What does the pharmacist need to know to counsel patients about colesevelam?
Epidemiological studies have established that elevated levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipo-protein B (Apo B), as well as decreased levels of HDL-cholesterol (HDL-C), are associated with an increased risk of atherosclerosis and cardiovascular-related mortality. Furthermore, it has been documented through numerous trials that aggressive reduction of lipid levels can significantly reduce the risk of cardiovascular disease. It is estimated that more than 50 million Americans currently have at least mild elevations of cholesterol (hyper-cholesterolemia or Fredrickson Type IIa hyperlipidemia) and would benefit from some form of lipid-lowering therapy. Diet and lifestyle changes generally represent the initial approach toward lipid reduction, but these often produce small and inconsistent results. For patients who continue to have elevated cholesterol levels following diet and lifestyle modifications, drug therapy is recommended. Currently available lipid-lowering drugs include the “statin” hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HMG-CoARIs), the bile acid sequestrants, nicotinic acid, the fibric acids (gemfibrozil, clofibrate) and probucol. The lipid-lowering market is one of the fastest growing in the nation, generating over $6 billion in sales and nearly 95 million prescriptions over the past year.
For initial cholesterol-lowering therapy, the National Cholesterol Education Program (NCEP) recommends bile acid sequestrant drugs used alone or in combination with other drugs, such as the statin HMG-CoARIs. The safety and efficacy of cholestyramine resin and colestipol hydrochloride, the most commonly prescribed bile acid sequestrants, have been demonstrated repeatedly. These bile acid sequestrants alone reduce LDL-C concentrations by 10% to 30%. Combination therapy of bile acid sequestrants with niacin or an HMG-CoARI produces even larger LDL-C reductions of up to 60%. Despite their proven efficacy and the lack of systemic effects resulting from nonabsorption from the gastrointestinal tract, the bile acid sequestrants currently available have a high drug discontinuation rate due, in large measure, to intolerable GI side effects. Constipation occurs in up to 39% of patients taking currently available bile acid sequestrants and in severe cases, this may result in fecal impaction. Other gastrointestinal side effects, such as bloating, flatulence, and cramping, also occur in a large percentage of patients who are treated with currently available bile acid sequestrants. Therefore, the development of effective cholesterol-lowering agents with greater tolerability than currently available bile acid sequestrants has been a priority of hypercholesterolemic drug research.
Colesevelam (WelChol/Sankyo) is a new, nonabsorbed polymer (water-absorbing hydrogel) that has been specifically designed to bind to bile acids in the GI tract. It is a poly-allylamine cross-linked with epichlorohydrin and alkylated with 1-bromodecane and brom hexyltrimethylammonium bromide. Colesevelam has a high affinity for both trihydroxy and dihydroxy bile acids in the intestine, leading to increased fecal bile acid excretion. Preliminary in vivo and in vitro studies suggest that colesevelam has superior bile acid binding efficacy compared to cholestyramine. Furthermore, its water-retaining characteristic creates a soft, gelatinous-like material that minimizes the potential for gastrointestinal irritation relative to other bile acid sequestrants.