How Do Peroxisome Proliferator Activated Receptor (PPAR) Agonists Work?

Peroxisome Proliferator Activated Receptor (PPAR) agonists are medications that are used to treat various conditions such as imbalance in the levels of blood fats (dyslipidemia), diabetes mellitus type II, and primary biliary cholangitis, an autoimmune liver disease. PPAR agonists work by stimulating the activity of PPARs, a family of proteins (transcription factors) in the nucleus of cells.

PPARs switch from an inactive form to an active form when activated, and perform a variety of important metabolic functions. There are three isoforms of PPARs in our body, PPAR-alpha, PPAR-gamma and PPAR-beta/delta, and each type has a unique function. PPAR agonists work by binding to one or more of the PPARs and activating them.

PPAR-alpha: Increases the good (HDL) cholesterol, and reduces triglycerides and bad (LDL and VLDL) cholesterol levels in blood. It also regulates the balance (homeostasis) between food intake and energy expenditure. Fibric acid agents such as fenofibrate and gemfibrozil are PPAR-alpha agonists used to treat hypertriglyceridemia and hypercholesterolemia.

PPAR-gamma improves cell response to insulin and enhances glucose metabolism. Drugs such as pioglitazone and rosiglitazone belonging to thiazolidinedione class of drugs are PPAR gamma agonists, used to treat diabetes mellitus type II as a single agent or in combination with other antidiabetic medications.

PPAR-beta/delta enhances the metabolism of fatty acids. Seladelpar is an investigative PPAR-delta agonist drug, being developed to treat primary biliary cholangitis (PBC), an autoimmune liver disease that damages the bile ducts and inflames the liver, eventually leading to cirrhosis. PPAR-delta agonists decrease bile acid synthesis and reduce inflammation.

Elafibranor activates all three isoforms of PPAR and is used to treat primary biliary cholangitis. Elafibranor is the first-in-class PPAR agonist to be approved by the FDA in June 2024. The exact mechanism of its therapeutic action in PBC is not well understood.

PPAR agonists are currently being studied for use in various other conditions including obesity, inflammatory conditions, certain cancers, and neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, brain injury and amyotrophic lateral sclerosis.

PPAR agonists are administered in the form of oral tablets or capsules. The FDA-approved uses of PPAR agonists include:

• PPAR-alpha agonists (fibric acid agents):
• Hypercholesterolemia
• Hypertriglyceridemia
• Mixed dyslipidemia
• PPAR-gamma agonists (thiazolidinediones):
• Type II diabetes mellitus
• PPAR (alpha, gamma and delta) agonists:
• Primary biliary cholangitis

Common side effects of Peroxisome Proliferator Activated Receptor (PPAR) Agonists include the following:

PPAR-Alpha Agonists (fibric acid agents):

• Indigestion (dyspepsia)
• Elevation in liver enzymes AST and ALT
• Headache
• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Constipation
• Back pain
• Fatigue
• Respiratory disorder
• Upper respiratory tract infection
• Nasal inflammation (rhinitis)
• Inflammation of nose and throat (nasopharyngitis)
• Muscle pain (myalgia)
• Increase in creatine phosphokinase (CPK)
• Vertigo
• Rash
• Eczema
• Heart rhythm disturbance (atrial fibrillation)

PPAR-Gamma Agonists (thiazolidinediones):

• Low blood sugar (hypoglycemia)
• Edema when used in combination with sulfonylurea or insulin
• Upper respiratory infection
• Increase in LDL, HDL and total cholesterol
• Congestive heart failure
• High blood pressure (hypertension)
• Heart attack (myocardial ischemia)
• Headache
• Edema
• Diarrhea
• Sinus inflammation (sinusitis)
• Throat inflammation (pharyngitis)
• Back pain
• Muscle pain (myalgia)
• Bone fracture
• PPAR (alpha, gamma and delta) agonists
• Weight gain
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Constipation
• Gastroesophageal reflux disease (GERD)
• Dry mouth
• Gastroenteritis
• Joint pain (arthralgia)
• Muscle pain (myalgia)
• Fracture
• Weight loss
• Rash
• Anemia
• Increase in blood creatinine
• Dizziness
• Gallstones (cholelithiasis)
• Increase in CPK
• Breakdown of muscle tissue (rhabdomyolysis)
• Acute kidney injury

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of Peroxisome Proliferator Activated Receptor (PPAR) Agonists include:

PPAR-Alpha Agonists (fibric acid agents):

• Antara
• fenofibrate
• fenofibrate micronized
• fenofibric acid
• Fenoglide
• Fibricor
• gemfibrozil
• Lipofen
• Lopid
• Tricor
• Triglide
• Trilipix

PPAR-Gamma Agonists (thiazolidinediones):

• Actos
• alogliptin/pioglitazone
• Avandia
• Oseni
• pioglitazone
• rosiglitazone
• PPAR-agonists:
• elafibranor
• Iqirvo
• seladelpar (Pending FDA approval)