Correspondence

Lovastatin in X-Linked Adrenoleukodystrophy

N Engl J Med 2010; 362:276-277January 21, 2010

Article

To the Editor:

As reported previously in the Journal, lovastatin lowers levels of very-long-chain fatty acids in plasma in patients with X-linked adrenoleukodystrophy (X-ALD).1 Further studies did not reproduce this finding with the use of simvastatin in patients or with the use of lovastatin in X-ALD–knockout mice.2,3 Still, many patients with X-ALD worldwide receive lovastatin.

We conducted a randomized, double-blind, placebo-controlled, crossover trial comparing lovastatin at a dose of 40 mg once daily with placebo (Current Controlled Trials number, ISRCTN31565393). Outcome measures were levels of hexacosanoic acid (C26:0) in plasma, low-density lipoprotein (LDL) particles, lymphocytes and erythrocytes, and plasma LDL cholesterol after 22 weeks of treatment. For some outcome measures, an intermediary analysis at 8 weeks was performed. A total of 14 men with X-ALD (adrenomyeloneuropathy phenotype) were enrolled in the study. Merck provided lovastatin for this study but did not participate in the trial design, data analysis, or drafting of the letter.

No patients dropped out of the study, and neither myopathy nor rhabdomyolysis or other adverse events were observed. Data on all major outcomes are summarized in Table 1Table 1Major Outcome Measures after 8 Weeks (if Applicable) and 22 Weeks of Treatment with Lovastatin at a Dose of 40 mg Once Daily.. There were significant decreases of 1.44 mmol per liter in the level of LDL cholesterol in plasma at 8 weeks and 1.35 mmol per liter at 22 weeks. At 8 weeks, the levels of plasma tetracosanoic acid (C24:0) and C26:0 had decreased by 14.2 μmol per liter and 0.39 μmol per liter, respectively. However, even with this decrease, C26:0 levels remained above the control level (mean ±SE) of 0.67±0.13 μmol per liter.4 Furthermore, the reduction in C26:0 was no longer significant at 22 weeks. There was a decrease of 0.38 mmol per liter in the level of oleic acid (C18:1) at 8 weeks and a decrease of 0.44 mmol per liter at 22 weeks. There was no change in levels of C26:0 in erythrocytes or lymphocytes at either measurement. Finally, the levels of C18:1, C24:0, and C26:0 in LDL lipoprotein particles remained unchanged.

This trial was designed to investigate whether lovastatin has a biochemical effect in vivo in patients with X-ALD and to provide pilot data for a possible large-scale trial with clinical outcome variables. We conclude that lovastatin leads to a small decrease in levels of C24:0 and C26:0 in plasma; this must be considered a nonspecific result of the decrease in the level of LDL cholesterol. Since very-long-chain fatty acids are virtually water insoluble, and only a small fraction binds to albumin,5 most of the very-long-chain fatty acids in plasma are transported as cholesterol esters in lipoprotein particles such as LDL. This finding is corroborated by the finding that the level of C18:1 was also reduced, and it is further supported by the lack of an effect on C26:0 levels in peripheral-blood lymphocytes and erythrocytes and in the content of very-long-chain fatty acids in the LDL lipoprotein fraction. Our data indicate that investment of substantial resources and time in a trial with clinical end points seems unwarranted. Lovastatin should not be prescribed as a therapy to lower levels of very-long-chain fatty acids in patients with X-ALD.

Marc Engelen, M.D.
Rob Ofman, B.Sc.
Marcel G.W. Dijkgraaf, Ph.D.
Michiel Hijzen, M.Sc.
Lucinda A. van der Wardt, B.Sc.
Academic Medical Center, Amsterdam, the Netherlands

Bjorn M. van Geel, M.D., Ph.D.
Medical Center Alkmaar, Alkmaar, the Netherlands

Marianne de Visser, M.D., Ph.D.
Ronald J.A. Wanders, Ph.D.
Bwee Tien Poll-The, M.D., Ph.D.
Stephan Kemp, Ph.D.
Academic Medical Center, Amsterdam, the Netherlands
s.kemp@amc.uva.nl

No potential conflict of interest relevant to this letter was reported.

5 References

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   N. Pérez Fernández, A. Yoldi Arrieta, J.F. Martí-Massó, I. Bilbao Garay. (2011) Adrenoleucodistrofia. Causa inusual de insuficiencia suprarrenal primaria. Revista Clínica Española 211:9, e55-e57
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