Do fibrates (fibric acid derivatives) increase the risk of developing gallbladder stones?

Do Fibrates Increase Risk for Gallbladder Stones?

Yes, fibrates do increase the risk of gallbladder stone formation, particularly during the first year of treatment, with clofibrate showing an 8-fold increased incidence of new gallstones. 1

Mechanism and Evidence

Fibrates alter biliary lipid composition and bile acid metabolism in ways that promote gallstone formation:

• Fibrates downregulate cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, which reduces bile acid production and creates a more lithogenic (stone-forming) bile composition 2
• This molecular mechanism has been demonstrated in human liver specimens from gallstone patients treated with bezafibrate, fenofibrate, and gemfibrozil 2

Clinical Evidence by Fibrate Type

Clofibrate carries the highest documented risk:

• During the first year of treatment, clofibrate increases the incidence of new gallstones approximately 8-fold compared to baseline 1
• The prevalence of gallstones is not inherently increased in patients with hyperlipidemia before treatment, indicating the risk is medication-induced 1

Fenofibrate also demonstrates gallstone formation:

• Case reports document gallbladder stone detection within 3 months of fenofibrate initiation in previously stone-free patients 3
• Fenofibrate significantly reduces CYP7A1 mRNA levels in human liver tissue, explaining its lithogenic potential 2

Gemfibrozil and bezafibrate share similar mechanisms:

• Both agents significantly reduce CYP7A1 expression and modify biliary lipid secretion patterns 2
• All three major fibrates (bezafibrate, fenofibrate, gemfibrozil) induce adverse changes in biliary lipid and bile acid composition 2

Important Clinical Caveats

The risk appears highest during initial treatment:

• The 8-fold increased incidence is most pronounced in the first year of clofibrate therapy 1
• Monitoring with imaging should be considered during this high-risk period, particularly in symptomatic patients 3

Cholestyramine may not increase risk when used alone or with fibrates:

• Cholestyramine at doses of 16 g per day does not appear to increase gallstone incidence, either as monotherapy or in combination with clofibrate 1
• However, cholestyramine should be given at least 4 hours after other medications to avoid interaction 4

Special Populations

In pregnancy, fibrate use requires careful consideration:

• Fibrates have been used in pregnant women with severe hypertriglyceridemia after the first trimester, but safety data are limited 4
• Decisions about fibrate use should be individualized based on the severity of maternal disease, weighing the gallstone risk against the need for triglyceride control 4

In chronic kidney disease, additional concerns exist:

• Fenofibrate is contraindicated in patients with eGFR <30 mL/min/1.73 m² 4
• The combination of statins and fibrates raises the risk for rhabdomyolysis and should not be used in CKD 4

Practical Monitoring Approach

When fibrates must be used despite gallstone risk:

• Obtain baseline imaging (ultrasound) before initiating therapy to document absence of stones
• Monitor for symptoms of biliary colic, particularly during the first year of treatment 1, 3
• Consider repeat imaging at 3-6 months if symptoms develop 3
• Renal function should be monitored before treatment, within 3 months after starting, and every 6 months thereafter 5