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Chin Med J (Taipei) 1997;59:217-24.
Division of Cardiology, Department of Medicine, 1804 Army Hospital, 2Veterans General Hospital-Taipei and 3National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.
Background. The purpose of the study was to evaluate the effects and safety of fenofibrate or gemfibrozil on plasma lipid profiles in Chinese patients with type IIb hyperlipidemia.
Methods. Patients with previously diagnosed type IIb hyperlipidemia were initially evaluated in this single-blind, randomized, cross-over study. Only those who had persistent hyperlipidemia after a two-month diet control period were included. The patients were randomized to either fenofibrate 100 mg tid or gemfibrozil 600 mg bid for three months, then shifted to alternate drug for another three months after a two-month washout period. During the whole 10-month period, a prudent diet was maintained. Each patient was followed up at Out-patient Clinic regularly for diet interview, compliance and possible adverse events.
Results. A total of 12 patients, 11 males and 1 female, completed the whole study. After a three-month treatment of fenofibrate, there was significant reduction in plasma total cholesterol (22.7%, p < 0.001), total triglycerides (43.2%, p < 0.001), and low-density lipoprotein (LDL)-cholesterol (25.7%, p=0.001). Serum high density lipoprotein (HDL) cholesterol was also increased by 30.2% (p=0.055). On the other hand, only total triglyceride was significantly reduced by 36.5% (p= 0.005) with gemfibrozil treatment. There was no significant change of serum total, HDL- and LDL-cholesterol after the three-month treatment of gemfibrozil. Besides, serum uric acid and alkaline phosphatase were significantly reduced with fenofibrate but not with gemfibrozil treatment. There was no obvious adverse event noted during each treatment period with either drug.
Conclusions. The findings suggest that in Chinese patients with type IIb hyperlipidemia, both fenofibrate and gemfibrozil can safely and significantly reduce serum triglyceride. Fenofibrate, but not gemfibrozil, could also reduce serum total cholesterol, LDL and uric acid. The results were compatible with the findings of previous studies in western patients with hyperlipidemia.
[Chin Med J (Taipei) 1997;59:217-24.]
Keywords: cholesterol, fenofibrate, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride, type IIb hyperlipidemia
Received: October 23, 1996.
Accepted: February 18, 1997.
Address reprint requests to: Jaw-Wen Chen, M.D., Division of Cardiology, Department of Medicine, Veterans General Hospital-Taipei, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan, R.O.C.
Dyslipidemia was caused by a number of disorders in lipid or apolipoprotein metabolism. According to the World Health Organization's definition [1], hyperlipoproteinemia commonly involves the elevation in plasma levels of low density lipoprotein (LDL) alone (type lla, hypercholesterolemia), LDL and very low density lipoprotein (VLDL) (type llb, combined hyperlipidemia), or of VLDL alone (type IV, hypertriglyceridemia). Epidemiological studies have confirmed that elevated plasma total and LDL-cholesterol levels are independent risk factors for coronary atherosclerosis. There is also a strong association between elevated serum triglycerides and coronary artery disease [2]. Besides, high density lipoprotein (HDL) appears to be involved in the transport of cholesterol and So have been identified as a protective factor against atherosclerosis [3]. Thus, the main goal of the current treatment in hyperlipidemia is to prevent or decrease atherosclerosis in coronary as well as other artery systems by either reducing the plasma total triglyceride, cholesterol and LDL levels or increasing the HDL level or both.
Drugs in the fibric acid series have been generally recommended for use in severe hypertriglyceridemia [4]. Fenofibrate is one of the new fibric acid derivatives which is effective in the treatment of both hypertriglyceridemia and hypercholesterolemia. Fenofibrate is the isopropyl ester of para-(4'-chlorobenzoil)-2-phenoxy-2-methyl propionic acid, structurally related to clofibrate. Since 1973, the effects of fenofibrate on lipid and lipoprotein profiles have been evaluated in all types of the hyperlipidemia except for the pure hyperchylomicronemia (type 1) [5]. Results of the studies in western countries showed that fenofibrate had a broad spectrum of lipid-lowering activity with total cholesterol level reduced by 20-25% in patients with type lla and the triglyceride level by 40-60% in those with type IIb or IV hyperlipidemia [6]. Further, a high level of LDL was reduced, and a HDL level, which had been low at baseline, was increased after fenofibrate administration. An associated activity was a 10-28% reduction in serum uric acid level. Adverse reactions of fenofibrate administration in most open clinical trials ranged from 2-15%, dominated by mild gastrointestinal problems, and occurring with a frequency similar to that in the placebo-treated groups. Recent studies in western patients with type IIa or IIb hyperlipidemia further showed a better therapeutic effect of fenofibrate than of clofibrate or gemfibrozil especially for reducing the high level of LDL [7]. However, it is unknown whether these were similar results in Chinese patients.
Thus, the present study was conducted 1) to compare the effect of fenofibrate (Lipanthyl) 300 mg daily (100 mg three times a day) with that of gemfibrozil (Lopid) 1200 mg daily (600 mg twice a day) on plasma lipid profiles, and 2) to evaluate the safety and tolerability of these two drugs by observing the adverse effects and measuring laboratory tests, over a three-month treatment period each, in Chinese patients with type IIb hyperlipidemia.
Patients, aged > 18 years, either male or female, with previous diagnosis of type IIb hyperlipidemia (serum total cholesterol level > 250 mg/dl, and total triglycerides level between 200 and 500 mg/dl) but otherwise in good health were screened over a two-year period. Only those who still fulfilled the inclusion criteria after a two-month diet control without lipid-lowering agents were included. The exclusion criteria were the following: 1) patients who were unable to understand the protocol or likely to leave the study before its completion; 2) pregnant (or child-bearing potential) or nursing females; 3) previous history of hypothyroidism, diabetes mellitus, pancreatitis, cholestasis, nephrotic syndrome, liver disease (the activities of SGOT, SGPT, Gamma-GT > twice of the upper normal limit), renal insufficiency (serum creatinin > 1.5 time of the upper normal limit), hyperglycemia (fasting plasma sugar > 120 mg/dl), chronic alcoholism, myocardial infarction, cerebrovascular stroke, cardiovascular surgery within three months prior to the study, unstable or recent angina pectoris, gastric or peptic ulcer within three months prior to the study, pathology requiring the care of specialists (cancer, mental illness...), hypersensitivity to lipid lowering agents; 4) concomitant medications such as oral contraceptive, Probucol, statins, oral anticoagulant (or with abnormal prothrombin time), and any medical medication capable of interfering with lipid metabolism. Other concomitant treatment including beta-blockers and diuretics could be accepted, provided that no changes in dosages took place during the study. The study was conducted according to the guidelines of local Ethic Committee and all patients entered the study after giving their written informed consents.
This study was conducted in a single-blind, randomized, cross-over design with the following five sequential stages: 1) a screening and diet initiation visit at which point all lipid-lowering medication was discontinued; 2) an initial two-month run-in period with a recommended diet only; 3) a three-month treatment period (period 1, T0-T3) with fenofibrate 100 mg tid or gemfibrozil 600 mg bid; 4) a two-month washout period between the two treatment periods; 5) another three-month treatment period (period 2, T5-T8) with the alternate drug (Figure 1).
Each included patient was first assigned a patient identification number. By using a blocked random number generation program, patients were randomized to either treatment first ,then followed by another.
The patients would be dropped from study if following conditions happened during their treatment periods: 1) non-compliance with drug treatment; 2)1ack of cooperation; 3) failure to come to one appointment; 4) if medication were temporarily interrupted, was done to less than five consecutive days or there was a total interruption of treatment during any study period of less than 10 days; 5) patient began a forbidden treatment as indicated in the non-selection criteria, 6) any other condition which might increase risk for the patient, or decrease the chance of obtaining satisfactory data to achieve the objectives of the study.
When entering the study, all patients were requested to have a suitable diet throughout the whole 10-month period. Dietary interview (food type and frequency, alcohol consumption) was conducted by a nutritionist at each visit, when a proper diet regimen was suggested and the importance of maintaining a stabilized diet was emphasized to each patient. Patients who underwent significant dietary changes during the study were excluded from the study when such changes occurred.
After an overnight fast, 10-15cc blood was drawn from the patient's antecubital vein in the morning hours both before (T0, T5) and after (T3, T8) each treatment period for the following serum lipid parameters: total cholesterol, total triglycerides, HDL, LDL, Apo B and Apo A1 these were determined in a central laboratory. The tourniquet was removed before blood sampling. These measurements were performed on EDTA plasma, the blood cells were removed from the plasma within one hour. Blood samples were stored at 4OC if the samples were to be assayed in a few days, or the samples were frozen at -20OC for more prolonged storage. The total cholesterol and triglyceride levels were assayed by enzymatic endpoint method. The HDL-cholesterol level was determined by heparin manganese chloride precipitation or the dextran sulfate-manganese methods. The LDL-cholesterol was calculated by the formula: LDL cholesterol = total cholesterol - HDL - cholesterol -1/5 total triglycerides.
To evaluate the possible additional or adverse effects of the treatment in the present study, the following laboratory tests were also performed at time T0, T3, T5 and T8, which included: SGOT, SGPT, plasma uric acid, serum creatinine, fasting plasma glucose, serum alkaline phosphatase, serum r-GT, red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, white blood cell count, and platelets.
The compliance of the patients was evaluated each month at the Out-patient clinic by the investigators.Events possibly related to the adverse effects of the drugs were asked and recorded. The patients who were not in accordance with the inclusion criteria or had significant adverse effect were excluded from the study.
All data were expressed as mean (+/- SD). Two-tailed paired Student t-test was used to compare the difference of all the variables between the two different treatment periods in the same group of patients. A p value < 0.05 was considered to be statistically significant.
Of the total 23 patients initially included, only 12 completed the whole study. In eight patients, lipid profiles were completely normalized after diet control for two months. One patient developed cardiac arrhythmia during the diet control period and another patient had intermittent angina from coronary artery disease during the first period of treatment. In addition, one patient died in a traffic accident during the wash-out period. Those were excluded from following study.
Table 1 shows the basic data of the 12 patients completing the study. Six patients in Group 1 were treated with gemfibrozil then followed by fenofibrate. Another six patients in Group 2 were treated in the opposite order. The age, gender, body height and weight were not different between the two groups of patients.
The patients' compliance was generally good in the present study. There was no significant adverse event noted during either treatment period. One patient developed mild epigastric distress after taking either fenofibrate or gemfibrozil. This symptom could be relieved if drugs were taken just after meal. Another patient had abnormal liver function with marked elevation of SGOT and SGPT (> twice of upper normal range) during wash-out period, this was related to a temporary alcohol drinking, values were returned to normal one month after alcohol drinking was stopped. Then, the patient completed the following study smoothly.
The baseline values (including total cholesterol, triglyceride, LDL, HDL, apoprotein A1 and B) obtained at To and T5 did not differ between two groups (Table 2).
To evaluate the individual lipid-lowering effect of fenofibrate and gemfibrozil, the data in T0 as well as T5 and in T3 as well as T8 were pooled, respectively, according to the drug used. Table 3 shows the lipid profiles before and after the three-month treatment by either drug. Though total triglyceride was significantly reduced both by fenofibrate and by gemfibrozil, total cholesterol and LDL were only reduced after fenofibrate treatment. The level of HDL was also increased by fenofibrate but not by gemfibrozil. There was no significant change of apoprotein A1 and B with either fenofibrate or with gemfibrozil treatment.
The percentage changes of lipid parameters after individual drug treatment [(T3T0)/T0] was also summarized in Table 4. Compared to gemfibrozil, fenofibrate produced a similar degree of reduction (43.2 +/- 17.1% versus 36.5 +/- 23.2%, p=NS) in total triglyceride and much more reduction in total cholesterol (22.7 +/- 13.3% versus 4.8 +/- 10.9%, p=0.001 ) as well as LDL (25.7 +/- 17.6% versus 4.3 +/- 17.5%, p=0.003).
The changes in biochemical and other laboratory parameters with fenofibrate or gemfibrozil are shown in Table 5. Most of the parameters are similar in the two treatments.
There was no significant change of SGOT or SGPT with either fenofibrate or gemfibrozil. However, serum alkaline phosphatase was significantly (p < 0.001) reduced by 31.8 +/- 13.9% with fenofibrate but remained unchanged (p=0.26) with gemfibrozil. Plasma uric acid was also significantly decreased by 24.4 +/- 28.1% (p= 0.005) with fenofibrate but not (p=0.26) with gemfibrozil treatment.
The results of the present study showed significant reduction of serum cholesterol, triglyceride and LDL by fenofibrate treatment in Chinese patients with type IIb hyperlipidemia. This is compatable with previous findings in Europe and the United States [5,6].1t has been shown that fenofibrate could produce a 15-30% reduction of serum total cholesterol in Type llb hyperlipidemia patients [4] Serum triglyceride was also reduced by 30% to 60% in these western patients [4]. In the present study, both fenofibrate and gemfibrozil could reduce serum triglyceride by 30-40%. However, only fenofibrate could significantly reduce serum cholesterol by 23% also reducing LDL by 26% in our patients. This is compatible with previous findings in western people that serum LDL-cholesterol was commonly reduced by 20 to 40% with fenofibrate treatment [6,8].
The therapeutic effect of fibric acid on serum HDL may not be so obvious as it is upon serum LDL. One previous studies demonstrated a 21% increase of serum HDL by fenofibrate treatment [8]. However, the effect of fenofibrate on serum HDL-cholesterol usually varied from little change to an increase as large as 40%, greatly depending on the baseline level [6]. In the present study, while the baseline level of serum total cholesterol was very high, serum HDL varied in these patients. The change of serum HDL after a three-month treatment of fenofibrate also varied between -21% and +271.4%, with a mean increase of 43%, inversely related to the baseline level of serum HDL. On the other hand, the levels of serum apoprotein A1 and B were unchanged by either fenofibrate or gemfibrozil treatment in the present study.
It has been suggested that fenofibrate may have more beneficial effects on blood chemistry in addition to lipid profile than other fibrates including gemfibrozil [7]. In the present study, plasma uric acid was significantly reduced by 24.4% with fenofibrate and unchanged with gemfibrozil treatment. The decrease of plasma uric acid with fenofibrate has been consistently found in previous studies [9]. This seems to be an additional advantage of fenofibrate since many hyperlipidemic patients also have increased serum uric acid, which has been considered as a potential risk factor for coronary heart disease [10]. On the other hand, serum alkaline phosphatase was significantly reduced by 32% with fenofibrate but not with gemfibrozil in the present study. Similar findings have also been reported previously in western patients [9].
There was no significant adverse effect of either fenofibrate or gemfibrozil treatment in the present study. However, a mild increase of SGOT was found in one patient with fenofibrate and in two patients with gemfibrozil treatment. Even though increased, the level of SGOT was still less than twice normal range in this laboratory. This is compatible with findings of previous study that SGOT was mildly increased in 9% of western patients with fenofibrate [6]. Though it has been reported that fenofibrate can induce chronic or active hepatitis in very rare case [11,12], findings have suggest that both fenofibrate and gemfibrozil could be safely used in Chinese patients with type IIb hyperlipidemia as long as their liver function was normal. In addition, one of our patients was found with marked elevation of SGOT and SGPT accompanying alcohol drinking during the wash-out period. This finding is a reminder that drinking alcohol should be avoided in patients who have recently taken or are currently taking lipid-lowering agents such as fenofibrate and gemfibrozil.
In conclusion, the results of the present study suggest that fenofibrate at a dose of 300 mg per day is safe and effective in lowering plasma lipids in Chinese patients with type IIb hyperlipoproteinemia. Compared to gemfibrozil, fenofibrate had more beneficial effects on both lipid and uric acid metabolism. These effects of fenofibrate could theoretically reduce the cardiovascular risk associated with hyperlipidemia in these patients.
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Copyright: 1997, Chinese Medical Association (Taipei)