- Easily missed
- Lipid disorders
- Metabolic disorders
- Drugs: cardiovascular system
- Ischaemic heart disease
It is true, as Gill et al. point out in their review about familial hypercholesterolemia (FH),1 that people aged 20-39 years with this genetic aberration have a 100-fold greater risk of dying from coronary disease compared with non-FH adults of the same age. However, this figure may easily mislead because heart mortality is extremely rare at this age. In the study by the Simon Broome Register Group which they refer to, there were only six men between age 20-39 who died during 1318 person-years of observation, and only two women during 1190 person-years of observation. As the participants in their study mainly were individuals who had relatives with cardiovascular disease, mortality is probably even lower among FH individuals without such heredity.
Furthermore, heart mortality in people with FH decreases sharply with increasing age and is close to normal after the age of sixty. According to a more recent paper from the Simon Broome Register Group2 the standardised mortality ratio (SMR) for coronary heart disease was significantly higher in FH than in the general population, but the difference was trivial, the all-cause SMR was the same, and the SMR for non-coronary mortality was significantly lower. It is therefore highly unlikely that statin treatment should be able to prolong the life of people with FH by nine years.
Gill et al. refer to a follow-up study3 said to have shown a delay of atherosclerosis in children and young adults with FH on statin treatment. From this finding it is tempting to conclude, that such treatment should be started already in childhood, but this interpretation is questionable. What the authors found was a delay of carotid intima-media thickness (cIMT) development, but this is not equivalent with a delay of atherosclerosis. For instance, a temporary contraction of the artery wall due to the influence of drugs, cold or stress may simulate an increase of cIMT, and such changes may be much greater than those seen as a result of atherosclerosis progress or cholesterol-lowering treatment. For instance, Brown et al. found that a handgrip sustained for 4,5 minutes resulted in a 35 % reduction of the luminal area of the coronary arteries,3 whereas no cholesterol-lowering trial has been able to change the diameter or the cIMT by more than a few per cent at most.
Other arguments against the interpretation of the follow-up study are, that there is no difference in cIMT between children with FH and normal children,4 and in the ENHANCE trial the cIMT increased, whether cholesterol was lowered a little or very much.5
We have only indirect evidence for the benefit from statin treatment in FH because hitherto no randomised, controlled statin trial including people with FH only has been performed with mortality or major vascular events as outcome, neither in children nor in adults. The question is therefore, whether the benefit from statin treatment outweighs possible adverse effects.
Two years ago Hippisley-Cox and Coupland reported the outcome after statin treatment in more than 200,000 patients treated by the general practitioners.6 More than four per cent had experienced moderate or serious adverse effects from the muscles, liver, kidneys or eyes. These numbers may even have been underestimated. For example, liver damage was recorded only if the alanine transaminase concentration was more than three times higher than the upper limit of normal, and to record muscle problems as a side effect they required the creatine kinase concentration to be four or more times higher than the upper limit of normal. Franc et al. have reported cramps, stiffness and tendonitis-associated pain in about 20 % of patients on lipid-lowering treatment,7 and according to Sinzinger et al. 25 % of those who exercise regularly have muscular problems.8 There is a good reason for these discrepancies, because the large majority of patients with biopsy evidence of structural damage of the muscles have a normal creatine kinase concentration.9 Furthermore, no attempts were done to record diabetes, or sexual or cerebral dysfunction.
Of particular concern is that an increased incidence of cancer has been reported in most animal experiments, in three statin trials and in several cohort and case-control studies, and many cohort studies have found that low cholesterol is a risk factor for cancer,, even after more than 30 years.10
There are no reasons to believe that the number of adverse effects is less common in FH. Statin treatment of an individual with FH should therefore not be started without informing him or her in detail about the risks.
1. Gill PJ, Harnden A, Karpe F. Familial hypercholesterolaemia. BMJ 2012;344:e3228 doi: 10.1136/bmj.e3228
2. Brown BG, Lee AB, Bolson EL, Dodge HT. Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circulation 1984;70:18-24.
3. Scientific Steering Committee on behalf of the Simon Broome Register Group. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Atherosclerosis 1999;142:105-12.
4. Riggio S, Mandraffino G, Sardo MA, Iudicello R, Camarda N, Ibalzano E, Alibrandi A et al. Pulse wave velocity and augmentation index, but not intima-media thickness, are early indicators of vascular damage in hypercholesterolemic children. Eur JClin Invest 2010;40:250-7
5. Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation 2007;116:664-8.
6. Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010, 40c2197, doi: 10.1136bmj.c2197.
7. Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G: A comprehensive description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc Drugs Ther 2003; 17: 459-465.
8. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharmacol 2002; 40:163-171.
9. Mohaupt MG, Karas RH, Babiychuk EB, Sanchez-Freire V, Monastyrskaya K, Iyer L et al.. Association between statin-associated myopathy and skeletal muscle damage. CMAJ 2009; 181: E11-18.
10. Ravnskov U. Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM doi:10.1093/qjmed/hcr243
Competing interests: None declared
None, Magle Stora Kyrkogata 9, 22350 Lund, Sweden
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