Women's HealthUpdateby Tori Hudson, NDwomanstime@aol.com

Two Important Interventions forWomen and Cardiovascular Disease

Dysliptdemia of Diabetes, Metabolic Syndrome, andElevated Fasting Glucose: How to Make the Most ofNiacin by Tim Polacek, guest author;edited by Martin Milner, ND, and Tori Hudson, ND

Type 2 diabetes, already an epidemic in the US,continues to increase. Additionally, untold numbers ofthe US population exhibit prediabetic conditions such asmetabolic syndrome or elevated fasting glucose. As up to80% of patients with diabetes will die of cardiovasculardisease, this column will focus on typical atherogenicdyslipidemias associated with these conditions.'

In the majority of patients with elevated lipoproteins,targeting LDL and total cholesterol reduction is the primarygoal identified in the National Cholesterol EducationProgram (NCEP) Adult Treatment Panel 111 guidelines.The use of a synthetic or naturally occurring statin asa single agent effectively achieves these reductions inabout 407o of patients.^ However, treating LDL targetsalone leaves significant residual risk, as roughly two-thirdsto three-fourths of individuals will still go on to have acardiovascular event, one example of which is the HeartProtection Study.̂ ••' In this study of simvastatin in 20,536high-risk individuals over 5 years, the major vascular eventrate for control and treatment groups was 25% and 20%respectively.

In diabetes and metabolic syndrome, LDL-targetedtherapy alone may leave patients at even greater risk. Thisis because the typical dyslipidemia of these conditions ismixed, and includes elevated triglycérides, low HDL, andsmall, very dense LDL.̂ Niacin favorably affects all ofthese lipid parameters, not only lowering LDL by 10% to25%, but shifting them from the smaller, dense particlesto larger, buoyant, less atherogenic particles. Triglycéridesare reduced by 20% to 5O7o.̂ With respect to HDL, niacinis widely regarded as the best single agent for increasingthis subfraction from 15% to 35%.^ Finally, niacin is theonly therapeutic agent known to lower Lp(a), a uniquelipoprotein with atherogenic, thrombotic, and inflammatoryproperties.''^

When comparing this therapeutic profile with otheragents, niacin appears in theory to be ideally suited tocorrect the mixed dyslipidemia of diabetes mellitus andmetabolic syndrome. Historically, however, there havebeen significant reservations about the use of niacin inthese patients. Since its use for cholesterol in the 1950s,niacin has been observed to increase fasting glucose insome patients.^ For many years, concerns of glycémiestability and even new onset diabetes led to these patients'being excluded from clinical studies. Gradually, with theincreasing need for lipid treatment in these patients, clinicalstudies have more closely examined the effects of niacinon fasting glucose and insulin sensitivity. Two trials inparticular, ADMIT and ADVENT, demonstrated favorableresults in lipid parameters in individuals with DM, withfew to no changes in glycémie status.^'" ADMIT usedimmediate-release (IR) niacin in doses up to 1500 mg twicedaily, and had modest effects on fasting glucose. Theseeffects appeared temporary, as fasting glucose returned tobaseline by week 16 ofthe trial. ADVENT used once-dailyextended-release (ER) niacin and had no effects on fastingglucose, a very modest increase in HbAlc at the higher1500 mg dose, and no changes in oral hypoglycémie agents.Another smaller study recently conducted in patients withMS is notable for using nonprescription, ER niacin 1000mg once daily to demonstrate significant improvementsin all lipid fractions, no changes in glycémie status, anda significant and sustained increase in adiponectin levelsover 12 months." The authors note that adiponectin hasemerged as an important marker of insulin resistanceand endothelial dysfunction, and low levels are stronglyassociated with MS and coronary heart disease.

While these placebo<ontro!led studies were reassuringwith regard to glycémie status, they were not designed todemonstrate the effect of niacin on clinical outcome. This iswhere the Coronary Drug Project (CDP) comes in. Originallya six-year, multiarmed, placebcxontrolled secondary

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Women's Health Update

prevention study, the niacin arm targeted an IR niacin doseof 1000 mg three times daily.'^ Due to tolerability issues,the average compliance-corrected dose reached was about2000 mg daily. These patients demonstrated reductions inrecurrent myocardial infarction (Mi), nonfatai Ml, coronaryheart disease death, stroke, transient ischémie attacií, newdefinite angina, and coronary surgery. A 15-year follow-upanalysis (average 9 years after iast study dose) demonstratedan 11% relative risk reduction in all<ause mortality.'^This totai mortality reduction was similar, if not greater,in patients with a baseline fasting plasma glucose >100mg/dl (5.5 mmol/dl). In 2001, an analysis of patients fromthe CDP with hyperglycemia or diabetes was reported.Grouped by baseline fasting plasma glucose, these six-yearresults demonstrated a trend for an increasing benefit in Mlamong those with the highest baseline glucose levels (seeTable!).'"

Table 1:Six-Year Results on Recurrent Nonfatal Ml in CDP by

Baseline Fasting Glucose

Fasting Plasma Glucose*(N in the nicotinic acid and plaœbo groups, respectively)

<5,3 mmol/L 5.3-5.8 mmoi/L 5.8-6.9 mmol.L a7.0 mmol/L'Niacin % 11.1 9.8 10.6 7,1'Placebo % 15.4 12.9 14.3 15.5

Odds ratio 0.68 0.73 0.71 0.42To convert to mg/dL, multiply by 18: ' percent with Ml

These analyses suggest that the long-term cardiovascularbenefits of niacin therapy in the CDP outweighedany potentially adverse effects of niacin on glycémieregulation.

Consensus panels and guidelines have recently reflectedthis shift. Position statements from the NCEP, the AmericanDiabetes Association, the American Heart Association,and the National Lipid Association share the opinion thatglucose increases, if they occur, are clinically modest, andamenable to adjustments in oral diabetic therapy.'^ DMpatients should be monitored closely for glucose controlduring the titration phase of therapy.

So what form of niacin should one use and how shouldit be dosed? This is where the guidelines seem to fallshort. Most practitioners are aware that IR forms causemore flushing, long-acting forms should not be used dueto the risk of hepatotoxicity, and ER forms are somewherein the middle. Inositol hexanicotinate (no-flush niacin)releases only trace amounts of nicotinic acid into plasma,and therefore has no effect on lipids.'^ There is alsoconsensus in that only niacin preparations with sufficientclinical data to define dissolution, bioavailability, safety,and efficacy should be recommended. Niaspan, having

*Nonprescription forms of niacin are sold as supplements and, as such,have not been evaluated by the FDA for therapeutic claims.

been approved by the FDA, has demonstrated safety andefficacy in numerous clinical trials, and is widely used bythe medical community.'*' According to Meyers et al. andIto, nonprescription* extended-release formulations thatshould be recommended are Slo-Niacin (Upsher Smith)and Endur-Acin (Endurance Products Co,).'^'^ A 2005dissolution study of Niaspan and selected nonprescriptionER niacin products demonstrated comparable dissolutiontimes for Niaspan and Endur-Acin, with Slo-Niacin releasingsomewhat faster (see Table 2).''*

Table 2: Estimated Dissolution Rate of Extended-Release

Formulations

Mean i S.D. % Niacin Estimated Mean ±S.D.

Products Released by 240 min Dissolution Rate* (mg/hr)

Niaspan 41.7±1.9 90,3±3.4

SLO Niacin 56.3±5.3 116J±9.1"

Endur-Acin 47,0±0,9 93.6±2,5•Calculations were nomialized to a 1000-mg niacin preparation (n=3)"Statistically higher compared with the reference formulation, Niaspan, p <0.05

These data demonstrate an "extended release" profile forthese preparations as differentiated in much of the medicalliterature, by "being absorbed over 8-12 hours, intermediatebetween IR and Long-Acting niacin."^"^ Niaspan and Slo-Niacin each use hydroxypropyl methylcellulose, a "polygel"formulation that is highly aquaphilic and has been noted tohave some variability in dissolution and release accordingto changes in peristaltic activity." Endur-Acin utilizes avegetable wax-matrix to produce a consistent, meteredrelease, and has demonstrated excellent Gl tolerability inclinical studies.'^

Sufficient clinical studies of these products andprescription Niaspan have been done to ensure safe andeffective dosing with once- and twice-daily regimens.What is less well understood are the pharmacodynamicdifferences of different formulations and regimens. WhileIR forms are the best at raising HDL and have been used atdoses up to 6 g, ER forms (dosed twice or three times daily)gain significant LDL effects at the expense of HDL andare generally limited to doses of 2 g. Dosing an extended-release form once daily more closely mirrors the kineticsand dynamics of IR niacin - that is, a total daily dose allat once results in a high serum peak that causes flushing,retaining the HDL improvements of IR, and equivalent LDLimprovements on a mg/mg basis.-' This was demonstratedin a study of Niaspan 1500 mg at night compared withplain niacin 1500 mg in divided doses. LDL, TG, and HDLchanges were all identical. Studies of nonprescriptionER niacin brands in divided doses have consistentlydemonstrated two to three times the potency of IR on LDLand are generally limited to not more than 2000 mg beforeliver enzyme elevation occurs.^^ This is also why once-dailyER can be pushed to higher doses (provided the patienttolerates the flush); higher doses increase the LDL responsewhile stiil allowing a significant trough with no exposure tothe liver.

126 TOWNSEND LETTER - MAY 2010

With these differences in mind, one should decide onthe primary goa! of niacin therapy in order to determinehow to dose niacin. If HDL elevation and TG reduction arethe primary goal, then either multiple-dosed IR or a once-daily ER should be chosen. This would be the reasonablechoice when adding niacin to an existing. LDL therapy,or using niacin in a patient with normal LDL but lowHDL. When tolerance due to flushing becomes an issue,or when LDL targeting is the primary goal, a twice-dailyER preparation can be used safely with careful titration atdoses up to 2000 mg.-'̂ Regardless of the form of niacin ordosing regimen you choose, patients must have LETs anduric acid monitored frequently during the titration phase,and periodically thereafter.

D-Ribose in Cardiac FunctionAdenosine triphosphate (ATP) is central to the function

of every cell in the body, and we rely on it as our energycurrency. Without ATP, energy to sustain life would cease,and ribose is the fundamental building block of ATP.While clinicians may be more familiar with the use ofribose supplementation in chronic fatigue syndrome andfibromyalgia, this column explores its use in cardiovasculardisease.

Cardiovascular disease is the most prevalent adult healthproblem in the US and the number one cause of death. Inaddition, 207o of men and women over age 40 are at riskfor developing congestive heart failure (CHE) during theirlifetimes.^" Diastolic dysfunction has been identified as amajor predictor of CHE risk, and ribose directly maintainsadenine nucleotide pools that are necessary to maintaincardiac diastolic function and increase the energy reserveof the heart.̂ '̂-'̂ Studies analyzing the effect of ischemiaon myocardial function and metabolism have reported areduction in ATP levels along with suppression of diastolicfunction after an ischémie episode.̂ ^ Other investigationshave hypothesized that an ATP insufficiency may beinvolved in ischémie CHE. Many CHE patients haveabnormal diastolic function, and based on animal studiesof ribose supplementation, demonstrating a shortenedtime to regenerate myocardial ATP levels followingischémie episodes, researchers asked whether ribosesupplementation may improve diastolic function andquality of life in individuals with CHE.̂ ^^^

A prospective, double-blind, randomized, crossoverstudy was conducted to assess the effect of D-ribosesupplementation on eardiae function and quality of lifein 15 individuals with coronary artery disease and CHE.̂ "D-ribose or plaeebo was administered as a powder 5 gthree times a day, for 3 weeks; and after a 1-week washout,patients took the alternative regimen for a second 3 weeks.Myocardial function was assessed with echoeardiography,quality-of-life questionnaire, and eyele ergometer testing.Neither D-ribose nor plaeebo significantly affected left-ventricular volume, stroke volume, or left-ventricularejection fraction. However, D-ribose resulted in a higher

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atrial contribution to left-ventricular filling, a smaller left-atrial dimension, and a shortened E wave decelerationcompared with placebo. Peak work capacity was notaltered by either D-ribose or placebo, but patients receivingD-ribose did have a significant improvement in their overallqualify-of-life index score and improved physical functionand improved exercise tolerance.

During the diastolic phase of the heartbeat, the heart'sability to relax depends on calcium ions' being pumpedout of the cell. In order for the ventricle to fill completely,complete relaxation is necessary so that adequate fillingof the ventricle can occur; and to achieve this ventricularrelaxation, a fully charged ATP pool is required. Riboseis directly related to ATP concentration and recovery anddiastolic cardiac function. Animal studies show that whenribose is given to hearts after a period of ischemia, cardiacATP levels increase and diastolic function increases.̂ ^ Thereare numerous clinical and laboratory studies showing thatsupplementing with ribose will enhance the recovery ofadenine nucleotide pools as well as enhancing diastolicfunction in heart pathology.^ '̂̂ ^

Ribose has also been shown to increase tolerance tomyocardial ischemia in individuals with coronary arterydisease (CAD).̂ ^ Twenty men with severe CAD underwenttreadmill stress testing. Patients were randomly assigned to3 days of placebo or 60 g daily of ribose supplementation.Exercise testing was repeated on day 5. ST-segmentdepression was significantly greater in the ribose group thanin the placebo group. The ribose-treated group also hadsignificant changes in both time to ST depression and timeto moderate angina, whereas these were not significant inthe placebo group. In essence, these individuals with CADwho received ribose for 3 days had an improved toleranceto ischemia.

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As a result of this research, clinicians are learning touse ribose supplementation to improve cardiac function,exercise tolerance, and quality of life in patients with CHF inparticular, but also in ischémie heart disease, angina pectoris,and cardiomyopathy. Additional research demonstrates thecardioprotective benefit of ribose supplementation in thosewith healthy hearts, to improve anaerobic energy reserves,and in raising the cardiac tissue hypoxic threshold such thatduring periods of intense exercise and endurance sports,cardiac stress is reduced because of greater cardiac muscleenergy stores.̂ "̂̂ ^ While the cardiac research on ribosesupplementation is small and preliminary, it suggests thatcardiac patients, especially those with CHF and ischémieheart disease, could benefit from the cardioprotectivebenefits of ribose supplementation. Future research willclarify the benefits of D-ribose supplementation to cardiacpatients and hopefully confirm these small studies.

DisclosureTim Pollack is the medical liaison for Endurance Products inc.

Tori iHudson, ND, is the conawner and director of Education andResearch for Vitanica, as well as on the scientific advisory board ofBiogenesis, Nordic Naturals, Natural Health International, and IntegrativeTherapeutics.

Notes1. O'Keefe )H et at. Improving the adverse cardiovascular prognosis of type 2

diabetes. Mayo Clin Proc. 1999;74:171-180.2. Pearson TA et al. The Lipid Treatment Assessment Project ÍL-TAP). Arch

Intern Med. 2000;160:459-467.3. Fruchart )C et al. The Residual Risk Reduction Initiative; a call to action to

reduce residual vascular risk in patients with dyslipidemia. Am I Cardiol.2008;102:10K-34K.

4. Heart Protection Sludy Collaborative Croup. MRC/BHF Heart ProtectionSludy of Cholesterol lowering with simvastatin in 20,536 high-risk individuals:a randomised placebo-controlled trial. Lancet. 2002:360:7-22.

5. Miller M. Niacin as a component of combination therapy for dyslipidemia.Mayo Clin Proc. 2OO3;78:735-742.

6. Aronov DM et al. Clinical trial of wax-matrix sustained-release niacin in aRussian population with hypercholesterolemia. Arch Fam Med. 1996;5;567-575.

7. Ariyo AA et al. Lp(a) lipoprotein, vasculardisease, and mortality in the elderly. N Engl IMed. 2OO3;349:21O8-2115,

8. Parsons WB Jr. Cholesterol Control WithoutDiet: The Niacin Solution. Lilac Press; 2008.

9. Elam MB et al. Effect of niacin on lipid andlipoprotein levels and glycaemic controlin patients with diabetes and peripheralarterial disease. The ADMIT Study. lAMA.2000;284:1263"1270.

10. Grundy SM et al. Efficacy, safety, and tolerabilityof once-daily niacin for the treatment ofdyslipidemia associated with type 2 diabetes:resulis of the assessmeni of diabetes control andevaluation of the efficacy of niaspan (rial. ArchIntern Med. 2OO2;162:1568-1576.

n.Vaccari CS et al. Efficacy of controlled-release niacin in treatment of metabolicsyndrome: Correlation to surrogate markersof atherosclerosis, vascular reactivity, andinflammation. / Clin iipid. 2OO7;l :605-613.

12. The Coronary Drug Project Research Croup.Ctofibrate and niacin in coronary heart disease.lAMA. 1975;231;360-381.

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Women's Health Update

13. Canner PL et al. Fifteen-year morfdiity in coronary drug project patients: long-term benefit with niacin. I Am Coll Cardíol. 1986;8;1245-1255.

14. Canner PL el ai. Niacin decreases myocardial infarction and total mortality inpatients with impaired fasting glucose or glucose intolerance: results from theCoronary Drug Project. Circulation. 2OO2;lO6|suppl):31-38.

15. Goldbefg RB el al. Effects of nidcin on glucose control in patients withdyslipidemia. Mayo Clin Proc. 2006;83:470-478.

16. Abbot Laboratories. Niaspan package insert.17. Meyers CD el al. Varying cost and free nicotine acid content in over-the-

counterniacin preparations for dyslipidemia./^nn Intern Med. 2003; 139:996-1002.

18. Ito MK et al. Key anieles, guidelines, and consensus papers relative to thetrealment of dysliptdemias. Pharmacotherapy. 2006;26:939-1010.

19. Poon IO et al. Dissolution profiles on nonprescription extended release niacinand inositol niacinate producís. Am / Health-Syst Pharm. 2OO6;63:2128-2134.

20. McKenny |. New perspectives on the use of r>iacirt in the treatment of lipiddisorders. Arch Intern Med. 2004;164:697-705.

21. Knopp RH et al. Equivalent efficacy of a time-release form of niacin (Niaspan)given once-at-night vs piain niacin in the management of hyperlipidemia.Meiabolism. 1998;47:1097-1104.

22. Birjmohun RSetal. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. / AmCo// Cardiol. 2OO5;45:185-197.

23. Keetian jM. A physician's guide to niacin therapy [online article].Enciiirance Research. 2009. http://www.enduranceresearch.com/index.cfm?fuseaction=content.display&pagelD = 73.

24. Redfield M, Jdcobson S, Burnen J, et al. Burden of systolic and diastolic ven-tricular dysfunction in the community. Appreciating the scope of the heartfailure epidemic. ¡AMA. 2OO3;289(2): 194-202.

25. Pduly D, Pepine C. D-ribose as a supplement for cardiac energy metabolism./ Cardiovasc Pharmacol Ther. 2000;5(4):249-258.

26. Omran H, Illien S, MacCarter D et al. D-Ribose improves diastolic functionand quality of life in congestive heart failure patients: a prospective feasibilitystudy, fur / Heart Fail. 2003;5:615-619.

27. Reibet D, Rovetto M. Myocardia! ATO synthesis and mechanical functionfollowing oxygen deficiency. Am ; Physiol. 1978;234:H620-H626.

28. St. Cyr J, Bianco R, Schneider j , el al. Enhanced high energy phosphate recov-ery with ribose infusion after global myocardial ischemia in a canine model. /SurgRes. I9a9;46:157-162.

29. Zimmpr H. Normalization of depressed heart function in rats by ribose. Sci-ence. 1983;220:81-82.

30. Omran, Illien, MacCarter D, et al,, op cit.31. Tveter K, St. Cyr j , Schneider ), et al. Enhanced recovery of diastolic func-

tion after global myocardial ischemid in the intdct animal. Pediatr Res.1988;23:226A.

32. Carter O, MacCarter D. Mannebach S, et al. D-Ribose improves peak exer-cise capacity and ventilatory efficiency in heart failure patients. / Am Col!Card/o/. 2005;45:185A.

33. Schneider J, St, Cyr j , Mahoney I, et al. Recovery of ATP and return of func-tion after global ischemia. C/rctz/dlion. 1985;72(4 pi 2):1l1-298.

34. Tdn Z. Ruthenium red, ribose and adenine enhance recovery of reperfusedrat heart. Coron Artery Dis. 1993:4Í3):3O5-3O9.

.Í5. Zimmer H. Normalization of depressed heart function in rats by ribose. .Sci-ence. 1983;220:81-82.

36. Pliml W, Arnim T, Stdblein A. et dl. Effects of ribose on exercise-inducedischaemia in stable coronary artery disease. Lancet. l992;340:507-510,

37. Seifert ), Subudhi A, Fu MS. et al. The effects of ribose ingestion on indi-ces of free radical production during hypoxic exercise. Free Rad Biol Med.2OO2;33(supph:S269.

38. Gradus-Pizio I, Sdwadd S, Lewis S, et al. Effect of D-ribose on the detection ofthe hibernating myocardium during the low dose dobutamine stress echocdr-diography. Círaí/aíio/i. 1999:100(18¡:3394.

39. Wallen 1, Belanger M, Wittnich C. Preischemic administration of ribose lodelay the onset of irreversible ischémie injury and improve function: studiesin normal and hypertrophied hearts. Can ¡ Physial Pharmacol. 2003;81:40-47.

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