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Pioglitazone may improve NASH, halt disease progression in type 2 diabetes
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Adults with type 2 diabetes randomly assigned Actos therapy were more likely to experience a reduction in nonalcoholic steatohepatitis activity vs. those assigned a placebo, according to study findings published in Annals of Internal Medicine.
In a single-center, parallel-group study, Kenneth Cusi, MD, FACP, FACE, chief of the division of endocrinology, diabetes and metabolism at the University of Florida in Gainesville and Endocrine Today Editorial Board member, and colleagues analyzed data from 101 patients with prediabetes or type 2 diabetes (confirmed via oral glucose tolerance test) and histologically confirmed nonalcoholic steatohepatitis activity (NASH). After baseline measurements (OGTT, euglycemic insulin clamp, DXA scan and liver biopsy), researchers assigned patients to a 500-kcal deficit diet and then randomly assigned them to 30 mg daily Actos (pioglitazone, Takeda Pharmaceuticals), titrated at 2 months to 45 mg daily (n = 50; mean age, 52 years; 72% men; 28% white; 48% with type 2 diabetes), or placebo (n = 51; mean age, 49 years; 69% men; 22% white; 55% with type 2 diabetes) for 18 months. At 18 months, patients again underwent metabolic measurements and a liver biopsy; those on pioglitazone were asked to continue therapy for another 18 months while participants in the placebo group whose NASH resolved were asked to discontinue use; those with persistent disease were invited to initiate pioglitazone therapy for 18 months.
Kenneth Cusi
The primary outcome was a reduction of at least two points in the nonalcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis at 18 months.
Within the cohort, 18 patients (nine in each group) withdrew from the study before 18 months after being informed in 2011 about a potential risk for bladder cancer with pioglitazone. An additional four patients in each group withdrew during the open-label phase (months 18 to 36) for similar reasons.
Researchers found that more patients assigned to pioglitazone achieved the primary outcome vs. those assigned placebo (58% vs. 17%; P < .001); more patients in the pioglitazone group also had resolution of NASH vs. placebo (51% vs. 19%; P < .001). Pioglitazone therapy also was associated with improvement in individual histologic scores, including fibrosis score, with progression of any fibrosis during 18 months occurring in 12% of pioglitazone patients vs. 28% of placebo patients (P = .039).
Pioglitazone also reduced hepatic triglyceride content from 19% to 7% vs. 15% to 11% in the placebo group, and improved adipose tissue, hepatic and muscle insulin sensitivity (P < .001 for all). All 18-month metabolic and histologic improvements persisted during 36 months of therapy.
There were no between-group differences for adverse events; weight gain was greater with pioglitazone (2.5 kg).
“This histologic benefit, combined with improvement in the mean fibrosis score, suggests that pioglitazone may alter the natural history of the disease,” the researchers wrote. “Evidence of this was the reduction in fibrosis progression over 18 months in patients treated with pioglitazone compared with those receiving placebo.”
The study results are likely to change management of patients with type 2 diabetes and fatty liver, Cusi told Endocrine Today. Pioglitazone, he said, could potentially become for NASH what metformin is to the treatment of type 2 diabetes.
“Until this study, we lacked definitive long-term treatment evidence of safety and benefit for such patients,” Cusi said in an interview. “This study shows now that if you have type 2 diabetes, or even prediabetes, and you take pioglitazone, more than half [of patients] have resolution of NASH. What this means is that endocrinologists will have to think about whether the patient has a fatty liver or not as they consider their second-line therapy after metformin.
“This really is a big game changer,” Cusi said. “NASH may lead to end-stage liver disease, and is currently the second cause of liver transplantation in the United States. We have a drug that may change the natural history of liver disease, prevent the onset of type 2 diabetes as shown in ACT NOW, and ameliorate the risk for coronary artery disease or that of stroke, as recently shown by Kernan et al this year in the New England Journal of Medicine. The cost of pioglitazone will decrease over time, as it currently has a generic formulation, and its safety profile has been tested for over 15 years with issues such as bladder cancer having been cleared from the study published by Lewis et al in JAMA last year. Now endocrinologists will think about and diagnose NASH more often in daily practice, having a safe and effective treatment option at hand.– by Regina Schaffer
Disclosure: The study was supported by the Burroughs Wellcome Fund and the American Diabetes Association. Cusi reports receiving nonfinancial support from Takeda Pharmaceuticals (provision of study medication and placebo), grants from Janssen Research & Development and Novartis, and consulting for Eli Lilly & Co., Pfizer and Tobira Therapeutics.
Perspective
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Yehuda Handelsman
In the early 2000s, both available thiazolidinediones, rosiglitazone and pioglitazone, were leading in the management of diabetes. In the mid-2000s the drugs in this class faced many obstacles, and their use diminished greatly. In fact, rosiglitazone was nearly eliminated, implicated in causing cardiovascular death, a charge of which it was recently exonerated by the FDA. Pioglitazone, despite better CV data, was not only dragged down by the fate of rosiglitazone, but was marred by its own issues, specifically an FDA warning on potentially causing bladder cancer. But then shortly following the clearing of rosiglitazone, a 10-year FDA-mandated study concluded that pioglitazone did not increase risk for bladder cancer (Lewis JD, et al. JAMA. 2015;doi:10.1001/jama.2015.7996), and recently a large European study reached the same conclusion (Korhonen P, et al. BMJ. 2016;doi:10.1136/bmj.i3903).
Health care stakeholders prefer diabetes medications that have effects beyond glycemia. Pioglitazone, which is now generic and inexpensive, may present an option for therapy. Several recent studies highlight the advantages that pioglitazone may have beyond glucose control.
In the IRIS trial, in a large group of subjects with no diabetes yet with metabolic syndrome and insulin resistance, pioglitazone showed a 24% reduction of secondary ischemic stroke and transient ischemic attack (Kernan WN, et al. N Engl J Med. 2016;doi: 10.1056/NEJMoa1506930). These results are in line with PROactive, an older study with pioglitazone, in people with diabetes (Dormandy JA, et al. Lancet. 2005. 366:1279-1289); although the primary outcome was barely missed, the secondary outcome results displayed reduction of stroke by 47% and myocardial infarction by 28%. In both studies, it seemed that reduction of glucose had no specific role in the CV outcome. Regardless of mechanism of action, which remains unclear, the final result is a fact.
Inzucchi and colleagues revealed that pioglitazone prevented diabetes by 51% in this population. These results support the findings of ACT NOW where pioglitazone reduced progression to diabetes by 72% and improved CV risk, significantly reducing the progression of carotid intima media thickness (a surrogate measure of atherosclerosis) by 31.5% (Defronzo RA, et al. BMC Endocr Disord. 2009;doi:10.1186/1472-6823-9-17). Of note in both trials, once pioglitazone was stopped, the progression to diabetes resumed.
Cusi and colleagues showed a reduction with pioglitazone of 58% in nonalcoholic fatty liver disease activity, and 51% had resolution of NASH as well as reduced hepatic triglyceride content. Of note the metabolic and histologic improvements seen in 18 months persisted over 36 months of therapy. This is the first pharmaceutical intervention to show such a significant effect on NASH.
Many health care systems restrict their members to use only the least expensive medications, typically generics. Until recently the only available agents were metformin, sulfonylureas and human insulin (whose price lately has also become quite high). Both insulin and sulfonylureas increase hypoglycemia when used in low doses.
All of a sudden pioglitazone becomes an attractive option. It is generic and inexpensive; recent trials highlight its safety and its efficacy beyond glucose control. In people with prediabetes and early diabetes, it may improve NAFLD and NASH and prevent diabetes. Not causing hypoglycemia, pioglitazone offers an attractive alternative to sulfonylurea as the second drug beyond metformin. It is recommended to use low-dose pioglitazone 15-30 mg, which helps to reduce its side effects. I propose that we are witnessing the comeback of pioglitazone.
Disclosure: Handelsman reports receiving research grants, consulting and speakers’ fees, or honoraria from Amarin, Amgen, AstraZeneca, BI-Lilly, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Grifols, Hamni, Intarcia, Janssen, Lexicon, Lilly, Merck, Novo Nordisk, Pfizer, Regeneron and Sanofi.
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