Merck Uses Legal Threats To Stifle Negative Advice About Zetia And Vytorin In Italy
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Showing posts with label Ezetimibe. Show all posts
Showing posts with label Ezetimibe. Show all posts
Monday, July 7, 2014
Merck Uses Legal Threats To Stifle Negative Advice About Zetia And Vytorin
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Read the complete article here.
Thursday, March 20, 2014
Ezetimibe Prescribing Fails to Keep Up With Evidence - JAMA
Ezetimibe Prescribing Fails to Keep Up With Evidence
Place holder to copy figure label and caption
JAMA. Published online March 19, 2014. doi:10.1001/jama.2014.2896
Although physicians like to think they practice evidence-based medicine, that appears to not be the case with prescribing the cardiovascular drug ezetimibe. And some critics say that use of surrogate markers to guide practice rather than clinical outcomes such as occurrence of myocardial infarction, stroke, or death has likely played a role.
Ezetimibe is an intestinal cholesterol absorption inhibitor found to reduce low-density lipoprotein cholesterol (LDL-C) levels by about 20% when given alone. It also further reduces LDL-C levels when added to statin therapy, which blocks cholesterol synthesis in the liver by inhibiting HMG-CoA reductase.
The Food and Drug Administration approved ezetimibe in 2002 for use in the United States primarily because it lowered LDL-C levels, a surrogate marker for prevention of cardiovascular disease. Whether ezetimibe improved clinically meaningful outcomes remained a question.
That question was somewhat answered in January 2008, with the announcement that the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, sponsored and conducted by industry, found that the addition of ezetimibe failed to reduce atherosclerosis progression compared with simvastatin alone, despite lowering LDL-C levels. Atherosclerosis progression was determined by a change in the intima-media thickness of the walls of the carotid and femoral arteries—yet another surrogate end point (Kastelein JJP et al. N Engl J Med. 2008;358[14]:1431-1443).
US and Canadian physicians continue to prescribe ezetimibe even after a study found giving the drug with a statin failed to reduce atherosclerosis progression compared with the statin alone.
The ENHANCE result prompted some leaders in the cardiology community to question ezetimibe’s place in cardiovascular disease treatment. Harlan Krumholz, MD, professor of medicine and epidemiology and public health at Yale University in New Haven, Connecticut, said the study should change practice. “Although not definitive, [ENHANCE] increases our uncertainty about the clinical value of this novel drug. Without some evidence of improved outcomes associated with its use, ezetimibe should be relegated to a last option for patients who need medication for hypercholesterolemia, and even in these cases, it is reasonable for clinicians and their patients to wait for further information before considering it,” he wrote in NEJM Journal Watch (http://tinyurl.com/pk9xr29).
So did the ENHANCE results change practice? In the United States, the answer is “somewhat,” while in Canada, the answer appears to be “no.”
In a study published in the American Heart Journal, researchers looked at ezetimibe prescription trends before and after ENHANCE, using data collected from CompuScript in Canada and IMS Health in the United States from January 1, 2002, to December 31, 2009. The researchers found the monthly number of ezetimibe prescriptions per 100 000 population rose from 6 to 1082 in the United States from November 2002 to January 2008 and then declined to 572 per 100 000 population by December 2009, a decrease of 47.1%. In Canada, however, use continuously increased from 2 to 495 per 100 000 from June 2003 (when the drug was approved in Canada) to December 2009 (Lu L et al. Am Heart J. doi:10.1016/j.ahj.2014.01.014 [published online February 27, 2014]).
Coauthor Cynthia A. Jackevicius, PharmD, MSc, a professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, California, and an adjunct scientist, Institute for Clinical Evaluative Sciences, in Toronto, said her team was initially surprised by the Canadian results.
“Previous findings showed ezetimibe use in Canada experienced a more conservative uptake, so we expected to see a decrease in use in response to the ENHANCE study,” Jackevicius said. “So we looked for different factors, and one is the Canadian lipid guidelines, which specifically said ezetimibe could be added to statins, and that didn’t change after ENHANCE came out.”
A study of ezetimibe use in Saskatchewan, the only Canadian province that lists the drug for open formulary access, even though guidelines say it’s a second-line agent for lowering cholesterol, reflects Jackevicius’s team’s findings. Using data from provincial health administrative databases, the Saskatchewan researchers found that ezetimibe prescriptions were 2.5% of cholesterol-lowering dispensations in 2004 and 8.8% of such dispensations in 2011 (Alsabbagh WM et al. Can J Cardiol. 2014;30[2]:237-243). The authors concluded that allowing unrestricted use of ezetimibe in Saskatchewan may have led to a large number of inappropriate prescriptions, at odds with Canadian clinical guidelines.
And although ezetimibe use declined in the United States, its use per 100 000 population is still greater than Canada’s, generating US expenditures of more than $2.2 billion in 2009.
Krumholz, one of the coauthors on the study with Jackevicius, remains perplexed as to the continuing popularity of ezetimibe. “The drug continues to defy gravity, and that’s probably a result of really strong marketing and the singular focus on cholesterol numbers,” he said.
Krumholz said heart health campaigns urging patients to “know your numbers” and treatment goals based on cholesterol measurements, such as getting asymptomatic individuals’ LDL-C levels below 130 mg/dL, have worked in ezetimibe’s favor at the expense of evidence-based medicine. “Is this the drug that lowers your LDL-C and helps you? We don’t know that,” he said. “The comfort of hitting a target offers little benefit if you don’t know that it is really protecting you.”
Although ENHANCE has not derailed ezetimibe prescribing, the newest cholesterol management guidelines just might. The guidelines, issued late last year by the American College of Cardiology and the American Heart Association, abandon the idea of reaching a target level for LDL-C, instead recommending the use of statins to reduce LDL-C levels only for certain types of patients.
Will this change in the guidelines affect ezetimibe prescribing? “It will be interesting to see what the guidelines will do,” Krumholz said.
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Tuesday, September 3, 2013
So is niacin a dead drug? Dayspring
Commentary on Niacin’s Effect on Lp(a) in AIM HIGH
Here are my thoughts as a clinical lipidologist (By: Thomas Dayspring, MD, FACP, FNLA, NCMP)
We must get apoB (LDL-P) to goal in all at-risk patients. Lifestyle therapies and statins are the mainstay of therapy. However residual risk is high if apoB (LDL) remains elevated despite at-goal LDL-C, non-HDL-C), any level of HDL-C or if Lp(a) mass is elevated.
So I would have no hesitancy in adding niacin to high and very high risk patients who have not achieved apoB (LDL-P) goals with whatever therapies they are using or using niacin as a monotherapy in those intolerant of other apoB lowering meds.
Data from HPS THRIVE 2 (discussed in a recent commentary) suggested statin plus ezetimibe was better at event reduction than statin plus niacin [9]. In view of that and the very significant side effects reported in HPS THRIVE 2 [bleeding (GI, intracranial, other) in the niacin group: 326 (2.5%) to 238 (1.9%) and infection 1031(8%) to 853 (6.6%)] [3] makes niacin a tertiary or quaternary add-on drug (some may prefer the bile acid sequestrant colesevelam as an apoB lowering medication).
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Thursday, August 29, 2013
Niacin’s Effect on Lp(a) in AIM HIGH - Dayspring
Commentary on Niacin’s Effect on Lp(a) in AIM HIGH
In AIM HIGH baseline apoB and apoA-I levels were low and baseline Lp(a) was elevated at 33.8 nmol/L [using Caucasian adult data from Framingham as a comparator, Lp(a) averaged 20 nmol/L]. Nearly 30% of AIM HIGH patients had severe Lp(a) elevations > 100 nmol/L compared to 20% of Framingham cohort. The addition of niacin to statin or statin + ezetimibe raised HDL-C by 25%, apoA-I by 7% and reduced LDL-C by 12%, TG by 30% and apoB by 13%. [5]
Lp(a) as expected was significantly associated with CV events despite the fact that LDL-C was at goal and thus elevated Lp(a) is associated with residual risk. A one standard deviation of Lp(a) was associated with a 21% increase in CV risk. There was a 21% overall reduction [but with a 20%, 39% and incredible 64% decreases in patients at the 50th, 75th and 90th percentile cut points] in Lp(a) in the niacin group compared to 6% in placebo group. So the higher the Lp(a) level, the more dramatic was niacin’s ability to lower it. Here is the shocker: there was no difference in event rate between those on or not on niacin (remember all were statin or statin + ezetimibe) DESPITE GREATER DECREASES in Lp(a) for those using niacin. Even in those in the highest Lp(a) quartile (> 125 nmol/L) there was no reduction in events when niacin was added.
So where do we stand with niacin? There is no level one evidence anywhere supporting the use of niacin to reduce clinical events: The Coronary Drug Project (CDP) is often quoted as proof of niacin’s efficacy but few realize that niacin monotherapy (high dose of immediate release preparation) had no impact on the primary endpoint of the study (mortality): thus the benefit of reducing non-fatal myocardial infarction (a secondary endpoint) makes this benefit hypothesis generating [6].Of course there is the famous 15 year follow up of CDP which encompassed 6 years of the trial where niacin was used and then a subsequent 9 year period off niacin. Mortality was significantly reduced in that post hoc analysis (data derived not from examination or in person review but questionnaires sent to participants): this is the weakest data imaginable [7]. So this supposedly late benefit of niacin is in fact analysis of post hoc follow data up from a trial where niacin failed to reduce the primary endpoint. If niacin was a new drug, it would have no prayer of gaining FDA approval based on the CDP. Several subsequent trials using angiographic or CIMT endpoints showed niacin monotherapy or combination with bile acid sequestrants or statins showed imaging benefit. One small (~500 patients) open-label outcome trial (Stockholm Ischemic Heart Disease Secondary Prevention Trial), combining clofibrate and IR niacin did reduce clinical events with statistical significance [8].
In my opinion niacin became a major lipid drug because of its ability to raise HDL-C and to lower Lp(a) and not for what is likely its real mechanism of action, namely lowering LDL-C and apoB and LDL-P. After extended-release niacin (Niaspan) hit the market, it was also heavily promoted because of its ability to increase both HDL and LDL size. KOS made a fortune by promulgating those messages as it seemingly made so much sense. Of course over time, we have learned that influencing LDL or HDL particle size or raising HDL-C and apoA-I has no effect on outcomes. Looking at lipid/lipoprotein risk factors in 2013 the outcome evidence only supports lowering apoB (LDL-P) or perhaps raising total HDL-P. At this time unfortunately, there is no support for reducing Lp(a) with niacin: admittedly the Lp(a) data from the much larger HPS THRIVE 2 study of 25,000 patients is pending.
So is niacin a dead drug? Here are my thoughts as a clinical lipidologist: We must get apoB (LDL-P) to goal in all at-risk patients. Lifestyle therapies and statins are the mainstay of therapy. However residual risk is high if apoB (LDL) remains elevated despite at-goal LDL-C, non-HDL-C), any level of HDL-C or if Lp(a) mass is elevated. So I would have no hesitancy in adding niacin to high and very high risk patients who have not achieved apoB (LDL-P) goals with whatever therapies they are using or using niacin as a monotherapy in those intolerant of other apoB lowering meds. Data from HPS THRIVE 2 (discussed in a recent commentary [ADD LINK]) suggested statin plus ezetimibe was better at event reduction than statin plus niacin [9]. In view of that and the very significant side effects reported in HPS THRIVE 2 [bleeding (GI, intracranial, other) in the niacin group: 326 (2.5%) to 238 (1.9%) and infection 1031(8%) to 853 (6.6%)] [3] makes niacin a tertiary or quaternary add-on drug (some may prefer the bile acid sequestrant colesevelam as an apoB lowering medication).
What about our patients with elevated Lp(a) mass or Lp(a)-P? The only therapy that has so far shown an inkling of success is LDL apheresis. For now we should all try to lower apoB (LDL-P as aggressively as possible and that often requires multiple combination therapies. What about future drugs: just published is the data the PCSK9 monoclonal antibody AMG 145 reduces Lp(a) by 32% in patients on statins [10]. There is also promising data that the remaining CETP inhibitors also reduce Lp(a) but the reality is that until such reductions by these drugs are linked to outcome benefit they are of hypothetical interest. Hopefully in the future there will also be development of an apoprotein (a) antisense oligonucleotide inhibitor.
References:
[2] The AIM-HIGH Investigators Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011;365:2255-67.
[3] Presentation by Jane Armitage on behalf of the HPS2 THRIVE group to the National Lipid Association Annual Scientific sessions, Las Vegas NV June 2013.
[6] Coronary Drug project group. Clofibrate and Niacin in Coronary Heart Disease. JAMA 1975;231:360-381.
[7] Fifteen Year Mortality in Coronary Drug Project Patients: Long Term Benefit with Niacin. JACC 1986;8:1245-55.
[8] Reduction of Mortality in the Stockholm Ischaemic Heart Disease Secondary prevention Study by Combined Treatment with Clofibrate and Nicotinic Acid. Acta Med Scand 1988;223:405-418.[9] Masana, A. Cabré, N. Plana. HPS2-THRIVE results: Bad for niacin/laropiprant, good for ezetimibe? Atherosclerosis 2013;229:449-450.
In 2013 we have already published two commentaries on niacin (Commentary on Niacin vs Ezetimibe as add on to Statin) and (Examination of the Recently Announced Preliminary Results of the HPS2-THRIVE Study), specifically extended release available as Niaspan, a seemingly potent lipid- and lipoprotein-modulating drug that dates back to the 1960’s. Initially it was used to reduce elevated cholesterol levels but eventually it was found to also raise HDL-C which for a variety of reasons was assumed to be very desirable (thought being that if low HDL-C is a strong CV risk factor, then raising it must be beneficial). Also of interest was niacin’s ability to significantly reduce lipoprotein (a) mass [Lp(a)]. Indeed, a group entitled European Atherosclerosis Society Consensus Panel issued a statement strongly advising niacin be used for CV benefits in patients with elevated Lp(a) [1]. Interestingly that panel noted there was virtually no clinical trial support for this recommendation other than the fact that niacin does indeed reduce Lp(a) mass. Most lipidologists agreed with the belief that even if reducing Lp(a) does not matter, niacin would at least reduce apolipoprotein B (apoB) which is seemingly always desirable. NCEP ATP-III simply advocated achieving LDL-C goals in persons with risk related to Lp(a) issues.
Recent trials [The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM HIGH) and large Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events (HPS THRIVE 2)] have not shown additional event reduction in well-treated patients with stable CHD related to adding niacin to a statin or statin/ezetimibe regimen [2,3]. To say the results of those studies were a shock to the lipidology community is an understatement. AIM HIGH (all of the patients had low HDL-C at baseline) was published first and for those who believed niacin’s benefit was related to raising HDL-C, the results were a punch to the jaw. Despite a substantial (25%) HDL-C increase (remember the old well accepted but never proven caveat that for every 1% rise in HDL-C there is a 3% event reduction) there was no CV outcome improvement. The usual side effects associated with niacin were present including a questionable nonsignificant rise in ischemic stroke. Then along came the still not published HPS THRIVE 2 (baseline HDL-C was not an enrollment criteria) where again the addition of niacin to a statin or statin/ezetimibe regimen provided no additional outcome benefit. Common to both AIM HIGH and HPS THRIVE 2 was the fact that the lifestyle with statin or statin/ezetimibe had normalized LDL-C, non-HDL-C and apoB. Thus niacin was being added to patients who were at those goals (keeping in mind that there is no NCEP ATP-III goal for HDL-C). Should we really have expected niacin, whose primary mechanism of action is to lower apoB (or its lipid surrogates) to do anything to CV events in persons with normal apoB? The answer is yes if raising HDL-C or lowering Lp(a) mass is critical to event reduction (well accepted concepts that have never ever been proven in any type of trial). Well we may have those answers now and at this point one has to reasonably conclude the evidence is strong that in patients on LDL-receptor inducing drugs (statins or statin + ezetimibe) raising HDL-C (note – niacin also raises apoA-I, but not apoA-II or total HDL-P) [4] or reducing Lp(a) mass with niacin provides no benefit in folks who are at apoB (LDL-C, non-HDL-C) goal.
References:
[2] The AIM-HIGH Investigators Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011;365:2255-67.
[3] Presentation by Jane Armitage on behalf of the HPS2 THRIVE group to the National Lipid Association Annual Scientific sessions, Las Vegas NV June 2013.
[6] Coronary Drug project group. Clofibrate and Niacin in Coronary Heart Disease. JAMA 1975;231:360-381.
[7] Fifteen Year Mortality in Coronary Drug Project Patients: Long Term Benefit with Niacin. JACC 1986;8:1245-55.
[8] Reduction of Mortality in the Stockholm Ischaemic Heart Disease Secondary prevention Study by Combined Treatment with Clofibrate and Nicotinic Acid. Acta Med Scand 1988;223:405-418.[9] Masana, A. Cabré, N. Plana. HPS2-THRIVE results: Bad for niacin/laropiprant, good for ezetimibe? Atherosclerosis 2013;229:449-450.
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Read the complete article here.
Friday, August 9, 2013
British Heart Foundation does not want to engage with the troubling science on sterols - Briffa
The medical director of the British Heart Foundation does not want to engage with the troubling science on sterols
Last month, I wrote a blog post about how there was no evidence that cholesterol-lowering ‘stanols’ and ‘sterols’ (found in some margarines and other ‘functional foods’) have benefits for health. In fact, the National Institute for Health and Care Excellence explicitly states that they should not be used. Yet, the British Heart Foundation (BHF) recommends the use of stanols and sterols, though I wondered if this might have something to do with the fact that one of its corporate partners is Flora pro.activ (a brand of sterol-enriched foods made by Unilever).
On the 17th July, I emailed the BHF about this. Here’s my email to them:
I think we deserve better to be honest. I genuinely believe that, based on the evidence, there is a case to answer regarding the health effects of sterols, and it’s simply not good enough for Professor Weissberg to dismiss the evidence based on rhetoric to do with, supposedly, the evidence being of ‘varying quality and validity’. This is true of all science, so is Professor Weissberg suggesting we just go back to the dark ages and believe what suits us?
How many people do you imagine look to the BHF as being a reliable and credible organisation dedicated to our heart health? Lots, I would imagine. How do you think they would feel to know that when legitimate concerns are raised about products they recommend (some of which are made by a company the BHF partners with), their medical director just flatly refuses to engage with the science?
There is absolutely no evidence that sterols benefit health, but it seems the BHF is going to recommend them anyway, even in light of significant evidence suggesting they have the potential for harm.
Professor Weissberg seems to claim that the BHF’s relationship with Unilever does not compromise them. In fact, Unilever is helping them raise awareness about the risk of cardiovascular disease in women! I wonder how many of these women will be concerned enough to put their faith in utterly bogus food products enriched with sterols?
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Read the complete article here.
On the 17th July, I emailed the BHF about this. Here’s my email to them:
The National Institute for Health and Care Excellence has this to say about dietary stanols and sterols: “People should not routinely be recommended to take plant sterols and stanols for the primary prevention of [cardiovascular disease].”
We are also advised by NICE that: “There is a need for trials to test both efficacy and effectiveness of plant sterols and stanols in people who are at high risk of a first CVD event.
These trials should test whether plant sterols or stanols change lipid profiles and reduce CVD events under best possible conditions. Randomised controlled trials are needed to test the effectiveness of advising people who are at high risk of experiencing a first CVD event to include food items containing plant sterols or stanols in a low-fat diet. The trial should last for at least 2 years and should consider appropriate outcomes.”
Yet, I notice that the BHF advocates stanols and sterols. Can someone explain the discrepancy, and whether the BHF believes the fact that Flora pro-avtiv is a corporate partner of represents a financial conflict of interest?
On the 30th July, I got a reply from Professor Peter Weissberg, the medical director of the BHF. Here are the highlights from his email:We are also advised by NICE that: “There is a need for trials to test both efficacy and effectiveness of plant sterols and stanols in people who are at high risk of a first CVD event.
These trials should test whether plant sterols or stanols change lipid profiles and reduce CVD events under best possible conditions. Randomised controlled trials are needed to test the effectiveness of advising people who are at high risk of experiencing a first CVD event to include food items containing plant sterols or stanols in a low-fat diet. The trial should last for at least 2 years and should consider appropriate outcomes.”
Yet, I notice that the BHF advocates stanols and sterols. Can someone explain the discrepancy, and whether the BHF believes the fact that Flora pro-avtiv is a corporate partner of represents a financial conflict of interest?
- They are not suggesting that plant sterols/stanols can prevent a heart attack
- They do help to reduce LDL cholesterol, which is a risk factor for heart disease
- Their information reflects this and has not been altered by their fundraising partnership with Flora pro.activ.
- The BHF has a very clear set of principles on the basis of which they work with commercial organisations.
- The amount of money they take from Flora pro.activ is a tiny percentage of their overall budget.
Dear Professor Weissberg
Thank you for getting back to me.
As you allude to, sterols/stanols have never been demonstrated to have clinical benefit, and it appears your support of them rests on their ability to reduce LDL-cholesterol levels (which you say is a risk factor for heart disease). Unfortunately, as I’m sure you’ll know, reduction of LDL-cholesterol most certainly does not assure clinical benefit. Ezetimibe – which has a similar mechanism of action to sterols/stanols – is a case in point.
Also, if arsenic and cyanide were found to be effective LDL-cholesterol reducing agents, it still would not make sense to recommend them for people for the reduction of cardiovascular disease risk, right?
The reason that I use this example is because, as you may know, there is a considerable body of evidence which suggests that sterols/stanols may have adverse effects on health. These are very well summarized in a paper published in the European Heart Journal in 2009 [Weingartner O, et al Controversial role of plant sterol esters in the management of hypercholesterolaemia. Europlean Heart Journal 2009;30:404-409]. If you have not already read it, I urge you to.
In this paper, the authors cite evidence linking the presence of sterols in the blood with an increased risk of cardiovascular disease. For example:
…there is evidence that elevated levels of plant sterols are associated with an increased cardiovascular risk. Glueck et al [Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives. Metabolism 1991;40:842–848] were the first to report that elevated plant sterols might be a risk factor for coronary heart disease. In a study with 595 hypercholesterolaemic patients, they found that slightly elevated plasma levels of plant sterols were a heritable marker for an increased cardiovascular risk.
Rajaratnam et al [Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol 2000;35:1185–1191]…found that in postmenopausal women, plant sterols were independently associated with coronary heart disease in a multivariate analysis. These findings were confirmed by Sutherland and his team in a study involving both sexes over all age groups [Association of plasma noncholesterol sterol levels with severity of coronary heart disease. Nutr Metab Cardiovasc Dis 1998;8:386–391].
The Scandinavian Simvastatin Survey Study (4S study) also identified a subpopulation of coronary artery disease patients with low endogenous synthesis of cholesterol and high absorption of cholesterol and plant sterols. The subjects of this subpopulation had the highest levels of plant sterols and the highest risk of recurrent coronary events despite lower levels of serum cholesterol due to simvastatin ingestion [Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ 1998;316:1127–1130]
Larger epidemiological studies reported similar data. Results of the PROCAM-study showed that patients afflicted with myocardial infarction or sudden cardiac death had increased plant sterol concentrations [Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case-control analysis of the Prospective Cardiovascular Munster (PROCAM) study. Nutr Metab Cardiovasc Dis 2006;16:13–21]. Upper normal levels of plant sterols were associated with a three-fold increase of risk for coronary events among men in the highest tertile of coronary risk according to the PROCAM-algorithm.
Similar data are available for the plant sterol campesterol from the MONICA/KORA-study. In this prospective study, campesterol correlated directly with the incidence of acute myocardial infarction [Abstract 4099: elevated campesterol serum levels–a significant predictor of incident myocardial infarction: results of the population-based MONICA/KORA follow-up study 1994–2005. Circulation 2006;114:II_884].
This is all epidemiological evidence, of course, but it supported by several animal, in vitro and clinical experiments that, I think, give us genuine cause for concern. Again, from the European Heart Journal paper [Weingartner O, et al Controversial role of plant sterol esters in the management of hypercholesterolaemia. Europlean Heart Journal 2009;30:404-409]:
Current experimental findings from our own research group show that a diet supplementation with plant sterol esters that is equivalent to a commercially available spread induces endothelial dysfunction and leads to an increase of ischaemic stroke size in wild-type mice [Vascular effects of diet supplementation with plant sterols. J Am Coll Cardiol 2008;51:1553–1561].
…in a clinical study, we demonstrated that patients who were consuming plant sterol ester enriched margarine had increased concentrations of plant sterols in cardiovascular tissue [Vascular effects of diet supplementation with plant sterols. J Am Coll Cardiol 2008;51:1553–1561].
Further mechanistic data suggest that vascular deposits of sterols, when compared with cholesterol, result in increased oxidation and release of oxygen radicals [Oxidized plant sterols in human serum and lipid infusions as measured by combined gas-liquid chromatography-mass spectrometry. J Lipid Res 2001;42:2030–2038].
…the induction of apoptosis is not limited to tumour cells, but extends also to vascular cells. Recent in vitro experiments demonstrated that the plant sterol sitosterol exerts a strong cytotoxic propensity inducing apoptosis in human endothelial cells, revealing detrimental effects on the vasculature [Beneficial or harmful influence of phytosterols on human cells? Br J Nutr 2008;100:1183–1191].
In fact, the first experimental study reporting negative cardiovascular effects dates back to the year 2000. Ratnayake et al. [Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr 2000;130:1166–1178 reported that increased serum levels of plant sterols increase rigidity of erythrocytes and shorten the life span of stroke-prone spontaneously hypertensive (SHRSP) rats.
These findings were the reason for Health Canada, the federal department responsible for helping Canadians maintain and improve their health, to raise significant safety issues and not to allow functional foods enriched with plant sterol esters to be sold in Canada.
I am sure you must be very busy, but please take some time to consider this evidence. From what I can see from the research, we have no evidence at all that sterols/stanols improve clinical outcomes, and considerable evidence linking them with potential for harm. Until we have positive evidence regarding outcomes, wouldn’t the most prudent and safety-conscious thing be to not recommend sterols/stanols (as NICE does)?
Thank you for your explanation regarding your corporate partners. If the funds derived from this relationship are so low, why not sever the link and have no conflict of interest at all, here?
I look forward to hearing from you.
Kind regards
John Briffa
On the 6th August, I got this response from Professor Weissberg:Thank you for getting back to me.
As you allude to, sterols/stanols have never been demonstrated to have clinical benefit, and it appears your support of them rests on their ability to reduce LDL-cholesterol levels (which you say is a risk factor for heart disease). Unfortunately, as I’m sure you’ll know, reduction of LDL-cholesterol most certainly does not assure clinical benefit. Ezetimibe – which has a similar mechanism of action to sterols/stanols – is a case in point.
Also, if arsenic and cyanide were found to be effective LDL-cholesterol reducing agents, it still would not make sense to recommend them for people for the reduction of cardiovascular disease risk, right?
The reason that I use this example is because, as you may know, there is a considerable body of evidence which suggests that sterols/stanols may have adverse effects on health. These are very well summarized in a paper published in the European Heart Journal in 2009 [Weingartner O, et al Controversial role of plant sterol esters in the management of hypercholesterolaemia. Europlean Heart Journal 2009;30:404-409]. If you have not already read it, I urge you to.
In this paper, the authors cite evidence linking the presence of sterols in the blood with an increased risk of cardiovascular disease. For example:
…there is evidence that elevated levels of plant sterols are associated with an increased cardiovascular risk. Glueck et al [Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives. Metabolism 1991;40:842–848] were the first to report that elevated plant sterols might be a risk factor for coronary heart disease. In a study with 595 hypercholesterolaemic patients, they found that slightly elevated plasma levels of plant sterols were a heritable marker for an increased cardiovascular risk.
Rajaratnam et al [Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol 2000;35:1185–1191]…found that in postmenopausal women, plant sterols were independently associated with coronary heart disease in a multivariate analysis. These findings were confirmed by Sutherland and his team in a study involving both sexes over all age groups [Association of plasma noncholesterol sterol levels with severity of coronary heart disease. Nutr Metab Cardiovasc Dis 1998;8:386–391].
The Scandinavian Simvastatin Survey Study (4S study) also identified a subpopulation of coronary artery disease patients with low endogenous synthesis of cholesterol and high absorption of cholesterol and plant sterols. The subjects of this subpopulation had the highest levels of plant sterols and the highest risk of recurrent coronary events despite lower levels of serum cholesterol due to simvastatin ingestion [Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators. BMJ 1998;316:1127–1130]
Larger epidemiological studies reported similar data. Results of the PROCAM-study showed that patients afflicted with myocardial infarction or sudden cardiac death had increased plant sterol concentrations [Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case-control analysis of the Prospective Cardiovascular Munster (PROCAM) study. Nutr Metab Cardiovasc Dis 2006;16:13–21]. Upper normal levels of plant sterols were associated with a three-fold increase of risk for coronary events among men in the highest tertile of coronary risk according to the PROCAM-algorithm.
Similar data are available for the plant sterol campesterol from the MONICA/KORA-study. In this prospective study, campesterol correlated directly with the incidence of acute myocardial infarction [Abstract 4099: elevated campesterol serum levels–a significant predictor of incident myocardial infarction: results of the population-based MONICA/KORA follow-up study 1994–2005. Circulation 2006;114:II_884].
This is all epidemiological evidence, of course, but it supported by several animal, in vitro and clinical experiments that, I think, give us genuine cause for concern. Again, from the European Heart Journal paper [Weingartner O, et al Controversial role of plant sterol esters in the management of hypercholesterolaemia. Europlean Heart Journal 2009;30:404-409]:
Current experimental findings from our own research group show that a diet supplementation with plant sterol esters that is equivalent to a commercially available spread induces endothelial dysfunction and leads to an increase of ischaemic stroke size in wild-type mice [Vascular effects of diet supplementation with plant sterols. J Am Coll Cardiol 2008;51:1553–1561].
…in a clinical study, we demonstrated that patients who were consuming plant sterol ester enriched margarine had increased concentrations of plant sterols in cardiovascular tissue [Vascular effects of diet supplementation with plant sterols. J Am Coll Cardiol 2008;51:1553–1561].
Further mechanistic data suggest that vascular deposits of sterols, when compared with cholesterol, result in increased oxidation and release of oxygen radicals [Oxidized plant sterols in human serum and lipid infusions as measured by combined gas-liquid chromatography-mass spectrometry. J Lipid Res 2001;42:2030–2038].
…the induction of apoptosis is not limited to tumour cells, but extends also to vascular cells. Recent in vitro experiments demonstrated that the plant sterol sitosterol exerts a strong cytotoxic propensity inducing apoptosis in human endothelial cells, revealing detrimental effects on the vasculature [Beneficial or harmful influence of phytosterols on human cells? Br J Nutr 2008;100:1183–1191].
In fact, the first experimental study reporting negative cardiovascular effects dates back to the year 2000. Ratnayake et al. [Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats. J Nutr 2000;130:1166–1178 reported that increased serum levels of plant sterols increase rigidity of erythrocytes and shorten the life span of stroke-prone spontaneously hypertensive (SHRSP) rats.
These findings were the reason for Health Canada, the federal department responsible for helping Canadians maintain and improve their health, to raise significant safety issues and not to allow functional foods enriched with plant sterol esters to be sold in Canada.
I am sure you must be very busy, but please take some time to consider this evidence. From what I can see from the research, we have no evidence at all that sterols/stanols improve clinical outcomes, and considerable evidence linking them with potential for harm. Until we have positive evidence regarding outcomes, wouldn’t the most prudent and safety-conscious thing be to not recommend sterols/stanols (as NICE does)?
Thank you for your explanation regarding your corporate partners. If the funds derived from this relationship are so low, why not sever the link and have no conflict of interest at all, here?
I look forward to hearing from you.
Kind regards
John Briffa
Dear Dr Briffa
Thank you for your further email on this subject. I am aware of a large number of publications, of varying quality and validity, on the subject of plant stanols and sterols and their potential benefits and harms. I would prefer not to enter into a debate on any one of them since they all have their strengths and weaknesses.
So, as with so much in science, interpretation of the data is not as straightforward as is sometimes presented. Nevertheless, we are agreed that, ideally, one would like to see appropriately designed outcome trials to test their role in protection against cardiovascular events. In the absence of such data (and I doubt they will ever be produced), it is a matter of judgement as to whether or not plant stanols should be included as part of a wider strategy to reduce cardiovascular risk, and different national bodies have come to different conclusions.
In drawing this correspondence to a close I would conclude by saying that the BHF only enters into partnerships after careful consideration of all the pros and cons of so doing. As discussed previously, the main objective of the partnership with Unilever is to utilise their considerable reach to help us highlight the risk of CVD to women.
I thank you for your interest in this project and assure you we take seriously all feedback we receive.
Yours
Notice here how Professor Weissberg makes no comment at all on the specifics of the studies, nor puts up one scrap of evidence to refute the concerns raised. And what are we to glean from his writing: “In drawing this correspondence to a close…” To me, that gives the impression Professor Weissberg wants to hear no more from me (or perhaps anyone else) on the matter. Case closed!Thank you for your further email on this subject. I am aware of a large number of publications, of varying quality and validity, on the subject of plant stanols and sterols and their potential benefits and harms. I would prefer not to enter into a debate on any one of them since they all have their strengths and weaknesses.
So, as with so much in science, interpretation of the data is not as straightforward as is sometimes presented. Nevertheless, we are agreed that, ideally, one would like to see appropriately designed outcome trials to test their role in protection against cardiovascular events. In the absence of such data (and I doubt they will ever be produced), it is a matter of judgement as to whether or not plant stanols should be included as part of a wider strategy to reduce cardiovascular risk, and different national bodies have come to different conclusions.
In drawing this correspondence to a close I would conclude by saying that the BHF only enters into partnerships after careful consideration of all the pros and cons of so doing. As discussed previously, the main objective of the partnership with Unilever is to utilise their considerable reach to help us highlight the risk of CVD to women.
I thank you for your interest in this project and assure you we take seriously all feedback we receive.
Yours
I think we deserve better to be honest. I genuinely believe that, based on the evidence, there is a case to answer regarding the health effects of sterols, and it’s simply not good enough for Professor Weissberg to dismiss the evidence based on rhetoric to do with, supposedly, the evidence being of ‘varying quality and validity’. This is true of all science, so is Professor Weissberg suggesting we just go back to the dark ages and believe what suits us?
How many people do you imagine look to the BHF as being a reliable and credible organisation dedicated to our heart health? Lots, I would imagine. How do you think they would feel to know that when legitimate concerns are raised about products they recommend (some of which are made by a company the BHF partners with), their medical director just flatly refuses to engage with the science?
There is absolutely no evidence that sterols benefit health, but it seems the BHF is going to recommend them anyway, even in light of significant evidence suggesting they have the potential for harm.
Professor Weissberg seems to claim that the BHF’s relationship with Unilever does not compromise them. In fact, Unilever is helping them raise awareness about the risk of cardiovascular disease in women! I wonder how many of these women will be concerned enough to put their faith in utterly bogus food products enriched with sterols?
============================================================
Read the complete article here.
Wednesday, May 8, 2013
Licence for another unproven cholesterol drug - Briffa
The FDA grants licence for another unproven cholesterol drug
Ezetimibe is a drug that lowers cholesterol levels by blocking its absorption from the gut. The drug is available under the brand name Zetia. Doctors can also prescribe ezetimibe in combination with the statin drug simvastatin. This combination medication is sold under the name Vytorin. Both Zetia and Vytorin have racked up billions of dollars in sales. What a shame, then, that neither of them has been found to have any benefit at all in terms of reducing the risk of heart disease, heart attacks, strokes or risk of death.
Zetia and Vytorin are licenced on the basis of their impact on cholesterol levels. The thinking is that LDL-cholesterol must be bad, so anything that reduces it must be good. However, we know from experience that many things that ‘improve’ cholesterol do not bring broad benefits to health. And besides, it’s simply not good science or medicine to assume that a drug has benefits for health based on its impact on what is known as a ‘surrogate marker’ such as cholesterol. I mean, if arsenic reduced cholesterol it still would not make sense for us to swig back arsenic each day, would it?
This seems like perhaps an extreme analogy, but it should be borne in mind, I think, the Vytorin use has in some studies been associated with an increase (not statistically significant) in the thickening of the arteries compared to simvastatin alone. Also, there was some early evidence the Vytorin increased the risk of death from cancer, though some more recent evidence is said to have allayed fears here.
While some doctors continue to prescribe Zetia and Vytorin it’s difficult (for me) to justify this. There is some evidence that since 2008 (when we saw the first of a few negative studies on Zetia/Vytorin emerge) sales of these drugs have fallen considerably, though profit remains considerable. Make no mistake, though, the fact that Zeta/Vytorin is still on the market and was licensed in the first place is seen by some doctors and researchers as testament to the ability of drug companies to bamboozle regulatory authorities such as the Food and Drugs Administration (FDA) in the US. Either that, or the FDA is perhaps putting the needs of drug companies above those of patients.
Against this background, it is interesting to note that Merck (manufacturer of Vytorin) has been for some years attempting to get another similar drug combination passed by the FDA. The drug combines ezetimibe with the statin atorvastatin and has the brand name Liptruzet. As with Vytorin, there exists no evidence that Liptruzet benefits so-called ‘clinical’ outcomes such as incidence of heart disease and stroke.
Now, given all the controversy around Vytorin and the lack of evidence for the benefit of this product, you might imagine the FDA would be keen not to repeat its mistake by granting Liptruzet a licence. Astonishingly, though, the FDA did just this last week.
Now, normally, when a new drug hits the market the press reports parrot the drug company rhetoric about, say, the benefits of the drug and the lives it could save. What is interesting about the press reports on the licensing of Liptruzet is how many of them report scepticism regarding the wisdom of this decision expressed by doctors and researchers. See here for an example.
The piece quotes Steven Nissen, chairman of cardiology at the Cleveland Clinic in the US. According to Dr Nissen, the FDA’s decision to approve the Liptruzet “just doesn’t make any sense.” He is quoted as saying:
Merck can be confident all it likes in ezetimibe and its products Zetia, Vytorin and Liptruzet, but the fact is, none of these have been shown to lower ‘cardiovascular events’. My personal opinion is that either Merck is full of idiots or is taking us for idiots. The good news is that the sort of rhetoric spouted by Merck is immediately being recognised by some as having a distinct whiff of b.s. about it.
================================================================
Reaqd complete article here.
Zetia and Vytorin are licenced on the basis of their impact on cholesterol levels. The thinking is that LDL-cholesterol must be bad, so anything that reduces it must be good. However, we know from experience that many things that ‘improve’ cholesterol do not bring broad benefits to health. And besides, it’s simply not good science or medicine to assume that a drug has benefits for health based on its impact on what is known as a ‘surrogate marker’ such as cholesterol. I mean, if arsenic reduced cholesterol it still would not make sense for us to swig back arsenic each day, would it?
This seems like perhaps an extreme analogy, but it should be borne in mind, I think, the Vytorin use has in some studies been associated with an increase (not statistically significant) in the thickening of the arteries compared to simvastatin alone. Also, there was some early evidence the Vytorin increased the risk of death from cancer, though some more recent evidence is said to have allayed fears here.
While some doctors continue to prescribe Zetia and Vytorin it’s difficult (for me) to justify this. There is some evidence that since 2008 (when we saw the first of a few negative studies on Zetia/Vytorin emerge) sales of these drugs have fallen considerably, though profit remains considerable. Make no mistake, though, the fact that Zeta/Vytorin is still on the market and was licensed in the first place is seen by some doctors and researchers as testament to the ability of drug companies to bamboozle regulatory authorities such as the Food and Drugs Administration (FDA) in the US. Either that, or the FDA is perhaps putting the needs of drug companies above those of patients.
Against this background, it is interesting to note that Merck (manufacturer of Vytorin) has been for some years attempting to get another similar drug combination passed by the FDA. The drug combines ezetimibe with the statin atorvastatin and has the brand name Liptruzet. As with Vytorin, there exists no evidence that Liptruzet benefits so-called ‘clinical’ outcomes such as incidence of heart disease and stroke.
Now, given all the controversy around Vytorin and the lack of evidence for the benefit of this product, you might imagine the FDA would be keen not to repeat its mistake by granting Liptruzet a licence. Astonishingly, though, the FDA did just this last week.
Now, normally, when a new drug hits the market the press reports parrot the drug company rhetoric about, say, the benefits of the drug and the lives it could save. What is interesting about the press reports on the licensing of Liptruzet is how many of them report scepticism regarding the wisdom of this decision expressed by doctors and researchers. See here for an example.
The piece quotes Steven Nissen, chairman of cardiology at the Cleveland Clinic in the US. According to Dr Nissen, the FDA’s decision to approve the Liptruzet “just doesn’t make any sense.” He is quoted as saying:
I find it astonishing that after all the controversy about ezetimibe the FDA would approve another combination product with a drug that has been on the market for a decade and has not been shown to improve cardiovascular outcomes. It seems like the agency is just tone deaf to the concerns raised by many members of the community about approving drugs with surrogate endpoints like cholesterol without evidence of a benefit for the disease we are truly trying to treat – cardiovascular disease.And what does Merck have to say for itself? According to spokeswoman Pamela Eisele, Merck is “confident in ezetimibe and in the established relationship between lowering LDL cholesterol and reducing cardiovascular events.”
Merck can be confident all it likes in ezetimibe and its products Zetia, Vytorin and Liptruzet, but the fact is, none of these have been shown to lower ‘cardiovascular events’. My personal opinion is that either Merck is full of idiots or is taking us for idiots. The good news is that the sort of rhetoric spouted by Merck is immediately being recognised by some as having a distinct whiff of b.s. about it.
================================================================
Reaqd complete article here.
Sunday, May 5, 2013
Fears of cancer link to statin - AB Rossebo,
Scientists raise fears of cancer link to statin used by thousands
This post includes
a synopsis of a study published in the New England Journal of Medicine
September 25, 2008; 359(13): 1343-56 and a recipe for roccoli, bacon and nut
salad.
Study title and authors:
Study title and authors:
Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.
AB Rossebo, TR Pedersen, K Boman, P Brudi, JB Chambers, K Egstrup, E Gerdts, C Gohlke-Barwolf, I Holme, YA Kesaniemi, W Malbecq, CA Nienaber, S Ray, T Skjaerpe, K Wachtell, R Willenheimer, and SEAS Investigators Division of Cardiology, Aker University Hospital, Trondheimsveien 235, N-0514 Oslo, Norway.
This study can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/18765433
This trial observed the effects of the drug
Inegy (a combination of simvastatin and ezetimibe).
The trial was a 
randomizsd, double-blind trial involving 1,873 patients with
mild-to-moderate, asymptomatic aortic stenosis (obstruction of blood flow across
the aortic valve). The patients received either 40 mg of simvastatin plus 10 mg
of ezetimibe or placebo daily and were followed for 52 months.
The study found:
The trial was a randomizsd, double-blind trial involving 1,873 patients with
mild-to-moderate, asymptomatic aortic stenosis (obstruction of blood flow across
the aortic valve). The patients received either 40 mg of simvastatin plus 10 mg
of ezetimibe or placebo daily and were followed for 52 months.The study found:
(a) Those taking the simvastatin/ezetimibe combination had a 4% increased risk of death compared to those taking placebo.
(b) Those taking the simvastatin/ezetimibe combination had a 21% increased risk of death from heart failure compared to those taking placebo.
(c) Those taking the simvastatin/ezetimibe combination had a 67% increased risk of death from cancer compared to those taking placebo.
(d) Those taking the simvastatin/ezetimibe combination had a 195% increased risk of death from violence or accidents compared to those taking placebo.
Professor Heinz Drexel, of the University of Innsbruck in Austria and spokesman for the European Society of Cardiology, said: "I am not sure that the efficacy is proven and I am not sure that the safety is proven. I wouldn't take the drug myself".
In Britain, about 300,000 NHS prescriptions have been dispensed for Inegy in the last two years.
==================================================================
Read the complete article here.
Friday, November 2, 2012
New cholesterol-lowering drug is licensed despite no evidence of benefits for health - Briffa
Another new cholesterol-lowering drug is licensed despite no evidence of benefits for health
I was reading here that there’s a new cholesterol-lowering drug in the pipeline. The Food and Drugs Administration in the US has approved the injectable agent mipomersen for the treatment of ‘homozygous familial hypercholesterolaemia – a genetic cause of raised cholesterol levels associated with cardiovascular disease developing early in life. Mipomersen has been shown to reduce low density lipoprotein (LDL) levels by about a quarter. The hope is that this will help reduce the risk of individuals suffering premature death from, most likely, heart attack.
I’ve used the word ‘hope’ in the preceding sentence but, in reality, the FDA panel that has ratified mipomersen has no idea whether it has health benefits or not. That’s because the studies used to assess this drug were not large enough in scope to detect change in ‘clinical endpoints’ such as risk of heart attack or death. In other words, the licensing of this drug has been on the basis of its impact on ‘surrogate endpoints’ (in this case, cholesterol levels), rather than clinical endpoints (the thing that really matters).
And I’m not splitting hairs either, as we already have examples in the not-too distant past of drugs that promised a lot in terms of their impact on cholesterol, but failed to deliver in terms of actual health. For example, the drug ezetimibe is a proven cholesterol-lowerer, yet not one single study to dates demonstrates it has benefits in terms of clinical endpoints. Also, the drug torcetrapib looked at one time to be a new hero of cholesterol management, until appropriately designed studies found it was killing people (it’s since been dropped).
But the principle that something that benefits cholesterol does not necessarily benefit health does seem to have been somewhat lost on the FDA. And worse still, it seems the panel may have put their faith in cholesterol modification above some quite troubling data. Here you can read how the FDA’s own review of mipomersen revealed a number of concerns about this drug. Here’s an excerpt from the article:
The FDA panel’s vote on mipomersen was relatively close (9 v 6), so at least some members of the panel had their doubts. It is said that the severe nature of homozygous familial hypercholesterolaemia was a major determining factor in swaying the vote. That’s laudable, perhaps, but I don’t think it excuses the fact that this drug has been licensed despite an absence of data that it benefits health, as well as the presence of data which points very much in the opposite direction.
====================================================================
Read the complete article here.
I was reading here that there’s a new cholesterol-lowering drug in the pipeline. The Food and Drugs Administration in the US has approved the injectable agent mipomersen for the treatment of ‘homozygous familial hypercholesterolaemia – a genetic cause of raised cholesterol levels associated with cardiovascular disease developing early in life. Mipomersen has been shown to reduce low density lipoprotein (LDL) levels by about a quarter. The hope is that this will help reduce the risk of individuals suffering premature death from, most likely, heart attack.
I’ve used the word ‘hope’ in the preceding sentence but, in reality, the FDA panel that has ratified mipomersen has no idea whether it has health benefits or not. That’s because the studies used to assess this drug were not large enough in scope to detect change in ‘clinical endpoints’ such as risk of heart attack or death. In other words, the licensing of this drug has been on the basis of its impact on ‘surrogate endpoints’ (in this case, cholesterol levels), rather than clinical endpoints (the thing that really matters).
And I’m not splitting hairs either, as we already have examples in the not-too distant past of drugs that promised a lot in terms of their impact on cholesterol, but failed to deliver in terms of actual health. For example, the drug ezetimibe is a proven cholesterol-lowerer, yet not one single study to dates demonstrates it has benefits in terms of clinical endpoints. Also, the drug torcetrapib looked at one time to be a new hero of cholesterol management, until appropriately designed studies found it was killing people (it’s since been dropped).
But the principle that something that benefits cholesterol does not necessarily benefit health does seem to have been somewhat lost on the FDA. And worse still, it seems the panel may have put their faith in cholesterol modification above some quite troubling data. Here you can read how the FDA’s own review of mipomersen revealed a number of concerns about this drug. Here’s an excerpt from the article:
Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”Other concerns were raised by the finding that mipomersen increased the levels of ‘liver enzymes’ and increased the amount of fat in the liver (both signs of damage to the liver). Here’s another except:
The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.And perhaps worse still, there’s even concern that mipomersen might have cancer-inducing potential:
According to the review, during clinical testing neoplasms, both benign and malignant, were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that ”there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”Forgive me, but personally I detect a hint of ‘sweeping the issue under the carpet’ here. The same thing, by the way, happened with ezetimibe, which has been shown to increase the risk of death from cancer, an effect which researchers put down to chance (even though the effect was statistically significant and therefore highly unlikely to be due to chance). See here for more about this.
The FDA panel’s vote on mipomersen was relatively close (9 v 6), so at least some members of the panel had their doubts. It is said that the severe nature of homozygous familial hypercholesterolaemia was a major determining factor in swaying the vote. That’s laudable, perhaps, but I don’t think it excuses the fact that this drug has been licensed despite an absence of data that it benefits health, as well as the presence of data which points very much in the opposite direction.
====================================================================
Read the complete article here.
Friday, August 24, 2012
Academic takes a well-aimed swipe at cholesterol drug ezetimibe - Briffa
Academic takes a well-aimed swipe at cholesterol drug ezetimibe
Aug, Fri 24th, 2012 By : Dr John Briffa
I am not particularly enthusiastic about cholesterol management. I don’t believe that the role cholesterol has in cardiovascular disease is as is popularly stated. But more importantly, when we use drugs to manage cholesterol the results are, by and large, disappointing. For example, treatment with statins does not save lives in people without a prior history of heart attack or stroke. Even in people at higher risk of cardiovascular disease, the great majority of treated individuals over a few years will not benefit. And then we have the problems of side effects.
The popularity of cholesterol management strategies in many way hinges on the idea that (LDL) cholesterol is bad, and lowering it is good. Yet, the scientific literature is littered with evidence that does not support either of these contentions. For example, we have evidence linking higher cholesterol levels with improved health outcomes and longevity in the elderly. We also have plenty of evidence which shows that cholesterol reduction will not always benefit health, and may in fact pose hazards here.
A case in point here concerns the drug ezetimibe. This medication reduces cholesterol, but unlike statins (which reduce cholesterol production in the liver), ezetimibe blocks the absorption of cholesterol from the gut. It’s generally very effective at reducing cholesterol levels, and because of this, the Food and Drugs Administration (FDA) licensed ezetimibe for use in the treatment of raised cholesterol in 2002. Since then, ezetimibe has gone to rack up sales in the order of $4 billion dollars annually.
Ezetimibe was licensed on the basis of its ability to lower cholesterol. At this time, no study has been published that it had benefits on health. So, what’s happened since? Well, there’s been a few studies that have looked at ‘clinical’ endpoints or disease processes (such as the build-up of plaque in the arteries), and the results have been far from encouraging.
For example, 2008 saw the publication of the so-called ENHANCE study which found that adding ezetimibe to simvastatin (a statin) led to an increase in the thickness of artery walls in the neck compared to simvastatin alone (though the difference was not statistically significant). The results of this trial were delayed by 2 years and had to be forced out of the manufacturers by the US Government.
Other studies have not only found no benefit, they’ve revealed worsening outcomes. In one study, treatment with ezetimibe was associated with (statistically significant) worsening of the narrowing of the arteries in the legs [1]. And then we have the inconvenience of the trials which link ezetimibe use to an increased risk of dying from cancer [2], which some researchers (in the pay of ezetimibe’s manufacturers) put down to ‘chance’, even though the data shows that the association is highly unlikely to be due to chance, and in all likelihood is a real effect.
Casual conversations with members of the medical profession reveal to me that the issues with ezetimibe are largely unrecognised, though there have been signs in the scientific literature that we are at last seeing some awareness of the issues. I came across a piece published recently in the journal Expert Opinion in Pharmcotherapy written by Dr Sheila Doggrell of the University of Queensland in Australia [3]. Dr Goggrell has reviewed the evidence and concludes this:
“…ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes and should not be used routinely in everyday practice.”
It is perhaps relevant that Dr Doggrell is an academic, which perhaps gives her the tools to take a cool hard look at the data and come to her own conclusions. Despite not being a clinician she is acutely aware that the only important thing is the impact ezetimibe has on health (not cholesterol levels). It’s an approach that I think more clinicians could do with adopting.
References:
1. West AM, et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis. 2011;218(1):156-62
2. Peto R, et al. Analyses of cancer data from three ezetimibe trials. NEJM 2008;359(13):1357-66
3. Doggrell SA. The ezetimibe controversy – can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin Pharmacotherapy 2012;13(10):1469-80
==========================================================================================================
Emphasis of bold text added by me - bd. Read thecomplete article here.
The popularity of cholesterol management strategies in many way hinges on the idea that (LDL) cholesterol is bad, and lowering it is good. Yet, the scientific literature is littered with evidence that does not support either of these contentions. For example, we have evidence linking higher cholesterol levels with improved health outcomes and longevity in the elderly. We also have plenty of evidence which shows that cholesterol reduction will not always benefit health, and may in fact pose hazards here.
A case in point here concerns the drug ezetimibe. This medication reduces cholesterol, but unlike statins (which reduce cholesterol production in the liver), ezetimibe blocks the absorption of cholesterol from the gut. It’s generally very effective at reducing cholesterol levels, and because of this, the Food and Drugs Administration (FDA) licensed ezetimibe for use in the treatment of raised cholesterol in 2002. Since then, ezetimibe has gone to rack up sales in the order of $4 billion dollars annually.
Ezetimibe was licensed on the basis of its ability to lower cholesterol. At this time, no study has been published that it had benefits on health. So, what’s happened since? Well, there’s been a few studies that have looked at ‘clinical’ endpoints or disease processes (such as the build-up of plaque in the arteries), and the results have been far from encouraging.
For example, 2008 saw the publication of the so-called ENHANCE study which found that adding ezetimibe to simvastatin (a statin) led to an increase in the thickness of artery walls in the neck compared to simvastatin alone (though the difference was not statistically significant). The results of this trial were delayed by 2 years and had to be forced out of the manufacturers by the US Government.
Other studies have not only found no benefit, they’ve revealed worsening outcomes. In one study, treatment with ezetimibe was associated with (statistically significant) worsening of the narrowing of the arteries in the legs [1]. And then we have the inconvenience of the trials which link ezetimibe use to an increased risk of dying from cancer [2], which some researchers (in the pay of ezetimibe’s manufacturers) put down to ‘chance’, even though the data shows that the association is highly unlikely to be due to chance, and in all likelihood is a real effect.
Casual conversations with members of the medical profession reveal to me that the issues with ezetimibe are largely unrecognised, though there have been signs in the scientific literature that we are at last seeing some awareness of the issues. I came across a piece published recently in the journal Expert Opinion in Pharmcotherapy written by Dr Sheila Doggrell of the University of Queensland in Australia [3]. Dr Goggrell has reviewed the evidence and concludes this:
“…ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes and should not be used routinely in everyday practice.”
It is perhaps relevant that Dr Doggrell is an academic, which perhaps gives her the tools to take a cool hard look at the data and come to her own conclusions. Despite not being a clinician she is acutely aware that the only important thing is the impact ezetimibe has on health (not cholesterol levels). It’s an approach that I think more clinicians could do with adopting.
References:
1. West AM, et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis. 2011;218(1):156-62
2. Peto R, et al. Analyses of cancer data from three ezetimibe trials. NEJM 2008;359(13):1357-66
3. Doggrell SA. The ezetimibe controversy – can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin Pharmacotherapy 2012;13(10):1469-80
==========================================================================================================
Emphasis of bold text added by me - bd. Read thecomplete article here.
Friday, July 20, 2012
The Polypill has never been proven to benefit anyone - Briffa
It’s easy to fall for the polypill hype, but the reality is this medication has never been proven to benefit anyone
There’s been a ton of press over the last couple of days regarding a study of what is termed the ‘polypill’ – a combination medication conceived more than a decade ago with, supposedly, the prevention of heart disease and stroke in mind. The original ‘formulation’ combined blood pressure- and cholesterol-lowering medications, along with aspirin and vitamin B12. From time to time in the scientific literature we have seen studies which purport to support the idea of polypill taking for disease prevention. And the latest of these was published this week. Here, in short, is the study design and what it showed. After that, I’ll offer my own interpretation of the data.
This latest study tested the impact of a polypill comprising the following drugs:
Individuals were selected for the study on the basis of two criteria:
But here’s the thing: this study simply can’t be used to judge whether the polypill prevent cardiovascular disease and delays death. These ideas are based on speculation based on the idea that lowering blood pressure and cholesterol translates into significant benefits for health. Yet, as I explored most recently here and here, blood pressure and statin medications are generally very ineffective for the purposes of disease prevention and preventing death. Most people who take these drugs just won’t benefit.
This is particularly the case when individuals are deemed to be at low risk of cardiovascular disease. Normally, medication is prescribed on the basis of, say, blood pressure or cholesterol levels. But not in this study: here people were selected on the basis of age, irrespective of perceived risk. Of course it’s possible that some might benefit from the polypill, but it’s also likely that many more will not.
And of course the drugs in the polypill are not without risk. Any one of these medications on its own might cause problems, but the risk is magnified when medication are taken in combination. The design of the study (individuals had to be on at least one of the drugs in the polypill prior to the study) essentially preselects for individuals who, compared to members of the general population, are more likely to tolerate the medication being tested. So, risk of side-effects in the study population would be generally lower than we would expect to see in real life.
But, all of this is a diversion from the main point that we simply cannot predict the value of a drug on its impact on so-called ‘surrogate markers’ such as blood pressure and cholesterol. I mean, who would have predicted that ezetimibe, a potent cholesterol-lowerer, would never be shown to have benefits for health, or that the drug torcetrapib (which lowers ‘bad’ cholesterol and raises ‘good’ cholesterol) happens to increase the risk of people dying?
If we want to know how effective the polypill is, we need to test its impact on health. What impact does the polypill have on risk of heart disease, stroke and overall risk of death? We just don’t know because this latest study does not tell us. There are four previous polypill studies in the literature, and none of them look at these critically important ‘end points’ or ‘outcomes’ either.
The lead author of the latest study is David Wald, son of Professor Sir Nicholas Wald, co-inventor of the polypill. Professor Wald and a colleague (Professor Malcom Law) hold a polypill patent. I suspect they have at least some desire to cash in on their invention. But if they want to do that, why not test the polypill in a way which does not lead to wild speculation but cool hard facts? Perhaps if the polypill was properly studied we’d get to see that, like so many drugs, the ‘expected’ benefits fail to materialise. Maybe it’s better to keep the dream alive with a string of studies and articles that allow rampant speculation and uber-enthusiasm but simply fail to tell us what we really need to know.
References:
1. Wald DS, et al (2012) Randomized Polypill Crossover Trial in People Aged 50 and Over. PLoS ONE 7(7): e41297. doi:10.1371/journal.pone.0041297
==============================================================================================
Please read the complete article here.
====================
Sept 8, 2014 - An FDA advisory committee looks at a new cardiovascular polypill about which FDA staff expressed serious reservations http://1.usa.gov/1CNj7AM
===============================================================================================
There’s been a ton of press over the last couple of days regarding a study of what is termed the ‘polypill’ – a combination medication conceived more than a decade ago with, supposedly, the prevention of heart disease and stroke in mind. The original ‘formulation’ combined blood pressure- and cholesterol-lowering medications, along with aspirin and vitamin B12. From time to time in the scientific literature we have seen studies which purport to support the idea of polypill taking for disease prevention. And the latest of these was published this week. Here, in short, is the study design and what it showed. After that, I’ll offer my own interpretation of the data.
This latest study tested the impact of a polypill comprising the following drugs:
- amlodipine (blood pressure lowering medication) – 2.5 mg
- losartan (blood pressure lowering medication) – 25 mg
- hydrochlorothiazide (blood pressure lowering medication) – 12.5 mg
- simvastatin (a statin) – 40 mg
Individuals were selected for the study on the basis of two criteria:
- They needed to be currently taking at least one of the medications in the polypill
- They needed to be aged 50 or over
But here’s the thing: this study simply can’t be used to judge whether the polypill prevent cardiovascular disease and delays death. These ideas are based on speculation based on the idea that lowering blood pressure and cholesterol translates into significant benefits for health. Yet, as I explored most recently here and here, blood pressure and statin medications are generally very ineffective for the purposes of disease prevention and preventing death. Most people who take these drugs just won’t benefit.
This is particularly the case when individuals are deemed to be at low risk of cardiovascular disease. Normally, medication is prescribed on the basis of, say, blood pressure or cholesterol levels. But not in this study: here people were selected on the basis of age, irrespective of perceived risk. Of course it’s possible that some might benefit from the polypill, but it’s also likely that many more will not.
And of course the drugs in the polypill are not without risk. Any one of these medications on its own might cause problems, but the risk is magnified when medication are taken in combination. The design of the study (individuals had to be on at least one of the drugs in the polypill prior to the study) essentially preselects for individuals who, compared to members of the general population, are more likely to tolerate the medication being tested. So, risk of side-effects in the study population would be generally lower than we would expect to see in real life.
But, all of this is a diversion from the main point that we simply cannot predict the value of a drug on its impact on so-called ‘surrogate markers’ such as blood pressure and cholesterol. I mean, who would have predicted that ezetimibe, a potent cholesterol-lowerer, would never be shown to have benefits for health, or that the drug torcetrapib (which lowers ‘bad’ cholesterol and raises ‘good’ cholesterol) happens to increase the risk of people dying?
If we want to know how effective the polypill is, we need to test its impact on health. What impact does the polypill have on risk of heart disease, stroke and overall risk of death? We just don’t know because this latest study does not tell us. There are four previous polypill studies in the literature, and none of them look at these critically important ‘end points’ or ‘outcomes’ either.
The lead author of the latest study is David Wald, son of Professor Sir Nicholas Wald, co-inventor of the polypill. Professor Wald and a colleague (Professor Malcom Law) hold a polypill patent. I suspect they have at least some desire to cash in on their invention. But if they want to do that, why not test the polypill in a way which does not lead to wild speculation but cool hard facts? Perhaps if the polypill was properly studied we’d get to see that, like so many drugs, the ‘expected’ benefits fail to materialise. Maybe it’s better to keep the dream alive with a string of studies and articles that allow rampant speculation and uber-enthusiasm but simply fail to tell us what we really need to know.
References:
1. Wald DS, et al (2012) Randomized Polypill Crossover Trial in People Aged 50 and Over. PLoS ONE 7(7): e41297. doi:10.1371/journal.pone.0041297
==============================================================================================
Please read the complete article here.
====================
Sept 8, 2014 - An FDA advisory committee looks at a new cardiovascular polypill about which FDA staff expressed serious reservations http://1.usa.gov/1CNj7AM
===============================================================================================
Friday, April 20, 2012
The hidden truth about statins
The hidden truth about statins
Statins are the most popular drugs in history. Drug companies made $26 billion selling statins alone in 2008. 25 million Americans take them, and the number is growing each year.One reason why statins are the best-selling drug category by far is that 92% of people taking them are healthy. The FDA has approved the prescription of statins to people at low risk for heart disease and stroke, who don’t even have high cholesterol. Two years ago the American Academy of Pediatricians recommended that statins be prescribed for kids as young as eight years old.
With sales statistics like this, you’d think statins are wonder drugs. But when you look closely at the research, a different story emerges. Statins have never been shown to be effective for women of any age, men over 65, or men without pre-existing heart disease. Early studies did suggest that statins are effective for men under 65 with pre-existing heart disease, but later, more rigorous clinical trials has not confirmed this benefit.
In addition, statins have been shown to have serious side effects and complications in up to 30% of people who take them. Studies have also shown that the majority of these adverse events go unreported, because doctors are largely unaware of the risks of statins.
Watch the two videos below to learn the whole story. Or, you can read this article for a concise summary of the evidence.
Video Presentation
linkHandouts
- Statin research summary: lists the eight statin studies performed in 2008 – 2009, including the drugs and populations studied and the results. If you’re currently taking a statin, you might consider printing this out and taking it to your doctor as a springboard for a conversation about whether statins are right for you.
References
ENHANCEKasteleinJJ, AkdimF, StroesES, for ENHANCE investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43
CASHMERE
O’Riordan M. CASHMERE: no IMT effect with atorvastatin over 12 months. (link)
ACHIEVE
O’Riordan M. ACHIEVE stopped: IMT study with Niacin/Laropiprant halted by Merck & Co. (link)
SEAS
Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56
GISSI-HF
GISSI-HF Investigators, Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomized, double-blind, placebo-controlled trial. Lancet 2008;372:1231-9
CORONA
Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61
AURORA
Fellström BC, Jardine AG, Schmieder ME, et al for the AURORA study group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-407
JUPITER
Ridker PM, Danielson E, Fonseca FA, et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-Reactive protein. N Engl J Med 2008;359:2195-207
Monday, March 5, 2012
FDA: Atorvastatin/ezetimibe combo needs more data
This from The Heart.org
Vytorin has been plagued by controversy in recent years, particularly given the lack of benefit with the drug in the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial. In addition, many in the clinical community have criticized the company, as well as the FDA, for the delays in reporting hard clinical outcomes data with the ezetimibe/simvastatin combination. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study is currently expected to be completed in June 2013.
Read the full article here.
Vytorin has been plagued by controversy in recent years, particularly given the lack of benefit with the drug in the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial. In addition, many in the clinical community have criticized the company, as well as the FDA, for the delays in reporting hard clinical outcomes data with the ezetimibe/simvastatin combination. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study is currently expected to be completed in June 2013.
Read the full article here.
Monday, September 12, 2011
Bad Science Used To Push Cholesterol-Reducing Drugs
By Cholesterol Truth
I had a patient in my practice this week who was seeking advice about the prevention of heart disease. He’d been on a statin for several years, and then started to get what he felt might be side-effects.
He stopped the statin and the side-effects went away. As he rightly pointed out, the relief from his symptoms might have been entirely coincidental and nothing to do with the fact that he stopped his statin medication. However, he was disinclined to restart. My patient told me that he expects his doctor to be up in arms about this. He has, apparently, an unbridled enthusiasm for statins and believes ‘everyone should be taking them’.
As I pointed out to my patient, the reality is the vast majority of people who take statins are destined not to benefit from them. And then we have the problem, of course, of toxicity and side effects.
Not to mention the cost. What is it then, that causes doctors to be so enthusiastic about drugs that, on balance, have limited benefits and can cause serious harm?
Well, some of this has to do with the fact that doctors make money from cholesterol reduction. In private medicine, the cholesterol concept suddenly makes ‘patients’ out of essentially healthy people.
Here in the UK, national health general practitioners are remunerated for their cholesterol-reducing efforts with patients.
But a major part of the problem too, I think, has to do with how the ‘benefits’ of statins and other drugs are communicated to doctors by drug companies. As I’ve pointed out before, the emphasis is usually on reductions in the ‘relative risk’ of, say, heart disease. But if the overall risk is small, the real reduction in risk (known as the ‘absolute risk’ reduction) becomes vanishingly small.
Another problem is that data can be presented to doctors that gives a misleading account of a drug’s effects for the unwary. I spotted a prime example of this recently in the on-line version of the GP magazine Pulse here.
One problem: the study that purportedly shows that ezetimibe saves lives actually does nothing of the sort. The study is ‘epidemiological’ in nature, and can only tell us that ezetimibe is associated with a reduced risk of death. You see, individuals who take ezetimibe may have a reduced risk of death that has nothing to do with ezetimibe. Maybe, for example, they’re particularly health conscious and in addition to pressing their doctors for more and stronger medication, they’re also active and eat good diets.
The fact that the study in question here is epidemiological means that the statement that ‘A cholesterol-lowering drug…has been shown to reduce mortality…’ is simply wrong and misleading.
To know if ezetimibe really does save lives, we need clinical ‘intervention’ studies. We now have several of these. And here’s what you and your doctor need to know: Not one of them has shown that ezetimibe benefits health or health markers. Some of the studies actually suggest the ezetimibe does more harm than good.
The Pulse piece ends with the following paragraph: ‘Dr Peter Fellowes, a GP in Lydney, Gloucestershire and a member of the GPC clinical and prescribing subcommittee, said: ‘I don't think it should be blacklisted. It is very useful in patients who are statin intolerant. The arguments against ezetimibe and the more potent statins are entirely cost based as I see it, and that is a sorry state of affairs.'’
I’ll tell you what’s a ‘sorry state of affairs’: When a doctor is advocating the use of an expensive and potentially toxic drug that has no proven benefits on health. And it doesn’t help that a magazine for GPs presents information on cholesterol-reducing drugs in a misleading and utterly imbalanced way, either.
To your good health,
Dr. John Briffa
for The Cholesterol truth
==============================================================
Read the full article here.
Saturday, June 11, 2011
Death blow for Zetia? (ezetimibe) Dr. William Davis
| Posted: 11/25/2009 11:14:54 AM | |
| The recent results of the ARBITER6-HALTS trial, I believe, should cause us to eliminate Zetia (ezetimibe) from our list of agents regarded as safe. In all honesty, despite some of the negative press on Zetia, especially in regards to the data suggesting no effect on carotid plaque in people with heterozygous familial hypercholesterolemia, I had maintained hope that a subset of people who are "hyperabsorbers" of sterol-backbone substances, such as the various forms of sterols, would benefit from Zetia's capacity to block their absorption. But the ARBITER trial, I believe, essentially closes the lid on Zetia, regardless of any potential effect on sterol absorption. The study demonstrates that niacin in combination with a statin (mostly Lipitor or Crestor) reduces carotid intimal-medial thickness (CIMT) modestly; while Zetia does not when added to statin. Most concerningly, greater LDL-reducing efficacy with Zetia was associated with an increase in CIMT. The authors raise the question, suggested in prior studies, that Zetia, despite being billed as only a cholesterol absorption inhibitor, exerts other effects when systemically absorbed, including impairment of reverse cholesterol transport. I believe that enough doubt has been cast on the efficacy and safety of Zetia that we should avoid its inclusion. Of course, speak to your doctor before making any changes. ============================================================= | |
Friday, June 10, 2011
Cholesterol-reducing drug ezetimibe appears to do more harm than good
Dr Briffa's article discusses cholesterol reducing drug ezetimibe and its harm.
"
Cholesterol is said to cause heart disease (I’m not so sure, myself), and a mainstay of treatment here is a class of drugs known as ‘statins’ that reduce the rate at which cholesterol is manufactured in the liver. Statins have been used in medicine for over 20 years, but more recently has seen the development and licensing of a cholesterol-reducing drug known as ezetimibe, which works in different way to statins. Instead of acting on the liver, it reduces cholesterol absorption from the gut.
There’s no doubt that ezetimibe reduces cholesterol levels effectively, and it is licensed on this basis. However, the impact that a drug (or food or anything) has on cholesterol is irrelevant – it’s its impact on health that matters. While we have been brainwashed into believing that whatever reduces cholesterol is good for health, this simply isn’t true. Actually, there is abundant evidence that reducing cholesterol per se is not broadly beneficial to health. And some evidence suggests that it might even be damaging to health.
As it happens, ezetimibe use has been linked with an increased risk of cancer, and enhanced narrowing of arteries (though not statistically significant) [1], as well as an increased risk of cancer in one study [2].
Ezetimibe is a drug that reduces cholesterol levels in the bloodstream. It does this in a different way to statins (the most commonly-prescribed cholesterol drugs). Statins work by inhibiting the rate at which cholesterol is manufactured in the liver, while ezetimibe impairs the absorption of cholesterol from the gut.
Ezetimibe was originally licensed on the basis of its cholesterol-reducing abilities. Yet, to date, no study has ever been published which demonstrates that it has the power to reduce the risk of actual disease or death. In fact, in one study, coupling ezetimibe with a statin (simvastatin) resulted in increased (though not statistically significant) narrowing of the arteries compared to the statin alone [1].
I was interested to read a recent study in which ezetimibe was again tested for its affects on narrowing in the arteries (atherosclerosis) [3]. In this study, individuals with ‘peripheral vascular disease’ (atherosclerosis in the arteries in the legs) had the extent of their disease measured using MRI. Here’s how the individuals in the study were treated:
1. those not previously on a statin were given simvastatin (40 mg a day) or simvastatin (40 mg a day) plus ezetimibe (10 mg a day).
2. those already taking a statin had ezetimibe (10 mg a day) added to their regime.
MRI was repeated after 1 and 2 years. Here’s what the results showed:
Overall, ezetimibe resulted in lower ‘unhealthy’ LDL-cholesterol levels when used in conjunction with the statin than the statin alone. However, individuals in group 2 saw a progression of their disease (by 8 per cent over two years), compared with no progression in group 1.
In other words, in those taking a statin, the addition of ezetimibe actually worsened their disease.
This study, on the back of previous evidence, strongly suggests that ezetimibe poses hazards for health. Yet, it remains on the market. This is what can happen when our attention is diverted away from the truly important thing (health), towards cholesterol or some other supposed marker of disease."
For references listed in the above article go here
"
Posted on 10 June 2011
There’s no doubt that ezetimibe reduces cholesterol levels effectively, and it is licensed on this basis. However, the impact that a drug (or food or anything) has on cholesterol is irrelevant – it’s its impact on health that matters. While we have been brainwashed into believing that whatever reduces cholesterol is good for health, this simply isn’t true. Actually, there is abundant evidence that reducing cholesterol per se is not broadly beneficial to health. And some evidence suggests that it might even be damaging to health.
As it happens, ezetimibe use has been linked with an increased risk of cancer, and enhanced narrowing of arteries (though not statistically significant) [1], as well as an increased risk of cancer in one study [2].
Ezetimibe is a drug that reduces cholesterol levels in the bloodstream. It does this in a different way to statins (the most commonly-prescribed cholesterol drugs). Statins work by inhibiting the rate at which cholesterol is manufactured in the liver, while ezetimibe impairs the absorption of cholesterol from the gut.
Ezetimibe was originally licensed on the basis of its cholesterol-reducing abilities. Yet, to date, no study has ever been published which demonstrates that it has the power to reduce the risk of actual disease or death. In fact, in one study, coupling ezetimibe with a statin (simvastatin) resulted in increased (though not statistically significant) narrowing of the arteries compared to the statin alone [1].
I was interested to read a recent study in which ezetimibe was again tested for its affects on narrowing in the arteries (atherosclerosis) [3]. In this study, individuals with ‘peripheral vascular disease’ (atherosclerosis in the arteries in the legs) had the extent of their disease measured using MRI. Here’s how the individuals in the study were treated:
1. those not previously on a statin were given simvastatin (40 mg a day) or simvastatin (40 mg a day) plus ezetimibe (10 mg a day).
2. those already taking a statin had ezetimibe (10 mg a day) added to their regime.
MRI was repeated after 1 and 2 years. Here’s what the results showed:
Overall, ezetimibe resulted in lower ‘unhealthy’ LDL-cholesterol levels when used in conjunction with the statin than the statin alone. However, individuals in group 2 saw a progression of their disease (by 8 per cent over two years), compared with no progression in group 1.
In other words, in those taking a statin, the addition of ezetimibe actually worsened their disease.
This study, on the back of previous evidence, strongly suggests that ezetimibe poses hazards for health. Yet, it remains on the market. This is what can happen when our attention is diverted away from the truly important thing (health), towards cholesterol or some other supposed marker of disease."
For references listed in the above article go here
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