Liver safety in patients with type 2 diabetes treated with pioglitazone: Results from a 3-year, randomized, comparator-controlled study in the US
ABSTRACT Non-alcoholic fatty liver disease (NAFLD), the major hepatic manifestation of type 2 diabetes mellitus, is the most common liver disease in the US. Thiazolidinediones, a commonly used drug class for the treatment of type 2 diabetes, have emerged as a potentially useful treatment for NAFLD. There are, however, lingering concerns about their potential toxicity as well as emerging concerns about how to monitor for and assess hepatotoxicity. We conducted a randomized, long-term, double-blind, hepatic safety study at 171 centres in the US in which 2097 patients with type 2 diabetes received either pioglitazone or glibenclamide (glyburide).
Patients were randomized to receive either pioglitazone (15-45 mg once daily) or glibenclamide (5-15 mg once daily) for 3 years. The primary objective was to evaluate drug-induced liver injury manifested by liver enzyme elevations, measured every 8 weeks for the first year and every 12 weeks thereafter. The primary endpoint was a confirmed ALT greater than three times the upper limit of normal (>3 x ULN) with a secondary endpoint of 8 x ULN.
The intent-to-treat population included 1051 pioglitazone-treated and 1046 glibenclamide-treated patients; of these, 411 pioglitazone patients and 413 glibenclamide patients completed the study. The incidence of hepatocellular injury was 0 with pioglitazone and 4 (0.38%) with glibenclamide (p = 0.0617). Analyses of the secondary endpoints revealed no ALT >8 x ULN for pioglitazone versus 1 with glibenclamide (p = 0.4988); no ALT >3 x ULN + total bilirubin 2 x ULN with pioglitazone versus 1 with glibenclamide (p = 0.4988); and fewer ALT >3 x ULN single elevations with pioglitazone (n = 3) than with glibenclamide (n = 9; p = 0.0907). Significantly (p < or = 0.05) fewer cases of ALT >1.5 x ULN, aspartate aminotransferase >1.5 x ULN and gamma-glutamyl transpeptidase >1.5 x ULN were seen with pioglitazone compared with glibenclamide. No case of hepatic dysfunction or hepatic failure was reported in either treatment group; two cases of hepatic cirrhosis with glibenclamide were reported.
This study demonstrates an hepatic safety profile of pioglitazone similar to that of glibenclamide in long-term use in patients with poorly controlled type 2 diabetes. Trial registration number (clinicaltrials.gov): NCT00494312.
- SourceAvailable from: Azza A K El-Sheikh
[Show abstract] [Hide abstract]
- "Hepatic safety of PIO is also still controversial. While long term followup in a 3-year human study declared that PIO have no substantial hazard on the liver ; another study reported that PIO might be the cause of sporadic cases of liver failure . Interestingly, both FEN   and PIO   were suggested to modulate hepatic oxidant/antioxidant parameters and inflammatory cytokines, which may suggest that they confer hepatoprotective effects. "
ABSTRACT: Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR)- α and - γ agonists, fenofibrate (FEN), and pioglitazone (PIO), respectively, against cyclophosphamide (CP)-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp.) were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p.) was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF)- α , evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR- γ , but not PPAR- α , conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy.PPAR Research 04/2014; 2014:626319. DOI:10.1155/2014/626319 · 1.64 Impact Factor
[Show abstract] [Hide abstract]
- "Non-alcoholic fatty liver disease (NAFLD) is one of character of obesity and insulin resistance in patients with type 2 diabetes mellitus (T2DM)  . In patients with obesity and NAFLD, hepatic endoplasmic reticulum (ER) stress plays a critical role in unvalancing metabolic homeostasis . "
ABSTRACT: Endoplasmic reticulum (ER) stress has been implicated in the pathology of type 2 diabetes mellitus (T2DM). Although SIRT1 has a therapeutic effect on T2DM, the mechanisms by which SIRT1 ameliorates insulin resistance (IR) remain unclear. In this study, we investigated the impact of SIRT1 on palmitate-induced ER stress in HepG2 cells and its underlying signal pathway. Treatment with resveratrol, a SIRT1 activator significantly inhibited palmitate-induced ER stress, leading to the protection against palmitate-induced ER stress and insulin resistance. Resveratrol and SIRT1 overexpression induced the expression of oxygen-regulated protein (ORP) 150 in HepG2 cells. Forkhead box O1 (FOXO1) was involved in the regulation of ORP150 expression because suppression of FOXO1 inhibited the induction of ORP150 by SIRT1. Our results indicate a novel mechanism by which SIRT1 regulates ER stress by overexpression of ORP150, and suggest that SIRT1 ameliorates palmitate-induced insulin resistance in HepG2 cells via regulation of ER stress.Biochemical and Biophysical Research Communications 04/2012; 422(2):229-32. DOI:10.1016/j.bbrc.2012.04.129 · 2.28 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Higher levels of lipid peroxidation and hypomagnesaemia are frequently associated with Type 2 Diabetes mellitus (T2DM). Addressing these issues would definitely help us in preventing or prolonging the onset of pathogenesis of micro and macrovascular complications. Pioglitazone is used as a trusted insulin sensitizer and an adjuvant to the conventional oral hypoglycemic agents. This study was planned to explore the effects of pioglitazone on oxidative stress, serum magnesium, blood pressure, hepato-biliary and renal systems in addition to its effects on glycemic control. Sixty-three T2DM cases, who were started on pioglitazone were included in this study. All the physiological and biochemical parameters were estimated prior to and following three months of therapy with pioglitazone. There was significant improvement in the glycemic control, serum magnesium and MDA levels with p values of 0.000, 0.023 and 0.000 respectively. Pioglitazone did not have any significant effects on the serum lipids and blood pressure in T2DM cases following three months of treatment. We did not observe any pronounced changes in hepato-biliary enzymes, serum urea and creatinine levels reaffirming safety of pioglitazone in T2DM. Three-month duration of treatment with Pioglitazone in T2DM cases helps in alleviating the levels of lipid peroxides, besides being associated with improved serum magnesium status and glycemic control.01/2013; 7(1):35-7. DOI:10.1016/j.dsx.2013.02.020