Materials and Methods: Total of 43 patients were randomized into one of 2 groups: One of them (n=20) treated with atorvastatin, other (n=23) with fenofibrate for 3 months. After 1 and 3 months of treatment with these drugs, blood samples were collected and plasma lipids, folic acid, vitamin B12 and homocysteine levels were determined.

Results: Both of the lipid lowering agents significantly decreased plasma lipid levels. Atorvastatin group showed a significant reduction in total cholesterol and LDL-C than those in fenofibrate group. On the other hand, fenofibrate caused a greater reduction in triglyceride levels compared to the atorvastatin. There was no change in plasma folic acid and vitamin B12 levels after treatment with both of these hypolipidemic drugs. There was a significant increase in homocysteine levels after treatment with fenofibrate and atorvastatin, although fenofibrate was more effective than atorvastatin (36 and 15% respectively).

Conclusions: We conclude that increases in plasma homocysteine levels are a result of the known impairment of renal function caused by fenofibrate and a result of impairment of liver function caused by atorvastatin.©2006, Fırat Üniversitesi, Tıp Fakültesi

Hyperlipidemia is a major risk factor for atherosclerosis and cardiovascular disease ^11-13. It is now well established that hyperlipidemia needs to be treated, especially in patients with a history of cardiac disease, including heart failure. Today, one of the most important classes of drugs for treating hyperlipidemia is the 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (also known statins). Statins decrease all LDL sub fractions including small, dense LDL-C ¹⁴. Fibrates have an established role as lipid regulating drugs with marked TG lowering and HDL elevating effects, in addition to modest total and LDL-c lowering. Administration of fibrates has been reported to elevate plasma homocysteine levels ^15-17. Folic acid supplementation prevents the elevation of plasma homocysteine in patients treated with fenofibrate ¹⁸. Whether this side effect of fenofibrate is due to its effect on renal function is not clear. There is one study comparing the effect of fenofibrate and atorvastatin on plasma homocysteine levels without determination of plasma folic acid and B12 vitamin, the main factors involving homocysteine metabolism ¹⁹.

Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both plasma homocysteine and biochemical parameters were compared in patients with combined hyperlipidemia. We also aimed to study the levels of plasma folic acid and vitamin B12 and their relation to homocysteine levels in these subjects.

Individuals taking scheduled medications concurrently (excluding oral contraceptives), those with significant medical histories, as well as smokers and pregnant females were excluded from the study. In addition patients who already treated with lipid-lowering drugs, or who had received dietetic advice for previously detected hyperlipidemia were also excluded. Plasma TSH and standard biochemical liver function tests (LFTs) were also performed, and patients excluded if these were not normal. Subjects were admitted to the clinical center, and physical examination and baseline laboratory measurements were obtained.

Patients were randomized into one of 2 groups: One of them treated with atorvastatin 10 mg daily for 3 months period (atorvastatin group) other with fenofibrate 200 mg daily for 3 months (fenofibrate group). Every group was composed with 30 subjects in the beginning of trial, but 20 patients in fenofibrate (10 women and 10 men) and 23 patients in atorvastatin group (11 women and 12 men) completed

Before starting to take lipid lowering agents and after 1 and 3 months of treatment with these agents, physical examination was performed, body weight and blood pressures were measured and blood specimens were withdrawn between 08:00-10:00 a.m. following an overnight fast. Blood samples were collected and plasma samples were separated and stored at –20ºC until analyzed.

Total Hcy levels were determined with an enzyme immunoassay kit (Axis-Shield AS, Oslo, Norway). Vitamin B12 and folic acid were determined by IMMULITE 2000 Analyzer using a Chemiluminescence kit (DPC, diagnostic Products Corporation, Los Angeles, CA).

Statistical Analysis
Biochemical and other parameters were compared for the whole group at 0, 1, and 3 months by means of ANOVA in conjunction with Bonferroni’s t-statistics. The baseline and post treatment values of all parameters of two groups were compared by student t test. Results were presented as mean ± SD. A level of significance of P <0.05 was used.

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Table I: Lipid and blood pressure levels in patients treated with atorvastatin or fenofibrate at pretreatment and after 1 or 3 months of treatment

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Table II: Plasma levels of homocysteine, folic acid, vitamin B12, uric acid, creatinin, albumin, ALT, AST amylase in patient treated with atorvastatin and fenofibrate at pretreatment and after 1 and 3 months of treatment

Fenofibrate significantly increased creatinin levels (p<0.01) while atorvastatin lead to nonsignificant elevation in creatinin levels (p>0.05). Fenofibrate induced a significant increase in uric acid levels both after 1 month and 3 months of treatment (p<0.05; p<0.01 respectively).

Baseline homocysteine levels were similar in both groups. After treatment for 1 month and 3 month with fenofibarete the levels of homocysteine progressively and significantly increased compared to the baseline levels (p<0.05 after 1 month treatment and p<0.01 after 3 month treatment). There was no significant elevation in homocysteine levels after 1 month treatment with atorvastatin but mild an significant increase in Hcy levels were found after 3 month treatment (p<0.05).

Baseline plasma folic acid and vitamin B12 levels were similar in both groups. There were no changes in both folic acid and vitamin B12 levels after 1 and 3 months treatment with both hypolipidemic agents.

Treatment with atorvastatin for 3 months significantly increased plasma alanine aminotransferase (ALT) levels ( p<0.05) while fenofibrate lead to a mild and non significant increase in its concentration. Plasma aspartate aminotransferase (AST) levels were also increased with atorvastatin (p<0.01) but no significant change was found in fenofibrate group.

One study reported that fenofibrate dramatically increases plasma homocysteine levels, though blood levels of vitamins were not reduced and they proposed that it may be related to the renal function ¹⁵. In the present study we also did not detect any change in vitamin B12 and folic acid concentration after treatment with both lipid lowering agents. The increase in homocysteine levels were not related with these vitamin levels. In addition Lipscombe et al. ²³ reported that a group of patients showed a reversible deterioration in renal function while being treated with a fibrate for hyperlipidemia. The possible explanation for the fenofibrate-induced increase in homocysteine levels may involve alteration in renal function. Indeed, in the present study uric acid and creatinin levels increased by the treatment with fenofibrate as reported previously ²⁴. On the other hand, atorvastatin treatment did not show any significant effects on the concentration of uric acid and creatinin.

We have found a mild but significant increase in homocysteine levels after treatment with atorvastatin for 3 months but not 1 month. There are a few studies concerning atorvastatin and homocysteine. Giral et al.¹⁹ reported that atorvastatin has no effect on plasma homocysteine levels. The increase in homocysteine levels was not related kidney function in the present study because uric acid, creatinin and albumin levels did not show any significant change after atorvastatin treatment. On the other hand, present findings show another important result which is the changes in ALT, AST and amylase levels with the treatment of atorvastatin but not of fenofibrate. Liver has a significant role in the regulation of plasma homocysteine levels ²⁵ with the help of the essential vitamins, including folic acid and vitamin B12, the liver converts homocysteine back into methionine. Impaired liver function could be a determinant in the development of hyperhomocysteinemia ²⁶.

In conclusion, elevated homocysteine levels are a risk factor for atherosclerosis. Plasma homocysteine levels increased in the hyperlipidemic patients while treating another cardiovascular risk factor, hyperlipidemia, both with atorvastatin and fenofibrate. The significant elevation by fenofibrate may be due to its side effect on renal function. On the other hand, atorvastatin lead to a mild increase in plasma homocysteine levels and it may be explained by its effect on liver function.

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