Does Pioglitazone Have the Same Effects on NASH in Patients With vs Without Diabetes?
Patients with prediabetes and nonalcoholic steatohepatitis (NASH) benefit nearly as much from pioglitazone therapy as those with type-2 diabetes, researchers report in the April issue of Clinical Gastroenterology and Hepatology. The diabetes drug reduced fibrosis in non-diabetic patients with NASH, the clinical study found, although to a lesser extent than in patients with diabetes.
Type 2 diabetes is associated with more rapid progression of fibrosis in patients with nonalcoholic steatohepatitis (NASH). Pioglitazone is effective for long-term treatment of patients with nonalcoholic steatohepatitis (NASH) with type 2 diabetes. The drug was also reported to reduce makers of liver injury and fibrosis in nondiabetic subjects.
There is controversy about whether pioglitazone is equally effective for patients with NASH with and without type 2 diabetes. Fernando Bril et al performed an 18-month trial to compare the effects of pioglitazone vs placebo for treatment of NASH in 52 patients with diabetes vs 49 without diabetes (with prediabetes).
The primary outcome of the study (a reduction in the nonalcoholic fatty liver disease activity score [NAS] of at least 2 points, with a reduction in at least 2 different categories, and without worsening of fibrosis) was achieved by 60% of patients with prediabetes and 70% of patients with diabetes given pioglitazone (see figure).
The magnitude of the effect, compared with placebo, was similar between groups—among nondiabetics, the primary outcome was achieved by 48% more patients given pioglitazone than placebo, and among diabetics the primary outcome was achieved by 46% more patients given pioglitazone than placebo.
However, NASH resolved in a significantly higher proportion of patients with diabetes given pioglitazone (60%) vs placebo (16%) (P = .002), but not in a significantly higher proportion of patients with prediabetes given pioglitazone (55%) vs placebo (29%) (P = .12).
Overall, changes in the NAS after 18 months of pioglitazone therapy were similar for patients with diabetes and prediabetes (reduction of 1.3±1.8 vs a reduction of 1.2±1.9). All individual histologic parameters (steatosis, inflammation, ballooning, and fibrosis) showed a similar response to pioglitazone therapy when patients with diabetes and prediabetes were compared.
However, when changes in fibrosis were assessed in more detail, Bril et al observed that only the group of patients with diabetes had significant reductions in fibrosis after 18 months of pioglitazone compared with placebo (reduction of 0.5±0.9 vs 0.2±1.2; P = .042). A significant difference was not observed in patients with prediabetes (reduction of 0.4±0.9 vs reduction 0.2±0.7; P = .66).
The authors point out that the difference could be accounted for by differences in the placebo groups of diabetic vs nondiabetic patients—fibrosis progressed more rapidly in the patients with diabetes receiving placebo than the nondiabetic patients receiving placebo.
Reductions in steatosis after pioglitazone therapy were observed in similar proportions of patients with and without diabetes (∼50% for both). However, only patients with diabetes had significant reductions in inflammation and ballooning in response to pioglitazone vs placebo.
Patients with and without diabetes had similar reductions in intrahepatic triglyceride content, measured by proton magnetic resonance spectroscopy, after pioglitazone treatment and compared with placebo.
In an anlysis of 63 patients followed for longer time periods, Bril et al found that the benefits obtained with 18 months of pioglitazone persisted after 36 months among patients with or without diabetes.
Bril et al conclude that pioglitazone is effective in patients with and without type 2 diabetes. Further studies are needed to determine the mechanisms by which pioglitazone reduces liver disease in patients with type 2 diabetes.