CLINICAL STUDY

LDL = 5: Virtues and Dangers of MultidrugTherapy of Low-Density LipoproteinCholesterol

William Phillips, MD, MPH; Saul Schaefer, MD

Multiple-drug therapy of dyslipidemia is fre-quently used to achieve treatment goals in high-risk patients with coronary artery disease. Theauthors report a case of a patient treated with astatin, fibrate, ezetimibe, and niacin in whom acalculated low-density lipoprotein cholesterollevel of 5 mg ⁄ dL was achieved. Prev Cardiol.2010;13:69–71. �2009 Wiley Periodicals, Inc.

Aggressive treatment of dyslipidemias hasbecome more common in high-risk patients.

Recent demonstration of the efficacy of loweringlow-density lipoprotein cholesterol (LDL-C) to<70 mg ⁄ dL,1 as well as modification of nationalguidelines,2 has led to the use of multiple-drugtherapy for dyslipidemia. We report a case inwhich combined therapy of dyslipidemia in apatient with coronary artery disease resulted in adramatic reduction in LDL-C.

CASE PRESENTATIONMr H is a 60-year-old man with coronary arterydisease, prior coronary artery bypass surgery, hyper-tension, and dyslipidemia with an initial fastinglevel of total cholesterol (TC) of 237 mg ⁄dL, LDL-C by Friedwald calculation of 130 mg ⁄dL, high-density lipoprotein cholesterol (HDL-C) of 33mg ⁄dL, and triglycerides of 372 mg ⁄dL on simvast-atin and fenofibrate therapy (Table I). The additionof ezetimibe 10 mg to simvastatin 40 mg, plus low-dose niacin (250 mg 3 times daily), lowered his

LDL-C to 72 mg ⁄dL, with no change in HDL-Cand a modest reduction in triglycerides to 277mg ⁄dL. Because of his persistently low HDL-C andelevated triglyceride levels, his niacin was progres-sively up-titrated to 3 g ⁄d over a 3-month periodand was well tolerated except for an increase in hisfasting glucose level from 98 mg ⁄dL to 133 mg ⁄dL.The patient had no history of excessive alcohol use,chronic kidney disease, or liver disease. Concurrentmedications included valsartan, metoprolol, aspirin,and fish oil capsules (1 g 4 times daily), which werenot altered during the course of therapy.

Three months after the initiation of niacin ther-apy, the patient’s fasting lipid panel was remarkablefor an LDL-C value of 5 mg ⁄dL (direct LDL-C,11 mg ⁄dL), TC value of 54 mg ⁄dL, and triglyceridevalue of 95 mg ⁄dL, with no change in HDL-C. Hisaminotransferase (AST) was 61 U ⁄L, but returnedto baseline within 1 month while niacin therapywas continued; other liver enzyme levels werewithin normal limits, as was his serum albuminlevel. He complained of mild nausea.

In view of this marked decrease in LDL-C, eze-timibe and simvastatin were reduced to 5 mg and20 mg daily without any appreciable change in lipidvalues. Elimination of ezetimibe resulted in anincrease of LDL-C to 46 mg ⁄dL, which again fell to14 mg ⁄dL with rechallenge. Withdrawal of niacinresulted in an increase of LDL-C to 60 mg ⁄dL withan HDL-C of 31 mg ⁄dL.

DISCUSSIONThe combination of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin), ezetimibe,fenofibrate, and niacin resulted in a profound 93%reduction in plasma LDL-C in this patient. Thewithdrawal of medications and subsequent rechal-lenge showed that both ezetimibe and niacin wererequired for this reduction in LDL-C, as neitheralone (on a background of a statin and fibrate) wassufficient to lower LDL-C to this extent.

Niacin is often used in addition to other lipid-modifying agents, with several reports of both

From the Division of Cardiovascular Medicine,University of California Davis, Davis, CAAddress for correspondence:Saul Schaefer, MD, Division of Cardiovascular Medicine,University of California Davis, One Shields Avenue, TB172, Davis, CA 95616E-mail: sschaefer@ucdavis.eduManuscript received May 13, 2009; revised July 26, 2009;accepted August 6, 2009

doi: 10.1111/j.1751-7141.2009.00052.x

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efficacy and safety. The HDL-Atherosclerosis Treat-ment Study (HATS)3 demonstrated that the combi-nation of niacin (mean dosage, 2.4 g ⁄d) andsimvastatin (mean dosage, 13 mg ⁄d) resulted in a42% decrease in LDL-C, a 25% increase in HDL-C, decreased progression of angiographic coronaryartery disease, and a significant reduction in thecomposite cardiovascular end point relative toplacebo. The addition of niacin to simvastatin ther-apy was associated with significant increases inAST, creatine kinase, and uric acid but was clini-cally well tolerated.

Guyton and associates,4 in a large prospectivestudy, showed that the addition of extended-release niacin to ezetimibe ⁄ simvastatin resulted inmodest but significant reductions in LDL-C andtriglycerides (4.9% decrease in LDL-C, 19.7%reduction in triglycerides) without significantincreases in liver enzymes or clinical complaints ofmyalgias. However, the use of niacin was associ-ated with flushing and new-onset diabetes. In acomplementary but retrospective study, Jelesoffand colleagues5 found that the addition of ezetim-ibe to niacin-based regimens (which usuallyincluded statins) was associated with a 25% reduc-tion in LDL-C and a 17% reduction in triglyce-rides, with no change in HDL-C. In these studies,combination therapy was well tolerated and notassociated with elevations in hepatic transaminases,although the mean doses of statins and niacin werelower than used here. Thus, the profound reduc-tion in LDL-C with combination therapy, includingezetimibe as in the current instance, has not beenreported previously.

While niacin alone has modest effects on LDL-Clevels, significant reductions in LDL-C have beenreported, likely as an adverse toxic reaction on hepa-tic synthetic function. Tato and associates.6 described3 cases of patients started on crystalline niacin whoexperienced 39% to 59% reductions in plasma LDL-C levels. These patients felt clinically ill after the initi-

ation of niacin therapy, with complaints includingfatigue, nausea, and pretibial edema. All patientsdemonstrated significant decreases in lecithin-choles-terol acyltransferase activity, and 2 of the 3 hadsignificant elevation in liver aminotransferases,suggesting an effect of niacin on hepatic syntheticfunction.

The cause of the extreme reduction in LDL-C inthe current patient may indeed be due to a toxicreaction as reported by Tato and colleagues.6 Useof higher doses of statins and niacin raise the poten-tial of an adverse interaction of these agents onhepatic function.7 Although the patient in this casedid not have evidence of hepatic dysfunction asmeasured by hepatic enzymes or serum albumin, hedid experience a significant increase in fastingglucose level. Glucose intolerance in patients treatedwith niacin, thought to be due to increased insulinresistance as a result of higher levels of circulatingnonesterified fatty acids,8 is usually modest andinfrequently seen using lower doses of statin andniacin, as reported in the HATS trial.9

Alternatively, a positive synergistic therapeuticeffect of ezetimibe and niacin is suggested by the data,since extremely low LDL-C was only seen when bothagents were employed (Table I); each drug alone hadonly modest effects on LDL-C. Ezetimibe inhibitscholesterol absorption at the intestinal brush borderthrough the Niemann-Pick C1–like 1 protein,10

thereby lowering hepatic cholesterol content. Niacinlowers LDL-C secondary to reductions in adipose-derived free fatty acids and reduced hepatic triglycer-ide synthesis and very low-density lipoproteinformation11 and increases HDL-C by decreasingexpression of cholesterol-ester transfer protein anddecreasing clearance of apolipoprotein A1 fromplasma.12 We postulate that in addition to the effectof the statin on cholesterol synthesis,13 the lowerhepatic cholesterol content from ezetimibe combinedwith niacin effects on hepatic synthesis caused theextremely low LDL-C concentration.

The question of whether an LDL-C value of5 mg ⁄dL may be harmful also arises. Cholesterol isrequired for membrane synthesis,14 and althoughmany patients are treated to levels of LDL-C<70 mg ⁄dL with proven benefit, there is potentiallya lower limit of LDL-C at which harm can ensue.Specifically, concern has been raised regarding theimpact of lowering LDL-C and TC on hormonalsynthesis and neural development. However, severalstudies have not shown impact on either adrenal ortesticular steroidogenesis with pharmacologic lower-ing of LDL-C to levels <70 mg ⁄dL,15,16 and statintherapy has been associated with a reduced inci-dence of dementia.17 Finally, there is concern of anincreased incidence of cancer with lipid-loweringtherapy. A recent meta-analysis demonstrated aninverse relationship between on-treatment LDL-Cand incident cancer but no effect per se of statintreatment.18

Table I. Medications and Serum Lipid Values in Patient

Over a 2-Year Period of Treatment

Statin Ezetimibe Niacin TC TG LDL-C HDL-C

a 40 237 372 130 33

s 40 10 250 162 277 72 35s 40 10 3000 57 95 5 33s 20 5 3000 54 63 13 28

s 20 3000 103 77 46 42s 20 5 3000 62 68 14 34s 20 5 122 157 60 31

Abbreviations: a, atorvastatin; HDL-C, high-density

lipoprotein cholesterol; LDL-C, low-density lipoproteincholesterol; s, simvastatin; TC, total cholesterol; TG,triglycerides. Medications included fenofibrate 145 mg ⁄ d.

Medication values are in mg and lipid values in mg ⁄ dL.

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In summary, this patient had a profound reduc-tion in LDL-C. This was seen as an effect of 4-drugtherapy with high-dose statin and niacin as well asezetimibe and fibrate. While this result may be dueto a positive therapeutic interaction, it is possiblyevidence of a toxic reaction in the liver. To ourknowledge, this is the lowest recorded on-treatmentvalue of LDL-C. While aggressive treatment ofLDL-C is a worthwhile goal, sometimes we succeedtoo well.

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