Statins work by blocking the production of cholesterol within liver cells. Since liver cells need cholesterol to perform their basic metabolism, when their production of it is blocked, they up-regulate their synthesis and surface expression of ApoB/E receptors & thereby start extracting cholesterol from the bloodstream by removing LDL and related beta-lipoprotein particles (most effectively large LDL particles) [see Image 1 below]. Statins are safe medications but should be used with extreme caution in individuals with any history of liver problems. Statins can block the production and function of coenzyme Q10 within the body and thus should probably be taken along with a good-quality coenzyme Q10 supplement. CoQ10 is manufactured in the liver whenever cholesterol is manufactured, is present in the phospholipid monolayer surface coat of lipoproteins as well as the phospholipid bilayer of cellular membranes where is serves as a potent anti-oxidant & also seems very important in electron transport, oxygen utilization, aerobic glycolysis and thus ATP/energy production within mitochondria.  

Image 1: Mechanism of Action of Statins

Other medications routinely used in the treatment of lipid/lipoprotein disorders include Niacin (vitamin B3), PPAR-alpha agents ('fibrates'  like Lopid and Tricor versus 'TZDs' like Actos and Avandia), prescription fish oil products (Omacor) and cholesterol absorption inhibitors (Zetia) [see Image 2 below]. Since all non-prescription Niacin products in this country (either immediate-release or sustained-release, 'no-flush' forms) are in the 'dietary supplement' category (where there is no FDA oversight whatsoever in terms of their safety, quality, content or efficacy), they can not be recommended for use (in fact the AHA empatically states that non-prescription Niacin products "must not be used").  Non-prescription Niacin products that are in the 'OTC (over-the-counter)' category (which would be regulated by the FDA) just do not exist. Thus, the only safe, reliable and effective Niacin product is basically prescription extended-release Niaspan [see Image 3 below]. The same argument can probably be made for the use of prescription Omacor instead of other non-prescription, non-FDA regulated dietary supplement fish oil products.

Image 2: Mechanisms of Action of Various LIpid-Modifying Drugs

Image 3: Non-Prescription Niacin Products are NOT Recommended for Use

Niaspan and PPAR-alpha agents are the most powerful substances at increasing the concentration of HDL particles within the bloodstream (Niaspan by blocking the catabolism of large HDL particles; TZDs by increasing the production of small HDL particles and their conversion into large HDL particles; fibrates by increasing the production as well as function of small HDL particles). Niaspan is the most potent substance at making LDL particles larger and probably less aggressive (Actos and Omacor being in second place while fibrates and Avandia are in third place).  Niaspan is very helpful at lowering IDL particle levels by enhancing their bloodstream clearance. Niaspan also proves quite effective in improving endothelial function by: 1) enhancing the function of endothelial nitric oxide synthetase (eNOS) to enhance plasma and tissue nitric oxide levels & thus promote vasodilatation (the root cause of the 'flushing' [see Image 4 below] symptomatology experienced by certain otherwise vasoconstricted individuals during the first few days/weeks of Niaspan therapy); 2) decreasing blood viscosity; 3) decreasing fibrinogen and platelet adhesion/aggregation; 4) inhibiting the clotting cascade; & 5) decreasing hepatic production of acute phase reactants such as CRP [see Image 5 below].

Image 4: Patient Instruction Sheet Regarding How Best to Handle 'Flushing'

Image 5: Known Physiologic Benefits of Niacin

Omacor may be the most powerful medication at reducing the concentration of VLDL particles within the bloodstream (fibrates and Niaspan being in second place with Actos in third place - Avandia actually seems to increase VLDL particles). PPAR-alpha agents (followed by Niaspan) are also quite potent at making VLDL particles smaller & probably less aggressive. PPAR-alpha agents do it by: 1) enhancing lipoprotein lipase (LPL) activity to promote VLDL particle clearance; 2) inhibiting apoC-III production which would otherwise block LPL as well as ApoB100 recognition by hepatic ApoB/E receptors; 3) increasing hepatocyte, adipocyte & myocyte free fatty acid uptake; 4) promoting free fatty acid metabolism within hepatocytes, adipocytes and myocytes; & 5) decreasing TG synthesis within hepatocytes. Niaspan does it by blocking visceral adipocyte synthesis and secretion of free fatty acid into the bloodstream which would otherwise inhibit LPL to block VLDL particle clearance & serve as the main substrate for heptocyte  TG production and thus VLDL particle formation. Omacor does it by blocking the secretion of VLDL particles. Tricor is probably the 'best' fibrate (when compared to Lopid) in terms of overall safety as well as lipoprotein effects. Actos is most definitely a superior lipid-modifying agent when compared to Avandia (although they are equally effective in terms of glycemic control) [see Image 6 below]. In my personal opinion and in my own practice of medicine, I no longer use Avandia in place of Actos because: 1) multiple clinical studies have shown that when total LDL-P is increased by 100 nmol/L, CV risk is increased 11% while when total LDL-P is decreased by 100 nmol/L, CV risk is decreased by 11%; 2) Actos has been shown to decrease total LDL-P by 50 nmol/L while Avandia has been shown to increase total LDL-P by 150 nmol/L; 3) Actos decreased future CV events in the PROACTIVE study by 16% whereas Avandia has no comparable CV event data at this point; 4) Actos, by decreasing total LDL-P by 50 nmol/L, should have reduced CV events by 5% in PROACTIVE so the additional 11% benefit may have been due to some TZD 'class effect;' 5) Avandia, by increasing total LDL-P by 150 nmol/L, might therefore increase CV events by 16% and, if you take away the 11% assumed CV risk reduction due to the TZD 'class effect,' Avandia might actually increase CV events by 5%.

Image 6: Lipid/Lipoprotein Differences Between Actos & Avandia

Zetia is the second most potent medication at lowering LDL particles within the bloodstream (again usually the large LDL particles). Zetia works by blocking the absorption of cholesterol (and other atherogenic sterols such as sitosterol) within the lining of the small intestine & possibly also by reducing the amount of chylomicron-remnants within the bloodstream. Sometimes when natural 'hyper-absorbers' of cholesterol are given statins to block their hepatic production of cholesterol, those individuals end up absorbing even 'that much more' cholesterol. Zetia proves quite helpful in this regard and would thus seem to be of potential great benefit when added to medical therapy with any statin. Remember that individuals having the ApoE4 genotype, where hepatic cholesterol ester production is usually quite limited, tend to receive minimal assistance from statins so, other than low saturated fat/cholesterol diets (and other such TLC measures), Zetia can be considered and usually proves effective.  A combination product containing Zocor and Zetia in a single pill (called Vytorin) is now available & proves extraordinarily effective in lowering most endogenous beta-lipoproteins particles (LDL, IDL and VLDL) & again possibly even highly-atherogenic exogenous beta-lipoproteins such as chylomicron-remnants.

In major scientific studies, certain statins (Lipitor, Mevacor, Pravachol and Zocor) have been shown to reduce the later likelihood of major adverse cardiac events (heart attack, stroke, premature death and/or bypass surgery). However, this reduction was on average only 20-40% - meaning out of 10 individuals each taking a statin medication who were destined to have a future related major adverse cardiac event, only 2-4 had this event prevented by taking the statin. Lopid (a fibrate) and Niacin have each also been shown to reduce major adverse cardiac events by about 20-30%. A recent trial (PROACTIVE) showed that Actos when added to statin therapy in type II diabetics was both safe as well as effective (16%) in preventing future major cardiovascular events. Although Tricor did show a significant 40% reduction in angiographically-determined coronary atherosclerotic progression in type II diabetics in the DAIS trial (with a nonsignificant 23% trend in decrease of future major cardiovascular events), the recent FIELD study showed that type II diabetics receiving both statin as well as Tricor therapy demonstrated only minimal clinical improvement (based on the results of FIELD, 100 individuals would need to be treated with Tricor in addition to a statin for 5 years to prevent 1 major adverse cardiac event over that period of time - not very impressive and probably not to be considered as even worthwhile in my opinion). As of yet, there are is no major clinical trial showing what happens to major adverse cardiac events (or to safety) when Zetia is used by itself or when it is combined with a statin.

However, there are 2 major (albeit smaller in size) scientific studies ('HATS' and 'FATS-FU') showing what happens to heart attack, stroke, premature death and bypass surgery when you combine statins with Niacin. The reduction of major adverse cardiac events was 90-95% - meaning out of 10 individuals each taking a statin medication plus Niacin who were destined to have a future heart attack, stroke, premature death and/or bypass surgery, from 9 to 9.5 had this event prevented by taking the statin along with Niacin [see Image 7 below]. The combination of taking a statin along with Niacin is also quite safe. A third trial, 'ARBITER2' (published in November of 2004 and involving a population of adults with coronary heart disease), demonstrated that those individuals taking a statin plus Niaspan at a dose of 1000 mg per day had a 67% trend in reduction of major adverse cardiac events and significantly 68% less progression of carotid artery atherosclerosis at 1 year when compared to those individuals taking the same dose of statin but no Niaspan. A follow-up to ARBITER2 called ARBITER3 (just presented at the 2005 AHA meeting in abstract form) showed that statin + Niaspan 1000 mg per day actually lead to significant regression of carotid artery atherosclerosis at 2 years [see Image 8 below].

Image 7: RRR in Major CV Events in Mono-Rx vs Statin + Niacin Combination Rx Trials

 There had been a lot of press regarding the 'PROVE-IT' trial which compared Lipitor at 80 mg per day (a high dose of a powerful statin) to Pravachol at 40 mg per day (a lower dose of a weaker statin). Lipitor was significantly 16% more effective than Pravachol at preventing major adverse cardiac events (which is pretty good) but there still were 22.4% of individuals taking Lipitor who suffered a heart attack, stroke, premature death and/or bypass surgery during the 2-year trial (which is really bad). The recent 'TNT' trial of Lipitor 80 mg per day compared to Lipitor 10 mg per day showed similar results (22% less events with high-dose Lipitor). Contrast this with the 'ARBITER2' study where statin plus Niaspan trended 67% more effective than statin alone at 1 year [see Image 9 below] and to the 'HATS' study where only 2.6% of individuals taking Zocor along with Niacin had a major adverse cardiac event during the 3-year study. Also, the Lipitor dose in the 'PROVE-IT' trial was relatively 10-times higher than the Zocor dose in the 'HATS' trial. So the individuals on drug therapy in the 'PROVE-IT' trial were taking about 10-times more statin than those comparable individuals in the 'HATS' trial yet had approximately 10-times more major adverse cardiac events in about 2/3 the interval of time - a 150-fold or 15,000% difference!!! Thus, what 'PROVE-IT' and 'TNT' really proved is that even taking a high dose of a potent statin medication still leads to failure if used by itself. On the contrary, 'HATS,' 'FATS-FU' and 'ARBITER2' all demonstrated that taking a statin along with Niacin leads to dramatic prevention of heart attack, stroke, premature death and/or bypass surgery. A combination product containing both Mevacor and Niaspan in a single pill (called Advicor) is commercially available & obviously quite convenient. 

Image 9: CV Event Reduction in ARBITER2 vs PROVE-IT/TNT/PROACTIVE/FIELD/IDEAL

Why this remarkable clinical synergy between statins and Niaspan? Clinical event and animal model data points to LDL particles as being the central mechanism by which cholesterol penetrates arterial walls & thus leads to atherosclerosis. Statins work by blocking cholesterol production in the liver which primarily leads to up-regulation of hepatic ApoB/E receptors and subsequently the direct removal of  large (preferentially) LDL particles from the bloodstream. Niaspan arguably works by increasing large HDL particle levels, blocking hepatic lipase and decreasing large VLDL particle levels to promote the conversion of small LDL particles into large LDL particles [see Image 10 below]. Zetia functions by blocking cholesterol absorption in the gut to further up-regulate hepatic ApoB/E receptors and thus complements any Statin in removing large LDL particles from the bloodstream. Actos functions by decreasing large VLDL particles (and increasing large HDL particles) to further increase LDL particle size and thus complements Niaspan in converting small LDL particles into large LDL particles [see Image 11 below]. Omacor functions by decreasing large VLDL particles (indirectly increasing HDL particle size) and serving as a potent anti-oxidant in lipoprotein particticle membranes.

Image 10: Mechanisms of Increasing LDL Particle Size

Image 11: Synergistic LDL Particle Size Effects of Niaspan + Actos

At the Heart Attack Prevention Institute, Dr. Varveris employs Statin + Niaspan combination lipid modifying therapy as his 'core' approach for dyslipoproteinemia (with the possible addition of Zetia and/or Omacor vs Actos whenever appropriate) in order to reduce any patient’s potential risk of future heart attack and/or stroke in the most effective manner possible.