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Clinical lipidology update for the integrative practitioner.

Clinical lipidology is a discipline of great opportunity for the integrative health practitioner. It is an area of primary preventive medicine of the utmost importance, one which is extremely amenable to natural interventions, and one in which alternative and conventional practitioners find themselves closely aligned in both philosophy and therapy.

The National Lipid Association (NLA) is a body of medical providers and scientists committed to "Enhance the practice of lipid management in clinical medicine." (1) The NLA held its annual scientific sessions in Las Vegas, Nevada, on May 30 through June 1, 2013. Of greatest import for the practice of complementary and alternative medicine (CAM) and integrative medicine were the updates on upcoming guidelines, approaches to familial hypercholesterolemia, selection of biomarker testing, and the HDL consensus statement.

Update of ATP Guidelines

The Adult Treatment Panel Four (ATP IV) guidelines from the National Heart Lung and Blood Institute (NHLBI) for the assessment and treatment of lipids and cardiovascular risks are several years overdue. When those guidelines are delivered, conventional targets and goals for lipid therapy and CVD prevention may change dramatically, or not at all. Several members of the panel were present at the 2013 NLA Scientific Sessions and there was some discussion that the ATP IV guidelines are in final review and due out very soon. There was also discussion that the NLA believes that it should be included in the drafting of future guidelines, that the field could be stronger if our expertise were pooled, that by standing as separate elements within the same discipline we are missing an important opportunity. Less than three weeks after the close of the conference, the NHLBI answered the call for collaboration. "On June 19 [2013], NHLBI issued a statement announcing that the review and guideline development process for ATP IV has changed, and that looking ahead, organizations will work in a collaborative fashion to author and distribute the guidelines." (2)

Clinical Guidance on Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) refers to a large group of heritable genetic polymorphisms that result in severe elevations of cholesterol fractions in the blood. The problem with cholesterol clearance in FH can result from a malformed apolipoprotein that does not fit the LDL receptor appropriately, or a malformed LDL receptor that does not fit the binding protein appropriately, or a problem with the frequency of LDL receptor recycling within the hepatocytes of the liver, or any one or more of many dysfunctions. The list of possible genetic malfunctions in cholesterol metabolism that can cause FH number more that 1600 at present and will likely continue to grow as our understanding of the molecular biology of cholesterol metabolism continues to expand. (3)

The clinical manifestation of FH is not uncommon, though it is both underdiagnosed and undertreated. (4) This issue is of particular interest and concern to us in the world of alternative and integrative medicine both because we are likely to see FH patients hoping to avoid a lifetime of statin drug therapy and because it is an issue of utmost importance with respect to conducting a practice focused on disease prevention. The incidence of heterozygous FH is 1 in 300 to 500; homozygous FH (HoFH) is much less common, about 1 in 1,000,000, but is also much more severe. (4-6) The mode of inheritance of the most common types of FH is autosomal dominant. Thus, in a scenario wherein we have one parent heterozygous for FH and one parent unaffected, 50% of their children will also be heterozygous for FH. Heterozygous FH (HeFH) is the condition which will present far more often to the CAM practitioner.

Patients with FH have both very high risk for early coronary heart disease (CHD) and very high lifetime risk for CHD. The clearance of LDL-C from the blood by the liver can be reduced by up to 27% in HeFH patients (up to 53% in HoFH), which results in total cholesterol (TC) concentrations in the blood that are often elevated to 300 to 550 mg/dL. (4), (7) This reduced LDL-C clearance translates into a risk for early CHD approximately 20 times higher than the average risk if left untreated. (4) Coronary artery calcification can be detected in HeFH patients as young as 11 years of age. (8) Many FH patients develop CHD in the absence of any other risk factors, though other traditional risk factors for CHD (family history, age, high blood pressure, smoking, diabetes) compound the risk of disease for the FH patient, especially the use of tobacco products or presence of diabetes mellitus. It is important to understand that the CHD risk for these patients cannot be appropriately assessed using routine risk assessment algorithms such as the Framingham Risk Score and others. Risk scores dramatically underestimate the true CHD risk in FH and create a false sense of security for the patient and potential mismanagement by the practitioner. (4), (9)

We should carry a high index of suspicion for the possibility of FH anytime we discover that a patient has an untreated LDL-C of greater than 190 mg/dL. In the typical case of FH, all of the lipid fractions will be elevated, TC, LDL, and HDL, while the triglyceride (TG) levels will typically be normal or near normal. However, low HDL or high TGs do not rule out the possibility of FH. Moreover, patients with poorly controlled diabetes mellitus (DM) or severe metabolic syndrome may have grossly elevated TC and LDL, often with elevated TGs, but not necessarily so. Therefore, we may suspect a patient for FH only later to find that her dyslipidemia was metabolic and not genetic; the reverse is also true, we may suspect a metabolic dyslipidemia that is revealed to be genetic. While clarification of the diagnosis comes from several points, the response to treatment is an important clue. Metabolic dyslipidemias typically respond robustly to treatment, while those of genetic etiology are often highly treatment resistant.

We can predict with about 80% certainty whether a patient will have FH based on age and LDL-C concentrations. For patients less than 20 years old with LDL-C greater than 190 mg/dL, 20 to 29 years old with LDL-C greater that 220 mg/dL, and greater than 30 years old with LDL-C greater than 250 mg/dL, the likelihood of FH is greater than 80%. Any of these findings should prompt us to complete a thorough family history and physical exam. The family history in a case of suspected FH should be focused toward uncovering cases of high cholesterol, known FH, early heart disease, known CHD, or cardiovascular events in all of the first-degree relatives and as far as possible thereafter out to relatives of third degree. It is important to record the age of onset of any positive findings in the family history, even if that age is approximate. The physical examination should pay special attention to those signs of hyperlipidemia that can be highly specific for FH. The most important of these are xanthomas (fatty deposits) on the Achilles tendons and on the extensor tendons of the fingers and hands. It is important to palpate these tendons with care, as the xanthomas are frequently palpable even if they are not obvious on visual inspection. Corneal arcus (a lightly colored ring at the periphery of the iris), xanthelasma (fatty, discolored deposits in the skin around the eyes), and tuberous xanthomas are less specific for FH, but are suspicious findings in younger patients and should prompt further investigation for FH. While any of these findings may help to substantiate the diagnosis or inform our index of suspicion, it is very important to remember that their absence does not rule out FH. (4), (5)

The diagnosis of FH is predicated on the use of one of several sets of validated criteria. The NLA recommends the Simon-Broome Registry, the Dutch Lipid Clinic Network, or the US Make Early Diagnosis to Prevent Early Death (MEDPED) criteria. The MEDPED is perhaps the most widely utilized of these criteria and uses the patient's untreated TC or LDL-C concentration along with the presence or absence of FH in the relatives of the first three degrees to substantiate the diagnosis of FH. In the majority of cases, genetic testing for FH is not necessary for diagnosis, treatment, or prognosis. It may occasionally be undertaken to clarify a diagnosis, but is not indicated in most cases. As discussed above, the number of possible genetic causes of FH is extensive, so genetic testing can be cost prohibitive; moreover, even exhaustive testing fails to produce the genetic locus of the condition in up to 20% of clinically confirmed cases of FH. (4), (5)

Testing the relatives of a confirmed FH patient is as important to disease prevention and saving lives as is making the initial diagnosis in a single patient. When we have confirmed a new diagnosis of FH, we must recommending testing, via a basic lipid panel, to all of the first-degree relatives of that patient. Likewise, we recommend testing to all of the first-degree relatives of any new cases we discover through our first round of screening. This process is known as cascade screening and it is the most cost-effective method available for detecting and caring for new cases of FH. Screening should be carried out in any potentially affected person who is at least 2 years of age. We are also encouraged to perform a first screening lipid panel in all of our patients by ages 9 to 11 years. (4), (5)

The treatment of FH can be difficult; it is often resistant to treatment, responding minimally or not at all to intervention. For instance, if the genetic anomaly present causes poor binding between the LDL particle and the LDL receptor, clearing LDL particles from the blood can be next to impossible, even with high-dose statin therapy. It is noteworthy that, while statin drugs (HMG-CoA reductase inhibitors) do block the rate-limiting step in cholesterol synthesis, their most important lipid-lowering effect results from the fact that reduced synthesis leads to increased cholesterol clearance from the blood for use in the liver, not from the reduced synthesis itself. Due to the resistance of FH to treatment, our goals for therapy are different in FH than other dyslipidemias.

In FH, the goal of therapy is a 50% reduction in the level of the untreated LDL-C. Persistent and tenacious treatment of FH is of the utmost importance, as long-term treatment can greatly reduce or even eliminate the excess CHD burden borne by FH patients and can result in CHD event rates at or near that of the general population. Due to the lifetime risk of CVD resulting from FH, conventional guidelines recommend beginning treatment at age 8. (4), (5)

Conventional practitioners and organizations recognize the importance of lifestyle modifications in the treatment of FH. The recommendation for drug therapy is for those adults and children who have an LDL-C greater than 190 mg/dL despite optimal lifestyle modifications; statin drugs are the initial pharmaceutical intervention of choice. For those whose condition resists treatment even on maximum optimal drug therapy, there are available several new pharmaceutical agents and even plasma LDL apheresis (filtering LDL out of the blood similar to renal dialysis for the removal of nitrogenous waste from the blood of patients with kidney failure). Yet, all parties agree, treatment begins with lifestyle modification. The NLA recommendations for lifestyle modifications in FH include abstention from use of tobacco products, limitation of alcohol consumption, exercise and calorie intake goals to achieve and maintain ideal body weight, use of 10 to 20 g/day of soluble fiber, a TLC diet (less than 25%-35% of daily calories from fat, less than 7% of daily calories from saturated fat, less than 200 mg/day of dietary cholesterol), and use of 2 g/day of plant sterols/stanols (PS).

PS are a powerful natural intervention for lowering cholesterol. They are extremely similar in molecular structure to cholesterol; sterols differ from cholesterol primarily by the presence of single methyl group and stanols by the presence or absence of an additional double bond. (10) In the small intestine, PS compete with cholesterol for absorption, resulting in less cholesterol uptake. In most cases, PS are then excreted back into the lumen of the gut and wasted, but use of PS is not without risks and cautions. In very rare instances, a genetic mutation in the ABCG5 or ABCG8 gene leaves individuals lacking the ability to excrete PS, a condition called sitosterolemia, which looks very similar to FH in many respects. (10-12) Sitosterolemia causes severe, early atherosclerosis, typically with tendon xanthomas. The evidence which led to the discovery of this rare condition also caused a scare about the safety of the routine use of PS and whether these substances are actually atherogenic. While that possibility is still contested, the results of a high quality meta-analysis published last year in the European Heart Journal, including 17 studies and over 11,000 patients, concluded that there is no evidence of an association between serum concentrations of plant sterols and CVD risk. (13)

Plant sterols are naturally occurring components of plant-based foods. The average American consumes between 150 and 400 mg/day of plant sterols, at best less than one-quarter of the amount recommended to lower cholesterol. Nuts and seeds are high in plant sterols, as is plant matter itself. Several manufacturers produce encapsulated PS products which can be taken with meals. Plant stanols are byproducts of industry, predominantly the paper production industry. These molecules are processed to food grade and then packaged as supplements or foods such as margarines, chocolates, caramels, and others. There are several easy ways to incorporate a recommendation for 2 g/day of PS into the daily regimen of almost any patient.

A plant-based diet is an affordable and natural way to meet several treatment goals at once in FH or hypercholesterolemia of any origin. A plant-based diet, with at least 50% of the vegetable matter consumed raw and 50% cooked, vegetable protein only, with no animal fats or proteins (i.e., a vegan diet), is one way to rapidly reduce serum lipid levels. This diet meets the recommendations of the TLC diet on fat restriction while dramatically increasing the amount of PS and fiber in most diets, thereby meeting several therapeutic goals simultaneously. We typically recommend that patients add 4 to 8 tablespoons of freshly ground flaxseed to their daily diet as well, which further increases their PS, fiber, and polyunsaturated fatty acid (PUFA) intake. Caramels or chocolates made with plant stanols typically contain another 500 mg of PS, and 1 or 2 each day after meals makes for a sweet treat that moves us further in the direction of our cholesterol goals. Over the past year, we have observed several patients (with very high lipid levels, but not FH), cut their TC and LDL-C levels by 30% to 40% in 3 months on this type of regimen. While the results in FH are not as dramatic, we have seen LDL-C levels drop 80 mg/dL in just 3 months on this type of regimen. In FH especially, every bit counts.

In the treatment of hypercholesterolemia in general, and FH in specific, there are some words of caution about the use of PUFAs and omega-3 (n-3) essential fatty acids (EFA) in particular. There are important differences in the effects of different n-3 EFAs on lipids. Part of the proposed mechanism for the TG lowering effects of EFAs is that they increase the activity of plasma lipoprotein lipase (LPL). (14-16) This increase in turn leads to increased conversion of VLDL to LDL. Therefore, supplementing with combined eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) frequently leads to a significant increase in LDL-C. Outstanding review work by Jacobson et al. has helped to clarify the effects of supplemental EPA and DHA on lipid levels. Our best evidence demonstrates that, while DHA significantly reduces TG more than EPA, it also significantly increases LDL-C more that EPA, whereas EPA appears to lower LDL-C, LDL particles (LDL-p), and apoB. (16-18)

Familial hypercholesterolemia is a condition that is underappreciated, underdiagnosed, and undertreated. As many FH patients come to us in the world of CAM and integrative medicine in the attempt to avoid a lifetime of drug therapy, we must be cognizant and vigilant with regard to their true CVD risk as well as their options for treatment. Appropriate treatment and follow-up in FH can be the epitome of opportunity for preventive medicine and to forestall a lifetime of suffering from our nation's most prevalent chronic disease.

Selection of Lipid Biomarkers

Since the majority of our patients will not have FH, a discussion of the best biomarkers for CHD risk and atherogenesis in them warrants some discussion. The evidence accumulating over the recent years and the guidelines that follow from them have encouraged us to become more interested in testing and tracking the sum total of atherogenic lipid particles and less interested in their individual types and subtypes. The Adult Treatment Panel Three (ATP III) updated guidelines published in 2004 helped to establish treatment targets for non-HDL-cholesterol (non-HDL-C). (19) The non-HDL-C is the concentration of cholesterol in all of the apoB-containing particles; the non-HDL-C is calculated from a standard lipid profile by simply subtracting the HDL-C from the TC. The lipid species which are the most atherogenic all contain apoB particles; therefore, some have advocated for the direct measurement of the number of apoB-containing particles as our target and point of interest. Approximately 90% of the apoB-containing particles are LDL particles (LDL-p); therefore, some parties have advocated for the idea of measuring LDL-p.

There are arguments on all sides as to which of these markers, apoB, LDL-p, or non-HDL-C, is our best single biomarker for CHD risk. In study after study, LDL-p has been demonstrated to have stronger associations with CVD than LDL-C. Likewise, apoB measurements have been shown to be a significant predictor of CHD, including in meta-analyses of very large observational studies. (20) Moreover, many patients demonstrate a discordance between their levels of LDL-C and LDL-p or apoB and this is important because those discordances are associated with higher risk for CVD. (21), (22) So these points argue in favor of making measures of biomarkers beyond the standard lipid profile. The LDL-p level closely mirrors the apoB level because about 90% of the apoB-containing particles are LDL-p. The two mirror one another closely enough that their indications are the same. In initial CVD risk assessment: they are not recommended for low-risk patients; they can be considered for patients with CHD or CHD equivalents; and they may be reasonable in patients with intermediate risk, positive family histories, or recurrent events. On treatment/management decisions: they are not recommended in low-risk patients; can be considered in those with positive family histories; and may be reasonable in intermediate-risk individuals, those with CHD or equivalents, or those with recurrent events. (23)

As a routine marker to be assessed in all patients, the non-HDL-C is still at the top of the heap. In a recent set of secondary data analysis from eight trials conducted between 1994 and 2008, including 62, 154 patients all treated with statin drugs, LDL-C, apoB, and non-HDL-C were all predictive of future CVD events, but the association was significantly greater for non-HDL-C than either of the other two. (24) Several other considerations may make non-HDL-C a superior measure to LDL-p or apoB for initial assessment and on-treatment/management decisions in the majority of circumstances, including the well-established targets for non-HDL-C, its ease of calculation, its well-documented intervention effects, and the fact that it can be obtained without additional cost or data collection beyond the standard lipid profile. (25) For now, the non-HDL-C remains a central metric of lipid management and should not exceed the LDL-C by more than 30 mg/dL.

HDL Consensus Statement

Low levels of HDL-C remain our best predictors of future CVD events. Yet there is a large and distinct difference between that observation and the notion that interventions which raise HDL-C might alter CVD risk and prevent events. The longstanding idea that increasing HDL-C levels would increase reverse cholesterol transport, clean atherosclerosis from the arteries, and prevent CVD is known as the HDL hypothesis. The failures of two recent and very large clinical trials to show any benefit in CVD prevention due to increased HDL-C, and the use of extended release niacin to achieve it, have resulted in statements from cardiovascular experts such as, "The HDL hypothesis is on the ropes," and, "This is the death knell for niacin for sure...." (26), (27)

In the AIM HIGH trial, 1718 participants took 1500 to 2000 mg/day of extended-release niacin (ERN) in addition to simvastatin 40 to 80 mg/day (with or without ezetimibe 10 mg/day) and were compared with 1696 patients who took a placebo plus simvastatin with or without ezetimibe. The purpose was to determine if ERN plus simvastatin was superior to simvastatin alone in reducing CVD deaths, events, hospitalizations, or revascularizations. Niacin significantly increased HDL-C and lowered LDL-C and triglycerides compared with placebo over 3 years of follow-up, but there was no difference between the two groups in terms of outcomes and the trial was stopped early due to lack of efficacy. (28)

The Heart Protection Study Two-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) was a multinational study which investigated the use of 2000 mg/day of ERN plus laropiprant 40 mg versus placebo in primary prevention of major cardiovascular events. All 25,673 patients also took simvastatin with or without ezetimibe. After nearly 4 years of follow-up, there were no significant differences between the two groups against the primary outcome, prevention of first myocardial infarction, stroke, or revascularization. Serious adverse events including diabetic complications, new onset diabetes, infections, myopathies, hemorrhages, and others were significantly higher in the ERN group. (29)

Over the last year, there has been enormous response to this pair of studies. The findings helped to motivate Merck to pull its drug Tredaptive (ERN plus laropiprant) from shelves worldwide in January 2013. They have led some authors to announce the death of the HDL hypothesis and others to openly criticize the investigators of these studies for wasting money on investigations designed to fail. There are many aspects of these studies that can be criticized, not the least of which is that, in both cases, the participants had baseline LDL-C levels which were already at or below the recommended treatment target, leaving us to wonder whether we should expect to see any differences in outcomes between two groups already at optimal LDL-C levels, regardless of the type of add-on intervention. This is not to mention the problems inherent in ending trials early (because you may miss an effect that hasn't yet occurred), or the confounding additional medication (laropiprant) which was added to ERN in the HPS2-THRIVE study.

In response to these data and the reaction to them, the NLA has produced a consensus statement on HDL that was discussed at the annual scientific sessions in May 2013 and will be published in late 2013. (30), (31) Among others, the following three points will be featured prominently: (1) We can no longer consider HDL-C to be a therapeutic target. There is very little evidence remaining to demonstrate that treating HDL-C makes any difference in CVD outcomes. The little evidence there is lives in the shadow of a mountain of evidence which indicates the contrary. (2) HDL cholesterol cannot be considered a biomarker of HDL particles (HDL-p). The best evidence for improved outcomes lies in increased HDL-p, but we have spent years focused on HDL-C and the two are not equivalent. (3) We must increase our efforts to understand HD--p, not abandon them. (30) The HDL molecule is complex and participates in inflammation, gene transcription, RNA transport, cholesterol transport, and perhaps countless other processes that we have not yet uncovered or begun to understand.

Peter Toth, MD, president of NLA, presented the HDL consensus statement at the May 2013 sessions and said, "... The fact that there are plausible reasons for why these trials [AIM HIGH, HPS2-THRIVE, and others] failed suggests that the HDL hypothesis has still not been tested. For this reason, it is far too premature to abandon the HDL hypothesis. On the contrary, we need much more research in order to understand the reason for the unexpected results of these failed trials. It is premature to abandon the research efforts to better elucidate how the modulation of HDL metabolism and functionality impacts risk for CHD." (31) Put simply, the HDL hypothesis is not dead; it may not yet have even been fully formed. Now is not the death of the HDL hypothesis, but its renaissance.

To contact the author or for further information:

Jeremy Mikolai, ND

Heart & Lung Wellness Center of Excellence in Naturopathic

Cardiovascular Medicine

Center for Natural Medicine Inc.

1330 SE Cesar E. Chavez Blvd.

Portland, Oregon 97214

503-232-1100

CNMWellness.com

drmikolai@cnmwellness.com

This author has no financial conflicts of interest to declare.

Notes

(1.) Mission of the National Lipid Association [Web page]. National Lipid Association. Accessed 2013 Jul 8. https://www.lipid.org/about/mission#.

(2.) NHLBI Issues ATP IV Statement [Web page]. National Lipid Association. Accessed 2013 Jul 8. https://www.lipid.org/communications/nhlbi_statement.

(3.) Guardamagna O, Restagno G, Rollo E, et al. The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J Pediatr. 2009;155:199.

(4.) National Lipid Association. Familial Hypercholesterolemia: PocketGuide. Lake Mary, FL: International Guidelines Center; 2013.

(5.) Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients. Clinical guidance from the national lipid association expert panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5:1330140.

(6.) Rosenson RS, de Ferranti SD, Durrington P. Inherited disorders of LDL-Cholesterol metabolism. In: Basow DS, ed. UpToDate. Waltham, MA; 2013.

(7.) Grossman M, Rader DJ, Muller DW, et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med. 1995;1:1148.

(8.) Gidding SS, Bookstein LC, Chomka EV. Usefulness of electron beam tomography in adolescents and young adults with heterozygous familial hypercholesterolemia. Circulation. 1998;98:2580.

(9.) Maki KC. CVD epidemiology I, risk assessment II. Masters in Lipidology Course; 2013 May 29-30; Red Rock Resort, Las Vegas, NV. Jacksonville, FL: National Lipid Association; 2013:18.

(10.) Jones PJH. Plant sterols and heart health. NCNM Integrative Cardiovascular Conference; 2013 May 18-19; National College of Natural Medicine, Portland, OR. Portland: NCNM; 2013 May.

(11.) Brown A. Lipoprotein metabolism and genetic disorders. Masters in Lipidology Course; 2013 May 29-30; Red Rock Resort, Las Vegas, NV. Jacksonville, FL: National Lipid Association; 2013:16-17.

(12.) Sehayek E. Genetic regulation of cholesterol absorption and plasma plant sterol levels: commonalities and differences. J Lipid Res. 2003 Nov; 44(11):2030-8.

(13.) Genser B, Silbernagel G, De Backer G, et al. Plant sterols and cardiovascular disease: a systematic review and meta-analysis. Eur Heart J. 2012; 33: 444-451.

(14.) Mathur J, Watt KR, Field FJ. Regulation of intestinal NPC1L1 expression by dietary fish oil and docosahexaenoic acid. Lipid Res. 2007; 48:395-404

(15.) Harris WS, Miller M, Tighe AP, Davidson MH, Schaefer EJ. Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis. 2008; 197:12-24.

(16.) Jacobson TA. Lipid-altering drugs: pharmacology-I. Masters in Lipidology Course; 2013 May 29-30; Red Rock Resort, Las Vegas, NV. Jacksonville, FL: National Lipid Association; 2013.

(17.) Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. I Clin Lipidol. 2012; 6(1):5-18.

(18.) Wei MY, Jacobson TA. Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Curr Atheroscler Rep. 2011; 13:474-483

(19.) Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004; 110(2):227-239. Erratum in: Circulation. 2004; 110(6):763.

(20.) Thompson A, Danesh J. Associations between apolipoprotein B, apolipoprotein Al, the apolipoprotein B/AI ratio and coronary heart disease: a literature-based meta-analysis of prospective studies. J Intern Med. 2006; 259(5):481-492.

(21.) Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol. 2002; 90:22i-29i.

(22.) Otvos JD, Mora S, Shalaurova I, Greenland P, Makey RH, Goff DC. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. I Clin Lipidol. 2011; 5:105-113.

(23.) Davidson MH, Ballantyne CM, Jacobson TA, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011; 5:338-367.

(24.) Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012; 307(12):1 302-1309.

(25.) Ramjee V, Sperling LS, Jacobson TA. Non-high-density lipoprotein cholesterol versus apolipoprotein B in cardiovascular risk stratification: do the math. J Am Coll Cardiol. 2011; 58:457-463.

(26.) Kolata G. Doubt cast on the 'good' in 'good cholesterol'. New York Times. May 16, 2012. Available at http://www.nytimes.com/2012/05/17/health/research/hdl-good-Cholesterol-found-not-to-Cut-heart-risk.html?_r-0. Accessed June 30, 2013.

(27.) Thomas K. Merck says niacin drug has failed large trial. New York Times. December 20, 2012. Available at http://www.nytimes.com/2012/12/21/business/merck-says-niacin-Combination-drug-failed-in-trial.html. Accessed June 30, 2013.

(28.) Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011; 365(24):2255-2267.

(29.) Armitage J, HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-Controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart). 2013; 34(17):1279-1291.

(30.) Toth PP, Rosenson R, Barter P, et al. NLA HDL consensus statement. J Clin Lipidol. Forthcoming 2006.

(31.) Toth PP. NLA HDL consensus statement. Presented at: NLA SS 2013. Proceedings of the annual scientific sessions of the National Lipid Association; 2013 May 3--June 1; Las Vegas, NV.

by Jeremy Mikolai, ND

Jeremy Mikolai, ND, is the Naturopathic Education and Research Consortium (NERC) Integrative Cardiovascular Medicine Fellow for 2013-2015. Along with Drs. Tori Hudson, Martin Milner, and Sheryl Estlund and the NERC, he has designed the first-ever clinical fellowship program for naturopathic physicians to develop special expertise in areas of medical emphasis. Dr. Mikolai is an assistant professor of naturopathic medicine, clinical medicine, and research at the National College of Natural Medicine (NCNM) and adjunct faculty/professor of cardiology in the Naturopathic Medicine Department at Universidad del Turabo in Gurabo, Puerto Rico. He is also a lead faculty member at the Heart and Lung Wellness Center of Excellence in Naturopathic Cardiovascular Medicine at NCNM and at the Naturopathic Institute of Cardiovascular and Pulmonary Medicine (NICVM).
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