drug Administration) in 2014. Also of note, rosiglitazone does not improve NASH."

"Metformin is the unquestionable first-line therapy in type 2 diabetes," Dr. Cusi said. "In patients with type 2 diabetes, pioglitazone would be the next drug of choice for patients who have a fatty liver (about 70%), especially if they have NASH (about 30%)."

"In patients with prediabetes, pioglitazone prevents the progression to type 2 diabetes by about 70%; it also reduces cardiovascular disease," he added. "However, the drug is not FDA-approved in non-diabetics."

Dr. Eduardo Vilar-Gomez of the University of Seville, Spain, who coauthored an accompanying editorial, told Reuters Health by email that pioglitazone has been linked to increased risks of recurrent heart failure and bone fracture.

He added that "pioglitazone could be considered as a very good pharmacological strategy for treating NASH patients with type 2 diabetes; however, the decision should be counterbalanced by the risk of adverse events, including weight gain, bone fractures, heart failure, macular edema, and possibly bladder cancer."

"While pioglitazone is highly effective for NASH patients, only half of the subjects using pioglitazone achieve NASH resolution," Dr. Vilar-Gomez said. "Thus, the early identification of patients with good response (probably at six months) should be crucial for avoiding unnecessary treatment prolongation and potential side effects. Unfortunately, the present and other studies have not been able to identify a clear profile of treatment responders."

"Although these results are exciting, efficacy and safety of long-term administration of pioglitazone in populations with higher risk (i.e., type 2 diabetes and advanced fibrosis) of progression must be confirmed in further trials," Dr. Vilar-Gomez added.

Dr. Vlad Ratziu from Pierre and Marie Curie University, Paris, France, who has also studied the use of thiazolidinediones for treating NASH, said, "This is mainly a confirmatory study that confirms the ability of pioglitazone to induce histological improvement in patients with NASH. This has been shown in other studies of one-year and two-year duration. It also confirms our report that there is no additional histological benefit beyond the first year of therapy, although the initial benefit is maintained."

"While waiting for better drugs, pioglitazone can be used in prediabetic or diabetic patients with advanced NASH," Dr. Ratziu told Reuters Health by email. "When considering optimization of antidiabetic therapy pioglitazone should be given high priority in case of NASH coexistence. But most importantly, diabetic patients should be screened for NASH, as recommended by the clinical practice guidelines of European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO)."

The study did not have commercial funding; Takeda Pharmaceuticals provided the pioglitazone and placebo pills. Dr. Cusi reported receiving support from pharmaceutical companies.

SOURCE: http://bit.ly/28Zs0Pu and http://bit.ly/28YnQWR

Ann Intern Med 2016.