Adverse Effects of Hypolipidaemic Drugs

Summary

Cholestyramine, colestipol, clofibrate, gemfibrozil, nicotinic acid (niacin), probucol, neomycin, and dextrothyroxine are the most commonly used drugs in the treatment of hyperlipoproteinaemic disorders. While adverse reaction data are available for all of them, definitive data regarding the frequency and severity of potential adverse effects from well-controlled trials using large numbers of patients (> 1000) are available only for cholestyramine, clofibrate, nicotinic acid and dextrothyroxine.

In adult patients treated with cholestyramine, gastrointestinal complaints, especially constipation, abdominal pain and unpalatability are most frequently observed. Continued administration along with dietary manipulation (e.g. addition of dietary fibre) and/or stool softeners results in diminished complaints during long term therapy. Large doses of cholestyramine (> 32 g/day) may be associated with malabsorption of fat-soluble vitamins. Most significantly, osteomalacia and, on rare occasions, haemorrhagic diathesis are reported with cholestyramine impairment of vitamin D and vitamin K absorption, respectively. Paediatric patients have been reported to experience hyperchloraemic metabolic acidosis or gastrointestinal obstruction. Concurrent administration of acidic drugs may result in their reduced bioavailability.

Serious adverse reactions to cloflbrate will probably limit its role in the future. Of particular concern are ventricular arrhythmias, induction of cholelithiasis and cholecystitis, and the potential for promoting gastrointestinal malignancy which far outweigh the reported benefits in preventing new or recurrent myocardial infarction, cardiovascular death and overall death. Patients with renal disease are particularly prone to myositis, secondary to alterations in protein binding and impaired renal excretion of cloflbrate. Drug interactions with coumarin anticoagulants and sulphonylurea compounds may produce bleeding episodes and hypoglycaemia, respectively.

Nicotinic acid produces frequent adverse effects, but they are usually not serious, tend to decrease with time, and can be managed easily. Dermal and gastrointestinal reactions are most common. Truncal and facial flushing are reported in 90 to 100% of treated patients in large clinical trials. Significant elevations of liver enzymes, serum glucose, and serum uric acid are occasionally seen with nicotinic acid therapy. Liver enzyme elevations are more common in patients given large dosage increases over short periods of time, and in patients treated with sustained release formulations. Effects on glucose and uric acid appear to be problematic, primarily in patients with pre-existing diabetes mellitus or gout.

Adverse drug reaction data for colestipol, gemfibrozil, probucol, and neomycin are derived from smaller clinical studies, and many of these studies are not adequately controlled to allow an accurate impression of risks associated with therapy. In contrast, dextrothyroxine was evaluated in over 1000 patients in the Coronary Drug Project (1972). Although the drug was shown to be effective in lowering serum cholesterol, excessive cardiovascular mortality was noted with dextrothyroxine. Therefore, this drug should be used cautiously, if at all, for the management of hyperlipoproteinaemia.

Gemfibrozil, a promising hypolipidaemic drug because of its action in lowering low density lipoprotein and very low density lipoprotein concentrations while elevating high density lipoprotein, is structurally similar to clofibrate and its long term use may be associated with similar liabilities. Adverse reactions reported with gemfibrozil to date are mild.

Few clinically significant adverse effects are reported with probucol administration. The most common effects are gastrointestinal in nature and include transient diarrhoea, flatulence, nausea and abdominal pain. However, the primary concerns with probucol relate to its effects on prolonging the QT_c interval, its accumulation in high concentrations in adipose tissue, and its possible effects on reducing high density lipoproteins.

In doses used to treat hyperlipidaemia (0.5 to 2.0 g/day), neomycin is generally free of intolerable or serious side effects. Diarrhoea, which spontaneously resolves within 1 to 3 weeks of initiation of therapy, is the most frequently reported side effect. Despite concerns related to its potential for ototoxicity and nephrotoxicity, hypolipidaemic doses produce extremely low serum concentrations, and these problems are not reported in patients with normal renal function. Neomycin has been shown to significantly reduce the absorption of digitoxin when administered concurrently and up to 6 hours after neomycin ingestion.