The thiazolidinediones, abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in the treatment of diabetes mellitus type 2 that were introduced in the late 1990s. As of 2024, there are two FDA-approved drugs in this class, pioglitazone and rosiglitazone.
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.
Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complications may include cirrhosis, liver cancer, and esophageal varices.
Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination telmisartan/hydrochlorothiazide, telmisartan/cilnidipine and telmisartan/amlodipine.
Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a type of chronic liver disease. This condition is diagnosed when there is excessive fat build-up in the liver, and at least one metabolic risk factor. When there is also increased alcohol intake, the term MetALD, or metabolic dysfunction and alcohol associated/related liver disease is used, and differentiated from alcohol-related liver disease (ALD) where alcohol is the predominant cause of the steatotic liver disease. The terms non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis have been used to describe different severities, the latter indicating the presence of further liver inflammation. NAFL is less dangerous than NASH and usually does not progress to it, but this progression may eventually lead to complications, such as cirrhosis, liver cancer, liver failure, and cardiovascular disease.
Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1DAs or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1 that is released by the gut after eating.
Saroglitazar is a drug for the treatment of type 2 diabetes mellitus, dyslipidemia, NASH and NAFLD It is approved for use in India by the Drug Controller General of India. Saroglitazar is indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, saroglitazar has demonstrated reduction of triglycerides (TG), LDL cholesterol, VLDL cholesterol, non-HDL cholesterol and an increase in HDL cholesterol a characteristic hallmark of atherogenic diabetic dyslipidemia (ADD). It has also shown anti-diabetic medication properties by reducing the fasting plasma glucose and HBA1c in diabetes patients.
Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.
Tropifexor is an investigational drug that acts as an agonist of the farnesoid X receptor (FXR). It was discovered by researchers from Novartis and Genomics Institute of the Novartis Research Foundation. Its synthesis and pharmacological properties were published in 2017. It was developed for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). In combination with cenicriviroc, a CCR2 and CCR5 receptor inhibitor, it is undergoing a phase II clinical trial for NASH and liver fibrosis.
Nidufexor (LMB-763) is a drug which acts as a partial agonist of the farnesoid X receptor (FXR). It has reached Phase II clinical trials for the treatment of diabetic nephropathy and nonalcoholic steatohepatitis.
Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist in clinical trials for the treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and primary sclerosing cholangitis (PSC). It is being investigated for use alone or in combination with firsocostat, selonsertib, or semaglutide. In rat models and human clinical trials of NASH it has been shown to reduce fibrosis and steatosis, and in human clinical trials of PSC it improved cholestasis and reduced markers of liver injury.
Resmetirom, sold under the brand name Rezdiffra, is a medication used for the treatment of noncirrhotic nonalcoholic steatohepatitis. It is a thyroid hormone receptor beta (NR1A2) agonist.
Efocipegtrutide (HM15211) is a triple agonist of the glucagon, GIP, and glucagon-like peptide 1 receptors. It is being studied for obesity and nonalcoholic steatohepatitis.
Pegozafermin (BIO89-100) is a long-acting, glycopegylated FGF21 analog developed for the treatment of nonalcoholic steatohepatitis and hypertriglyceridemia.
PXL065 (d-R-pioglitazone) is a drug candidate for the treatment of nonalcoholic steatohepatitis (NASH). It is the deuterium-stabilized (R)-enantiomer of pioglitazone which lacks PPARγ agonist activity and the associated side effects of weight gain and edema. PXL065 (formerly known as DRX-065) has demonstrated preclinical efficacy for both NASH and X-linked adrenoleukodystrophy (X-ALD). In 2022, it successfully completed a 9 month Phase 2 trial in biopsy-proven NASH patients where it met the primary endpoint for reduction in liver fat without weight gain or edema.
Aldafermin is a fibroblast growth factor 19 (FGF19) analogue developed for non-alcoholic steatohepatitis.
ARO-HSD, also known as GSK4532990, is a small interfering RNA developed for the treatment of fatty liver disease. Based on the observation that "loss-of-function HSD17β13 mutations protect against the development of chronic liver disease," the therapeutic attempts to induce this loss of function and thus improve liver disease. The therapy is developed by a partnership of GlaxoSmithKline and Arrowhead Pharmaceuticals that might be worth more than $1 billion.
EDP-305 is a non-bile acid farnesoid X receptor (FXR) agonist developed by Enanta Pharmaceuticals for non-alcoholic fatty liver disease. According to preclinical research CYP3A4 is the main enzyme used to metabolize the drug and there is a low potential for drug interactions.
Azemiglitazone (MSDC-0602) is a novel insulin sensitizer designed to retain the effect of thiazolidinediones on mitochondrial pyruvate carriers with limited PPAR-gamma binding. It is hoped to have fewer adverse effects than the thiazolidinediones and is being developed by Cirius Therapeutics for type 2 diabetes and non-alcoholic fatty liver disease. It is formulated as its potassium salt, azemiglitazone potassium (MSDC-0602K).
HU6 is a controlled metabolic accelerator of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) that is intended to "minimize the rapid absorption and high peak blood concentrations of DNP to provide a wider therapeutic index and improve safety." Developed by Rivus Pharmaceuticals, the drug is tested to reduce weight and liver fat in humans with risk factors for metabolic dysfunction-associated steatohepatitis. In a phase 2a trial, the higher dosage levels reduced liver fat on average by more than 30 percent and also reduced body weight significantly. A phase 2b trial was launched in late 2023.
