[ Scientific Activities - Actividades CientÝficas ]
Lowering Blood Cholesterol
When, How and How Much?
JosÚ Pablo Werba, MD
Chief of the Center for Dyslipidemias and Early Detection of Atherosclerosis
ICYCC-Favaloro Foundation and Favaloro University.
In the last few years, physicians have been the target of an intense educational campaign (from health authorities and further support from drug companies) aimed to set down which is the general opinion (through consensus of experts) about indications and timing (when?), interventions (how?) and goals (how much?) of cholesterol reduction in hypercholesterolemic (HC) subjects. Many of these answers have been obtained or backed by the results of recent several large and well designed trials of primary and secondary prevention with hypocholesterolemic therapies. So, in certain patients and conditions, cholesterol lowering may now be considered "medicine based on a high level of evidence and grade of recommendation". However, not all the answers have a definite conclusion and not every patient gets similar benefits (if any) from cholesterol lowering. In addition, the cost/benefit ratio of lipid lowering in some groups of patients remains to be fully explored. Moreover, perhaps one important question is missing in the title of this presentation and it is: how long is the treatment of HC?. In fact, now that potent drugs are available and cholesterol lowering is generally not a hard task and can be reached rather quickly (usually in a few weeks), low adherence and continuity of the therapy are probably the main aspects that hinder the possibility of a succesful prevention of cardiovascular events.
Allow me now to take you into a more detailed analysis of each of these questions.
When?I will start by saying that hipercolesterolemia is just a biochemical sign and not a defined pathological entity. Therefore, care should be taken not to treat "cholesterol" but hypercholesterolemic patients. It has been said many times that secondary hyperlipidemias should be excluded before tagging a patient as a "hypercholesterolemic", an unfortunate term which mostly stands for a subject with a genetic (primary) hypercholesterolemia. A diagnosis solely based on the laboratory results (a "piece-of-paper-based diagnosis") may be inappropiate for several reasons: first, because an underlying pathology, sometimes serious and sometimes correctable, may not be detected and treated in time. Second, because hypolipidemic drugs may be unsuitable for many of these conditions. You may find a very nice representative case from my records in Insert 1.
This was a 23 y.o man. His doctor had detected a severe HC 12 months before and had prescribed a statin and a tiacidic diuretic (he was also found hipertensive). Throughout that year, he had lost weight (10 kg) and had started to feel a reduction in his muscular strength, which was attributed to the loss of salts. He had normalized blood presure but the cholesterol response was not satisfactory and he consulted our Institution. A complete clinical anamnesis yielded that he had absolutely no family history of hyperlipidemia or CVD (a very leading information to consider a secondary hyperlipidemia) and that he had had edemas in his legs (and even some "not mentioned" edema in his genitals!) when he had first seeked medical advice. To make a long story short, he was proteinuric, his renal biopsy showed minimal change glomerulopathy and so, he had a nephrotic-nephritic syndrome with preserved glomerular filtration. Paradoxically, his cholesterol levels were reduced by corticosteroids.
Many similar authentic cases might be narrated, including mainly hypothiroidism, uncontrolled NIDDM, use of beta blockers and cholestasis at the basis of the HC. The message is that a comprehensive clinical anamnesis and physical examination is most desirable in the first approach to the HC patient.
Once a secondary HC is excluded, primary HC is diagnosed and reinforced by a strong family history of HC or CHD. At this point, it is proper to make an effort to establish a specific diagnosis of the primary HC. In fact, monogenic dyslipidemias with HC, mostly represented by heterozigous familiar hipercholesterolemia (HetFH) and more rarely by dysbetalipoproteinemia (Dys▀ or broad beta disease) have their own characteristics and may be adequately distinguished (insert 2). The rationale for this approach is that uncontrolled HetFH and Dys▀ are metabolic disorders associated with a variable but usually with a very very high risk of atherosclerotic disease, even in the abscense of any further risk factors. The prognosis of course worsens if other RF are present and when the patient is a male, but these additional conditions are not absolutely necessary to put him in a condition of high risk.
An even more unusual monogenic HC condition is the hyperLipoprotein(a), a disorder characterized by very high Lp(a) levels and an increased risk of CHD and peripheral vascular disease (you may find out more about "Lipoprotein (a)" in this same Virtual Congress).
So, these "monogenic" dyslipidemias (in which a culprit mutated gene has been clearly identified), although not very frequent, are very severe a nd generally call for an intensive treatment.
HetHF may be considered "defined" if an adult has a plasma total cholesterol (TC) level > 290 mg/dl or LDL-C > 190 mg/dl (or a person aged < 16 y has a TC > 250 mg/dl) and there are tendon xanthomas (hands, elbows and/or Achilles tendons) in the patient or in his first degree relatives. HetHF is regarded as "probable" in patients with those lipid values, without personal or family xanthomas but with similarly increased cholesterol levels or a history of premature acute miocardial infarction (before age 60) in their first degree relatives.
Dys▀ should be suspected if cholesterol and triglycerides are similarly increased (a 1:1 ratio) and the normal gap between prebeta and beta lipoproteins is absent in an electrophoretic lipidogram. Agravatting factors like obesity, NIDDM or hypothiroidism are common and should be looked for. Tools in a specialized lipid clinic and laboratory may be useful to confirm the diagnosis.
However, youll find that the HC in most of your patients is much more probably accounted for by any type of primary "polygenic" hyperlipidemia. In these entities, many of them with numerou overlapping clinical and biochemical characteristics (Insert 3), the "when to treat" depends on the absolute risk of a vascular event or vascular death in the short and intermediate term in the individual patient.
Polygenic hyperlipidemias include
It is clear from epidemiological studies that this risk is very high in patients that have already had a coronary event. Indeed, the 10-year risk of a subsequent CHD event (angina, non-fatal AMI or coronary death) in such patients is ..."usually over 20%, and for many of them over 40%"(from Task Force Report, Atherosclerosis 140 (1998): 225). Morover, intervention studies have consistently shown that this risk may be significantly reduced by cholesterol lowering therapies (4S, CARE, LIPID studies) and that the number of subjects that are to be treated to prevent a single event during follow-up (the "NNT" term, from Number Necesary to Treat) would be reasonable (it was 11, 33 and 25 subjects in 4S, CARE, LIPID, respectively, to prevent CHD death and non-fatal AMI). These data are the basis for a general consensus that recognizes an acceptable cost/benefit ratio of treating hypercholesterolemic subjects in secondary prevention. However and beyond understanding, the current situation is that high blood cholesterol is not adequately controlled (or it is not treated at all !!) in a large number of patients in this situation, as was demonstrated by recent European studies (ASPIRE, EUROSPIRE). Routine medical practice patently indicates that the circumstances in Argentina are very similar (if not worse). It should be interesting to further study the reasons for this behaviour that might even be taken as "malpractice by omission" (many coronary patients are deprived of being healthy or even of being alive in the intermediate and long term) and to prospectively test some ways to resolve the problem. As a collegue recently said: "by now the best evidence is that many patients do not receive the treatment that evidence based medicine highly recommends".
If we talk about "when?" (indications), then "when to start" the treatment (opportunity or timing) is an accompanying neccesary question. In the context of the previously mentioned monogenic dyslipidemias and/or secondary prevention, it is advisable to start the control of lipids as soon as possible in life. Well see "how" later on.
Very different is the situation in primary prevention. In fact, whereas in secondary prevention there is factual evidence of susceptibility to risk factors, in primary prevention it is mandatory to speculate about the risk of a future atherosclerotic event in the individual, using probability tools which were built on the basis of epidemiological prospective studies. Different tables have been recently published by American and European scientific societies to estimate the individual risk, and these may be consulted in the corresponding journals. These tables help to establish the absolute 10-year individual risk of having a vascular event, and this figure was proposed as the basis to determine "intensive risk modification" (including drug therapy). However, whereas European guidelines suggest this approach when the absolute 10y-risk is higher than 20% (or will exceed 20% if projected to age 60), the American group did not set any threshold for treatment. Why?. Probably because recent trials (i.e AFCaps-TexCaps) demonstrate that subjects in primary prevention obtain a "relative" benefit from cholesterol lowering even if their baseline risk is not high or even if it is low. In that study, for example, LDL-C lowering for more than 5 y with a statin in low-risk men and women (1.25% per year of a fatal and nonfatal coronary event in the placebo group as a whole) was associated with a 37% reduction in a combined vascular primary endpoint (fatal or non-fatal AMI, unstable angina or sudden cardiac death). However, a critical look at that data shows that, as a whole population, the NNT for CHD death and non fatal AMI is 63, near 6-fold that in 4S, almost twice that in CARE and more than twice that in LIPID. Moreover, these numbers are much higher for the female subgroup. So, many more patients should be subjected to a continuous hypolipidemic treatment in this low risk population than in high risk patients (secondary prevention) to prevent an individual event. A similar conclusion can be obtained from a subgroup analysis of the WOSCOPS, in which the largest clinical benefit of cholesterol lowering is obtained in those subjects with a high basal vascular risk profile. Therefore, in primary prevention we are somehow forced to make a compromise. A massive treatment, including low and high risk patients might save more events but at an unacceptable cost (economical and possibly biological). Treating just high risk patients should be more cost/effective. However, some "statistically low risk subjects" might actually be at a high risk because of an individual high susceptibility to a relatively low exposure to risk factors or to the presence of additional uncovered risk factors. To overcome this problem, low risk subjects may be subjected to a non-invasive exploration of accesible arteries (carotid, abdominal aorta and femoral arteries), to early detect atherosclerotic damage, an objective index of susceptibility, in the asympthomatic "low-risk?" patient. As several studies have clearly demonstrated that subclinical peripheral atherosclerosis is highly predictive of coronary risk during follow-up, the detection of some degree (not yet fully determined) of atherosclerosis might be of value to reclassify the individual risk. This approach was also considered by the American Heart Association in a recent meeting about "Identifying the high-risk patient in primary prevention", held in San Francisco in October 1998. Moreover, a proposal that came from that meeting of experts was that subjects with subclinical atherosclerosis should be treated with similar goals of LDL-cholesterol lowering as secondary prevention.
In summary, the current concept is that cholesterol should be intensively and treated early when:
How?Treatment of patients with HetFH should be considered from childhood. Nutritional advice, including energy intake to control overweight, avoidance of foods rich in saturated fat and cholesterol and inclusion of soluble fibers and soy protein in the diet may be enough changes to satisfactorily control cholesterol levels in children. However, sometimes it is neccesary to add cholestyramine, the only drug formally accepted for use in children after age 10. Early adoption of active physical exercise and education about the benefits of smoking avoidance is essential.
Adults with HetFH mostly normalize cholesterol levels with a statin at a sufficient dose, either alone or combined with cholestyramine at low-moderate doses. The choice of the statin mostly depends on the basal LDL-C level, with simvastatin, cerivastatin or atorvastatin as elective molecules in severe hypercholesterolemias. In very severe or resistant cases, a statin at a top-high dose and/or the addition of cholestyramine at high doses and/or a fibrate may be required but in such cases the consultation to a lipid specialist is strongly suggested, mainly in view of the long-lived nature of the treatment (see later).
Dys▀ generally dramatically improves with the control of aggravating factors (obesity, NIDDM or hypothyroidism). However, a fibrate may be needed to attain lipid goals.
HyperLp(a) has no specific treatment and the energic control of hypercholesterolemia and any additional modifiable risk factors is reccomended. A trial with nicotic acid my be attempted, but intolerance usually prevents a continuous treatment with sufficient doses.
In the most prevalent polygenic forms of primary hypercholesterolemia, the initial treatment is modifying lifestyles. Smoking cessation, dietary modifications and regular physical exercise may well normalize the lipid profile. The evolution should be monitored for up to 2 months (in secondary prevention or high risk patients) or up to six months (in primary prevention in low risk patients) before adding any hypolipidemic medication. The choice of the drug depends on the prevalent lipid profile. In isolated moderate hypercholesterolemia, the first choice is a statin, the second is cholestiramine and the third is a 2nd generation fibrate (fenofibrate, bezafibrate or ciprofibrate). In combined hyperlipidemias with high LDL-C as the predominant trait and TG slightly increased (less than 300-400 mg/dl), a statin may normalize both parameters, taking into account that the efficacy of the statin to reduce TG is proportional to its efficacy to reduce LDL-cholesterol. Alternatively, a 2nd generation fibrate may be used. In resistant cases, the combination of a statin and a 2nd generation fibrate may prove useful. Again, in this cases, a lipid specialist may provide advice on the selection of drugs, monitoring schedule and further precautions to avoid unnecesary risky side effects in the short or long term. In those cases with predominant hypertriglyceridemia (more that 400 mg/dl) and a mild LDL-C increase, a 2nd generation fibrate is the choice drug, followed by nicotinic acid. A third option is a treatment with a 2nd generation fibrate, followed by the addition of cholestyramine, only after TG levels have been completely normalized by the fibrate (cholestyramine should never be used in hypertriglyceridemic states) and regularly monitoring TG levels.
Although goals of LDL-C lowering have been reccomended by different expert panels (see ATP II, British Hyperlipidemia Association, European Atherosclerosis Society), the former, published in 1994, received much more diffusion and gained much wider acceptance in our medical community. However, the issue of "how much to lower LDL-C?" was not fully answered and remains very controversial. What I can say with certainty is that if the original data from the main interventional studies (LRC-CPPT, WOSCOPS and AFCaps-TexCaps in primary prevention and POSCH, 4S, CARE and LIPID in secondary prevention) are carefully considered, there is a distinct direct relationship (r2=0.82) between the extent of LDL-C reduction (in % vs basal) and the relative reduction (in % vs placebo group) in the risk of a major coronary event (death or non fatal AMI), in a range of LDL-C change from 19% (LRC-CPPT) to 37% (POSCH). It is clear from these data that the lipid lowering efficacy influences the clinical results. However, more investigations are neccesary to know if the goal of the treatment is the reduction of a percentage from the basal LDL-C level or if a defined LDL-C value should be reached. Moreover, some secondary prevention ongoing studies (SEARCH, TNT) are aimed to establish if lowering LDL-C beyond the current ATPII guideline of 100 mg/dl may yield a substantial additional clinical benefit. For now, the best evidence available suggest that in secondary prevention the minimal goal should be to attain an LDL-C of less that 130 mg/dl and, if possible in terms of cost and tolerance, to reach an LDL-C level lower than 100 mg/dl. The rationale for this goal is supported by a recent angiographic study (PostCABG) that showed less progression of atherosclerotic lesions in bypass grafts from patients subjected to an intensive treatment as opposed to a moderate treatment to reduce plasma LDL-C concentrations. This study was not powered to evaluate clinical outcomes and thus, we will have to wait some years to have a definite answer about how much to lower LDL-C in secondary prevention. The goals of LDL < 130 mg/dl in high-risk primary prevention or < 160 mg/dl in moderate risk primary prevention are very practical although arbitrary, and I am not aware of any current investigation to obtain more objective evidences that might help to accept or refute these goals. For now, lets take them as reasonably good.
It should remain clear that cholesterol lowering therapies take much longer to reduce risk than to reduce cholesterol. Whereas plasma cholesterol levels may reach acceptable levels in less than two months on adequate hypolipidemic therapy, the risk of cardiovascular events, the basic purpose of cholesterol lowering, need much more extended periods of time to be favourably modified. Indeed, all the large trials with hypolipidemic therapies in primary or secondary prevention show that the minimum period of continuous treatment to detect a difference in the number of events (AMI or coronary death) between the placebo group and the actively treated group varies between 6 months and 3 years., then these differences progressively broaden to become significant only after 4-5 years of uninterrupted therapy. The presence of this " gap" between cholesterol reduction and risk reduction strongly argues against the rational of prescribing hypolipidemic treatments for short periods of time, a circumstance extremely common in the medical practice, just " to lower cholesterol" .
When?Intensive treatment of hypercholesterolemia should be routinely practiced in secondary prevention, in high-risk subjects in primary prevention or in "low-risk?" subjects with subclinical atherosclerosis (and then-on high-risk). The general concept is to start medication as soon as possible in these conditions, usually after a trial of lifestyle modifications. If cholesterol is basally very high or a monogenic dyslipidemia is the basic disorder, the nutritional anamnesis demonstrates healthy eating habits and there is no overweight, it is reasonable to start an adequate hypolipidemic drug treatment without further delay. Of most importance, in the first approach to the hypercholesterolemic patient, attention should be paid to not overlook a secondary hyperlipidemia. Particular considerations merit the management of hypercholesterolemic children, premenopausal women and the elderly, topics that go beyond this presentation.
How? An appropiate trial of lifestyle modifications is advisable and then drugs may be added, if neccesary. Good efficacy and tolerance should be periodically monitored by interrogation and laboratory tests (mainly liver and muscle enzymes) and compliance should be pursued and continuously reinforced by comprehensive chats with the patient about terms and goals.
How much? There is good recent clinical research data to accept the general strategy that the NCEP proposed in 1994 through the ATPII guidelines. If attaining LDL-C levels beyond these thresholds provides further clinical benefit is still an ananswered question, although intermediate measures of benefit (i.e angiographic changes) suggest that this might be the case.
How long? Once the appropriateness of drug therapy is decided, the treatment should be uninterrupted. At least with fibrates and statins, the most commonly used hypolipidemic medications, there is good evidence on the lack of significant long term side effects (lovastatin was marketed in 1989 and some fibrates are much older). Simultaneously, healthy lifestyle conditions should be continued and regularly encouraged.
Thus, we have virtually (informatically) seen all the virtually (substantially) important aspects of cholesterol lowering in this original First Virtual Congress.
Thank you very much for your virtual attention.
JosÚ Pablo Werba, MD
The following contribute to this Congress: