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Showing posts with label cardiovascular disease. Show all posts
Showing posts with label cardiovascular disease. Show all posts

Tuesday, January 10, 2017

Study says there's no link between cholesterol and heart disease

Mon, 13 Jun 2016 12:33:00 EST
"Controversial report claims there's no link between 'bad cholesterol' and heart disease," the Daily Mail reports, while The Times states: "Bad cholesterol 'helps you live longer',".
The headlines are based on a new review which aimed to gather evidence from previous observational studies on whether LDL cholesterol (so-called "bad cholesterol") was linked with mortality in older adults aged over 60. The conventional view is that having high LDL cholesterol levels increases your risk of dying of cardiovascular diseases, such as heart disease.
Researchers chose 30 studies in total to analyse. 28 studies looked at the link with death from any cause. Twelve found no link between LDL and mortality, but 16 actually found that lower LDL was linked with higher mortality risk – the opposite to what was expected.
Only nine studies looked at cardiovascular mortality link specifically – seven found no link and two found the opposite link to what was expected.
However, there are many important limitations to this review. This includes the possibility that the search methods may have missed relevant studies, not looking at levels of other blood fats (e.g. total and HDL cholesterol), and the possibility that other health and lifestyle factors are influencing the link.
Most importantly, as the researchers acknowledge, these findings do not take account of statin use, which lowers cholesterol. People found to have high LDL cholesterol at the study's start may have subsequently been started on statins, which could have prevented deaths. 

Where did the story come from?

The study was carried out by researchers from the University of South Florida, the Japan Institute of Pharmacovigilance and various other international institutions in Japan, Sweden, UK, Ireland, US and Italy.
Funding was provided by the Western Vascular Institute. The study was published in the peer-reviewed BMJ Open and, as the journal name suggests, the article is open-access, so can be read for free.
Four of the study authors have previously written book(s) criticising "the cholesterol hypothesis". It should also be noted that nine of the authors are members of THINCS – The International Network of Cholesterol Skeptics. This is described as a group of scientists who "oppose…that animal fat and high cholesterol play a role [in heart disease]".
If you were playing Devil's Advocate, you could argue that this represents a preconceived view of the authors regarding the role of cholesterol, rather than the open, unbiased mind you would hope for in the spirit of scientific enquiry. That said, many important scientific breakthroughs happened due to the efforts of individuals who challenged a prevailing orthodoxy of thinking.
In general, the UK media provided fairly balanced reporting, presenting both sides of the argument – supporting the findings, but with critical views from other experts.



Read the complete article here.

Monday, December 9, 2013

Ask This Question Before Taking Statins - Penberthy

This article may be reprinted free of charge provided 1) that there is clear attribution to the Orthomolecular Medicine News Service, and 2) that both the OMNS free subscription link http://orthomolecular.org/subscribe.html and also the OMNS archive link http://orthomolecular.org/resources/omns/index.shtml are included.
FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, December 3, 2013

Ask This Question Before Taking Statins

Commentary by W. Todd Penberthy, PhD

(OMNS Dec 3, 2013) Before taking statins, ask yourself one question. Why is it, given two people with identical environmental backgrounds, that on average one of them dies early due to cardiovascular disease? Is it because that individual has taken less statin drugs? Of course not. It is likely due to something different in their genetics, which causes differences in enzymes and levels of other proteins. This leads to differing requirements for essential vitamins and minerals.
Cardiovascular disease is largely caused by deficiencies of essential nutrients. Thus adjusting the diet makes sense. When your car breaks down, do you have the repair shop install a gadget not in the car's parts list? Of course not. We clean, tighten, remanufacture, or replace the correct part. Similarly, the body needs maintenance and some tender loving care. Statins are not one of our parts. Essential nutrients are what we need.
The reason people die of cardiovascular disease usually begins with inflammation and progressive calcification, not cholesterol levels. The correlations between inflammation, calcification and death by cardiovascular disease (CVD) are much stronger than for correlations between cholesterol levels and death by CVD (Bolland et al, 2008).
Following the guidelines of the American Heart Association (AHA) may be useful for liability and good business, but is not always useful for maintaining optimal health. To understand what's going on inside of the body, just take a look at the images of vascular calcification. In response to inflammation in arteries, plaques form. At the center of an arterial plaque sits a hard calcification that contains calcium carbonate. Around this calcified nucleus, the plaque develops with fat deposits and a fibrous cap. In many cases the plaque can be reversed with excellent nutrition.
Considering the media attention given to statins, it's quite remarkable to learn that they only reduce the risk of mortality from CVD by less than 1 percent. In contrast, in clinical trials involving over 8,000 patients over 6 years, high dose niacin (3,000 mg daily) reduced mortality by 11%. And this lowered risk was tabulated 15 years after the clinical trial ended! (Canner et al., 1986) That represents a huge improvement over treatment with statins. Recent advances in molecular biology explain how this works. Niacin's amazing sustained effect is likely due to its effect on regulating sirtuin proteins that cause long lasting epigenetic changes in the structure of DNA. This type of epigenetic modulation is known to have long-lasting effects. The nutrition you get in early childhood, or even that your parents got before you were born, can affect your genes over a long period. The data from this study implies that 3,000 mg of niacin is far superior to statins for preventing CVD death. And it only costs about 35 cents per day.
Anyone who has the risk factors for death from CVD would be well advised to consider taking up to three 1,000 mg daily doses (or, for less flushing, 12 doses of 250 mg) of regular "fast-release" niacin (Hoffer et al, 2012). It would also be wise to add 100 mg of the MK7 form of vitamin K2 and 1,000 mg flax seed oil with every dose of niacin. These nutrients reduce flushing and provide anti-inflammatory benefits. For a healthy heart, include 3,000-10,000 mg of vitamin C (Roberts and Hickey, 2011), 400-1200 IU natural vitamin E, and five cups of kale mixed with colorful vegetables and a bit of grass fed butter every day. Further, to remove calcifications, it may help to daily take two 200-400 mg doses of magnesium (citrate, chelate, malate, or chloride). This can help to dissolve the calcium deposits in arteries (Dean, 2007). None of these essential nutrients requires any prescription, and together they have tremendous advantages for health compared to a statin pill.
(Dr. Todd Penberthy is a research consultant, medical writer and one of the world's prominent niacin researchers. A list of his recent papers is posted at http://www.cmescribe.com/resume/ )

References:

Bolland, M.J., Barber, P.A., Doughty, R.N., Mason, B., Horne, A., Ames, R., Gamble, G.D., Grey, A., and Reid, I.R. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. Bmj; 2008. 336(7638): 262-266.
Canner, P.L., Berge, K.G., Wenger, N.K., Stamler, J., Friedman, L., Prineas, R.J., and Friedewald, W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol; 1986. 8(6): 1245-1255.
Dean, C. The Magnesium Miracle. New York, NY: Ballantine, 2007.
Hoffer A, Saul AW, Foster HD. Niacin: The Real Story. Basic Health Publications, 2012.
Roberts H, Hickey S. The Vitamin Cure for Heart Disease: How to Prevent and Treat Heart Disease Using Nutrition and Vitamin Supplementation. Basic Health Publications, 2011.

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Editorial Review Board:

Ian Brighthope, M.D. (Australia)
Ralph K. Campbell, M.D. (USA)
Carolyn Dean, M.D., N.D. (USA)
Damien Downing, M.D. (United Kingdom)
Dean Elledge, D.D.S., M.S. (USA)
Michael Ellis, M.D. (Australia)
Martin P. Gallagher, M.D., D.C. (USA)
Michael Gonzalez, D.Sc., Ph.D. (Puerto Rico)
William B. Grant, Ph.D. (USA)
Steve Hickey, Ph.D. (United Kingdom)
Michael Janson, M.D. (USA)
Robert E. Jenkins, D.C. (USA)
Bo H. Jonsson, M.D., Ph.D. (Sweden)
Peter H. Lauda, M.D. (Austria)
Thomas Levy, M.D., J.D. (USA)
Stuart Lindsey, Pharm.D. (USA)
Jorge R. Miranda-Massari, Pharm.D. (Puerto Rico)
Karin Munsterhjelm-Ahumada, M.D. (Finland)
Erik Paterson, M.D. (Canada)
W. Todd Penberthy, Ph.D. (USA)
Gert E. Schuitemaker, Ph.D. (Netherlands)
Robert G. Smith, Ph.D. (USA)
Jagan Nathan Vamanan, M.D. (India)
Atsuo Yanagisawa, M.D., Ph.D. (Japan)
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This article may be reprinted free of charge provided 1) that there is clear attribution to the Orthomolecular Medicine News Service, and 2) that both the OMNS free subscription link http://orthomolecular.org/subscribe.html and also the OMNS archive link http://orthomolecular.org/resources/omns/index.shtml are included.
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Sunday, October 27, 2013

BMJ editor casts doubt on veracity of statin trials funded by the statin makers - Godlee

Statins for all over 50? No

Fiona Godlee, editor, BMJ

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f6412 (Published 23 October 2013)                                         Cite this as: BMJ 2013;347:f6412    
 
Should you prescribe statins to everyone over the age of 50, even those at low cardiovascular risk? A new Cochrane review seems to suggest that you should. An article in this week BMJ cries caution (doi:10.1136/bmj.f6123).

Current guidance from the UK’s National Institute for Health and Care Excellence (NICE) and the American Heart Association recommends statins only when the 10 year risk of cardiovascular disease is 20% or greater. But since these guidelines were written, a large meta-analysis of individual patient data reached a different conclusion. Published in the Lancet in 2012, the Cholesterol Treatment Trialists (CTT) Collaboration meta-analysis found that statins significantly reduced major cardiovascular events and all cause mortality in people at low risk, a benefit which, the paper said, “greatly exceeds any known hazards of statin therapy.”

As John Abramson and colleagues explain, it’s this meta-analysis that led the Cochrane reviewers to embrace the idea that statins should be used far more widely, even perhaps to everyone over 50, as a Lancet editorial suggested at the time.

But Abramson and colleagues’ detailed critique of the CTT meta-analysis should give us pause. Their own analysis of the data finds no evidence of a reduction in all cause mortality or in the total number of serious events. They also highlight the failure of the trials included in the CTT analysis to adequately report important harms of statin treatment, including myopathy and diabetes. They conclude that broadening the use of statins to low risk individuals “will unnecessarily increase the incidence of adverse events without providing overall health benefits.”

There is a concern underlying their critique that will be familiar to BMJ readers. It is that all of the trials included in the CTT meta-analysis were funded by the manufacturer of the statin being studied. They list the various ways in which these trials might have exaggerated the benefits of statins and minimised the harms, and they summarise what low risk patients need to know. Top of the list is the benefit of lifestyle change, something that the dominance of industry sponsored clinical trials too often obscures.

None of this does much to bolster confidence in the published literature. Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available (doi:10.1136/bmj.f1636). AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA (doi:10.1136/bmj.f4728).

As for a way forward, I can’t improve on the list of solutions proposed by Richard Lehman when emailing out his journal review blog this week (http://bit.ly/HcKvjy): “All phase 3 trials to be designed and conducted independently of manufacturers, using the best available comparator. Research priorities to be determined by patients (James Lind Alliance). Value-based pricing. All data available from all trials, with meta-data: IPD [individual patient data] level for qualified independent centres. Big increase in comparative effectiveness research, much more research into non-pharmacological treatments.”

Notes

Cite this as: BMJ 2013;347:f6412

Footnotes

  • Follow BMJ Editor Fiona Godlee on Twitter @fgodlee and the BMJ @bmj_latest
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Emphasis added.
Read the complete article here.

Thursday, October 24, 2013

Saturated fat is not the major issue - Malhotra

Saturated fat is not the major issue

BMJ 2013; 347 doi: http://dx.doi.org/10.1136/bmj.f6340 (Published 22 October 2013)
Cite this as: BMJ 2013;347:f6340

Let’s bust the myth of its role in heart disease

Scientists universally accept that trans fats—found in many fast foods, bakery products, and margarines—increase the risk of cardiovascular disease through inflammatory processes.1 But “saturated fat” is another story. The mantra that saturated fat must be removed to reduce the risk of cardiovascular disease has dominated dietary advice and guidelines for almost four decades.

Yet scientific evidence shows that this advice has, paradoxically, increased our cardiovascular risks. Furthermore, the government’s obsession with levels of total cholesterol, which has led to the overmedication of millions of people with statins, has diverted our attention from the more egregious risk factor of atherogenic dyslipidaemia.

Saturated fat has been demonised ever since Ancel Keys’s landmark “seven countries” study in 1970.2 This concluded that a correlation existed between the incidence of coronary heart disease and total cholesterol concentrations, which then correlated with the proportion of energy provided by saturated fat. But correlation is not causation. Nevertheless, we were advised to cut fat intake to 30% of total energy and saturated fat to 10%.”3 The aspect of dietary saturated fat that is believed to have the greatest influence on cardiovascular risk is elevated concentrations of low density lipoprotein (LDL) cholesterol. Yet the reduction in LDL cholesterol from reducing saturated fat intake seems to be specific to large, buoyant (type A) LDL particles, when in fact it is the small, dense (type B) particles (responsive to carbohydrate intake) that are implicated in cardiovascular disease.4

Indeed, recent prospective cohort studies have not supported any significant association between saturated fat intake and cardiovascular risk.5 Instead, saturated fat has been found to be protective. The source of the saturated fat may be important. Dairy foods are exemplary providers of vitamins A and D. As well as a link between vitamin D deficiency and a significantly increased risk of cardiovascular mortality, calcium and phosphorus found commonly in dairy foods may have antihypertensive effects that may contribute to inverse associations with cardiovascular risk.6 7 8

One study showed that higher concentrations of plasma trans-palmitoleic acid, a fatty acid mainly found in dairy foods, was associated with higher concentrations of high density lipoprotein, lower concentrations of triglycerides and C reactive protein, reduced insulin resistance, and a lower incidence of diabetes in adults.9 Red meat is another major source of saturated fat. Consumption of processed meats, but not red meat, has been associated with coronary heart disease and diabetes mellitus, which may be explained by nitrates and sodium as preservatives.10

The notoriety of fat is based on its higher energy content per gram in comparison with protein and carbohydrate. However, work by the biochemist Richard Feinman and nuclear physicist Eugene Fine on thermodynamics and the metabolic advantage of different diet compositions showed that the body did not metabolise different macronutrients in the same way.11 Kekwick and Pawan carried out one of the earliest obesity experiments, published in the Lancet in 1956.12 They compared groups consuming diets of 90% fat, 90% protein, and 90% carbohydrate and showed that the greatest weight loss was in the fat consuming group. The authors concluded that the “composition of the diet appeared to outweigh in importance the intake of calories.”

The “calorie is not a calorie” theory has been further substantiated by a recent JAMA study showing that a “low fat” diet resulted in the greatest decrease in energy expenditure, an unhealthy lipid pattern, and increased insulin resistance in comparison with a low carbohydrate and low glycaemic index diet.13 In the past 30 years in the United States the proportion of energy from consumed fat has fallen from 40% to 30% (although absolute fat consumption has remained the same), yet obesity has rocketed.

One reason: when you take the fat out, the food tastes worse. The food industry compensated by replacing saturated fat with added sugar. The scientific evidence is mounting that sugar is a possible independent risk factor for the metabolic syndrome (the cluster of hypertension, dysglycaemia, raised triglycerides, low HDL cholesterol, and increased waist circumference).

In previous generations cardiovascular disease existed largely in isolation. Now two thirds of people admitted to hospital with a diagnosis of acute myocardial infarction really have metabolic syndrome—but 75% of these patients have completely normal total cholesterol concentrations.14 Maybe this is because total cholesterol isn’t really the problem?

The Framingham heart study sanctified total cholesterol as a risk factor for coronary artery disease, making statins the second most prescribed drug in the US and driving a multibillion dollar global industry. In the United Kingdom eight million people take statins regularly, up from five million 10 years ago. With 60 million statin prescriptions a year, it is difficult to demonstrate any additional effect of statins on reduced cardiovascular mortality over the effects of the decline in smoking prevalence and primary angioplasty.15

Despite the common belief that high cholesterol is a significant risk factor for coronary artery disease, several independent population studies in healthy adults have shown that low total cholesterol is associated with cardiovascular and non-cardiac mortality, indicating that high total cholesterol is not a risk factor in a healthy population.16 17 18

A recent “real world” study of 150 000 patients who were taking statins showed “unacceptable” side effects—including myalgia, gastrointestinal upset, sleep and memory disturbance, and erectile dysfunction—in 20% of participants, resulting in discontinuation of the drug.19 This is massively at odds with the major statin trials that report significant side effects of myopathy or muscle pain in only one in 10 000.

A meta-analysis of predominantly industry sponsored data reported that in a low risk group of people aged 60-70 years taking statins the number needed to treat (NNT) to prevent one cardiovascular event in one year was 345.20 The strongest evidence base for statins is in secondary prevention, where all patients after a myocardial infarction are prescribed maximum dose treatment irrespective of total cholesterol, because of statins’ anti-inflammatory or pleiotropic (coronary plaque stabilising) effects. In this group the NNT is 83 for mortality over five years. This doesn’t mean that each patient benefits a little but rather that 82 will receive no prognostic benefit.21 The fact that no other cholesterol lowering drug has shown a benefit in terms of mortality supports the hypothesis that the benefits of statins are independent of their effects on cholesterol.

Adopting a Mediterranean diet after a heart attack is almost three times as powerful in reducing mortality as taking a statin. The recently published PREDIMED randomised controlled trial was stopped early after it showed that in high risk people the Mediterranean diet achieved a 30% improvement over a “low fat” diet in terms of cardiovascular events.22

Pharmacotherapy can assuage the symptoms but can’t alter the pathophysiology. Doctors need to embrace prevention as well as treatment. The greatest improvements in morbidity and mortality have been due not to personal responsibility but rather to public health. It is time to bust the myth of the role of saturated fat in heart disease and wind back the harms of dietary advice that has contributed to obesity.

Notes

Cite this as: BMJ 2013;347:f6340
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Read the complete article here.

Read also - Top heart doctor: Unprocessed fatty foods may actually be good for you

Watch this excellent video on saturated fat and heart disease. http://www.abc.net.au/catalyst/stories/3876219.htm
Here are some quotes from the video:

Dr Johnny Bowden
"Sugar is far more damaging to the heart than fat ever was, and we're beginning to see this now. So, this focus on cholesterol has been incredibly destructive because we haven't looked at these real promoters of heart disease - inflammation, oxidative damage, sugar in the diet, and number one with a bullet - stress."


Dr Johnny Bowden
"Margarine is the perfect example of the stupidest nutritional swap-out in history. We had this trans fat-laden crappy manufactured product that we were eating because we were so phobic about saturated fat and cholesterol."

Dr Stephen Sinatra
"To switch to polyunsaturated fats with the vegetable oils, that's horrific advice. The polyunsaturated fats, the vegetable oils, these omega-6 oils, are inflammatory because they're very prone to oxidation."


Dr Stephen Sinatra
"It took decades to really entrench this myth. It's probably going to take a few more decades to get us out of this myth. But to vilify saturated fats I think is one of the worst things the medical profession has done."

Dr Ernest Curtis
"I'd love to see the medical establishment saying, 'Whoops, we were wrong'. That's not going to happen. Frankly, that generation is going to have to die off, and perhaps the generation coming up can do better."

Thursday, September 5, 2013

Wake Up CALL

Wake-up call for sleep related CVD risk

Geneva, Switzerland - Those who sleep badly, and not for long, have a 65% increased risk of cardiovascular disease—and an even greater risk of coronary heart disease—compared with normal sleepers, according to new research presented at the EuroPRevent 2011 meeting this past weekend.
 
Researcher Marieke Hoevenaar-Blom (National Institute for Public Health and the Environment, Bilthoven, the Netherlands) explained that several investigations have found an increased risk of CVD in short sleepers compared with normal sleepers, but this is the first study to take into account whether people rise feeling rested. The results should help confirm that suboptimal sleep is a risk factor for cardiovascular disease, something she says is not widely appreciated in the cardiology community.
 
Hoevenaar-Blom, who is studying for a PhD in primary prevention of cardiovascular disease by lifestyle, reported her findings from 12 years of follow-up in a Dutch cohort during an oral session; she was nominated for a young investigator award for her research, which has also been accepted by the journal Sleep for publication [1].
 
"The message is that you have to assess sleep, and especially sleep quality, when you see a patient, because it might be a risk factor for cardiovascular diseases," Said Hoevenaar-Blom "When a patient is sleeping poorly, you can very easily fix that," she noted, although she acknowledged that this involves figuring out what is causing the sleep disturbance. However, simple advice—such as restricting intake of caffeinated drinks after a certain time and not watching TV late—can often be useful, she suggested.
 
Is sleep quality a modifying factor in association with CVD?
 
In the Monitoring Project on Risks Factors and Chronic Diseases in the Netherlands (MORGEN) study, Hoevenaar-Blom and her colleagues explored the combined associations of sleep duration and quality with CVD and CHD incidence.
The message is that you have to assess sleep, and especially sleep quality, when you see a patient, because it might be a risk factor for cardiovascular diseases.
Information on sleep duration and quality was obtained by a self-administered questionnaire filled in by 20 432 participants (9217 men and 11 215 women aged 20 to 65 years) between 1993 and 1997. Over 10 to 15 years of follow-up, data on morbidity and causes of death were obtained through linkage with several national registries.
 
Average sleep duration was assessed by asking participants how many hours of sleep they usually got in a 24-hour period. Short sleep duration was defined as six hours or less, while long sleep duration was sleeping for nine hours or more per 24-hour period. Sleeping for seven to eight hours was designated "normal." Sleep quality was assessed in the first two years of baseline measurements with the question, "Do you usually rise feeling rested?"
"Our research questions were: 'What is the association between sleep duration and cardiovascular disease and coronary heart disease? And is sleep quality a modifying factor in this association?' " Hoevenaar-Blom explained.
 
After 10 to 15 years of follow-up (mean 11.9 years), 1486 participants developed CVD, of whom 177 had a fatal event. After adjustment for multivariate confounders, short sleepers had a 15% higher risk of incident CVD compared with participants with normal sleep duration, a finding that was significant, and short sleepers had an even stronger, 23% higher risk of CHD compared with normal sleepers.
 
It's not just quantity, but quality, that is important
 
On its own, no association was found between sleep quality and CVD incidence, but when assessing quality in combination with sleep duration, short sleepers with poor-quality sleep had a 65% higher risk of CVD and an 85% higher risk of CHD than participants with a normal sleep duration and good sleep quality.
 
The investigators found no association between long sleep duration and CVD, a finding that contradicts previous studies, said Hoevenaar-Blom. She noted that there has never been any biological mechanism to explain why people who sleep longer have increased risk, but she hypothesized it could be due to reverse causality—that these people were perhaps ill in the first place and therefore slept longer.
 
Asked whether psychosocial stress could be contributing to poor sleep quality and short duration of sleep, she acknowledged that, of course, this was likely. "We do need more research," she observed.
 
"In conclusion, short sleepers have an increased risk of total CVD and CHD; the risk in short sleepers is the largest when they are not rising rested; it's really the combination" that is important, she said.
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Read the complete article here.

Friday, July 12, 2013

Statin = substantial increase in diabetes risk in postmenopausal women

Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women's Health Initiative

ABSTRACT

Background  This study investigates whether the incidence of new-onset diabetes mellitus (DM) is associated with statin use among postmenopausal women participating in the Women's Health Initiative (WHI).


Methods  The WHI recruited 161 808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 with ongoing follow-up. The current analysis includes data through 2005. Statin use was captured at enrollment and year 3. Incident DM status was determined annually from enrollment. Cox proportional hazards models were used to estimate the risk of DM by statin use, with adjustments for propensity score and other potential confounding factors. Subgroup analyses by race/ethnicity, obesity status, and age group were conducted to uncover effect modification.

Results  This investigation included 153 840 women without DM and no missing data at baseline. At baseline, 7.04% reported taking statin medication. There were 10 242 incident cases of self-reported DM over 1 004 466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM (hazard ratio [HR], 1.71; 95% CI, 1.61-1.83). This association remained after adjusting for other potential confounders (multivariate-adjusted HR, 1.48; 95% CI, 1.38-1.59) and was observed for all types of statin medications. Subset analyses evaluating the association of self-reported DM with longitudinal measures of statin use in 125 575 women confirmed these findings.

Conclusions  Statin medication use in postmenopausal women is associated with an increased risk for DM. This may be a medication class effect. Further study by statin type and dose may reveal varying risk levels for new-onset DM in this population.
 
Given the success of statins in both primary and secondary prevention of cardiovascular morbidity and mortality,16 their use is progressively increasing, especially among older Americans.7 With such widespread use, even small risks are apparent alongside benefits. One emerging risk is an increased incidence of diabetes mellitus (DM). There is evidence that incident DM associated with statin use may be more common in the elderly, in women, and in Asians.812 A recent analysis suggests that preexisting metabolic risk factors control incident DM rate with statin medication.13 It is unclear if this risk varies with individual statins or if this is a dose-driven class effect.9,14 Although experimental and clinical studies find that individual statins act differently on glucose homeostasis as a function of relative lipophilicity and/or potency of action,15 other findings differ. A recent meta-analysis of 17 randomized controlled trials by Mills et al16 found a class effect increase of new-onset DM with statins (odds ratio [OR], 1.09; 95% CI, 1.02-1.16) similar to that reported by Sattar et al.9 Possibly, the grouping of statins masks the effect variation of individual statins. Still, at some given dose threshold, differences may be overcome, as implied by a meta-analysis of 5 trials comparing intensive to moderate dosing regimens using mainly atorvastatin and simvastatin.13,17 Notably, meta-analysis results display intertrial and intratrial variability in diagnostic and statistical methods and do not consistently consider confounding factors. Moreover, contributing sample sizes do not permit balanced comparison by statin type, sex, race/ethnicity, and age. Similarly, single studies may uncover only part of a greater topography.
 
As a large part of the aging population, postmenopausal women have not been fully represented in past clinical trials.16 Sex differences in DM pathogenesis are well recognized.1819 Using the Women's Health Initiative (WHI) data, we evaluated the overall effect of statin medication use on incident DM risk and examined these associations by specific statin agent. We stratified analyses by race/ethnicity, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) category, and age group to determine if any associations were modified by these factors. In addition, we conducted subgroup analysis in women with and without self-reported cardiovascular disease (CVD) at baseline to address potential confounding and selection bias.

METHODS

The WHI recruited 161 808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 and followed consenting participants. Of these women, 68 132 were enrolled in 1, 2, or all 3 of the clinical trial (CT) arms: the Dietary Modification Trial, the Hormone Trial, and the Calcium and Vitamin D Trial. Another 93 676 women were enrolled into a prospective observational study (OS).2023 The WHI eligibility criteria included the ability to complete study visits with expected survival and local residency for at least 3 years. Original exclusion criteria addressed conditions that would limit full participation in the study. This analysis used WHI data through 2005. After exclusion for prevalent DM, missing data, and use of cerivastatin (this medication was withdrawn from the market in 2001 for safety reasons), a total of 153 840 women were included (Figure).
 
Figure. Flowchart for statin users and diabetes mellitus (DM) analyses using data sets from the Women's Health Initiative.                    
+Image not available.
MEASUREMENT AND CLASSIFICATION OF STATIN MEDICATIONS
The current medication regimens of all CT participants were inventoried at baseline and at years 1, 3, 6, and 9. In the OS, medication data were inventoried at baseline and year 3. At each inventory, the brand or generic name on the medication label was matched to the corresponding item in the Master Drug Data Base (Medi-Span, Indianapolis, Indiana). We sorted for statin use as users or nonusers at baseline and year 3. Given that Sattar et al9 found a null effect of lipophilicity among statins, and in the absence of dose information, we determined statin categories by relative potency of action to decrease low-density lipoprotein cholesterol. Accordingly, statins were designated as low (fluvastatin, lovastatin, pravastatin) or high (simvastatin, atorvastatin) potency.2425
IDENTIFICATION OF DM
At baseline and at each semiannual (CT) or annual (OS) contact, incident treated DM was identified by questionnaire and was defined as a self-report of a new physician diagnosis of treated DM. This method of identification of prevalent and incident DM has been used in prior publications by the WHI investigators.18,2628 The accuracy of self-reported DM in the WHI trials has been assessed using medication and laboratory data, and self-reported DM was found to be reliable.29
COVARIATES
Baseline questionnaires ascertained demographic and health history information, including race/ethnicity, age, educational attainment, family history of DM, family history of depression, self-report of CVD, hormone therapy use, and smoking status. Baseline self-report for CVD has been previously validated in the WHI3031 and found to have reasonable agreement with hospital discharge International Classification of Diseases, Ninth Revision (ICD-9) codes.
 
The metabolic equivalents of physical activities and average daily nutrient intake were computed, using detailed methods described elsewhere.3233 Trained and certified clinic staff measured height using a fixed stadiometer and weight by a calibrated balance-beam scale. Relative weight as BMI was calculated from these values. Blood was analyzed for glucose and insulin for the random 6% WHI-CT blood subsample at baseline, year 1, year 3, year 6, and year 9. Fasting glucose was analyzed using the hexokinase method with interassay coefficients of variation less than 2%.26 Insulin was measured by enzyme-linked immunosorbent assay. The WHI used the homeostasis model assessment of insulin resistance (HOMA-IR), which was developed for application in large epidemiologic investigations as an alternative to the glucose clamp. HOMA-IR = fasting plasma insulin (μIU/mL) × fasting plasma glucose (mmol/L)/22.5.34
STATISTICAL ANALYSIS
Cox proportional hazards (PH) models were used to estimate hazard ratios (HRs) of DM by statin medication use. The dependent variable was time to occurrence of DM determined by self-report (ie, time to event). The time to event was calculated as the interval between enrollment date and the earliest of the following: (1) date of annual medical history update when new DM was ascertained (observed outcome) and (2) date of the last annual medical update during which DM status was ascertained (censored outcome). The primary independent variable in these analyses was statin use at baseline, coded as a binary variable. We present 3 Cox PH models to examine the association between baseline statin use and DM: model 1 estimates the unadjusted HRs (and associated 95% CIs) of the effects of statin use on incident DM; model 2 presents age- and race/ethnicity–adjusted HRs; and model 3 presents HRs adjusted for all potential confounding variables at baseline (age, race/ethnicity, education, cigarette smoking, BMI, physical activity, alcohol intake, energy intake, family history of DM, hormone therapy use, study arm, and self-report of CVD). Similar analyses were conducted for specific type of statin medication use at baseline, categorized as low vs high potency.
 
Since individuals using statins may have different underlying conditions that could put them at elevated risk for DM, we conducted several subgroup analyses to control confounding by indication. First, we conducted subgroup analyses by age, race/ethnicity, and BMI categories to examine whether the associations of statin use and onset of DM differed by categories of these variables. Age was categorized into 3 groups (50-59 years, 60-69 years, and ≥70 years). Race/ethnicity was assessed according to 4 major groups (white, African American, Hispanic, Asian). Body mass index was categorized into 3 groups (<25 .0="" 25.0-29.9="" 2="" analyses="" analysis="" at="" baseline.="" conducted="" cvd="" either="" finally="" in="" of="" or="" propensity="" score="" second="" self-reported="" similar="" subgroups="" sup="" we="" with="" without="" women="">35
was performed to reduce the confounding effects of other factors in the evaluation of the association between statin use and DM risk within an observational study setting. Participant-specific propensity scores were estimated from a logistic regression model to predict the probability of statin prescription. Covariates considered for inclusion into the logistic regression model included age, BMI, self-report of hypertension, self-report of CVD, family history of DM, smoking status, and physical activity. The final propensity score model retained all covariates noted herein with the exception of physical activity, which was an insignificant predictor of statin use. The association between statin use and DM risk was evaluated in Cox PH models after adjusting for the estimated propensity score.
 
After exclusion for cases of DM before year 3 (146 women), use of cerivastatin (651 women), and missing medication data at year 3 (2 women), our longitudinal analyses were conducted in a subset of 125 575 women from the OS and the CT arm at baseline and year 3 visits. Statin use was sorted into 4 categories: (1) never took statin; (2) use at both baseline and at the year 3 visit, (3) use only at baseline; and (4) use only at the year 3 visit. The HRs for DM by statin use were estimated similarly based on Cox PH models.

RESULTS

Participant characteristics are listed in Table 1. At baseline, the mean (SD) age of women included in our sample was 63.2 (7.3) years. Approximately 16.30% of the women were from racial/ethnic groups other than white, of which the largest representation was African American (8.32%). Only 2.56% (3922 women) were Asian. At baseline, 7.04% of participants took statin medication. Of these, 30.29% took simvastatin; 27.29%, lovastatin; 22.52%, pravastatin; 12.15%, fluvastatin; and 7.74%, atorvastatin. Comparison between statin users and nonusers showed significant differences in baseline characteristics.
 
Table Graphic Jump Location Table 1. Characteristics of 153 840 Study Participants, Women's Health Initiativea
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A total of 10 242 incident cases of DM were reported over 1 004 466 person-years of follow-up. Table 2 presents results regarding the association between statin use at baseline and risk of incident DM. In unadjusted models, statin use at baseline was significantly associated with an increased DM risk (HR, 1.71; 95% CI, 1.61-1.83) when compared with nonuse. This association was decreased but remained significant after adjusting for potential confounders (HR, 1.48; 95% CI, 1.38-1.59). This association was observed for all types of statin. Similar risk associations were found in use of either high- or low-potency statins, with multivariate-adjusted HRs of 1.45 (95% CI, 1.36-1.61) and 1.48 (95% CI, 1.36-1.61) compared with nonusers, respectively. Table 3 shows subgroup analyses by race/ethnicity, BMI category, and age group. In both unadjusted and adjusted models, statin use was consistently associated with increased risk of DM across subgroups by age. We observed significantly increased risk of DM by statin use within subgroups of white, Hispanic, and Asian women in both unadjusted and adjusted models. In adjusted models, we observed HRs of 1.49 (95% CI, 1.38-1.62), 1.18 (95% CI, 0.96-1.45), 1.57 (95% CI, 1.14-2.17), and 1.78 (95% CI, 1.32-2.40) among whites, African Americans, Hispanics, and Asians, respectively. Statin use was also associated with a significantly increased risk of DM within 3 subgroups according to BMI (<25 .0="" 1.09-1.33="" 1.20="" 1.48-1.87="" 1.57-2.29="" 1.66="" 1.89="" 25.0-29.9="" 25.0="" 29.9="" 30.0="" a="" adjusted="" adjusting="" after="" all="" among="" and="" associated="" bmi="" ci="" compared="" confounders.="" dm="" for="" groups="" higher="" hrs="" in="" increased="" less="" lower="" models="" moreover="" observed="" of="" or="" p="" potential="" respectively.="" risk="" significantly="" statin="" than="" the="" to="" use="" was="" were="" when="" with="" within="" women="">
 
Table Graphic Jump Location Table 2. Association Between Diabetes Mellitus (DM) Risk and Statin Use Status at Baseline in 153840 Participants
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To address potential confounding and selection bias, we conducted subgroup analyses among postmenopausal women with and without a history of CVD (Table 4). Among a subset of 24 842 women who self-reported CVD at baseline, we found that statin use was associated with an increased risk of DM (HR, 1.52; 95% CI, 1.36-1.71). These associations remained significant after adjusting for potential confounders (HR, 1.46; 95% CI, 1.29-1.65). Similar findings were observed among women without CVD at baseline.
 
Table Graphic Jump Location Table 4. Risk of Diabetes Mellitus (DM) by Statin Use Among Women With and Without Medical History of Cardiovascular Disease (CVD) at Baseline                    
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In unadjusted models, statin use was significantly related to DM risk (HR, 1.71; 95% CI, 1.61-1.83). When the propensity score was included, the estimated HR attenuated to 1.38 (95% CI, 1.29-1.47). On inclusion of other confounders in the model, the HR was essentially unaltered (HR, 1.40; 95% CI, 1.31-1.51). Propensity score adjusted models yielded HRs of 1.38 (95% CI, 1.23-1.54) and 1.40 (95% CI, 1.29-1.53) for respective increased risk with either high- or low-potency statin use at baseline compared with nonuse.
LONGITUDINAL MEASURES OF STATIN USE AND RISK OF DM
When compared with those who never received statin therapy, unadjusted HRs of 1.82 (95% CI, 1.65-2.00), 1.75 (95% CI, 1.43-2.14), and 1.81 (95% CI, 1.67-1.97) were observed for the groups of women who reported statin use at both baseline and at the year 3 visit, reported statin use only at baseline, and reported statin use only at the year 3 visit, respectively (Table 5). The risk associations remained significant after adjusting for age, race/ethnicity, other potential confounders, and propensity score. The multivariate adjusted HRs were 1.47 (95% CI, 1.32-1.64), 1.44 (95% CI, 1.15-1.80), and 1.60 (95% CI, 1.47-1.75), respectively.
 
Table Graphic Jump Location Table 5. Risk of Diabetes Mellitus (DM) by Statin Use at Baseline and 3-Year Follow-up in 125575 Participants
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SENSITIVITY ANALYSIS
A sensitivity analysis was conducted on a subset of 3706 women without DM at baseline and enrolled in the WHI CT for whom fasting glucose measurements were available at baseline and at least 1 additional follow-up visit. Diabetes mellitus was identified based on fasting glucose levels of 126 mg/dL (6.99 mmol/L) or higher. In unadjusted models, statin use at baseline was not significantly related to DM risk (HR, 1.06; 95% CI, 0.61-1.86). However, using baseline through year 6 data in the CT arm, we found that the statin users had higher fasting glucose levels and HOMA-IR compared with non–statin users, with increasing values from baseline to year 6 follow-up.
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Friday, June 7, 2013

Preventing Glucose-Induced Cardiovascular Damage - Michaels

Preventing Glucose-Induced Cardiovascular Damage

Conditions Associated With Elevated Blood Glucose and Advanced Glycation End Products
Elevated cholesterol and atherosclerosis49,50
Symptoms of carotid artery atherosclerosis (major risk for stroke)51
Risk of developing high risk cardiac rhythm disturbances following heart attack52
Cataracts of the eye35
Overall risk of developing cancer53
Risk of developing fatal cancer54
Increased prostate size in benign prostatic hyperplasia (BPH)55
Abnormal elevation in liver enzymes, markers of liver damage56
Incidence and severity of obstructive sleep apnea57
Blood vessels are lined by a thin layer of cells called the endothelium which constantly regulates blood pressure and flow. Damage to the endothelium, which occurs in response to elevated glucose levels, is an important first step in producing heart attacks, heart failure, and stroke.

Studies now show that benfotiamine can prevent endothelial dysfunction and substantially improve blood vessel and heart muscle function, even in the face of glucose-induced tissue damage.

The process of healthy endothelial cell replication is vital to maintaining healthy arteries. Excess levels of glucose can reduce endothelial cell replication. The addition of benfotiamine to endothelial cells grown in a high-glucose environment corrects the defective replication. Benfotiamine accomplishes this through normalization of advanced glycation end product production.

High glucose levels also trigger early death of endothelial cells through the process called apoptosis; benfotiamine supplementation reverses increased apoptosis in cultures of endothelial cells by several mechanisms.

The body produces toxic alcohol-like compounds called polyols during periods of high blood sugar. Polyols disrupt endothelial and cardiovascular cell function. Benfotiamine reduces production of polyols, accelerates the rate of glucose breakdown, and reduces free glucose levels within cells. All of these effects further contribute to protection of endothelial cell function.

After a heart attack, or as a result of persistently high blood pressure, heart muscle cells beat more weakly than they should, resulting in heart failure. High glucose levels and advanced glycation end products substantially contribute to this diminished heart muscle function. Studies show that benfotiamine abolishes many of the abnormalities in heart muscle cell contractility, which may "rescue" impaired heart muscle and improve its ability to pump blood effectively. Benfotiamine activates important cell survival signaling pathways in heart muscle cells failing under the effects of elevated glucose.

Preventing Glucose-Induced Cardiovascular Damage
Atherosclerosis
Not all advanced glycation end products (AGEs) are produced internally in the body. Consuming a meal rich in AGEs (such as one abundant in browned meats or caramelized sugars) can increase blood levels of AGEs and impair endothelial function. Supplementation with benfotiamine, 1,050 mg/day for 3 days, completely prevented the changes in endothelial function and blood flow produced by such a meal in a group of human subjects.

In addition to its effective control of AGE-related endothelial dysfunction, benfotiamine exerts powerful direct antioxidant effects. In rats with experimentally induced vascular endothelial dysfunction, benfotiamine reduced oxidative stress and enhanced favorable generation of nitric oxide, a compound that contributes to blood vessel relaxation.33,34 The result was an improvement in endothelial integrity and function.

All of these endothelium-protecting effects make benfotiamine an essential nutrient in your fight against the devastating effects of elevated blood glucose on your cardiovascular system.
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