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Combined hyperlipidemia, familial

In medicine, combined hyperlipidemia (or -aemia) is a commonly occurring form of hypercholesterolemia (elevated cholesterol levels) characterised by increased LDL and triglyceride concentrations, often accompanied by decreased HDL. On lipoprotein electrophoresis (a test now rarely performed) is shows as a hyperlipoproteinemia type IIB. more...

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The elevated triglyceride levels (>5 mmol/l) are generally due to an increase in VLDL (very low density lipoprotein), a class of lipoprotein that is prone to cause atherosclerosis.

There are roughly two forms of this lipid disorder:

  • Familiar combined hyperlipidemia (FCH) is the familiar occurrence of this disorder, probably caused by polymorphisms in molecules and enzymes that participate in lipoprotein metabolism, such as ApoCII and ApoCIII and CETP (cholesterylester transferring protein).
  • Acquired combined hyperlipidemia is extremely common in patients who suffer from other diseases from the metabolic syndrome ("syndrome X", incorporating diabetes mellitus type II, hypertension, central obesity and CH). Excessive free fatty acid production by various tissues leads to increased VLDL synthesis by the liver. Initially, most VLDL is converted into LDL until this mechanism is saturated, after which VLDL levels elevate.

Both conditions are treated with fibrate drugs, which act on the peroxisome proliferator-activated receptors (PPARs), specifically PPAR╬▒, to decrease free fatty acid production. Statin drugs, especially the synthetic statins (atorvastatin and rosuvastatin) can decrease LDL levels by increasing hepatic reuptake of LDL due to increased LDL-receptor expression.


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Statins: underused by those who would benefit - Editorial
From British Medical Journal, 10/21/00 by Stephen B Hulley

But caution is needed for young people at low risk of cardiovascular disease

The United States Food and Drug Administration has recently rejected proposals by the manufacturers of lovastatin and pravastatin to make these drugs available over the counter. Advisers to the Food and Drug Administration decided that physicians should probably determine who should get the drugs as well as monitoring them for side effects. The main arguments for allowing over the counter sales were summarised in a recent conference sponsored by the industry: statins are effective, easy to take, and relatively safe, and many people who should be taking these drugs are not doing so.[1]

The underuse of statins is most apparent in the secondary prevention of heart disease in patients with known atherosclerotic disease, for whom there is overwhelming evidence that statins are highly beneficial.[2 3] In one recent survey, for example, only 37% of patients with recent myocardial infarction and blood cholesterol concentrations above 2 g/1 had been given drugs to lower their lipid concentrations and few had reached their target cholesterol concentrations.[4] Most patients with heart disease have concentrations of low density lipoprotein cholesterol that warrant treatment, and making statins available over the counter might increase their use (as has occurred with aspirin).[5]

Undertreatment is also a problem for the much larger population of people who do not have manifest atherosclerotic disease (primary prevention). There is no longer any doubt that treatment benefits those who are at substantial coronary risk. An updated meta-analysis in this issue of the BMJ (p 983) shows that drugs that lower lipid concentrations prevent nearly a third of myocardial infarctions and coronary deaths.[6] All cause mortality was not reduced significantly, but this is not surprising because statins affect only cardiovascular mortality,[2 3] and most of the deaths in people without heart disease were not due to cardiovascular causes.[7]

Practice guidelines have been devised to identify patients who need treatment.[8] The recently revised Sheffield table is easy to use and an excellent example. It provides cut-off points for ratios of total cholesterol to high density lipoprotein cholesterol (based on age, sex, diabetes, hypertension, and smoking) that identify people whose coronary risk exceeds 30% per decade.[9] The table also gives cut-off points for treating the larger numbers of people whose coronary risk exceeds 15% per decade "where resources permit."[9] This lower cut-off point has the virtue of more closely resembling the 10 year coronary risk of participants in trials of primary prevention.[6]

Age is the most important determinant of coronary risk,[10 11] and the two main primary prevention trials of statins both set the lower limit for enrolment at the relatively mature ages of 45 for men and 55 for women.[6] This decision made sense when designing these trials: younger participants would have too few coronary events to provide adequate power to detect an effect of treatment. But in clinical practice physicians may ask why not extrapolate these results and use statins to help prevent the few coronary events that do occur in younger people? Treating younger people may be reasonable if they have other strong risk factors, such as familial hypercholesterolaemia or diabetes. But the reasons for not doing so in most younger people are the remaining concerns about safety and the harsh realities of cost.

Statins do seem to be reasonably safe and are probably less likely to cause serious harm than aspirin. Earlier concerns that lipid lowering drugs might increase the risk of death from injuries were a false alarm.[2 3] Serious adverse effects such as liver failure and rhabdomyolysis are rare, and more common side effects such as myositis and raised serum transaminase activity are usually reversible. There remains the theoretical possibility that statins may have adverse effects years later. A recent follow up report from the first major trial of statins was reassuring on this point, showing trends towards continued benefits in survival and fewer cancer deaths for two years beyond the five years of randomised statin treatment.[12] The evidence for both safety and efficacy have led statins to outstrip other lipid lowering drugs and to eclipse the role of diet in coronary prevention (which has a far smaller effect on low density lipoprotein concentration and is resisted by many patients).[13] However, there are two caveats about the safety of these powerful drugs. Firstly, not every statin has been studied in large clinical trials with disease end points; use of the newer formulations is based on surrogate end points and analogy.[14] And secondly, seven years is not long enough to eliminate concerns about long term adverse effects such as cancer. While we await the findings of continued follow up of the statin trials, it is prudent to hold back from prescribing statins for patients who have a low risk of coronary events over 10 years.

Cost is the other reason to hesitate before recommending statins to people at low risk of heart disease. Coronary heart disease is so rare among young adults that starting drug treatment for life in people in their 30s costs up to 1m [pounds sterling] ($1.4) per year of life extended.[15] Until the price of statins comes down a lot, this is not a reasonable expenditure of medical resources.

Of course, people who are well off can ignore concerns of cost. In a world that allows statins to be bought over the counter, they could also bypass the need to persuade a physician to prescribe them. But the problems of deciding who should be treated and how to monitor adverse effects underscore the wisdom of the Food and Drug Administration's conclusion to leave decisions about taking statins in the hands of healthcare providers.

However, this does leave us with the obligation to do it right. Many people who could substantially benefit from statins are not getting them, perhaps due to a lack of understanding by physicians or to organisational and fiscal policies that do not support prevention.[4 16] It is time to get serious about identifying and removing these obstacles. Physicians must do a better job of following practice guidelines for using statins to treat undesirable cholesterol concentrations in people at substantial risk of coronary events over 10 years, including most patients with a history of coronary disease and a good many (mostly older) people who may soon develop it.

Stephen B Hulley department chair

Deborah Grady vice chair

Warren S Browner associate professor, medicine

Department of Epidemiology, Biostatistics, and Medicine, University of California San Francisco, School of Medicine, 500 Parnassus Avenue, 420 MU-W, San Francisco, CA 94143-0560, USA

[1] Smith SC. A symposium: expanding the impact of statin therapy: would patients benefit from broader treatment and access? Am J Cardiol 2000;85:1-23E.

[2] Hebert PR, Gaziano M, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA 1997;278:313-21.

[3] Gordon DJ. Cholesterol lowering reduces mortality: the statins. In: Grundy SM, ed. Cholesterol-lowering therapy: evaluation of clinical trial evidence. New York: Marcel Dekker, 2000:299-311.

[4] Majumdar SR, Gurwitz JH, Soumerai SB. Undertreatment of hyperlipidemia in the secondary prevention of coronary artery disease. J Gen Intern Med 1999;14:711-7.

[5] Schrott HG, Bittner V, Vittinghoff E, Herrington DM, Hulley S. Adherence to national cholesterol education program treatment goals in postmenopausal women with heart disease. JAMA 1997;277:1281-6.

[6] Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ 2000;321:983-6.

[7] Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998:279:1615-22.

[8] Jackson R. Guidelines on preventing cardiovascular disease in clinical practice. BMJ 2000;320:659-61.

[9] Wallace EJ, Ramsay LE, Haq I, Ghahramani P, Jackson PR, Rowland-Yeo K, et al. Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population. BMJ 2000;320:671-6.

[10] Avins AL, Browner WS. Improving the prediction of coronary heart disease to aid in the management of high cholesterol levels: what a difference a decade makes. JAMA 1998;279:445-9.

[11] Ulrich S, Hingorani AD, Martin J, Vallance P. What is the optimal age for starting lipid lowering treatment? A mathematical model. BMJ 2000;320:1134-40.

[12] Pedersen TR, Wilhelmsen L, Faergeman O, Strandberg TE, Thorgeirsson G, Troedsson L, et al. Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering. Am J Cardiol 2000;86:257-62.

[13] Hunninghake DB, Stein EA, Dujovne CA, Harris WS, Feldman EB, Miller VT, et al. The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolemia. N Engl J Med 1993;328:1213-9.

[14] Furberg CD, Herrington DM, Psaty BM. Are drugs within a class interchangeable? Lancet 1999;354:1202-4.

[15] Prosser LA, Stinnet AA, Goldman PA, Williams LW, Hunink MGM, Goldman L, et al. Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics. Ann Intern Med 2000;132:769-79.

[16] Hoerger TJ, Bala MV, Bray JW, Wilcosky TC, LaRosa J. Treatment patterns and distribution of low-density lipoprotein cholesterol levels in treatment-eligible United States adults. Am J Cardiol 1998;82:61-5.

COPYRIGHT 2000 British Medical Association
COPYRIGHT 2000 Gale Group

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