THE HEART

Home | 2-PAGE SUMMATION ON STATINS | Understanding Atherosclerosis & its MI Link--jk | understanding heart attack | lipids, lipoproteins, the basics | ABOUT Cholesterol | Tables of Risk Factors plus STATS | Niacin prevents MI 25% | Statins, inflammation & atherogenesis--their failure | inflammation, obesity and atherosclerosis | Risk Factors Athereosclerosis | High Cholesterol and treatments | STATINS, lowering cholesterol doesn't prolong life | MMP role in atherogenesis and statins | COX-2 Suppression and statins | High HDL not Prophylactic | Other Markers for Cardiovascular Disease | $70,000 standard heart treatment per year following a MI | Why improving cholesterol profile with statins has little effect | Statins side effects | Statins over prescribed | Recommendation for your heart | New Major Study Pans Statins | STATIN COMBO STUDY, NO BENEFITS | C-Reactive Protein and Statins | Ozone & cholesterol combine to cause heart disease | Calcium score and coronary disease--a review | Serious cognitive impairment from bypass operation, Scientific American | ARRHYTHMIA, sudden early death and prevention for relatives | STEM CELLS GROW HEART MUSCLE | BYPASS & STENTS over sold
High Cholesterol and treatments

Around 75% of the heart attacks and about 85% of the strokes are caused by a clogging of an artery (caused by atherosclerosis) with plaque that has leaked from the artery wall.  There are three effective ways to slow the development of atherosclerosis:  diet, exercise, and drugs (nicotinic acids, statins, fibrates, and resins). 

 

Considering that around 40% of Americans do not have medical insurance and that niacin is inexpensive, effective, safer than prescription drugs, obtained without a prescription; it ought to be taken in medicinal amounts (2-3 grams per day) by those in the higher risk group for coronary disease—those with elevated levels of LDL and cholesterol.

 

SOURCES:  2002 Conn’s Current Therapy, Goodman and Gilman 11th Edition (2006), Britannica 2002 Expanded Edition, Merck Manual 11th Edition (2006), Refernce.com, Wikipedia.org.  Goodman and Gilman references are noted as G&G.

Hyperlipoproteinemia

 

 

Hyperlipidemia, hyperlipoproteinemia or dyslipidemia is the presence of elevated or abnormal levels of lipids and/or low-density lipoproteins in the blood. Lipids (fatty molecules) are transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence on metabolism.  Abnormal levels of certain lipids, particularly cholesterol, triglycerides, and low-density lipoproteins are risk factors for atherosclerosis which elevates the risk for coronary heart disease and strokes.    

 

Deaths from CHD, cerebrovascular disease, and peripheral vascular disease account for 38.5% of the 2.4 million deaths in the United States in 200.  Two-thirds of atherosclerosis deaths were due to CHD.  About 85% of CHD deaths occurred in individuals over 65 years of age.  Among the 15% dying prematurely, 80% died during their first CHD event.  Among those dying of sudden cardiac death in 1997, 50% of the men and 64% of the women had previously been asymptomatic.  It is estimated that an average of 11.5 years of life are lost as a consequence of having a myocardial infraction (G&G 940). 

 

Modifiable risk factors account for 85% of excess risk (risk over and above that of individuals with optimal risk-factor profiles) for premature CHD.  The presence of one or more conventional risk factor in 90% of patients with CHD belies claims that a large percentage of CHD, perhaps as much as 50%, is not attributable to conventional risk factors.  Studies indicate that when total cholesterol levels are below 160 mg/dl, CHD risk is markedly attenuated, even in the presence of additional risk factors.  

 

Risk factors:  LDL, low density lipoprotein are associated with coronary heart disease (CHD).  Statins lower primarily LDL.  However, many patients with coronary heart disease (CHD) do not have substantially elevated LDL, instead, low high-density lipoprotein (HDL) [thus the ratio of LDL to HDL is important].  HDL greater than 60 is a negative risk factor.  Other lipid abnormalities associated with CHD risk are elevations of triglyceride and lipoprotein(a), and a preponderance of small, dense LDL particles.  Oxidized LDL is central to the process.   Low HDL increases CHD risk and is the primary lipid abnormality in many patients with CHD. 

 

Hypertriglyceridemia is an independent risk factor for CHD, but is often associated with low HDL levels, insulin resistance, and hyperinsulinemia.  LDL poses a risk for cardiovascular disease when it invades the endothelium and becomes oxidized since the oxidized form is more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of free radicals in the endothelium. Nitric oxide down-regulates this oxidation process catalyzed by L-arginine. Correspondingly when there are high levels of asymmetric dimethylarginine in the endothelium, production of nitric oxide is inhibited and more LDL oxidation occurs.

 

LDL particles actually vary in size and density, and studies have shown that a pattern that has more small dense LDL particles—called "Pattern B"—equates to a higher risk factor for coronary heart disease(CHD) than does a pattern with more of the larger and less dense LDL particles ("Pattern A"). This is because the smaller particles are more easily able to penetrate the endothelium. "Pattern I", meaning "intermediate", indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).  Because of difficulty in acquiring the measurement of these two types of LDLs, these values are not routinely obtained.   {Given the cost, side effects, and inconvenience of most drug treatments for high LDL, such measurement ought to be made, even thought it is not in the economic interest of the physician—jk}  If the LDL is elevated, the primary goal of therapy is to lower LDL, with the reduction of triglyceride by nicotinic acid; a fibrate is a secondary consideration. 

 

Inflammation which runs unchecked can also lead to a host of diseases such as hay fever, atherosclerosis, and rheumatoid arthritis.  Prolonged inflammation (chronic) leads to a progressive shift in the type of cells which are present at the site of inflammation and is characterized by a simultaneous destruction and healing of the tissue from inflammatory process.  Causes:  burns, chemical irritants, frostbite, toxins, infection, necrosis, physical injury, immune reaction due to hypersensitivity, ionizing radiation, and foreign bodies. 

 

Moderately elevated triglycerides (150-400 mg/dl) are of concern because they often occur as part of the metabolic syndrome, which includes insulin resistance, obesity, hypertension, low HDL levels, and substantially increased CHD risk.  The metabolic syndrome affects ~25% of adults and is common in CHD patients; hence identification of moderate Hypertriglyceridemia should trigger an evaluation to identify this disorder. 

 

DRUG INTERVENTIONS

There are 5 principle types of drug intervention.  Most used are the statins which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors (they also reduce blood clotting); bile acid-binding resins, nicotinic acid, fibric acid derivatives, the cholesterol absorption inhibitior ezetimibe.  (Statins primary reduction in cardiac events is not, as big PHARMA suggests, through their effect on LDLs, but rather through the reduction of thrombosis.  This effect can be obtained through daily aspirin.)  Drug intervention can reduce CHD and strokes in the high-at-risk populace by 30-40%. 

 

 

http://www.aspirin-foundation.com/uses/cardio/thrombosis.html

Aspirin and Coronary Thrombosis

Once the anti-aggregant effect of aspirin on platelets had been described in the mid 1960s, calls for trials of aspirin in myocardial infarction were made by John O’Brien in the
UK (19) and by Harvey Weiss and others in the USA.21

In fact, these calls had been anticipated. Laurence Craven, a family practitioner in
Glendale, California, published a series of three papers on aspirin in the early 1950’s (22-24).  Each of these focused on some aspect of bleeding.

In the first, Craven pointed out that women take aspirin rather often for their pains and aches, while men tend to scorn such an ‘effeminate’ remedy and he went on to wonder if this difference might explain the sex difference in the incidence of heart attacks. (22) In his second paper,

Craven described bleeding in tonsillectomy patients given Aspergum, a mint flavoured gum impregnated with aspirin. (23) His third paper reports uncritically a remarkable benefit of aspirin on heart attacks and strokes (see panel). Craven’s ideas were however so unacceptable at that time, and his experimental work so flawed that he had difficulty reporting his findings and had to submit his papers to a rather obscure journal. (24)

Craven died of an MI a few years later.
The calls of O’Brien and Weiss were however heard in the MRC Epidemiology Unit in
Cardiff, and in 1969 a double-blind placebo-controlled randomised trial of low-dose aspirin was commenced. (25) Men who had been recently discharged from local hospitals following an MI were invited to cooperate. Those who agreed were randomised to receive either 300 mg aspirin in a gelatine capsule or a placebo capsule.

Two points about the published report on this first trial are worth noting (see panel below). First, the journal published it under the headline: ‘For debate’. This was totally appropriate. Clinical practice should never be based on the results of a single trial, however convincing these are.

Replication is essential and if a drug or a preventive measure truly works then it will show in different patient groups, in different situations and in trials run by different trialists. Secondly, the results of the trial were evaluated only in terms of a reduction in total deaths. The inclusion of non-fatal events gives opportunity for bias due to a possible differential reporting of symptoms. Cardiovascular disease makes a substantial contribution to all-cause deaths, and if a measure does reduce it, an effect on total mortality should be seen.

For debate
A Randomised Controlled Trial of Acetyl Salicylic Acid in the Secondary Prevention of Mortality from Myocardial Infarction.

P.C.Elwood, A.L.Cochrane, M.L.Burr, P.M.Sweetnam, G.Williams, E Welsby, S.J.Hughes, R.Renton
British Medical Journal 1974,1, 436-440

Summary
The results of a randomised controlled trial of a single daily dose of acteyl salicylic acid (aspirin) in the prevention of re-infarction in 1,239 men who had had a recent myocardial infarct were statistically inconclusive. Nevertheless, they showed a reduction in total mortality of 12% at six months and 12% at twelve months after admission to the trial. Further trials are urgently needed to establish whether or not the effect is real.

Naturally, clinicians at that time were somewhat more than sceptical of the whole situation, and there was no detectable change in clinical practice. However research groups around the world took note, a number of trials were set up and by 1980 six trials had been reported. (25-30)

An early overview (Seoul conference on aspirin 1980)
TRIAL No of patients Reduction by aspirin


Cardiff 1 (1974)25 1239 26% n.s.
CDP (1976) 26 1529 30% n.s.
Cardiff 2(1979)27 1725 30% n.s.
German (1979)28 626 18% n.s.
AMIS (1980)29 4524 10% n.s.
PARIS (1980)30 1216 18% n.s.

These trials involved 10,859 patients, and the weighted overall effect was:

23% reduction by aspirin (P < 0.0001)

Each of these early trials suggested a beneficial effect of aspirin, but the results of none achieved an acceptable level of statistical significance. Overall, however, there is clearly convincing evidence of benefit.

The reporting of overviews of the results from all relevant published trials relating to a particular clinical intervention is becoming increasingly common throughout clinical practice and the first such overview, or meta-analysis, based on these six trials was presented by Richard Peto and his colleagues of Oxford to the inaugural meeting of the Society for Clinical Trials in Philadelphia in 1980.(31)

This overview was one strand in the thinking that led eventually to the setting up of the Cochrane Collaboration, the worldwide initiative that aims to conduct overviews within every area of clinical activity. (32)

Since that first report, the Oxford group have produced several monumental overviews of aspirin and cardiovascular disease: in 1988 (33) ,1994 (34). and 1997 (35).

The following is based on the overview published in 1994, which combines results from 145 RCTs, with a total of 102,459 patients and 10,943 outcome events. A remarkably consistent reduction in vascular events is demonstrated (22 to 32%).

An overview of RCT's of aspirin and cardiovascular disease

(BMJ 1994;308:81-106)

Patient group No. of trials Reduction in MI stroke or vasc. death.
Prior MI 11 25%
Acute MI 9 29%
Prior stroke/TIA 18 22%
Other high risk 104 32%

All trials 25%

Patient group No. of trials Reduction in MI stroke or vasc. death.
Non-fatal MI 122 34%
Non-fatal stroke 124 25%
Vascular death 144 17%
All-cause death 144 16%

Also considering the following factors
male/female; under/over 65yrs; hypertensive / normotensive; diabetic / non-diabetic gave no evidence of any significant differences in benefit.

An overview of studies with such a large number of clinical outcomes enables the drawing of conclusions from sub-group analyses with a fair degree of confidence. The benefit of aspirin is similar in all groups of patients whatever the prior indication for prophylaxis. Furthermore, there is no evidence of differences in the proportionate reduction by aspirin in different patient groups: males and females, older and younger subjects, diabetic and non-diabetic, hypertensive and normotensive subjects etc.

Together with this overview a Press Release by the group in
Oxford was widely reported by the media. (36) This gave the estimate that around 100,000 premature deaths from cardiovascular disease could be prevented world-wide by the appropriate use of low-dose aspirin together with at least this number of non-fatal heart attacks and strokes.

 

 

Nicotinic Acid (Niacin, B3)

Nicotinic acid has been used to treat hyperlipidemias for 40 years.  Niacin is a water-soluble B-complex vitamin that functions as a vitamin only after its conversion to NAD or NADP (in the energy production cycle), in which it occurs as an amide (acid COOH, amide CONH2).  Both niacin and its amide may be given orally as a source of niacin for its functions as a vitamin, but only niacin affects lipid levels, and at very large doses.  It is the best agent available for increasing HDL—the good cholesterol.  In addition to improving LDL, HDL, and triglyceride, niacin is one of the few agents know to reduce Lp(a).  Niacin is especially effective in treating patients with mixed dyslipidemia.  Niacin reduces the production and release of VLDL and thereby leads to a reduction in IDL and LDL.  Niacin also decreases the release of free fatty acids, a substrate of triglyceride synthesis, from adipose tissue into the circulation.  Niacin may also decrease HDL catabolism.  The mechanism by which niacin reduces Lp(a) is not known. 

 

Efficacy, Niacin at a dosage of 1.5 to 6g/d decreases LDL by approximately 20-30%, increases HDL by 30-40%, and decrease triglyceride by 35-50%; and Lp(a) by 40% (G&G, p. 955).  Combination therapy with resins can reduce LDL levels by as much as 40-60% (G&G 956).

 

Absorption, fate, and excretion:  Niacin is almost complete absorbed, and peak plasma concentratioins are achieved within30 to 60 minutes.  The half-life is about 60 minutes, which accounts for the necessity of twice- or thrice-daily dosing.  At lower doses, most niacin is taken up by the liver; only the major metabolite, nicotinuric acid is found in the urine.  At higher doeses, a greater proportion of the drug is excreted in the urine as unchanged nicotinic acid (G&G 956).    

 

Mechanism of action: In adipose tissue, niacin inhibits the lipolysis of triglycerides by hormone-sentive lipase, which reduces transport of free fatty acids to the liver and decreases hepatic triglyceride synthesis.  IT may exert tis effect on lipolysis by inhibiting adipocyte adenylyl cyclase.  Niacin may also inhibigt a rate-limiting enzyme of triglyceride synthesis.  In the liver, niacin reduces triglyceride synthesis by inhibiting both the synthesis and esterification of fatty acids.  This reduction of triglyceride synthesis reduces hepatic VLDL production, which accounts for the reduced LDL levels.  HDL levels (good Cholesterol) are raised by decreasing the fractional clearance of apoA-1, but not of cholesteryl esters, thereby increasing the apoA-1 content of plasma and augmenting reverse cholesterol transport.  The net effect of niacin on monocytic cells (foam  cells) is HDL-mediated reduction of cellular cholesterol content. 

 

Immediate-release (crystalline) niacin is typically started at a dosage of 100 mg once or twice daily and gradually titrated up to 2 to 3 g/d over a period of 1-3 weeks, often with a schedule of 1 g two or three times daily.  (Niaspan is a sustained release formulation). 

 

Side Effects & Drug Interactions: Cutaneous flushing and pruritis (itching) of the trunk and face limit patient compliance. Flushing is worse when therapy is initiated or the dosage increased, but ceases in most patients after 1 to 2 weeks.  It can reoccur if one to two doses are missed, and it is more likely to occur when niacin is consumed with hot beverages or ethanol.  Flushing and prutitis is minimized if therapy is initiated with low doses, are taken with meals, and by concomitant administration of aspirin (325 mg hour prior).  Dry skin, a frequent complain, can be dealt with by using skin moisturizers.    Acanthosis nigricans (brown, poorly defined, velvety hyperpigmentation of the skin) can be dealt with by suing lotions or creams containing salicylic acid..  Increased hepatic transaminases occur in 1-2% of patients.  Combining niacin with a statin increases the risk of hepatitis and myopathy (muscle disease).  Niacin can cause uric acid elevations and occasionally precipitates gout, and may activate peptic ulcers.    The most common, medically serioius side effects are hepatotoxicity,  manifested as elevated serum transaminase and hyperglycemia.  Affected patients experience flu-like fatigue and weakness.  A reduction of LDL of 50% or more should be viewed as a sign of niacin toxicity.  High doses of niacin may also elevate blood sugar.  Niacin can adversely affect glucose metabolism, particularly in patients with underlying insulin resistance--about 4% of type 2 diabetics.     

 

Therapeutic Uses:  Crystalline niacin tablets are available over the counter.  To minimize the flushing and pruritus, it is best to start with a low dose (100 mg. Twice daily taken after breakfast and supper).  The dose may be increased stepwise every 7 days by 100 to 200 mg to a total dose of 1.5 to 2 g.  After 2 to 4 weeks at this dose, transaminases, serum albumin, fasting glucose, and uric acid levels should be measured.  Lipid levels shoud be checked and doses increased further until the desired effect on plasma lipids is achieved.  After a stable dose is attained blood should be drawn every 3 to 6 months.  All doses of sustained-relase niacin, but particlulary doses above 2 g per day, have been reported to cause hepatotoxicity (G&G 956). 

 

One popular form of dietary supplement is inositol hexanicotinate, usually sold as "flush-free" or "no-flush" niacin (although those terms are also used for regular sustained-release.) While this form of niacin does not cause the flushing associated with the nicotinic acid form, it is not clear whether it is pharmacologically equivalent in its positive effect. 

 

 

 

Statins

These drugs produce the greatest reduction in blood borne lipoproteins the most marked reduction of CHD.  This association has been overstated for they also reduce thrombi—just like aspirin.  Their aspirin like effect in reducing MI (myocardia infraction) ought to be included in the evaluation of statins’ effectiveness.   

 

Statins are competitive inhibitors of 3-hydroxy-3methylgultaryl coenzyme A (HMG-CoA) reductase, which catalyzes an early, rate limiting step in cholesterol biosynthesis.  They can also reduce triglyceride levels caused by elevated VLDL.  Rates of side effects approach that of the placebo group. 

           

Statin affect cholesterol levels by inhibiting hepatic cholesterol synthesis, which results in increased expression of the LDL receptor gene. Triglyceride levels >250  mg/dl are reduced substantially by statins, and the percent reduction is similar to the reduction in  LDL-C.  For the highest dose (simvastatin and atorvastitin, 80 mg/day) reduction of 35-45% for both LDL-C and triglycerides.  A similar reduction in triglycerides can be achieved with fibrates or niacin.  Statins also raise HDL levels, though studies have not shown if the modest rise is clinically significant.  A multitude of potentially cardio-protective effects are being ascribed to these drugs [by big PHARMA]; however, the mechanisms of action for non-lipid lowering roles has not been established and thus it is not known of these putative effects are biologically or clinically relevant. 

 

The vulnerability of plaques to rupture and thrombosis is of greater clinical relevance than the degree of stenosis they cause.  Statins may affect plaque stability in a variety of ways.  They reportedly inhibit monocyte infiltration into the artery wall in a rabbit model, and inhibit macrophage secretion of matrix metalloproteinases in vitro.  The metalloproteinases degrade extracellular matrix components and thus weaken the birous cap of atherosclerotic plaques.  Other effects proffered by big PHARMA include inhibiting of smooth muscle cells in artery walls, and enhancing apoptotic cell death.  Statins decrease C-reactive protein (CRP), an independent marker for inflammation and high CHD risk.  However, CRP might be a marker for the metabolic syndrome (obese, insulin resistant)—and not for atherosclerosis.  CRP reduction has been shown to modestly reduce CHD, this might be because of better managing of those with metabolic syndrome. 

Statins have been shown to reduce the oxidation of LDL in both in vitro and ex vivo studies.  Statins reduce [like aspirin] platelet aggregation and reduce the deposition of platelet thrombi in the porcine aorta model.  [The separating of the thrombi effect from that of LDL effect on reduction of CHD would significantly impact statins prudent usage—jk]. 

 

After an oral dose, plasma concentrations of statins peak in 1 to 4 hours.  The half-lives of the parent compounds are 1 to 4 hours, except atorvastatin and rosuvastatin which have half-lives of about 20 hours, which probably account for these drugs greater effect upon LDL.  More than 70% of statins metabolites are excreted by the liver with subsequent elimination in feces. 

 

Serious adverse effects are truly rare when administered alone.  There are serious drug interactions.  The myopathy (muscle pain) syndrome is characterized by intense myalgia similar to flu-related myalgia. Since myopathy rarely occurs in the absence of combination therapy routine CK monitoring is not recommended unless the statins are used with one of the predisposing drugs. 

 

Bile-Acid Sequestrants

The two established bile-acid sequestrants resins (cholestyramine and colestipol) are among the oldest of the hypolipidemic drugs, and they are probably the safest, since they are not absorbed from the intestine.  Because statins are so effective at lowering LDL, resins are used as a second agent if statin therapy does not lower LDL sufficiently.  Maximal doses (24-30 g) can reduce LDL by up to 25%, but are associated with unacceptable gastrointestinal side effects (bloating and constipation) that limit compliance.  In a 1984 study cholestyramine therapy reduced total cholesterol by 13% and LDL by 20% (diet 5% and 8%) and CHD events by 19%. 

 

The bile-acid Sequestrants are highly positively charged and bind negatively charged bile acids.  Because of their large size the resins are not absorbed, and the bound bile acids are excreted in the stool.  Since over 95% of bile acids are normally reabsorbed, interruption of this process depletes the pool of bile acids, and hepatic bile-acid synthesis increases.  As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors, an effect similar to that of statins.  The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels, but this effect is partially offset by enhanced cholesterol synthesis caused by up-regulation of HMG-COA reductase.  Inhibition of reductase activity by statin substantially increases the effectiveness of the resins. 

 

Fibric Acid Derivatives

Fibrate are a class of amphipathic carboxylic acids used mainly for hypercholesterolemia.  In 1967 the ester form (clofribrate) was approved by the FDA.  Fibratres most effectively reduce triglycerides and raise HDL levels.  Its use declined dramatically after the World Health Organization reported in 1978 that despite a 9% reduction in cholesterol levels, clofibrate treatment did not reduce fatal cardiovascular events.   Subsequent drug company sponsored studies have shown a modest reduction in mortality. 

 

Fibrates decrease plasma triglyceride by increasing the activity of lipoprotein lipase, which hydrolyzes triglycerides from VLDL particles.  Fibrates also decrease hepatic cholesterol synthesis and increase cholesterol excretion in bile.   Commonly prescribed are bezafibrate, cirofibrate, clofibrate, gemfibrozil, and fenofibrate. Despite extensive studies in humans, the mechanisms by which fibrates lower lipoprotein levels and raise HDL levels remains unclear.    Recent studies have shown that fibrates activate PPAR (peroxisome proliferators activated receptors) especially PPARα., and there effect seems to be through enhanced clearance of VLDL.  Fibrates are structurally and pharmacologically related to the thiazolidinediones, a novel class of anti-diabetic drugs that also act on PPARs (more specifically PPARg.  Most of the fibric acid agents have antithrombotic effects including the inhibition of coagulation and enhancement of fibrinolysis.  Thus the salutary effects could be mostly from altering cardivovascular outcomes by mechanisms unrelated to any hypolipidemic activity; this lead to the conclusion for this reviewer to recommend aspirin instead of fibrates except for severe hypertriglyceridemia and chylomicronemia syndrome.  Goodman and Gilman recommends fibrates for subjects with triglycerides  >1000 mg/dl who are at risk for pancreatitis and have a role in subjects with high triglycerides and low HDL levels associated with pancreatitis or type 2 diabetes mellitus.  Many experts first treat such patients with a statin, and then add a fibrate.  However, statin-fibrate combination theapy has not been evaluated in outcome studies. 

 

            In a 5-year study of hyperlidemic men, gemfibrozil reduced total cholesterol by 19% and LDL by 11%, raised HDL by 11%, and decreased triglycerides by 35%.  Overall there was a 34% decrease in the sum of fatal plus nonfatal cardiovascular events, but without effecting total morality.  Again Goodman and Gilman suggest that this benefit was from the same mechanism as for aspirin and not its effect on lipids.

 

            Side effects occur in 5-10% of patients, but most often are not sufficient to cause discontinuation of the drug.  The usual dose is 2 g per day in divided doses for clofibrate, 600-mg dose for gemifbrozil taken twice a day, fenofibrate 145 mg daily.

 

 

Ezetimbe and the Inhibition of Dietary Cholesterol Uptake

Ezetimibe is the first compound approved for lowering total and LDL-C levels that inhibits cholesterol absorptioin by enterocytes in the small intestine.  It lowers LDL-C levels by about 18% and is used primarily as adjunctive therapy with statins.  Outcome studies have recently started.  Dual therapy with these two classes of drugs prevents enhanced cholesterol synthesis induced by ezetimibe and the increase in cholesterol absorption induced by statins; there is thus a 15-20% reduction in LDL-C.  Increasing statin dosages from the usual starting dose of 20 mg to 80 mg normally yields only an additional 12% reduction in LDL-C, whereas adding ezetimibe, 10 mg daily to 20 mg of a statin will reduce LDL-C by an additional 18-20%. 

 

Ezetimibe is highly water insoluble, precluding studies of bioavailability.  After ingestion, it is glucuronidated in the intestinal epithelium, absorbed, and enters an enteroheptic recirculation.  Pharmacokinetic studies indicate that about 70% is excreted in the feces and aboutg 10% in the urine.  Bile acid Sequestrants inhibit absorption of ezetimibe. 

 

 

 

Other risk factors high levels of lipoprotein A, homocysteine, Apoprotein B

Publicity about Recent Studies on the Cholesterol-lowering Statin Drugs: Misinterpretations

Return to Top

There has been an extraordinary amount of news attention focused on recent studies concerning statins and heart disease, presented at the American College of Cardiology meetings in March and, in one case, published in the April 8, 2004 New England Journal of Medicine.

 

Without disparaging the importance of the studies themselves, we believe that spin-doctors and a scientifically uncritical news media have interpreted and stretched the findings in ways that go far beyond the actual data from the studies. A few examples will illustrate this:

 

Misinterpretation #1

Statins will prevent heart disease even in people who have not yet had a heart attack, stroke, angina or other kinds of cardiovascular disease if they have elevated cholesterol levels.


These recent studies are so-called secondary prevention studies. That is, the drugs were given to people who, in the case of one study, had been hospitalized with an “acute coronary syndrome,” meaning either a heart attack or high risk unstable angina.

{WEAK EVIDENCE FOR STATINS FOR THOSE WITH ONLY HIGH CHLOSTERAL}:

Although there are some earlier studies involving people without previous evidence of cardiovascular disease (angina, heart attacks, bypass surgery, angioplasty or strokes), the evidence for treatment of these people, especially with cholesterol-lowering drugs, is weaker and is known as primary prevention. This is especially so for those people who do not have more than one of the risk factors listed below:

These risk factors include hypertension, diabetes, smoking, obesity, or a close family history of premature heart attacks or strokes. Other predisposing risk factors include a sedentary life style and a high-fat diet. It is likely that millions of people being given cholesterol-lowering drugs such as statins for primary prevention do not have more than one of these risk factors and are only being treated because of their total cholesterol or LDL cholesterol levels.

Thus, it is extremely important to look at the global risk of cardiovascular disease rather than focusing on just the blood pressure or just the cholesterol level. For primary prevention, it is usually most prudent to attempt to improve your cardiovascular risk through sensible programs of diet and exercise.

A case example of primary prevention involving someone who will, unfortunately, more times than not be recommended to start statins follows:

Ben is a 55-year-old man with a total cholesterol of 240 and an HDL of 50. However, his blood pressure is a normal 120/90 and he is neither a diabetic nor does he smoke. Ben turns out to have a 5-year risk of having a cardiovascular event (heart attack, stroke, etc) of only 5.1%, about one-half of the 5-year risk of over 10% that might merit drug treatment. It would be a good idea for Ben — or most people, for that matter—-to adopt the non-drug approaches to lowering his cholesterol discussed above, but since his global risk is as low as it is, drug treatment is not indicated even if his total cholesterol and HDL cholesterol stay the same.

In summary, these new studies did not even examine the role of statins in primary prevention. There are many people who have had heart attacks and strokes with elevated cholesterol levels who are not being aggressively enough encouraged and helped to lower their subsequent risk with diet, exercise or statins, the very kinds of secondary prevention the studies did address.

Misinterpretation #2

The study showed that atorvastatin (LIPITOR) prevents heart attacks.


The study published in the New England Journal of Medicine was designed primarily to see if the subsequent occurrence of a combination of adverse cardiovascular events was different in those taking a high or “intense” dose of atorvastatin (LIPITOR) versus those using the “standard” dose of pravastatin (PRAVACHOL). The combination included death from any cause, a heart attack, unstable angina (chest pain) requiring hospitalization, bypass surgery or angioplasty, or a stroke.

It is correct that the study showed that those taking atorvastatin were significantly (16%) less likely than those taking pravastatin to have any of the above events — and this is an important finding. However, there was not a significant reduction in heart attacks alone, death alone, or in the combination of death and heart attacks. The most significant reduction in the Lipitor group was in the subsequent occurrence of unstable angina requiring hospitalization.

Misinterpretation #3

The studies prove that atorvastatin (LIPITOR) is superior to pravastatin (PRAVACHOL).

As mentioned above, the purpose of the study was to see how intensive statin therapy (80 milligrams daily of atorvastatin) compared to standard therapy (40 milligrams of pravastatin) in people who had already had a cardiovascular event. There is reason to believe that the most important variable may be the intensity of the treatment rather than characteristics of the individual drugs.

Ideally, the study should have explored both the different drugs and different doses — standard or intense — of each.

Cholesterol-lowering Drugs For People 70 or Older

Aside from these recent papers, there is still some misinformation about the evidence for treating — in the form of primary prevention — elevated cholesterol levels in people over 70 years of age.

It is clear that the relationship between moderately elevated cholesterol levels and increased risk of heart disease is not as clear as people get older. As geriatricians Fran Kaiser and John Morely have written: “Given the uncertainty of the effects of cholesterol manipulation in older individuals, what should be the approach of the prudent geriatrician to hypercholesterolemia [elevated blood cholesterol levels]? In persons over 70 years of age, lifelong dietary habits are often difficult to change and overzealous dietary manipulation may lead to failure to eat and subsequent malnutrition. Thus in this group minor dietary manipulations such as the addition of some oatmeal [or other sources of oat bran or soluble fiber] and beans and modest increases in the amount of fish eaten, may represent a rational approach. Recommending a modest increase in exercise would also seem appropriate. Beyond this, it would seem best to remember that the geriatrician’s dictum is to use no drug for which there is not a clear indication.”

The use of cholesterol-lowering drugs in people 70 or older should be limited to patients with very high cholesterol levels (greater than 300 milligrams) and those who manifest cardiovascular disease (previous history of heart attack or angina, stroke). More recent reviews of this topic have reached similar conclusions: In one review, it was concluded that “unanswered questions include cholesterol treatment for primary prevention in the elderly, gender effect, and benefit of treatment in persons older than 70.” There are even questions as to whether elderly people who are hypertensive should have their cholesterol lowered by drugs. One review concluded that “Further trials are required before routinely suggesting that it is advantageous to lower cholesterol in an elderly hypertensive who does not have pre-existing evidence of coronary heart disease.”

What You Can Do

If your doctor recommends a cholesterol-lowering drug, especially for primary prevention, ask on what basis this is being done. This is especially true if you either are over age 70 or have no more than one risk factor.

Those who have a financial interest in the outcome manipulate the results, Major study finds that all 37 journal articles positive effects over stated; the average was 32%. Statins cause erectile dysfunction, cognitive imparement, and cancer.  

Lipitor (2011) lifetime sales $131 billion, tops all drugs.  Plavix at $60 billion is second.

 

STATINS CANCER Link

52% short term

 

LA Times, Health section, July 21, 2008  --  excerpts

Vytorin, the combination drug (simvastatin (better known by its commercial name Zocor) and ezetimibe--known as Zetia) prescribed to lower cholesterol, sustained another blow today, when the author of a major clinical trial announced that the medication had failed to drive down hospitalization and death due to heart failure in patients with narrowing of the aortic valve. In the process, researchers in Norway detected a significant blip in cancers in the 1,800 subjects they followed

Today's findings suggested something more ominous: the incidence of cancer -- and of dying of cancer -- was significantly higher in the patients taking Vytorin. Altogether, 67 patients on placebo developed cancer during the trial. Among subjects on Vytorin, 102 developed cancers of various kinds.*  This is the second adverse press—the first being in March 08, when the ENHANCE trial found that Vytorin fared no better than a placebo at reducing plaque buildup on the walls of patients' arteries.* *

Comments by jk

Simvastatin (Zocor) is off patent.  Thus in a scramble for profits a combination drug (on patent) was introduced.  Direct to consumer market cost $155 in 07—mainly TV ads. 

*  The pressing issue is that since the development  of Statins, the very first animal studies in the 60s it has been known that Statins increase the incidents of cancer.  However, nearly all studies done thereafter have not included cancer. 

*  Several studies have failed to find a reduction in the build of plaque, even thought the statins including Zocor, reduce LDL and cholesterol.  Few studies include the principle reason for taking a statin, namely a reduction in the death rate.  Claims for such reduction probably entail a failure to control the contravening variable, aspirin usage.  Given a pile of evidence, including the very mechanism of plaque formation, which involves inflammation process, I must conclude that the use of statins is highly suspect.  Given the harm done including cognitive impairment, weakness, and cancer, if my skepticism is born out, the harm done by statins as a course of treatment will far surpass that of VIOXX which killed over 200,000 people world wide by accelerating atherosclerosis. 

 EXTENDED RELEASE NIACIN IS A SAFER, AND A MORE EFFECTIVE WAY TO LOWER MI RISK!