Cardioprotective Strategies to Close the Statin Gap: “News to Use” from the Latest Research

Cardiovascular disease, which now afflicts more than 80 million Americans – 36.3% of the U.S. population, including 38,100,000 individuals ≥ 60 – continues to be the No. 1 cause of death in the U.S., despite widespread use of statins, which, in 2002,  were being taken by >30% of Medicare patients ≥ 65.¹ Statins, the most successful pharmacotherapy agents used to treat atherosclerosis, remain ineffective for the primary or secondary prevention of myocardial infarction in about two-thirds of patients.²

Heart disease and stroke are still the first and third most common causes of death, accounting for 35.3% of all deaths each year (1 of every 2.8 deaths).   Although those ≥65 years of age are most at risk, as this age group accounts for nearly three-quarters of all strokes and 82% of deaths due to coronary heart disease (CHD), cardiovascular disease begins much earlier. According to current statistics, after age 40, lifetime risk of CHD is 49% for men and 32% for women. Deaths from coronary disease decreased during the period between 1980 and 2000, but recent increases in Americans’ body mass index and the prevalence of metabolic syndrome and type 2 diabetes have offset any reductions since individuals with diabetes are two to four times more likely to develop cardiovascular disease.³ In 2006, 66.7% of the adult population was overweight or obese, 34.6% had MetS, and 5.9% had been diagnosed with type 2 diabetes.^{4 5}

Given this scenario, the following four recently published studies may offer significant “news to use” to promote the health and longevity of patients with, or at risk for, cardiovascular disease – in other words, virtually everyone.

Anthocyanin supplementation significantly improves cholesterol profiles in dyslipidemic subjects in 12 weeks

Anthocyanins – the water-soluble plant pigments that impart colors ranging from violet to blue to most shades of red – are highly concentrated in bilberries, black currants and wild blueberries. In this double-blind, placebo-controlled clinical trial, 120 dyslipidemic subjects (mean total cholesterol 225 mg/dL, LDL 159 mg/dL, and HDL 46 mg/dL) aged 40-65 years, were given 160 mg anthocyanins extracted from bilberry and black currant, or placebo, twice daily (after breakfast and supper) for 12 weeks.⁶ By the end of the trial, in those receiving anthocyanins, LDL had decreased 13.6%, and HDL had increased 13.7%, in contrast to those in the placebo group in which LDL increased 0.6% and HDL increased 2.8%. Cellular cholesterol efflux to serum—the first and most critical step of reverse cholesterol transport—increased 20% in the anthocyanin group compared to 0.2% in the placebo group. Study authors noted that the changes in lipid profile seen in subjects receiving anthocyanins would result in a nearly 27.3% reduction in their risk of coronary heart disease.

For comparison, simvastatin (20 mg/day) reduced LDL-C by 35% in 12 weeks and has also been shown to reduce hsCRp.⁷ However, statins have no effect on cellular cholesterol efflux and little effect on HDL, and thus, as noted in a recent paper reporting on the outcomes of the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Trial, a double-blind, randomized 18 month trial at 34 centers in the U.S. that involved 654 patients and compared the effect of two different statins on atherosclerotic burden:

“Even intensive LDL cholesterol and CRP reduction did not reverse coronary atherosclerosis. Perhaps, emerging therapies designed to enhance HDL cholesterol can produce clinically meaningful regression of coronary atherosclerotic disease burden.” [italics added]

As demonstrated by the above study, anthocyanins significantly increase concentrations of HDL cholesterol.

Diet is another therapy that has repeatedly been shown to affect lipid profiles – for better and for worse. Specifically, it is well known that the Standard American Diet, high in processed foods, meat and saturated fat, promotes an atherogenic lipid profile. In contrast, a Mediterranean diet reduces total and LDL-cholesterol, and concomitantly increases HDL-cholesterol and reduces the total cholesterol/HDL-cholesterol ratio.⁸ Expecting patients hooked on the Standard American Diet (aptly given the acronym “SAD”) to suddenly switch from the convenience of their processed, prepared, pop-in-the-microwave foods to a diet based on largely unprocessed plant foods seasoned with olive oil, may be a bit of a stretch, but most people enjoy berries. Berries demand virtually no prep time, provide significant health benefits even when frozen, and are easily accessible year round. Explaining anthocyanins’ cardioprotective health benefits may encourage patients to begin selecting a more heart-healthy diet. According to the USDA database⁹, 100 grams (3.5 oz) of raw blueberries contains ~160 mg of anthocyanins, and even frozen, blueberries deliver ~90 mg per 100 grams. Raspberries and strawberries are not as effective a source, containing ~40 mg of anthocyanins per 100 grams if fresh, but only ~20 mg if frozen. Raw bilberries provide 430 mg anthocyanins per 100 grams and, for this reason, are often used as a source for these phytonutrients in high quality supplements – obviously, the easiest way for patients to receive their cardioprotective benefits.

EPA (eicosapentaenoic acid) significantly reduces incidence of cardiovascular events in dysglycemic as well as normoglycemic patients

Further analysis of data from the Japan EPA Lipid Intervention Study (JELIS), a large clinical trial involving 18,645 hypercholesterolemic patients followed over 4.6 years, divided the subjects into two groups—those with impaired glucose metabolism (IGM), i.e., diabetic patients and those with a fasting plasma glucose of ≥110 mg/dL (n=4565), and those with normal glucose levels (NG, n=14,080). Not surprisingly, IGM patients had a significantly higher risk of coronary artery disease (CAD) (1.71 in the group that did not receive EPA) than NG patients. However, treatment with EPA (two 300 mg capsules t.i.d. for a total of 1,800 mg/day) resulted in a 22% decrease in CAD incidence in IGM patients, and an 18% decrease in NG patients.

Of special interest is that EPA supplementation was shown to be highly effective in decreasing CAD incidence among IGM and NG Japanese, a population in which fish intake, and therefore consumption of EPA/DHA (docosahexaenoic acid) is already high. The Japanese consume 0.8 to 1.5 g/day of EPA/DHA, which is between 8 and 15 times more EPA/DHA than is consumed by typical Westerners.^{10 11} In the JELIS study, the EPA concentration among Japanese individuals, given as the EPA concentration in the non-EPA-treated IGM patients, was 2.9 mol%, which is approximately 10-fold higher than that of white Americans – yet EPA supplementation in this cohort substantially decreased CAD risk.^{12 13}

Another compelling fact is that all patients in the JELIS were prescribed a statin. As a result, during the course of the study, LDL cholesterol levels decreased from a baseline of 180mg/dL to 137–138 mg/dL in NG patients, and from a baseline of 180mg/dL to 133–134 mg/dL in IGM patients. Despite this statin-related decrease in LDL cholesterol, IGM patients still had a significantly increased risk for CAD. Another large scale study performed in Japan, the Japan Lipid Intervention Trial (J-LIT), has also reported that CAD risk is significantly higher in diabetic than non-diabetic patients, even if they receive statin treatment.¹⁴ Both the JELIS and J-LIT studies found increased CAD risk in diabetic patients despite statin therapy’s reduction of LDL cholesterol levels by ~28%. The results of the present study concur, clarifying that abnormal glucose metabolism is a CAD risk factor independent of the level of LDL cholesterol, and further showing that EPA significantly decreases CAD risk via mechanisms independent of decreasing hemoglobin A1C (HbA1C) or fasting plasma glucose.

In other recent studies in type 2 diabetic patients, EPA has been found to reduce carotid intima-media thickness (an indicator of arteriosclerosis), and, while not lowering total LDL concentrations, to significantly reduce levels of small dense LDL.^{15 16} EPA is also known to have anti-inflammatory effects, to reduce platelet aggregation, inhibit cell proliferation and stabilize plaque – beneficial effects all of which contribute to lessening risk of major coronary events in IGM as well as NG patients.^{17 18 19 20 21 22 23 24}

If EPA supplementation is so effective in reducing CAD risk in fish-loving Japanese dysglycemic patients taking statins, shouldn’t supplementation with this essential fatty acid be first line therapy for Americans at risk of cardiovascular disease, especially those with metabolic syndrome or type 2 diabetes?

DHA – determining the optimal dosage for its effects on platelet reactivity and redox status

Some studies suggest that DHA may be even more cardioprotective than EPA. DHA appears to be more effective than EPA in suppressing arrhythmia and is the principal omega-3 responsible for the vasorelaxant and hypotensive effects of fish oils. DHA is a much more potent inducer of nitric oxide (NO) production, and NO, in addition to its vasodilating effect as endothelium-derived relaxing factor (EDRF), has inhibitory effects on platelet aggregation and adhesion, and vascular smooth muscle cell proliferation and migration.²⁵

Research published in The FASEB Journal, September 2009, looked at the effects of varying dosages of DHA on both platelet activity and redox status in 12 healthy men, aged 53-65 years.²⁶ Over 4 successive 2-week periods, the men consumed 200, 400, 800 and 1600 mg of DHA per day. Blood and urine samples were collected before and after each dose of DHA and at 8 weeks, after supplementation was stopped.

DHA was incorporated in a dose-response fashion in platelet phospholipids. After supplementation with 400 and 800 mg/day, but not with 200 mg/day of DHA, platelet reactivity was significantly decreased. On the other hand, levels of urinary isoprostane, a marker of lipid peroxidation/oxidative injury, were significantly lowered after 200 mg/day of DHA, but increased after 1600 mg/day, leading the researchers to suggest daily intake of 200 mg of DHA/day as an effective way to protect healthy men from platelet-related cardiovascular events.

We disagree. This study shows that higher doses of DHA – in the range of 400 – 800 mg/day – are needed to decrease platelet reactivity. The findings show, not that higher doses of DHA should not be used, but that higher doses of DHA must be complemented with increased levels of vitamin E. The reason for this is that DHA – and EPA – are highly susceptible to oxidation, thus higher amounts of these omega-3 fatty acids require additional lipid-soluble antioxidant protection, e.g., vitamin E.

A further consideration is that vitamin E should be supplied in the form of mixed tocopherols rather than alpha tocopherol alone since gamma tocopherol is significantly more effective in preventing platelet aggregation and lipid peroxidation from reactive nitrogen species (RNS) than alpha tocopherol, which is more effective in neutralizing reactive oxygen species (ROS). For a full discussion of these issues and a review of the current research, please see Beyond α-Tocopherol: A Review of Natural Vitamin E’s Potential in Human Health and Disease, Part I: In Defense of Vitamin E and Part II: Vitamin E in Action.

Lowering the burden of cardiovascular disease

Although slight differences in biological activity exist between EPA and DHA, both exert numerous actions protective against cardiovascular disease. Both EPA and DHA inhibit platelet aggregability, reduce serum triglycerides, reduce production of pro-atherogenic cytokines, improve endothelial function, reduce vascular occlusion, reduce heart rate, increase heart rate variability and prevent arrhythmia. Most importantly, a number of large studies have shown reductions in clinical endpoints like sudden cardiac death or major adverse cardiac events. As a consequence, European and American Cardiac Societies have incorporated EPA and DHA into recent treatment guidelines, recommending 1 gram/day for cardiovascular prevention, after a myocardial infarction and for prevention of sudden cardiac death.^{27 28}

Advocating the use of anthocyanins (160 mg b.i.d) — which significantly increase HDL and may therefore help fill the treatment gap left by statins – as well as EPA/DHA, may greatly improve the likelihood of clinically meaningful regression in coronary atherosclerotic disease.

References