sitagliptin-phosphate and Chemical-and-Drug-Induced-Liver-Injury

Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns.. The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug.. The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN), 5 × ULN, and 10 × ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3 × ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50 mg daily. The cumulative incidence of elevations in serum ALT > 3 × ULN was higher in the first 6 months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT > 3 × ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy's Law case and the two remaining cases were considered to closely approximate Hy's Law cases.. Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.

Topics: Adult; Aged; Alanine Transaminase; Benzofurans; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Liver; Male; Middle Aged; Sitagliptin Phosphate; Sulfones; Sulfonylurea Compounds

Sitagliptin is known for its anti-diabetic activity though it has other pleiotropic pharmacological actions. Its effect against concanavalin A (Con A)-induced hepatic fibrosis has not been investigated yet. Our target was to test whether sitagliptin can suppress the development of Con A-induced hepatic fibrosis and if so, what are the mechanisms involved? Con A (6 mg/kg) was injected once weekly to male Swiss albino mice for four weeks. Sitagliptin was daily administered concurrently with Con A. Results have shown the potent hepatoprotective activity of sitagliptin against Con A-induced hepatitis and fibrosis. That was evident through the amelioration of hepatotoxicity serum parameters (ALT, AST, ALP, and LDH) and the increase in the level of serum albumin in sitagliptin treated mice. Simultaneously, there was amendment of the Con A-induced hepatic lesions and repression of fibrosis in sitagliptin-treated animals. Hydroxyproline, collagen content and the immuno-expression of the fibrotic markers, TGF-β and α-SMA were depressed upon sitagliptin treatment. Sitagliptin suppressed Con A-induced oxidative stress and increased antioxidants. RT-PCR analysis showed enhancement of mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes (GCLc, GCLm, NQO-1, HO-1) by sitagliptin. Furthermore, sitagliptin ameliorated the level and immuno-expression of nuclear factor kappa-B (NF-κB) alongside the immuno-expression of the inflammatory cytokine, TNF-α. Taken together, this study demonstrates the hepatoprotective activity of sitagliptin which may be in part related to enhancement of Nrf2 signaling pathway and inhibition of NF-κB which interact inflammatory response in liver. Sitagliptin might be a new candidate to suppress hepatitis-associated fibrosis.

Topics: Animals; Anti-Inflammatory Agents; Antifibrotic Agents; Chemical and Drug Induced Liver Injury; Concanavalin A; Liver; Liver Cirrhosis, Experimental; Male; Mice; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Signal Transduction; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha

Sitagliptin is an oral hypoglycemic drug that acts by selective inhibition of dipeptidyl peptidase-4 (DDP-4) enzyme.. This study scrutinized the hepatoprotective impact of sitagliptin) against thioacetamide (TAA)-induced liver damage in mice.. Male mice were injected with TAA (500 mg/kg) then treated with sitagliptin (20 mg/kg) orally for 5 days.. Histopathological results of TAA group revealed severe degree of centrolobular hepatic necrosis. Additionally, biochemical findings showed marked elevation in the serum transaminases and gamma glutamyl transpeptidase (GGT) levels in TAA group. Injection of TAA significantly disrupted oxidant/antioxidants hemostasis of the hepatic tissues. Also, TAA markedly increased the expression of nuclear factor kappa-B (NF-KB); and enhanced Toll like receptor 4 (TLR4) as well as NLPR3 inflammosome production. Moreover, there was an elevation in the hepatic levels of tumor necrosis factor-alpha (TNF-α) and interleukin -1 beta (IL-1β) besides increased immunoexpression of Bcl-2-associated X protein (Bax) as well as caspase 3. In contrast, treatment with sitagliptin significantly attenuated TAA-induced histopathological, biochemical and immunohistochemical alterations.. Our results suggest that the hepatoprophylactic impact of sitagliptin might be arbitrated via modulating TLR4 and NK-KB signaling cascade followed by depression of inflammation besides apoptosis.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Chemical and Drug Induced Liver Injury; Dipeptidyl-Peptidase IV Inhibitors; Liver; Male; Mice; NF-kappa B; Oxidative Stress; Signal Transduction; Sitagliptin Phosphate; Thioacetamide; Toll-Like Receptor 4

Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes.

Topics: Animals; Apoptosis; Blotting, Western; Chemical and Drug Induced Liver Injury; Enzyme-Linked Immunosorbent Assay; Liver; Male; Methotrexate; Mice; Necrosis; NF-kappa B; Oxidative Stress; Real-Time Polymerase Chain Reaction; Sitagliptin Phosphate

A 58-year-old man with a 10-year history of type II diabetes mellitus presented with progressive jaundice that began three days before admission. Thorough history-taking revealed that the patient had started on a new medication, sitagliptin, one month previously for the treatment of diabetes mellitus. Laboratory investigations showed severe liver dysfunction. Ultrasonography detected no extrahepatic biliary duct dilatation or gallstones. Abdominal computed tomography excluded pancreatic and hepatic focal lesions. Liver function improved upon discontinuation of sitagliptin. Drugs are an important, often unrecognized, cause of acute liver injury. This report presents a rare case in which sitagliptin was responsible for acute hepatic damage. As demonstrated, a thorough drug history is helpful in any case of unexplained liver injury.

Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Jaundice; Liver; Male; Microscopy, Electron, Transmission; Middle Aged; Pyrazines; Sitagliptin Phosphate; Triazoles