#statin

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2014.3.28 JR東海道本線 小田原駅 Odawara Station

[michaelsnaithblog-blog]

HIV Is Linked to a Doubled Heart Disease Risk

A new analysis of a massive amount of global data reached a conclusion similar to that of previous research.

[yourarchiesmith01-blog]

Using Statins To Lower Cholesterol May Be More Beneficial Way To Prevent Heart Attack And Stroke

Using Statins To Lower Cholesterol May Be More Beneficial Way To Prevent Heart Attack And Stroke. Broader use of cholesterol-lowering statins may be a cost-effective aspect to slow sensibility attack and stroke, US researchers suggest. In the study, published online Sept 27, 2010 in the annual Circulation enhancers. The researchers also found that screening for exuberant sensitivity C-reactive protein (CRP) to identify patients who may benefit from statin remedy is only cost-effective in certain cases. Elevated levels of CRP indicate inflammation and suggest an increased hazard for heart attack and stroke trusted2all.com. Currently, statin therapy is recommended for high-risk patients - those with a 20 percent or greater imperil of some type of cardiovascular event within the next 10 years. But statins may also forward people with a lower risk, according to Dr Mark Hlatky, professor of health delve into and policy and of cardiovascular medicine at Stanford University School of Medicine in Stanford, Calif, and colleagues proextenderworld.com. Hlatky's yoke set out to determine the cost-effectiveness of three statin therapy approaches in patients with regular cholesterol levels and no evidence of heart disease or diabetes: following current guidelines; conducting CRP screening in patients who don't carry out current statin treatment guidelines and offering statins to those with animated CRP levels; and providing statin therapy based on a patient's cardiovascular danger alone, with no CRP testing. The researchers analyzed which of the three approaches met the generally accepted cost-effectiveness beginning of no more than $50000 per quality-adjusted life-year. They found that statin therapy based on cardiovascular endanger alone, without CRP testing, was the most cost-effective strategy. Initiating statin treatment at lower jeopardy levels - without CRP testing - "would further improve clinical outcomes at pleasing cost, making it the optimally cost-effective strategy in our analysis," the researchers wrote in a university report release. "Ideally, a marker would tell us who will benefit from drug treatment and who will not," Hlatky biting out in the release. "If a test could give us that information, it would be very cost-effective luxembourg. But there's not good evidence yet that CRP, or any other test, parts that well".

[didanawisgi]

Abstract

The role of blood cholesterol levels in coronary heart disease (CHD) and the true effect of cholesterol-lowering statin drugs are debatable. In particular, whether statins actually decrease cardiac mortality and increase life expectancy is controversial. Concurrently, the Mediterranean diet model has been shown to prolong life and reduce the risk of diabetes, cancer, and CHD. We herein review current data related to both statins and the Mediterranean diet. We conclude that the expectation that CHD could be prevented or eliminated by simply reducing cholesterol appears unfounded. On the contrary, we should acknowledge the inconsistencies of the cholesterol theory and recognize the proven benefits of a healthy lifestyle incorporating a Mediterranean diet to prevent CHD.

INTRODUCTION

Nearly twenty years ago two landmark randomized clinical trials appeared in The Lancet which forever changed the course of medicine for patients with coronary heart disease (CHD). The 4S study employed a cholesterol-lowering statin drug and reported a 30% mortality reduction[1]. The Lyon Diet Heart Study utilized the Mediterranean diet and reported a 70% mortality reduction[2]. Subsequent studies of the Mediterranean diet have confirmed these findings and also shown a reduced risk of cancer, diabetes, and Alzheimer’s disease[3-6]. Subsequent statin studies have led the United States Food and Drug Administration to issue warnings regarding the increased risk of diabetes and decreased cognition with statin drugs. Paradoxically, statins have gone on to become a multi-billion dollar industry and the foundation of many cardiovascular disease prevention guidelines while the Mediterranean diet has often been ignored. We believe this statin-centric cholesterol-lowering approach to preventing CHD may be misguided.

ASSOCIATION DOES NOT EQUAL CAUSATION

The cholesterol hypothesis links cholesterol intake and blood levels to cardiovascular disease. Because cholesterol is considered a risk factor for atherosclerosis many believe that lowering cholesterol in the blood is the best way to prevent CHD. Ideally, risk factors should help us distinguish those who will develop a disease from those who will not. However, if one examines the original Framingham Heart Study data (as an example) it is clear that the cholesterol levels of those who developed CHD and those who did not overlap except when the total cholesterol level exceeded 380 mg/dL or was less than 150 mg/dL (Figure ​(Figure1).1). Moreover, cholesterol may be associated with CHD but that does not prove causation. Despite the fact that high triglycerides and low HDL have long been associated with CHD, studies designed to raise HDL or lower triglycerides have failed to reduce CHD mortality. Similarly, cholesterol should not automatically become a treatment target. It may be a leap of faith to assume that lowering cholesterol is the best way to prevent CHD.

Figure 1

Serum cholesterol distribution among coronary heart disease and non-coronary heart disease patients in the Framingham Heart Study[43]. Reprinted with permission of the publisher. CHD: Coronary heart disease.

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LOWERING CHOLESTEROL MAY NOT LOWER CARDIOVASCULAR MORTALITY

The rare occurrence of CHD in isolated, rural societies such as Tukisenta, New Guinea has been attributed to low cholesterol levels[7]. However, it is equally plausible that the diets and lifestyles of these individuals may protect them from CHD. While we may never be certain if low cholesterol or a healthy lifestyle (or both) are responsible for preventing CHD in these societies, there is ample evidence that lowering cholesterol does not consistently lower CHD mortality. Reducing cholesterol blood levels by reducing dietary saturated fats is commonly recommended, but an exhaustive review and meta-analysis of 72 dietary studies concluded that reduced consumption of saturated fat does not reduce cardiovascular mortality[8]. Many drugs such as niacin, fibrates, and bile acid sequestrants can lower cholesterol levels, but the recent AHA/ACC guidelines on cholesterol concluded that these drugs do not lower CHD mortality rates[9]. Moreover, the results of cholesterol-lowering statin trials, as will be discussed and analyzed later, do not consistently lower mortality rates[10]. Consider also the dramatic mortality benefit of the Mediterranean diet in the Lyon Diet Heart Study which was achieved without a reduction in cholesterol levels[2-4]. Thus, the hypothesis that lowering cholesterol lowers mortality from CHD is not supported by many clinical research studies.

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EARLY STATIN TRIALS MAY HAVE BEEN FLAWED

Early statin trials reported significant mortality benefits, yet serious concerns have been raised in some studies regarding biased results, premature trial terminations, under reporting of adverse events, high numbers of patients lost to follow-up and oversight by the pharmaceutical company sponsor[10]. Heightened awareness within the scientific community regarding problems in clinical trial conduct and analysis - exemplified by the unreported risk of heart attacks in patients taking the pain killers Vioxx and Celebrex - led to new regulatory rules for clinical trials in 2005[11]. Curiously, statin trials conducted after 2005 have failed to demonstrate a consistent mortality benefit[10].

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MORTALITY RESULTS ARE MORE IMPORTANT THAN COMBINED CLINICAL ENDPOINTS

Cholesterol-lowering statin trials are often viewed as supporting the cholesterol hypothesis by reporting significant reductions in combined clinical endpoints. Clinical endpoints are valuable and should not be ignored, but the ultimate measure of efficacy is total mortality that reflects both the treatment effect and potentially fatal side effects. Utilizing combined endpoints may lead to an exaggeration of perceived benefit by assigning equal importance to disparate clinical events such as a hospital admission for angina and death from a heart attack[12,13]. Some have argued that there is a linear relation between low-density lipoprotein (LDL) levels and CHD events[14]. This analysis may be inaccurate because it combines different types of CHD events from diverse studies into one endpoint even though each study defines CHD events differently. A more meaningful analysis compares total mortality rates to LDL cholesterol levels. When we performed such an analysis on these same statin trials - those analyzed in reference 14 - we found no statistically significant relationship (Figure ​(Figure22).

Figure 2

Comparison of mortality rates to low-density lipoprotein cholesterol levels using the randomized clinical trials cited in reference 14 (taken as an example).

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MORTALITY BENEFITS OF STATINS ARE INCONSISTENT

Although a number of statin trials have reported a mortality benefit, quite a few have not. A corollary to the cholesterol hypothesis posits that patients at highest risk should derive the greatest benefit from cholesterol lowering. However, statin trials in the elderly (PROSPER), in patients with heart failure (CORONA, GISSI-HF), and in patients with renal failure (4D, AURORA, SHARP) have all failed to demonstrate a mortality benefit[10,15]. A Cochrane meta-analysis of 18 cholesterol-lowering trials (some with statins) in patients with peripheral arterial disease also failed to demonstrate a mortality benefit[16]. A separate meta-analysis of 11 statin trials for high-risk primary prevention similarly failed to demonstrate a mortality benefit[17]. Another Cochrane meta-analysis of statin usage after acute coronary syndromes concluded there was no mortality benefit[18]. The Cholesterol Treatment Trialists (CTT) performed a meta-analysis of 27 statin trials and concluded that statins were clearly beneficial in reducing cardiovascular events[19]. However, when the same 27 trials were assessed for mortality outcomes, no benefit was seen[20]. The coronary calcium score is considered to be one of the best predictors of cardiovascular risk, yet the St. Francis Heart Study showed no clinical benefit in asymptomatic patients with coronary calcium scores > 80th percentile randomized to statin therapy[21]. Finally, diabetes mellitus is considered a CHD risk equivalent, but the three randomized controlled trials specifically designed and powered to assess the effect of statins in diabetes all failed to demonstrate a mortality benefit (CARDS, 4D, ASPEN)[22-24].

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ALTERNATIVE THEORIES OF ATHEROSCLEROSIS AND CHD COMPLICATIONS ARE CHOLESTEROL INDEPENDENT

The dramatic benefits of the Mediterranean diet are likely due to multiple mechanisms which do not directly involve cholesterol. Independent of cholesterol metabolism are the true fatal complications of coronary atherosclerosis - thrombotic coronary occlusion, acute myocardial ischemia, left ventricular dysfunction, and malignant arrhythmias. The hemostatic system appears to be a principal modulator of atherosclerotic plaque formation and progression and the Mediterranean diet can favorably alter elements of the coagulation cascade[25,26]. Plaque rupture and intra-plaque hemorrhage leads to progressive atherosclerosis, thrombosis causes acute coronary syndromes, and sudden cardiac death is the main cause of cardiac mortality. At the genetic level large scale, genome-wide association studies have identified 46 loci directly linked to CHD, yet a majority of these loci have no apparent relation to cholesterol or traditional risk factors[27]. Although we can’t change our genes, epigenetic studies have shown that the Mediterranean diet can favorably alter the expression of atherogenic genes[28], whereas a recent cholesterol-lowering statin trial failed to demonstrate a similar effect[29]. At the cellular level we now know that atherosclerosis is an inflammatory disease where macrophages and T lymphocytes likely play a dominant role. Whether or not specific anti-inflammatory therapies will be successful remains to be determined, but prior experience with Vioxx and Celebrex, which unexpectedly increased cardiovascular deaths, emphasizes the importance of proceeding cautiously. Recent studies have demonstrated that the Mediterranean diet can reduce markers of inflammation[26]. Accumulating evidence also implicates sugar in the pathogenesis of atherosclerosis. Diabetes is considered a coronary artery disease equivalent yet diabetics typically have average cholesterol levels. Other studies indicate that those who drink sugar-sweetened beverages are at much higher risk for CHD[30]. How elevated levels of blood glucose lead to atherosclerosis and why cholesterol lowering statins increase the risk of diabetes remains enigmatic, yet the totality of evidence suggests molecular mechanisms of atherosclerosis that are independent of cholesterol metabolism. The Mediterranean diet has been shown to reduce the risk of developing diabetes and the metabolic syndrome[31,32]. Elegant research into the gut microbiota is also providing an alternative theory of atherosclerosis[33]. Consider that L-carnitine, a component of red meat, is metabolized by the gut microbiota into trimethylamine oxide (TMAO). TMAO, in turn, promotes atherosclerosis and has been associated with a higher risk of cardiovascular events independent of traditional risk factors such as cholesterol. The gut microbiota can also adapt to changes in diet, which may explain why some vegans do not produce any TMAO after an L-carnitine challenge and how the Mediterranean diet may exert its anti-inflammatory and anti-atherosclerotic effects[34].

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STATIN DRUGS HAVE UNINTENDED CONSEQUENCES

If statins have failed to consistently reduce mortality one must ask if statins improve the quality of life. Serious or fatal statin adverse events are rare, but side effects are not. The incidence of muscular aches and weakness in statin trials is highly variable, and real world experiences may differ from clinical trial reports. Consider that the adherence rates for statins in the elderly are poor with nearly 75% of primary prevention patients stopping the drug within the first two years[35]. More recently a cohort study of statin users reported a 53% discontinuation rate although a very high percentage were able to continue statin therapy after being rechallenged[36]. In the largest statin survey ever conducted, the National Lipid Association observed that roughly 30% of statin patients reported experiencing muscle pain and weakness and 57% of surveyed patients reported stopping the drug due to side effects[37]. One may debate the relationship of statins to diabetes and dementia, but the fact remains that the FDA now requires disclosure of these warnings. Most distressing is the recent report of gluttonous behavior among statin users who mistakenly believe they are “protected” by taking statins and can eat whatever they want[38].

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CONCLUSION

The debate over the cholesterol hypothesis and statins has raged for decades. Some may point to the recent decline in cardiovascular deaths in the United States as proof of statin effectiveness, but this view fails to incorporate the impact of smoking cessation, lifestyle changes, and dramatic improvements in heart attack survival rates due to timely reperfusion and the availability of external and implantable defibrillators. Others may argue that statins are started too late in life to be effective (the horse may already be out of the barn) and reference Mendelian randomization studies which show that rare individuals with genetically low cholesterol levels have a much lower incidence of CHD[39]. However, this concept should not be extrapolated to the 99.99% of us who lack these genes and also fails to explain how the Mediterranean diet reduces mortality within months of initiation[2-4]. In 1996 Nobel laureates Brown and Goldstein anticipated the eradication of coronary disease in their Science editorial, “Exploitation of recent breakthroughs - proof of the cholesterol hypothesis, discovery of effective drugs, and better definition of genetic susceptibility factors - may well end coronary disease as a major public health problem early in the next century”[40]. History has proven otherwise, and the global prevalence of CHD, despite worldwide statin usage and cholesterol lowering campaigns, has reached pandemic proportions. Coronary heart disease is an extremely complex malady and the expectation that it could be prevented or eliminated by simply reducing cholesterol appears unfounded. After twenty years we should concede the anomalies of the cholesterol hypothesis and refocus our efforts on the proven benefits of a healthy lifestyle incorporating a Mediterranean diet to prevent CHD[2-4,41,42].

[travelroute66]

Tuesday, June 19, 2012 continued... Side pumps at the Ambler-Becker filling station in Dwight, Illinois. Wonderfully restored, as I'm sure that working gas pumps never look this good past opening day. "The Fine Art photography of Frank Romeo." Look for my Route 66 Galleries here: http://frank-romeo.pixels.com/

[didanawisgi]

BACKGROUND

Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear.

Full Text of Background...

METHODS

We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24).

Full Text of Methods...

RESULTS

The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan–Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen.

Full Text of Results...

CONCLUSIONS

Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels.

[didanawisgi]

Emerging evidence shows that insulin resistance is the most important predictor of cardiovascular and type 2 diabetes.

Aggressive lowering of low-density lipoprotein cholesterol (LDL-C) has been the cornerstone of preventative cardiology for decades. Statins are widely used as the go-to solution for the prevention of heart disease owing to their ability to slash LDL-C levels, a ‘surrogate marker’ of cardiovascular disease (CVD). Indeed, statins are one of the most widely prescribed class of drugs in the world. But this phenomenon begs two questions: is the enthusiasm for aggressive lowering of LDL-C justified; and is pharmacotherapy superior to lifestyle intervention?

Over the years, medical guidelines have continually expanded the number of individuals for whom statin therapy is recommended. Proponents argue that statins are ‘life-savers’ and that ‘people will die’ if they discontinue their medicine[1],[2]. Prominent researchers from reputable universities have declared that ‘everyone over 50’ should be on a statin to reduce their risk of CVD and that even children with high LDL-C as young as 8 years should be afforded statin therapy[3].

However, the true benefit of statins in altering risk of CVD is increasingly being questioned by respected members of the medical community, creating bitter divisions within the ranks. Several cardiologists have countered that the benefits of statins have been grossly exaggerated (especially as primary prevention), while their risks have been consistently underemphasised. In some quarters, the scepticism about statins has reached fever pitch. Some say that the preponderance of statin trials has been tainted by ‘industry sponsorship’, influenced by ‘statistical deception’, and riddled with ‘flawed methodology’[4],[5],[6].

Those who challenge the cholesterol hypothesis are accused of ‘cherry-picking’ the data. Ironically, pro-statin researchers themselves are the ones who are guilty of cherry-picking. A recent article in The Lancet, published in 2016, purported to end the statin debate, ostensibly to silence dissenting views[7]. Yet, despite billions invested in developing medicines to reduce LDL-C drastically, there remains no consistent evidence for clinical benefit with respect to either events or mortality.

For instance, there are 44 randomised controlled trials (RCTs) of drug or dietary interventions to lower LDL-C in the primary and secondary prevention literature, which show no benefit on mortality[8]. Most of these trials did not reduce CVD events and several reported substantial harm. Yet, these studies have not received much publicity. Furthermore, the ACCELERATE trial, a recent well-conducted double-blind randomised controlled trial, demonstrated no discernible reduction in CVD events or mortality, despite a 130% increase in high-density lipoprotein cholesterol (HDL-C) and a 37% drop in LDL-C. The result dumbfounded many experts, sparking renewed scepticism about the veracity of the cholesterol hypothesis[8].

There also appears to be no clear reduction in coronary heart disease mortality in western European countries from statins for primary and secondary prevention[9]. More recently, a post-hoc analysis showed no benefit of statins (pravastatin) in elderly people with moderate hyperlipidaemia and hypertension in primary prevention, and a non-significant direction toward increased all-cause mortality among adults 75 years and older[10]. Alarmingly, an assessment of industry-sponsored RCTs showed the median increase in life expectancy for selected participants in secondary prevention trials who adhered to taking statins every day for several years was a mere four days[11].

Similarly, the recent report of the efficacy of the latest ‘blockbuster’ drug evolocumab (Repatha, a PCSK-9 inhibitor) was underwhelming, despite the media hype. Published in The New England Journal of Medicine, the paper reported that evolocumab (together with a statin) lowered LDL-C by a whopping 60%, yet translated into only a 1.5% reduction in (non-fatal) CVD events[12]. Furthermore, evolocumab did not reduce total or cardiovascular mortality. Rather, there was a non-significant increase in mortality from CVD (n=251) compared with placebo (n=240), and a non-statistically significant increase in overall mortality in the experimental group (n=444) compared with placebo (n=426).

Put simply, none of the patients who took the drug lived longer than those taking placebo. Hence, while the drug might synergise with a statin to prevent a non-fatal (or minor) heart attack, it seems to increase the risk of some other equally life-threatening pathology, resulting in death. As noted in an article in The Daily Telegraph (UK) in May 2017, European participants in the trial had no benefit in preventing any hard outcomes[13].

When looking at the totality of the evidence, the sobering results of these studies have left many doctors wondering whether the directive to lower LDL-C aggressively using pharmacotherapy has been misguided. ‘Big Pharma’ has certainly triumphed, yet the patients have not.

There is an ethical and moral imperative that the true benefits and potential harms of these drugs are discussed to protect patients from unnecessary anxiety, manipulation, and iatrogenic complications. Furthermore, contrary to reports about stopping statins as a consequence of media scare stories about side effects resulting in thousands of heart attacks and deaths, there is no scientific evidence from registry data of a single person suffering such a fate.

It is an ethical and moral imperative that the true benefits and potential harms of these drugs are discussed to protect patients

One of the most compelling arguments against LDL-C as the primary target of CVD prevention or treatment is the Lyon Diet Heart Study[14]. Adopting a Mediterranean diet for secondary prevention improved both recurrent myocardial infarction (number needed to treat [NNT]=18) and all-cause mortality (NNT=30), despite no significant difference in the reduction of LDL-C between the Mediterranean diet and control diet groups. It is clear that appropriate lifestyle interventions deliver far more impressive results compared with those of current medications (and without the side effects, and at a much lower cost). Given that statins can give the illusion of CVD protection, predispose the development of type 2 diabetes in up to 1 in 50 patients taking these drugs, and cause reversible side effects in up to 29% of users, stopping statins may paradoxically ‘save more lives’ and improve quality of life in those taking them[15].

Is the calorie the right target?

Non-communicable chronic disease is now the biggest killer on the planet. Surpassing war, tobacco, and HIV, the diseases of metabolic syndrome account not only for most of the disease burden in the developed world, but also for the majority of the 35 million deaths per annum in the developing world as well[16]. The cause of this increase is routinely ascribed to the continued advancement of the obesity epidemic, which, in turn, is ascribed to global caloric surfeit.

However, there are four separate lines of reasoning that question this thesis. Firstly, while obesity prevalence and diabetes prevalence correlate, they are not concordant[17]. There are countries with populations who are obese without being diabetic (such as Iceland, Mongolia, and Micronesia), and there are countries with populations who are diabetic without being obese, such as India, Pakistan, and China (they manifest a diabetes prevalence of 11%; the United States, one of the world’s most obese country, has a 9.3% diabetes prevalence).

This is further elaborated by looking at years of life lost from diabetes versus obesity[18]. Many normal weight people (up to one-third) succumb to type 2 diabetes as well.

Secondly, although it is true that 80% of the obese population harbour at least one of the diseases of the metabolic syndrome (hypertension, dyslipidaemia, fatty liver disease, and type 2 diabetes), 20% of morbidly obese individuals do not (termed “metabolically healthy obese” or MHO), and have normal life spans[19],[20],[21]. Conversely, up to 40% of normal weight adults harbour the same diseases of the metabolic syndrome, including hypertension, dyslipidaemia, fatty liver disease, and CVD[22],[23]. Thirdly, the secular trend of diabetes in the United States from 1988 to 2012 has demonstrated a 25% increase in prevalence in both the obese and the normal weight population[24]. Thus, obesity, and by inference, caloric balance, does not explain the worldwide pandemic of non-communicable disease. Although obesity is clearly a marker for the pathology, it is clearly not the cause — because normal weight people get metabolic syndrome, too.

Finally, lipodystrophy is a disease syndrome characterised by too little, rather than too much body fat[25]. Yet these patients have the highest risks for CVD and type 2 diabetes of all; clearly unrelated to calories or obesity.

Current thinking about obesity and related diseases holds that quantifying calories is the principal concern and target for intervention. The basis for this directive is that consumed calories, regardless of their sources, are equivalent; i.e. ‘a calorie is a calorie’. Rather, a focus on the sources of those calories consumed (i.e. processed versus real food) and on the metabolic changes that result from consuming foods of different types needs to be addressed[26]. In particular, calorie-focused thinking is inherently biased against high-fat foods, many of which appear to be protective against obesity and the diseases of metabolic syndrome, and supportive of refined starch and sugar replacements, which are clearly detrimental, and exclusive of their calories and effects on weight gain[27],[28].

Shifting the focus away from quantitative and toward qualitative food distinctions (i.e. that the diseases of metabolic syndrome are due to food-induced changes in physiology; for example, neurohormonal and mitochondrial metabolic pathways) is required to see chronic disease abatement. This cannot be accomplished through arithmetic caloric restriction (i.e. calorie counting). Calorie balance sheets — targeting ‘calories in’ and/or ‘calories out’ — reinforce the message of overeating and inactivity as the underlying causes, rather than the resultant effects, of this aberrant physiology[29].

Insulin resistance: the main culprit

Using the lowering of LDL-C as a surrogate marker, accomplished through either diet or medicines, has proven to be, at best, inconsistent and, at worst, misguided. Furthermore, using weight or body mass index (BMI) as a surrogate marker has been uniformly ineffective. While some people lose weight acutely through self-imposed dieting, they routinely gain it back, often with worsening of their metabolic state.

Rather, we should examine other risk factors, which more clearly drive the aberrant pathophysiology. The risk factor that has been most consistently associated with CVD, type 2 diabetes and obesity is ‘insulin resistance’ — defined as an impaired biological response to insulin. In fact, insulin resistance plays a primary and causative role in the pathogenesis of hypertension, dyslipidaemia, fatty liver disease, and type 2 diabetes, collectively termed ‘metabolic syndrome[30]’.

We propose that insulin resistance is the most important predictor of CVD and type 2 diabetes

We propose that insulin resistance is the most important predictor of CVD and type 2 diabetes, a view that is strongly borne out of the work of Gerald Reaven and colleagues[31]. In a seminal natural history study, these researchers took a group of healthy people who were insulin sensitive and free from heart disease. After five years they found that none of the people who remained insulin sensitive developed heart disease whereas 14% of people in the highest tertile of insulin resistance developed heart disease in the same period[31].

In another study, up to 69% of patients who were admitted to hospital with acute heart attacks were found to have metabolic syndrome[32], which was associated with increased risk of death or readmission over the following 12 months.

Mathematical modelling has demonstrated that correcting insulin resistance in young adults could prevent 42% of episodes of myocardial infarction[33]. The study reported the next most important determinant of CVD is systolic hypertension, prevention of which would reduce myocardial infarctions by 36%, followed by low HDL-C (31%), high BMI (21%) and LDL-C (16%). Of note, insulin resistance belies each of these phenomena[33].

Metformin and thiazolidinediones are two drugs that mildly improve insulin sensitivity. While metformin has been shown to reduce CVD in type 2 diabetics, no data on primary prevention has yet been elaborated. Furthermore, rosiglitazone increased mortality in those with type 2 diabetes[34]. This may be one reason why using insulin resistance as a surrogate marker has received little attention over the decades. Another reason may be that since fasting insulin correlates poorly with obesity (i.e. the calorie hypothesis), the American Diabetes Association eschews its use. In contrast, good old-fashioned lifestyle interventions can significantly reduce insulin resistance, CVD, and mortality.

Excessive consumption of refined carbohydrates (especially sugar) and the resultant glycaemic load can overwhelm hepatic mechanisms that regulate the body’s blood glucose levels[35]. Evidence surrounding the use of low carbohydrate, high fat diets for the prevention and treatment of CVD, type 2 diabetes, and obesity is accumulating[36]. Unfortunately, other than Brazil, there has been little change to any nation’s dietary guidelines, which continue to recommend a low fat diet, which often results in diets high in refined carbohydrates (especially sugar).

Furthermore, dietary guidelines (as well as a recent presidential advisory by the American Heart Association) recommend replacing saturated fat with unsaturated fat in order to reduce LDL-C[37]. In practice, this translates to recommending vegetable oils and margarines rich in omega-6 polyunsaturated fatty acids (PUFA). Hence, the consumption of omega-6 PUFA has skyrocketed in recent decades and dwarfed the intake of omega-3 PUFA.

In traditional societies, the ratio of omega-6 to omega-3 polyunsaturated fatty acids was 1:1[38]. This came about due to diets rich in fish, plant foods and free-grazing animals, and eggs from chickens that ate plants high in omega-3 fats. But now in industrialised countries, the dietary ratio is closer to 20:1. This is a more ‘pro-inflammatory’ mix of PUFAs and may contribute to worsening of inflammatory atherosclerotic plaques. The benefits of the Mediterranean diet have been attributed to its high alpha-linolenic acid (omega-3) and polyphenol content present in nuts, extra virgin olive oil, vegetables and oily fish, which act to dampen the inflammatory response. What little carbohydrate there is exists along with its inherent fibre, thus reducing glycaemic load, liver fat, and insulin response.

Furthermore, even minimal exercise can help to reverse insulin resistance. A recent article stated that regular brisk walking, just 30 minutes per day more than three times per week, can reverse insulin resistance[39], while another study suggested that just 15 minutes of moderate-intensity exercise per day can increase lifespan by 3 years[40].

Time to redefine CVD risks

In summary, for many patients at high risk of CVD, one of the safest and most effective ways to reduce the risk of heart attack and stroke is to consume a high fat and low glycaemic load Mediterranean diet and engage in regular exercise. At the very least, exercise interventions are often similar to drug interventions in terms of their mortality benefits in the secondary prevention of coronary heart disease, and do not come with side effects[41].

Instead of funnelling billions to drug research and development, perhaps more of that money could be spent encouraging the implementation of policy directives that encourage population-wide behavioural change

Currently 75% of healthcare dollars are spent treating chronic metabolic disease. Instead of funnelling billions to drug research and development, perhaps more of that money could be spent encouraging the implementation of policy directives that encourage population-wide behavioural change (similar to the efforts to combat tobacco and alcohol) to reverse insulin resistance. Even a 20% reduction in sugar consumption can evidence marked cost savings[42]. Public health should work primarily to support the consumption of real food that help protect against neurohormonal and mitochondrial dysfunction, and not continue to promote calorie-directed messages that blame victims, and exacerbate these pandemics. Then, and only then, might we achieve the goal of attenuating the prevalence of CVD and the other chronic diseases of the metabolic syndrome.

Maryanne Demasi is an investigative medical reporter

Robert H. Lustig is professor of paediatrics at the University of California, San Francisco, USA

Aseem Malhotra is honorary consultant cardiologist at Lister Hospital, Stevenage

Declaration of interest: Dr Malhotra is co-producer of the documentary film ‘The big fat fix’ and co-author of ’The Pioppi Diet: a 21-day lifestyle plan’.

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Citation: Clinical Pharmacist, Vol 9, No 8, online | DOI: 10.1211/CP.2017.20203046

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Crestor 40 mg | Advanced Strength Statin for Cholesterol Control

Crestor 40 mg (rosuvastatin) helps sharply lower LDL “bad” cholesterol, raise HDL “good” cholesterol and reduce heart-attack & stroke risk w

Crestor 40 mg | Advanced Strength Statin for Cholesterol Control