Long-term increase in serum cholesterol levels in ulcerative colitis patients treated with cyclosporine: an underdiagnosed side effect frequently associated with other drug-related complications
Twenty patients, of both sexes, suffering from ischaemic heart disease and/or atherosclerotic peripheral vascular disease have been studied in a long-term trial of tetranicotinoylfructose (Bradilan) by mouth. Cholesterol levels fell in Type II cases and triglycerides in Type IV, the falls being well maintained at 6 months. Significant falls in fibrinogen, free fatty acids, and platelet stickiness were also observed and maintained at 6 months. Fibrinolytic activity increased significantly and over a similar period of time. These results bore no relation to Fredrickson types. Only one important side-effect, namely flushing, was observed. It was infrequent and tolerable and it diminished with time and adjustment of dosage.
Normal human diet contains small amounts of phytosterols, mainly sitosterol and campesterol. Intestinal absorption of these plant sterols is low, about one tenth of that of cholesterol, such that their serum concentrations are also low, about 0.1 to 1% of the cholesterol levels. Like cholesterol they are transported by lipoproteins, mainly by LDL, and secreted unchanged in bile. Addition of plant sterols, or especially of their delta-5 saturated derivatives plant stanols into diet as fat-soluble esters inhibit cholesterol absorption and lower serum cholesterol similarly in short-term studies. Long-term consumption of plant stanol esters lowers serum cholesterol to the extent expected to reduce clinical manifestation of coronary heart disease by over 20% without detectable side effecs, cholesterol lowering being especially effective in combination with cholesterol synthesis inhibitors statins.
Introduction:
Cholesterol lowering is associated with a reduction in cardiovascular morbidity and mortality. Statins are the main drugs for cholesterol lowering. Ezetimibe when added to statins gives further reduction in cholesterol but its long-term effect on cardiovascular morbidity and mortality and ischemic events is not known. This study sought to determine whether further cholesterol lowering with ezitimibe will also results in a reduction of myocardial ischemia during daily life.
Hypothesis:
Further cholestrol with ezetimibe lowering may reduce silent ischemia.
Methods:
We enrolled 50 patients with proven stable coronary artery disease (CAD) and at least one episode of ST-segment depression on ambulatory ECG monitoring. All of them were receiving optimal therapy for CAD including statin therapy for cholesterol reduction. 25 patients were randomized to continue their statin therapy (Statin only group) and 25 to recieve statin plus Ezitimibe 10mg/day (ezitimibe group). Serum cholesterol and LDL cholesterol levels and ambulatory monitoring were repeated after 4 to 6 months of therapy. The two groups were comparable with respect to baseline characteristics, number of episodes of ST-segment depression, and baseline serum cholesterol levels. Holters were read by a blinded cardiologist.
Results:
The ezitimibe group had lower mean total and LDL cholesterol levels at study end and experienced a significant reduction in the number of episodes of ST-segment depression compared with the statin only group. ST-segment depression was completely resolved in 13 of 25 patients (52%) in the ezitimibe group versus 3 of 25 (12%) in the statin only group. The ezitimibe group exhibited a highly significant reduction in ambulatory ischemia (P<.001). By logistic regression, treatment with ezitimibe was an independent predictor of ischemia resolution.
Conclusions:
Further cholesterol lowering with ezitimibe can result in reduction or resolution of myocardial ischemia recorded as episodes of ST-segment depression in ambulatory monitoring of the ECG. A larger study is required to confirm this results. This may be translated into long term mortality reduction for CAD by adding ezetimibe.
P449 Long-term increase of serum cholesterol level in ulcerative colitis patients treated with cyclosporine: an underdiagnosed side effect frequently associated with other drug-related complications