Therapy with statins is effective in some patients with homozygous familial hypercholesterolemia

Abstract

Patients with homozygous familial hypercholesterolemia have elevated markedly low-density lipoprotein (LDL) cholesterol levels that are refractory to commonly used doses of hypolipidemic drugs, including statin [ [1] Goldstein J.L. Brown M.S. Familial hypercholesterolaemia. in: Stanburg J.B. Wyngaarden J.B. Fredrickson D.S. The Metabolic Basis of Inherited Disease. 7th edn. McGraw–Hill, New York1992: 1215-1250 Google Scholar ]. We read with great interest the recently published report by Raal et al. who showed that high doses of atorvastatin (80 mg/day) are effective in lowering LDL cholesterol by 28% in patients with homozygous FH through inhibition of VLDL (and possibly LDL) synthesis by the liver cell [ [2] Raal F.J. Pappu A.S. Illingworth D.R. et al. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia. Atherosclerosis. 2000; 150: 421-428 Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar ]. High doses of statins (simvaststin 80–160 mg/day or atorvastatin 80 mg/day) have been shown previously to be partially effective in lowering LDL cholesterol levels in these patients [ 3 Raal F.J. Pilcher G.J. Illingworth D.R. Expanded-dose sinivastatin is effective in homozygous familial hypercholesterolaemia. Atherosclerosis. 1997; 135: 249-256 Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar , 4 Marais A.D. Naoumova R.P. Firth J.C. Penny C. Neuwirth C.K.Y. Thompson G.R. Decreased production of low density lipoprotein by atorvastatin in homozygous familial hypercholesterolaemia. J. Lipid Res. 1997; 38: 2071-2078 PubMed Google Scholar , 5 Postiglione A. Montefusco S. Pauciullo P. Mancini M. Effects of atorvastatin in patients with homozygous familial hypercholesterolaemia. Atherosclerosis. 1999; 147: 423-424 Abstract Full Text PDF PubMed Scopus (9) Google Scholar ]. Interestingly, statins reduced LDL cholesterol, not only in patients with defective LDL receptors but also in patients with no functioning LDL receptors. However, there are no data concerning the effect of statins in patients with class V mutations of the LDL receptor. In class V mutation, the LDL receptor retains the ability to bind and internalise its ligand but fails to release it in the endosome and thus the receptor does not recycle to the cell surface [ [6] Hobbs H.H. Russell D.W. Brown M.S. Goldstain J.L. The LDL receptor locus in familial hypercholesterolemia. Ann. Rev. Genet. 1990; 24: 133-170 Crossref PubMed Scopus (568) Google Scholar ]. It has been pointed out that individuals with such mutations have lower lipid levels and are more responsive to hypolipidemic drug therapy [ [6] Hobbs H.H. Russell D.W. Brown M.S. Goldstain J.L. The LDL receptor locus in familial hypercholesterolemia. Ann. Rev. Genet. 1990; 24: 133-170 Crossref PubMed Scopus (568) Google Scholar ]. We have identified recently five patients who are homozygous for the G1775A mutation, which has been previously characterized as a class V mutation. These patients had relatively low serum total and LDL cholesterol levels (422±80 and 354±75 mg/dl, respectively) and they were treated with relatively high doses of statins (lovastatin 40 mg/day, pravastatin 40 mg/day, simvastatin 40 mg/day or fluvastatin 80 mg/day) before atorvastatin was available in our country. As shown in the Table 1, significant decreases in the LDL cholesterol levels (mean decrease by 23.5%) were achieved, comparable to those which were noticed after atorvastatin administration in previous studies [ 2 Raal F.J. Pappu A.S. Illingworth D.R. et al. Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia. Atherosclerosis. 2000; 150: 421-428 Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar , 4 Marais A.D. Naoumova R.P. Firth J.C. Penny C. Neuwirth C.K.Y. Thompson G.R. Decreased production of low density lipoprotein by atorvastatin in homozygous familial hypercholesterolaemia. J. Lipid Res. 1997; 38: 2071-2078 PubMed Google Scholar , 5 Postiglione A. Montefusco S. Pauciullo P. Mancini M. Effects of atorvastatin in patients with homozygous familial hypercholesterolaemia. Atherosclerosis. 1999; 147: 423-424 Abstract Full Text PDF PubMed Scopus (9) Google Scholar ]. When atorvastatin (80 mg/day) was administered in these patients, a more pronounced decrease in LDL cholesterol levels by 35% was observed. It is suggested that therapy with statins and especially with the most potent drugs of this class should be considered in patients with homozygous FH either as an adjuvant to apheresis or as monotherapy for those patients who do not have access to apheresis or other such treatment modalities.