Statins, Statistics and Statinistics - Sigurdsson

Statins, Statistics and Statinistics

12, May, 2014 by Axel F. Sigurdsson MD

Current medical knowledge is to a large extent based on results from scientific studies. Traditionally, these results are published in peer-reviewed medical journals. Before being accepted, a scientific paper has to go through critical assessment by expert reviewers who will assess the paper’s suitability for publication. The peer review process is intended to guarantee standards of quality and provide credibility. The highest ranked medical journals only accept a small fraction of papers submitted to them for publication.

Clinical medicine relies on the scientific literature. For a clinical cardiologist like myself, this is a key issue. The procedures I decide to perform, and the therapy I recommend is, and should be, based on scientific evidence. For the clinician, evidence based medicine is the holy grail.

But what if  scientific studies are flawed? What if evidence based medicine relies on erroneous data? Then, obviously, clinical medicine is broken.

Unfortunately, the scientific community is not free from dishonesty and greed. Scientific fraud is hard to deal with. Faked data exists and is often difficult to expose. However, we should be able to rely on high quality medical journals when it comes to wrong use of statistics, erroneous calculations and wrong conclusions. These journals should guarantee that papers plagued with such problems are not accepted for publication. But, are they up to the task?

The Statins and the Elderly Saga
One of the most important questions facing clinical cardiology today is when to use statin drugs for individuals who have not been diagnosed cardiovascular disease (CVD). Clinical trials have shown that these drugs lower mortality and reduce the risk of future cardiovascular events among people with CVD. However, in those without established CVD, the magnitude of effect is less clear end it is uncertain when the benefits of therapy outweigh the risks.

Age itself is independently associated with the risk of CVD, and risk factors such as high blood pressure, lipid disorders and diabetes are common among the elderly. However, limited clinical research is available addressing statin treatment among healthy people above 65 years old.
Four months ago I read with interest a paper by Gianlugi Savarese and colleagues, published in the Journal of the American College of Cardiology (JACC) presenting a meta-analysis of the  benefits of statins in elderly subjects without established CVD. The authors concluded that their “meta-analysis provided the first-time evidence that the benefits of statins on major cardiovascular events extended to people above 65 years old”.

In the paper, the authors came to the conclusion that statins significantly reduce the incidence of myocardial infarction (MI) and stroke, but do not significantly prolong survival in the short term.
Their numbers show that 83 patients have to be treated with statins to prevent one case of MI and 142 patients have to be treated with statins to prevent one stroke, for a mean follow-up of 3.5 years. However, they did not present these numbers in their paper. Instead they claimed that 24 patents needed to be treated for 1 year to prevent one MI and that 42 patients needed to be treated for one year to prevent one stroke.

I guess anybody with some statistical knowledge will see that the Number Needed to Treat (NNT) for one year should be a higher number than the NNT for 3.5 years. If one is performing a clinical trial in order to test an effect of a drug, a higher number of patents is needed if the study is planned to run for 1 year than if it is supposed to run for 3.5 years. There will be fewer events in one year than in 3.5 years, therefore the NNT for 1 year is a higher number than the NNT for 3.5 years. If you’re still doubtful, read my earlier blog post on the issue.

My Letter to the Editor of JACC
After discovering the error in the paper by Savarese and colleagues I wrote a letter to the editor of JACC which has been published online before print. I pointed out that the authors appeared to have made an erroneous calculation when reporting the NNT for a period of one year. By using data from their paper I had calculated that the NNT for one year to prevent one MI and one stroke was approximately ten times higher than reported in the paper, given that NNT is constant over time. In other words, the statin effect was exaggerated by a factor of ten.

I also suggested that the most appropriate approach would have been to report the NNT for the mean follow-up of 3.5 years, instead of calculating the NNT for one year.

A correction was published by the authors in JACC on March 25. It’s not very substantial:

“The authors report the number needed to treat (NNT) for the entire mean follow-up of studies was 83 and 142 for myocardial infarction and stroke, respectively. The authors apologize for this error.”

 

Strangely, not a word about the erroneous calculation. The wrong NNT numbers per year are left uncorrected.

Two of the authors of the paper, Gianlugi Savarese and Pasquale Perrone-Filardi, responded to my letter. Their response was published online together with my letter. They agreed that it was more appropriate to report the NNT for the mean follow-up of 3.5 years than presenting the NNT for one year. Furthermore they write:

“As previous authors did (citation) using the same formula adopted in our meta-analysis, our aim was to calculate the NNT per year dividing the overall NNT calculated for the entire trial duration by the length of the follow up. We agree with dr Sigurdsson that this may represent an oversimplification, since this calculation assumes that the effect of the treatment (relative risk reduction) is constant over time and that events occur at a constant rate over time”

Oversimplification is not the right word. Simply put, this is a completely wrong approach. But to my surprise, Savarese and colleagues don’t seem to realize or understand it. In fact dividing, when you should multiply will provide numbers that are very far from the truth.

Repeating an Error Won’t Make it Right 
Of course I was curious to see the paper cited by Savarese and Perrone-Filardi in their response to my letter. It turns out that it’s a paper published in Circulation 2008; “Lipid Management to Reduce Cardiovascular Risk: A New Strategy is Required“, written by H. Roberto Superko and Spencer King III. Dr. King is a world-famous senior cardiologist, a pioneer in cardiac catheterization and coronary angiography.

These two renowned cardiologists address the NNT from a number of statins trials in primary and secondary prevention. Interestingly, they also calculate the NNT per year. The results are published in Table 2. The table shows that the NNT per year is always a higher number than the NNT for the whole study period (which is always longer than one year). For example the NNT to prevent one MI in the famous 4S (SSSS) trial was 11.7 for the whole study period, but the NNT per year of the study was 63.2. The NNT for the WOSCOP trial was 44.2 for the whole study period, but 216.6 per year of the study. In fact, this all looks very reasonable and correct.

But the strange thing is that in the paper’s text, Superko and King use a different approach which is in complete disagreement with the table. They write:

“… such as the Scandinavian Simvastatin Survival Study (SSSS), which achieved an NNT of 11.7 and an NNT per year of 2.2″

And they do this again and again, as if they never saw the table in their own paper. So, Superko and King are dividing the overall NNT by the length of follow-up in order to find the NNT per year. If they continue to do this they will find that the NNT per six months in the 4S-trial was 1.1. This would mean that only one patient had to be treated for six months to prevent one event. Completely absurd.
I wonder, do these renowned scientific authors don’t understand what they’re talking about, or is this just a slight oversight. Whatever it is, it’s serious and unprofessional. How can a respected peer-reviewed paper such as Circulation publish such rubbish? And, five years later Savarese and colleagues decide it’s time to repeat the error. And now it’s accepted by JACC, another highly respected medical journal.

Surprisingly, Savarese and Perrone-Filardi don’t acknowledge their error. Instead, they cite the old paper where the same error was made, and believe that’ll make it right. Furthermore, despite the real NNT being a tenfold higher number than the one they reported (meaning the drug effect is ten times less), they have no intention to reconsider the main conclusion of their study.

I must admit I’m deeply disappointed. The medical community expects much more responsibility from the editorial boards of these medical journals. If the medical literature is full of such errors, our knowledge is worthless? Maybe, in this particular context, lying with numbers, whether it’s done on purpose or not, could be called statinistics instead of statistics. Statinistics could be the new word for badly treated statistics.
==============================================================
Read the complete article here.

Also see "Statins For Elderly People – A Deceptive Message" by Axel F. Sigurdsson MD

Statins For Elderly People - Sigurdsson

Statins For Elderly People – Was the Message Corrupted?

Doc's Opinion | January 7, 2014 at 8:36 pm | URL: http://wp.me/p2urWY-Me

People older than 65 years are at increased risk for cardiovascular disease (CVD). Such disease accounts for more than 80 percent of deaths in this population. Age itself appears independently associated with risk, and risk factors such as high blood pressure, lipid disorders and diabetes are common among the elderly. An important question facing the medical community is whether statin drugs can reduce risk among elderly people without established CVD. Limited clinical research is available addressing statin treatment among healthy individuals above 65 years old.

Recently a meta-analysis was published by Savarese and coworkers in the Journal of the American College of Cardiology (JACC) addressing the effects of statins in elderly subjects without established cardiovascular disease. Eight trials were included in the final analysis. The results made the headlines and the message was quite clear. The authors concluded that their “meta-analysis provided the first-time evidence that the benefits of statins on major cardiovascular events extended to people above 65 years old”. Such a message is certainly something for authors of clinical guidelines to chew on.

In an accompanying editorial in JACC, David D. Waters, MD, wrote: “Older people differ more among themselves than younger people do in many ways, and the decision to treat or not treat an older individual with a statin often requires clinical discernment. The clear results of this meta-analysis will hopefully lead to more older individuals receiving treatment that vill reduce their cardiovascular risk”.

Savarese and coworkers conclude from their meta-analysis that 24 patients need to be treated with statins for a year to prevent one heart attack (myocardial infarction) and 42 patents need to be treated for a year to prevent one stroke. However, I suspect they may have miscalculated their data. My calculation, based on data presented in the paper, indicates that the number needed to treat (NNT) is approximately ten times higher. If this is true the effect of statin therapy is seriously exaggerated in the paper.

The Number Needed to Treat.

The meta-analysis by Savarese and coworkers did not show a significant effect of statin treatment on mortality compared to placebo. Myocardial infarction occurred in 2.7% of subjects allocated to statins compared with 3.9% of those on placebo during a mean-follow up of 3.5 years. The annual rate of myocardial infarction was 1.1% on placebo and 0.8 percent on statins. The absolute risk reduction is about 0.3 percent. Although the risk reduction is statistically significant, it is obvious that the number of patients needed to be treated for a year to prevent one event can not be 24.

The NNT is the inverse of the absolute risk reduction (ARR): NNT = 1/ARR.

• If ARR is 1 percent, the NNT will be 100 (1/0.01).
• If ARR is 10 percent, the  NNT will be 10 (1/0.1).
• If ARR is 0.1 percent, the NNT will be 1.000 (1/0.001).

Accordingly, if the absolute risk reduction that is less than 1 percent, the NNT will always be above 100.

My calculation based on data from Table 2 in the paper indicates that about 234 patients need to be treated for one year to prevent one myocardial infarction, and that about 389 patients need to be treated for one year to prevent one stroke. I hope someone corrects me if I’m wrong. If I’m right, I may have a hard time understanding how such miscalculation can survive a peer-reviewed process in a respected medical journal. NNT is an important number to look at when deciding whether to give a certain treatment or not.

Studies of statins in primary and secondary prevention suggest these drugs increase the risk of diabetes. For comparison, it is estimated that 250 patients need to be treated with a statin for one case of diabetes to be caused. So by looking at the data we can assume that by treating 250 elderly people with statins for a year, we may actually exchange one myocardial infarction for one case of diabetes .

The Emperors New Clothes

One of the authors of the above mentioned meta-analysis, Dr. Antonio Gotto JR said in an interview following the publication of the paper: “Taking statins may not prolong life in older adults, but it may certainly improve the quality of life for people who might otherwise become disabled by heart attacks and strokes”.

Savarese and coworkers point out that statins reduce the risk of myocardial infarction by 39.4 percent and the risk of stroke by 23.8 percent compared with placebo. These are the numbers they get when calculating relative risk reduction. The results are statistically significant, certainly suggesting a positive effect of statin therapy.

However, let’s look closer at the magnitude of treatment effect. An individual not given statin therapy has a 98.9 percent chance of not having a heart attack, and a 99.2 percent chance of not having a stroke in a year. If given statins, the chance of not having a heart attack will be increased to 99.2 percent and the chance of not having a stroke will be increased to 99.4 percent. Not very impressive if we look at it this way.

Keep in mind when looking at these numbers that we don’t have access to data on the side effects of statins from these trials. Furthermore, it is possible that older people are more vulnerable to side effects than young people. There is evidence of harm linked to statins when given to elderly individuals, including muscle pain, liver disorders, impaired memory, increased risk of diabetes and gastrointestinal stress.

In my opinion, the meta-analysis by Savarese and coworkers does not provide strong support for statin treatment of elderly people with elevated cardiovascular risk. More data is needed until such marching orders are given to practicing clinicians.
===================================================
Read the complete article here.

Could statins be adding to the epidemic of heart failure? - Briffa

Could statins be adding to the epidemic of ‘heart failure’?

Jan, Fri 4th, 2013 By : Dr John Briffa

 

Statins are drugs that reduce cholesterol by inhibiting an enzyme in the liver known as ‘HMG-CoA reductase’ which ‘drives’ cholesterol production (most of the cholesterol in the bloodstream is made in the liver and does not come directly from the diet). But HMG-CoA reductase also facilitates the production of a substance known as ‘coenzyme Q10’ which itself participates in the production of what is known as ‘adenosine triphosphate’ (ATP) – the most basic unit of energy ‘fuel’ in the body. The major biochemical process which involves CoQ10 that drives ATP and energy production in the body is known as ‘oxidative phosphorylation’.

Now that we have the potted biochemistry lesson over, we can see that statins have the potential, by lowering CoQ10 levels, to put a break on oxidative phosphorylation and ATP production in the muscles. The end result may be fatigue? Muscle pain is another potential consequence.

In a study published this week in the Journal of the American College of Cardiology (JACC), Danish researchers measured CoQ10 levels in individuals taking simvastatin (a commonly-prescribed statin), and compared them with those not taking statins [1]. The levels in those taking the statin were significantly lower.

Now, studies such as this one are what is termed ‘epidemiological’ in nature, which means it looks at associations between things, but cannot prove that one thing is causing another. However, of relevance here is other evidence which finds that giving statins to people does indeed have the capacity to lower levels of CoQ10 in the body [2].

What was also interesting about the JACC study is that it found that those treated with statins had lower levels of oxidative phosphorylation than those not taking them. They also had reduced ‘insulin sensitivity’. This is relevant for a number of reasons, including the fact that insulin facilitates the uptake of nutrients such as glucose into the cells. Lowered insulin sensitivity can therefore ‘starve’ the cells of essential nutrients. Reduced insulin sensitivity is also the underlying fault in type 2 diabetes. It is perhaps worth bearing in mind that statin use has been proven to increase the risk of type 2 diabetes.

Another thing worth bearing in mind here, I think, is the fact that the heart is a muscle, and depleting it of CoQ10 may be hazardous for cardiac health. Specifically, it may weaken the heart and lead to what is known as ‘heart failure’ (also known as ‘congestive cardiac failure’). I think the ‘benefits’ of statins are vastly overstated, generally speaking. However, if someone is to take statins, I think it’s a reasonable safeguard to take CoQ10 on a daily basis. 100 mg a day is a decent dose, I think, though higher doses are likely to better when symptoms of statin toxicity are present.

In researching this article, I came across an interesting review of the evidence for statin-inducted CoQ10 depletion in both humans and animals [3]. Here’s what the authors of this review have to say in their concluding remarks:

Statin-induced CoQ10 deficiency is completely preventable with supplemental CoQ10 with no adverse impact on the cholesterol lowering or anti-inflammatory properties of the statin drugs. We are currently in the midst of a congestive heart failure epidemic in the United States, the cause or causes of which are unclear. As physicians, it is our duty to be absolutely certain that we are not inadvertently doing harm to our patients by creating a wide-spread deficiency of a nutrient critically important for normal heart function.

References:
1. Larsen S, et al. Simvastatin Effects on Skeletal Muscle – Relation to Decreased Mitochondrial Function and Glucose Intolerance. J Am Coll Cardiol. 2013;61(1):44-53
2. Passi S, et al. Statins lower plasma and lymphocyte ubiquinol/ubiquinone without affecting other antioxidants and PUFA. Biofactors 2003;18(1-4):113-24.
3. Langsjoen PH, et al. The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications. Biofactors 2003;18(1-4):101-11.
=========================================================================================================
Read the complete article here.

Current State of Niacin in Cardiovascular Disease Prevention - JACC

The Current State of Niacin in Cardiovascular Disease Prevention: Title and subTitle BreakA Systematic Review and Meta-Regression

Paul M. Lavigne, MD; Richard H. Karas, MD, PhD

Abstract

 

Objectives This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial.

.

.

.

Conclusions The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration.

.

.

.

Conclusions

 

Although potentially indicative of limited efficacy in select patients, the recently published findings of AIM-HIGH are insufficient to alter the aggregate available data supporting the clinical efficacy of niacin therapy as a means to reduce CVD risk. The present analysis demonstrates the summary effect of niacin across a broad clinical population to confer atheroprotection and cautions against the extension of recent isolated findings to substantially alter overall clinical practice. These results thus underscore the need for further analysis, including that offered by the ongoing HPS2-THRIVE (Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events) trial, to more clearly define the role of niacin in current practice.

References

 

1 +

Adult Treatment Panel III, Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report, Circulation 2002 106 () 3143-3421
PubMed

2 +

Grundy S.M., Cleeman J.I., Merz C.N.B.. et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines, J Am Coll Cardiol 2004 44 () 720-732
PubMed | CrossRef

3 +

Smith S.C., Benjamin E.J., Bonow R.O.. et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association, J Am Coll Cardiol 2011 58 () 2432-2446
PubMed | CrossRef

4 +

Baigent C., Keech A., Kearney P.M.. et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins, Lancet 2005 366 () 1267-1278
PubMed | CrossRef

5 +

Baigent C., Blackwell L., Emberson J.. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials, Lancet 2010 376 () 1670-1681
PubMed | CrossRef

6 +

Cannon C.P., Steinberg B.A., Murphy S.A., Mega J.L., Braunwald E.. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy, J Am Coll Cardiol 2006 48 () 438-445
PubMed | CrossRef

7 +

Cannon C., Braunwald E., McCabe C.. et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes, N Engl J Med 2004 350 () 1495-1504
PubMed | CrossRef

8 +

LaRosa J.C., Grundy S.M., Waters D.D.. et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease, N Engl J Med 2005 352 () 1425-1435
PubMed | CrossRef

9 +

de Lemos J., Blazing M., Wiviott S.. et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial, JAMA 2004 292 () 1307-1316
PubMed | CrossRef

10 +

Pedersen T., Faergeman O., Kastelein J.. et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction, JAMA 2005 294 () 2437-2445
PubMed | CrossRef

11 +

Armitage J., Bowman L., Wallendszus K.. et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial, Lancet 2010 376 () 1658-1669
PubMed | CrossRef

12 +

Kamanna V.S., Kashyap M.L.. Mechanism of action of niacin on lipoprotein metabolism, Curr Atheroscler Rep 2000 2 () 36-46
PubMed | CrossRef

13 +

Kamanna V.S., Kashyap M.L.. Nicotinic acid (niacin) receptor agonists: will they be useful therapeutic agents?, Am J Cardiol 2007 100 () S53-S61
PubMed | CrossRef

14 +

Kamanna V.S., Kashyap M.L.. Mechanism of action of niacin, Am J Cardiol 2008 101 () 20B-26B
PubMed | CrossRef

15 +

Coronary Drug Project Research Group, Clofibrate and niacin in coronary heart disease, JAMA 1975 231 () 360-381
PubMed | CrossRef

16 +

Brown B., Zhao X., Chait A.. et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease, N Engl J Med 2001 345 () 1583-1592
PubMed | CrossRef

17 +

Taylor A.J., Sullenberger L.E., Lee H.J., Lee J.K., Grace K.A.. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins, Circulation 2004 110 () 3512-3517
PubMed | CrossRef

18 +

Taylor A.J., Lee H.J., Sullenberger L.E.. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3, Curr Med Res Opin 2006 22 () 2243-2250
PubMed | CrossRef

19 +

Taylor A., Villines T., Stanek E.. et al. Extended-release niacin or ezetimibe and carotid intima-media thickness, N Engl J Med 2009 361 () 2113-2122
PubMed | CrossRef

20 +

Villines T.C., Stanek E.J., Devine P.J.. et al. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis): final results and the impact of medication adherence, dose, and treatment duration, J Am Coll Cardiol 2010 55 () 2721-2726
PubMed | CrossRef

21 +

Lee J.M.S., Robson M.D., Yu L.-M.. et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study, J Am Coll Cardiol 2009 54 () 1787-1794
PubMed | CrossRef

22 +

Boden W.E., Probstfield J.L., Anderson T.. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med 2011 365 () 2255-2267
PubMed | CrossRef

23 +

Bruckert E., Labreuche J., Amarenco P.. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis, Atherosclerosis 2010 210 () 353-361
PubMed | CrossRef

24 +

Duggal J.K., Singh M., Attri N.. et al. Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease, J Cardiovasc Pharmacol Ther 2010 15 () 158-166
PubMed | CrossRef

25 +

Brown G., Albers J., Fisher L.. et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B, N Engl J Med 1990 323 () 1289-1298
PubMed | CrossRef

26 +

Guyton J.R., Brown B.G., Fazio S., Polis A., Tomassini J.E., Tershakovec A.M.. Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia, J Am Coll Cardiol 2008 51 () 1564-1572
PubMed | CrossRef

27 +

Jadad A.R., Moore R.A., Carroll D.. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?, Control Clin Trials 1996 17 () 1-12
PubMed | CrossRef

28 +

Whitney E.J., Krasuski R.A., Personius B.E., Michalek J.E., Maranian A.M., Kolasa M.W.. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels□: effects on progression of coronary heart disease and clinical events, Ann Intern Med 2005 142 () 95-104
PubMed

29 +

Blankenhorn D.H., Nessim S.A., Johnson R.L., Sanmarco M.E., Azen S.P., Cashin-Hemphill L.. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts, JAMA 1987 257 () 3233-3240
PubMed | CrossRef

30 +

Carlson L.A., Rosenhamer G.. 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
PubMed | CrossRef

31 +

Kane J.P., Malloy M.J., Ports T.A., Phillips N.R., Diehl J.C., Havel R.J.. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens, JAMA 1990 264 () 3007-3012
PubMed | CrossRef

32 +

Larosa J.C., He J., Vupputuri S., Headings M.S.. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials, JAMA 1999 282 () 2340-2346
PubMed | CrossRef

33 +

Jafri H., Alsheikh-Ali A.A., Karas R.H.. Meta-analysis: statin therapy does not alter the association between low levels of high-density lipoprotein cholesterol and increased cardiovascular risk, Ann Intern Med 2010 153 () 800-808
PubMed

34 +

Gordon T., Castelli W., Hjortland M., Kannel W., Daber T.. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study, Am J Med 1977 62 () 707-714
PubMed | CrossRef

35 +

Wilson P., Garrison R., Castelli W., Feinleib M., McNamara P., Kannel W.. Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols, Am J Cardiol 1980 46 () 649-654
PubMed | CrossRef

36 +

Castelli W., Garrison R., Wilson P., Abbott R., Kalousdian S., Kannel W.. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study, JAMA 1986 256 () 2835-2838
PubMed | CrossRef

37 +

Gordon D.J., Probstfield J.L., Garrison R.J.. et al. High-density lipoprotein cholesterol and cardiovascular disease, Circulation 1989 79 () 8-15
PubMed | CrossRef

38 +

Kuvin J.T., Dave D.M., Sliney K.A.. et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease, Am J Cardiol 2006 98 () 743-745
PubMed | CrossRef

39 +

Digby J.E., McNeill E., Dyar O.J., Lam V., Greaves D.R., Choudhury R.P.. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin, Atherosclerosis 2010 209 () 89-95
PubMed | CrossRef

40 +

Linke A., Sonnabend M., Fasshauer M.. et al. Effects of extended-release niacin on lipid profile and adipocyte biology in patients with impaired glucose tolerance, Atherosclerosis 2009 205 () 207-213
PubMed | CrossRef

41 +

Lee J.M.S., Robson M.D., Yu L.-M.. et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study, J Am Coll Cardiol 2009 54 () 1787-1794
PubMed | CrossRef

42 +

Wu B.J., Yan L., Charlton F., Witting P., Barter P.J., Rye K.-A.. Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids, Arterioscler Thromb Vasc Biol 2010 30 () 968-975
PubMed | CrossRef

43 +

Lukasova M., Malaval C., Gille A., Kero J.. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109a expressed by immune cells, J Clin Invest 2011 121 () 1163-1173
PubMed | CrossRef

44 +

Holzhäuser E., Albrecht C., Zhou Q.. et al. Nicotinic acid has anti-atherogenic and anti-inflammatory properties on advanced atherosclerotic lesions independent of its lipid-modifying capabilities, J Cardiovasc Pharmacol 2011 57 () 447-454
PubMed | CrossRef

45 +

Roche Inc, Roche Provides Update on Phase III Study of Dalcetrapib [press release]. May 2012, () -
PubMed

46 +

Stein E.A., Stroes E.S.G., Steiner G.. et al. Safety and tolerability of dalcetrapib, Am J Cardiol 2009 104 () 82-91
PubMed | CrossRef

47 +

Voight B.F., Peloso G.M., Orho-Melander M.. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study, Lancet 2012 6736 () 1-9
PubMed

48 +

Alsheikh-Ali A.A., Karas R.H.. The safety of niacin in the US Food and Drug Administration adverse event reporting database, Am J Cardiol 2008 101 () 9B-13B
PubMed | CrossRef

49 +

Alsheikh-Ali A.A., Karas R.H.. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system), Am J Cardiol 2007 99 () 379-381
PubMed | CrossRef

50 +

Ballantyne C.M., Davidson M.H., McKenney J.M., Keller L.H., Bajorunas D.R., Karas R.H.. Comparison of the efficacy and safety of a combination tablet of niacin extended-release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high-dose) study, J Clin Lipidol 2008 2 () 79-90
PubMed | CrossRef
================================================================

Reas the complete article here.

The diet–heart hypothesis: a critique

An article under VIEWPOINT AND COMMENTARY in the Journal of the American College of Cardiology (JACC) titled "The diet–heart hypothesis: a critique" by Sylvan Lee Weinberg, MD, states the following in the final paragraph. Please read the complete article here.

"A balanced appraisal of the diet–heart hypothesis must recognize the unintended and unanticipated role that the LF-HCarb diet may well have played in the current epidemic of obesity, abnormal lipid patterns, type II diabetes, and the metabolic syndrome. Defense of the LF-HCarb diet, because it conforms to current traditional dietary recommendations, by appealing to the authority of its prestigious medical and institutional sponsors or by ignoring an increasingly critical medical literature, is no longer tenable. The categoric rejection of experience and an increasingly favorable medical literature, though still not conclusive, which suggests that the much-maligned LCarb-HP diet may have a favorable impact on obesity, lipid patterns, type II diabetes, and the metabolic syndrome, is also no longer tenable."