What is the mechanism of action of colestipol?

From the Guidelines

Colestipol works by binding to bile acids in the intestine, preventing their reabsorption and promoting their elimination in the feces, which leads to increased conversion of cholesterol to bile acids in the liver and ultimately decreases serum cholesterol levels. This mechanism is supported by the most recent and highest quality study, which describes the action of bile acid sequestrants, including colestipol, as nonabsorbed, lipid-lowering polymers that bind bile acids in the intestine and impede their reabsorption 1. As the bile acid pool decreases, the hepatic enzyme cholesterol 7-a-hydroxylase is upregulated, which increases the conversion of cholesterol to bile acids, causing an increased demand for cholesterol in the liver cells. This results in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme HMG-CoA reductase and increasing the number of hepatic LDL receptors, leading to increased clearance of LDL particles from the blood and decreased serum LDL-C levels.

Some key points to consider when using colestipol include:

• Dosing: typically 5-30 grams daily, divided into two or three doses, and available as granules or tablets
• Administration: should be taken with meals and plenty of fluids to minimize gastrointestinal side effects
• Potential interactions: may decrease absorption of certain medications, so other drugs should be taken at least 1 hour before or 4 hours after colestipol
• Side effects: may include gastrointestinal upset, increases in triglyceride levels, and interference with the absorption of fat-soluble vitamins and some medications

It's also important to note that colestipol has been shown to be effective in reducing LDL cholesterol levels, with studies demonstrating a mean percentage reduction in LDL-C of 16.3%, 22.8%, and 27.2% with doses of 5,10, and 15 g, respectively 1. However, the use of colestipol may be limited by its potential side effects and interactions, and patients should be closely monitored for any adverse effects. Overall, colestipol is a useful agent for lowering LDL cholesterol levels, but its use should be carefully considered and monitored in clinical practice.

From the FDA Drug Label

Cholesterol is the major, and probably the sole precursor of bile acids. During normal digestion, bile acids are secreted via the bile from the liver and gall bladder into the intestines. Bile acids emulsify the fat and lipid materials present in food, thus facilitating absorption A major portion of the bile acids secreted is reabsorbed from the intestines and returned via the portal circulation to the liver, thus completing the enterohepatic cycle. Only very small amounts of bile acids are found in normal serum. Colestipol hydrochloride binds bile acids in the intestine forming a complex that is excreted in the feces This nonsystemic action results in a partial removal of the bile acids from the enterohepatic circulation, preventing their reabsorption. The increased fecal loss of bile acids due to colestipol hydrochloride administration leads to an increased oxidation of cholesterol to bile acids This results in an increase in the number of low-density lipoprotein (LDL) receptors, increased hepatic uptake of LDL and a decrease in beta lipoprotein or low density lipoprotein serum levels, and a decrease in serum cholesterol levels.

Mechanism of Action: Colestipol works by binding to bile acids in the intestine, forming a complex that is excreted in the feces, thereby removing bile acids from the enterohepatic circulation and preventing their reabsorption. This leads to an increased oxidation of cholesterol to bile acids, resulting in a decrease in serum cholesterol levels.

• Key Effects:
  • Increased fecal loss of bile acids
  • Increased oxidation of cholesterol to bile acids
  • Increased number of LDL receptors
  • Increased hepatic uptake of LDL
  • Decrease in beta lipoprotein or low density lipoprotein serum levels
  • Decrease in serum cholesterol levels 2

From the Research

Mechanism of Action of Colestipol

• Colestipol is an anion exchange resin with bile acid sequestering properties, similar to cholestyramine 3.
• It works by preventing the reabsorption of bile acids from the intestinal tract into the enterohepatic circulation, resulting in a net loss of bile acids and cholesterol 4.
• This leads to a reduction in total plasma cholesterol concentrations, primarily low-density lipoprotein (LDL) cholesterol, by about 15-30% 3.
• The reduction in LDL cholesterol is due to the increased excretion of bile acids, which are then replaced by the liver, using cholesterol as a precursor 4.

Effects on Lipid Profiles

• Colestipol has been shown to reduce LDL cholesterol, total cholesterol, and apolipoprotein B levels, while increasing high-density lipoprotein (HDL) cholesterol levels 5.
• However, it may not significantly alter triglyceride levels, and in some cases, may even increase them 3, 4.
• The effects of colestipol on lipid profiles are dose-dependent, with higher doses resulting in greater reductions in LDL cholesterol and total cholesterol 5, 6.

Clinical Efficacy and Safety

• Colestipol has been shown to be effective in reducing LDL cholesterol levels in patients with primary hypercholesterolemia, with significant reductions in LDL cholesterol and total cholesterol observed in several studies 3, 4, 5, 7.
• The drug is generally well-tolerated, with gastrointestinal side effects such as constipation, bloating, and gas being the most common adverse events 3, 4, 5, 6.
• Long-term treatment with colestipol has been shown to be safe and effective, with no evidence of nutritional or metabolic disturbances, and significant reductions in xanthoma size and stabilization of atherosclerotic lesions 7.