Is it time to rethink the prevention and treatment of heart and circulatory diseases? Almost certainly. One common assertion regarding cardiovascular diseases is that there have been improvements as a result of cholesterol lowering drugs, primarily statins. Oddly, almost none of the trials investigating statins for primary prevention of heart disease have proven successful. Reduced rates of smoking have helped, whereas the widespread use of statins has not. Indeed, the trials supposedly intended to test the effects of statins for primary prevention generally have been ill-designed to ever demonstrate such an outcome.1 Cardiovascular diseases as such have been mounting in tandem with the increasing rates of overweight, obesity and diabetes in America. This has been masked by the fact that medical interventions, primarily in the form of emergency services at the time of heart attacks, have improved survival. Hence, the death rate from heart attack has decreased slightly over the last 10 or 12 years, yet the rates of hospital admissions, etc. have continued to increase. (See Heart disease and stroke statistics—2010 from the American Heart Association.) Alternatives to the failing cholesterol hypothesis, such as the roles of the liver and blood sugar/insulin regulation, remain poorly examined.

Sadly, some of the prized “natural” remedies intended to mimic medical models based on cholesterol lowering have delivered no better results than the statins when examined thoroughly. The elephant in the room with regard to recent experiments with heart health dietary supplements is the failure of extended release niacin to improve cardiovascular outcomes in two large trials. Until these trials, it had been assumed broadly that the LDL cholesterol lowering and HDL-elevating benefits of niacin would translate into cardiovascular benefits. A 3,000 patient NIH trial using Niaspan ended in 2011 failed to show benefits above those of the use of statins alone. (NY Times May 26, 2011) At the beginning of December 2012, Merck’s drug Tredaptive similarly failed to provide any benefit in the HPS2- THRIVE trial. (NY Times December 20, 2012) This second prescription form of niacin also failed to prevent heart attacks and strokes. There was a troubling spike in "the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant," although Merck did not spell out these serious adverse events.

One take-away message from the foregoing is that a focus on “markers,” such as lowering LDL cholesterol—one of the triumphs in pharmaceutical marketing over the last 50 years— often is seriously misleading. An especially instructive example of this is the prescription for decades of hormone replacement therapy to women going through menopause. Hormone replacement therapy once was widely and vigorously touted as improving cardiovascular health in women because it lowers LDL cholesterol. Endpoints told a different story, as finally emerged almost a decade and a half ago from studies such as the Women’s Health Initiative. Cardiovascular events and death rates went up, not down, with hormone replacement therapy despite the oh-so-reassuring lowering of serum cholesterol.

More recently, a similar supposed paradox cropped up when it was discovered that statin use, again to lower total and LDL cholesterol, increased the risk of developing diabetes mellitus in women.2 More generally, studies often tout minor successes in the area of heart disease without even considering whether this is merely a substitution effect in which total morbidity and mortality is not improved. Caveat emptor.

The following paragraphs provide an overview of the cholesterol theory, a closer look at the claims for statins, and then suggest how blood glucose and insulin levels may be the real culprits in most instances of cardiovascular disease.

Cholesterol Theory and Statins in Depth
The major premise of the cholesterol hypothesis is that elevated serum cholesterol is the cause of cardiovascular disease. Today, most people would be surprised to learn that it was only the results of large trials in the 1990s with statin drugs that putatively proved the pathogenic role of cholesterol. Initially, the issue was viewed as simply one of “too much cholesterol,” or, if the term hyperlipidemia was used, too much cholesterol and too much other lipids, such as triglycerides. Only later after these initial claims failed under examination were ever further subcategories defined as in LDL cholesterol, LDL cholesterol subfractions, HDL and its subfractions, and so forth and so on.

Roughly speaking, the argument runs that small dense LDL particles at some crucial concentration begin to stick to and penetrate vulnerable sections of the artery wall. It is presented as a numbers game: the higher the circulating LDL, the greater the risks of such events occurring. Once penetrated, the artery wall becomes the locus of an accumulation of cholesterol-rich particles that then undergo oxidation and other transformations that, in turn, attract macrophages and additional immune cells which try, and fail, to clear the artery. The macrophages become lipid-laden foam cells embedded in the artery wall, ultimately leading to the formation of atherosclerotic plaque. The theory thus is that lowering cholesterol, and especially lowering certain lipid subfractions, reduces the potential for the initial damage to the intima of the arteries and improves the rate of clearance and that such measures also reduce the formation of plaques.

If the issue is framed as above, then one obvious answer would seem to be to reduce cholesterol levels and one way to do this is to reduce cholesterol synthesis. Cholesterol is synthesized mainly in the liver from precursor molecules in a process that reaches a common endpoint—mevalonate—before branching to lead to either cholesterol or one of two other compounds, which are coenzyme Q10 and squalene. The formation of mevalonate is the conversion of 3-hydroxy- 3-methylglutaryl coenzyme A (HMG CoA). The fundamental way to block cholesterol synthesis thus is by interrupting the conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) to mevalonate so that mevalonate cannot be transformed into cholesterol. In order for HMG CoA to become mevalonate, the reaction must be catalyzed by the enzyme HMG CoA reductase. If this enzyme is blocked, mevalonate cannot be generated and cholesterol cannot be synthesized. Statin drugs inhibit the synthesis by acting as HMG CoA inhibitors.

The next section deals with the supposed benefits of statin drugs and the often deliberately obscured side effects. At this point, there is little reason to debunk the decades-old claims that dietary consumption of cholesterol and saturated fat cause heart disease. The US FDA itself recently abandoned advice to control cholesterol in the diet on the grounds that this advice is not backed by good science. The rumor is that the usual condemnation of saturated fat intake likely will be the next FDA long-standing position to be revised. The real dietary culprits among fats, it turns out, are consumption of artificial trans-fatty acids, too much preformed arachiadonic acid and an elevated consumption of omega-6 fatty acids.

Statins and CVD
One major weakness in the use of statins for cardiovascular health, aside from the rather weak statistical basis, is that the evidence does not seem to support the argument that their benefits are derived from lowering cholesterol levels, either total cholesterol or LDL-C. Although this observation may seem surprising, it follows directly from the findings that statins provide cardiovascular benefits regardless of starting cholesterol levels. Further analysis has led many researchers to conclude that anti-inflammatory actions at the site of the artery or related actions are responsible for the benefits associated with statins. Significantly, these last benefits have been reported using traditional red yeast rice that is extremely low in statin-like compounds.3

In addition, statins are not particularly useful either for lowering circulating triglycerides or for raising HDL levels. More surprising yet, statins actually increase the proportion of small dense LDL found in serum although reducing total LDL cholesterol, absolute amounts of small, dense LDL, and absolute amounts of large, buoyant LDL.4 It further should be considered that statins do nothing significant for blood pressure and are weak for improving overall inflammation.

Many of the side effects of statins are linked to a handful of mechanisms, including CoQ10 depletion and mitochondrial damage. Statin adverse effects are strikingly under-reported for many reasons, including commonly being dismissed by physicians when brought to their attention by patients.5

  • Statins reduce the body’s own production of CoQ10; this is thought to account for the increased number of cases of congestive heart failure in statin users. Supplemental CoQ10 is a possible solution.
  • Statins increase the risk of diabetes. The exact degree is in
  • dispute, but it is not a negligible increase in risk.6
  • Statins increase the incidence of muscle pain and weakness. There is limited evidence that maintaining adequate vitamin D may reduce the risk. CoQ10 may be helpful.
  • Statins increase the risk of peripheral neuropathy. It is possible that alpha-lipoic acid and, perhaps, benfotiamine may prove helpful.
  • Statins increase the risk of cognitive impairment and depression. This finding is so common that it clearly implicates statins’ own mechanism of action. It turns out that cholesterol acts as a signaling molecule for memory and other brain functions. Also, chronic cholesterol depletion using statin impairs the function and dynamics of human serotonin(1A) receptors.7 Very low cholesterol levels are associated with, for instance, greater rates of accidents and suicides.
  • Statins increase the risk of heart failure.
  • Statins appear to make it harder to exercise, especially for older populations of patients. Statins increase muscle damage during and after exercise and also interfere with the body’s ability to repair that damage. One journal article title captures the problem: “Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems.” Among those who are extremely active, only about 20 percent can tolerate statin therapy.8
  • Statins depress fat metabolism in older individuals.
  • According to a report in the British Medical Journal, statin use was associated with decreased risks of esophageal cancer, but increased risks of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataract. A study published in a different journal indicated that statins raise the risk of prostate cancer in obese men.

There is a vast disparity between the rates of side effects reported by pharmaceutical-sponsored trials and the rates reported by independent observers, and this already was evident years ago. For instance, as reported in “The Lipitor Dilemma” by Eleanor Laise (Smart Money November 2003), the pharmaceutical industry insists that only 2–3 percent of patients get muscle aches and cramps, yet a study performed by Dr. Beatrice Golomb of the University of California-San Diego School of Medicine found that 98 percent of patients taking Lipitor and one-third of the patients taking Mevachor suffered from muscle problems. Dr. Golomb is reported to have found that 15 percent of statin patients develop cognitive side effects of some type. However, inasmuch as physicians routinely dismiss such reports from their patients on statins, it is difficult to know what the true figure is. Neuropathy is a similar case, with few instances reported in the “gold standard” trials, yet real life studies have found increases as much as 14 fold that of controls.9

Even in secondary prevention trials, that is, trials with individuals who already have had heart attacks, the benefits have been underwhelming. Absolute risk reductions across such trials by one estimate average only three percent. This is not impressive in the light of assessments such as this one from 2013, "[t]here is a categorical lack of clinical evidence to support the use of statin therapy in primary prevention. Not only is there a dearth of evidence for primary cardiovascular protection, there is ample evidence to show that statins actually augment cardiovascular risk in women, patients with Diabetes Mellitus and in the young. Furthermore statins are associated with triple the risk of coronary artery and aortic artery calcification."10 Still more recent work has identified potential mechanisms for these supposedly paradoxical effects.11

Roles for Blood Glucose and Insulin Levels
It usually comes as a great surprise to those not involved in medical research to learn the smallness of the improvement in heart attack risk accomplished by most pharmaceutical interventions. Conversely, real risk factors often are overlooked. On the medical side there is so much data that, as statisticians sometimes put it, the gnoiseh drowns out the relevant signals. On the lay side very few have the time or the energy to devote to researching issues. Recent findings by Harry G. Preuss, MD of Georgetown University provide an instructive example of the first case.

Cardiovascular diseases are strongly linked to diabetes mellitus, which can be defined as two fasting blood glucose measurements .126 mg/dl with the risks climbing along with blood sugar levels. Preuss' striking finding is that increases in various risk factors, in fact, already are increasing with blood sugar readings in the prediabetic range, i.e., .125 mg/dl, despite no or few significant correlations with cholesterol levels. In effect, Preuss demonstrates that in a wide-ranging subject population the metabolic syndrome is active much earlier than anyone had suspected. In Preussf test group, as blood sugar became more elevated and yet remained in the supposedly "safe" range, all the following also went up: body weight, body fat mass, systolic/diastolic blood pressure, HbA1C (glycosylated hemoglobin), white blood cell count/neutrophil count (linked to inflammation), circulating levels of insulin, triglycerides, C-reactive protein (a measure of inflammation) and ALT (an indicator of liver health). Conversely, HDL-cholesterol went down. In other words, a very broad range of indicators of overall health moved in the direction of poor metabolic and inflammatory performance despite the individuals involved supposedly being healthy in terms of fasting blood sugar.12

In another interesting finding, this one coming from Swedish researchers, unstable plaque formation linked to cardiovascular incidents was discovered to be related in time to insulin spikes regardless of blood cholesterol markers or blood pressure.13 This is a validation of the theory of metabolic syndrome and of Preuss' findings. Work by Gerald Reaven and others in this area generally has demonstrated that in individuals otherwise showing no blood lipids markers for cardiovascular disease, insulin levels alone accurately can predict risks in approximately 35 percent of those surveyed.

Finally, there is gunifying hypothesish involving the liver that goes far in explaining the development of the metabolic syndrome/insulin resistance in the absence of the overt overconsumption of calories and/or refined carbohydrates. In this theory, four common items in the diet in chronic excess can lead to the metabolic syndrome through a negative impact on the liver. These items are trans-fats, branched-chain amino acids (from excessive intake of some forms of protein, such as beef), ethanol and fructose. No single pharmaceutical-style drug intervention is likely to be successful according to this model. Instead, the options are (1) dietary modification, (2) inclusion of greater amounts of fiber to improve liver clearance of substrates and (3) regular exercise to increase the efficiency of the mitochondria.14

The Road Not Taken
Despite many decades for possible validation, the cholesterol hypothesis as the driver of cardiovascular disease has failed to establish unambiguous scientific backing. Recent FDA pronouncements abandoning, for instance, advice to restrict consumption of dietary cholesterol are but the tip of the iceberg regarding the decline of the lipid theory of heart disease. Extremely low fat diets have never been shown to be productive of lower total morbidity and mortality over the long term. Pharmaceutical interventions with statins to lower LDL-C have delivered no real benefits in primary prevention and anemic benefits in secondary prevention of heart attacks while at the same time bring in train significant side effects.

What might be called the gsugar hypothesish of cardiovascular disease is tantamount to the road not taken in treatment in the US for more than sixty years. After such long neglect, it finally is beginning to be taken more seriously. Unlike low fat diets, low sugar/low refined carbohydrate diets appear to offer real benefits across the board for most individuals. Preuss' conclusion from his study mentioned above is simple and direct: "Keeping circulating glucose levels as low as possible, even when they fall in the so-called normal range, without creating signs and symptoms of hypoglycemia may be a wise choice for better health."

  1. Huded C, Prasad V. Meta-Analyses of Statin Therapy for Primary Prevention Do Not Answer Key Questions: An Empirical Appraisal of 5 Years of Statin Meta-Analyses. Am J Cardiovasc Drugs. 2015 Dec;15(6):379–86.
  2. Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012 Jan 23;172(2):144–52.
  3. Clouatre D. Red Yeast Rice—Beyond Cholesterol. Total Health Magazine (March 2010).
  4. Choi CU1, Seo HS, Lee EM, Shin SY, et al. Statins do not decrease small, dense low-density lipoprotein. Tex Heart Inst J. 2010;37(4):421–8.
  5. Golomb BA, McGraw JJ, Evans MA, Dimsdale JE. Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance. Drug Saf. 2007;30(8):669–75.
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  8. Sinzinger H, O’Grady J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol. 2004 Apr;57(4):525–8.
  9. Gaist D, Jeppesen U, Andersen M, García Rodríguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002 May 14;58(9):1333–7.
  10. Sultan S, Hynes N. The Ugly Side of Statins. Systemic Appraisal of the Contemporary Un-Known Unknowns. Open Journal of Endocrine and Metabolic Diseases, 2013, 3, 179–185.
  11. Okuyama H, Langsjoen PH, Hamazaki T, Ogushi Y, et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015 Mar;8(2):189–99. Erratum in: Expert Rev Clin Pharmacol. 2015;8(4):503–5.
  12. Preuss HG, Mrvichin N, Clouatre D, Bagchi D, Preuss JM, et al. Importance of Fasting Blood Glucose in Screening/Tracking Overall Health. The Original Internist. 2016 forthcoming. A longer detailed version will be published elsewhere later in the year.
  13. Hägg S1, Salehpour M, Noori P, Lundström J, Possnert G, et al. Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin. PLoS One. 2011 Apr 7;6(4):e18248.
  14. Bremer AA, Mietus-Snyder M, Lustig RH. Toward a unifying hypothesis of metabolic syndrome. Pediatrics. 2012 Mar;129(3):557–70.

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