HYPERLIPIDEMIA/POLYPHARMACY
| ADVANCES IN TREATMENT CHOICES FOR HYPERLIPIDEMIA —Ronald B. Goldberg, MD, Professor of
Medicine, University of Miami Miller School of Medicine, Miami, FL
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| Low-density lipoprotein (LDL) and coronary heart disease (CHD): each 30 mg/dL change in level of LDL results
in ≈30% change in relative risk for CHD; lowest risk at LDL ≈40 mg/dL; high LDL not only risk—mean total cholesterol
level (210-220 mg/dL) similar in patients with and without CHD; CHD may be present in patients with no
elevation in LDL
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| High-density lipoprotein (HDL) and risk for CHD: Framingham study data show that at any given LDL-cholesterol
(LDL-C) level, range of risk for CHD contingent on HDL-cholesterol (HDL-C) levels; patient with low LDL and
low HDL at higher risk than patient with low LDL and high HDL
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| Triglycerides and CHD: risk for CHD rises with triglyceride level (somewhat more in women); although triglycerides
absent from plaque, when triglycerides >100 mg/dL, large fluffy LDL particles supplanted by more atherogenic
small dense LDL
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| Other risk factors: include hypertension, diabetes, glucose intolerance, and cigarette smoking; risk in patient with
somewhat elevated LDL and hypertension equivalent to patient without hypertension and significantly elevated
LDL; these risk factors affect inflammatory process in plaque
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| Assessing risk in individual patient: based on likelihood of major coronary event in next 10 yr; CHD risk
equivalent—20% risk for major event in next 10 yr; same as minimal risk after myocardial infarction (MI); risk
present in patients with cerebrovascular disease, peripheral vascular disease, and aortic aneurysms; risk also
present in diabetes (but absent in younger patients with mild disease; may affect treatment decision); most aggressive
therapy indicated in these patients; patients without clearcut risk—range of risk 4-fold, from little risk to approaching
(or at) CHD risk equivalent; patients with ≥2 major risk factors—warrant most aggressive treatment;
calculate patient’s Framingham score to decide level of risk and therapy; patients with low risk—no MI expected
in next 10 yr; Adult Treatment Panel (ATP) III says therapy not indicated unless LDL level significantly elevated
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| Evidence base for recommendations: Scandinavian Simvastatin Survival Study (4S)—reported in 1994; in high-risk
patients, lowering high LDL to average level reduced CHD ≈35%; Cardiac Assessment Risk Evaluation (CARE)
study—2001; lowering average LDL to ≈100 mg/dL reduces risk ≈30%; recommended to lower LDL ≥130 mg/
dL to 100 mg/dL; class effect—different statins produce similar results
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 | Moderate risk: in patients with ≥2 risk factors and above-average LDL, lowering LDL to below average reduced
risk 35%; recommended to lower LDL >160 mg/dL to 130 mg/dL
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| Few risk factors and very high LDL: West of Scotland Study—found benefit in lowering LDL to 150 mg/dL
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| CHD or diabetes and LDL <100 mg/dL: Heart Protection Study—found statin produced significant reduction in
risk; recommended to reduce LDL in high-risk patients with optimal LDL; lower is better in high-risk patients—
LDL plays pathogenic role in patients with low LDL and high risk factors; lowering LDL slows process
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| Elderly patients without CHD and 2 risk factors: in upper end of moderate-risk group; lowering LDL from ≈130
mg/dL to 100 mg/dL showed benefit
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| Lowering average LDL: Treating to New Targets (TNT) study—80-mg statin dose lowered LDL to ≈78 mg/dL
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| In patients with CHD and LDL 75 mg/dL: evidence supports aiming for 30% reduction in LDL (ie, to ≈50 mg/dL);
studies under way
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| High-risk patients: reduce LDL level to 70 mg/dL
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| Moderate-risk patients: LDL in lower range—10-yr risk <10%; begin statin at LDL between 160 mg/dL and 190
mg/dL; LDL in higher range—eg, 3 risk factors and 10-yr risk 15%; treat same as high risk patients
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| Establish goal: internists currently reach LDL goal of 100 mg/dL in only 50% of patients; uncertainty about statin
dose needed to reach goal; starting dose provides most benefit, compared with subsequent titration; first determine
percentage of LDL lowering needed—use highest recommended starting dose to reach goal; alternatively, combination
therapy, eg, simvastatin-ezetimibe tablet (38% lowering with statin alone; adding ezetimibe [Vytorin] 10/20
achieves goal; reduces LDL from ≈135 mg/dL to 70 mg/dL)
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| Acute coronary syndromes: Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT)— atorvastatin
80 mg/dL produced 16% reduction in major CHD events at 2 yr; patients with acute coronary syndromes should receive
maximal statin therapy upon entering hospital; benefits seen at 4 mo, suggesting anti-inflammatory mechanism;
rate of reccurrence lowest when both LDL and C-reactive protein (CRP) reduced (use of CRP under
investigation)
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| Safety of high-dose statin therapy: compared to 10 mg/dL, 80-mg/dL dose elevated alanine aminotransferase
(ALT)/ aspartate aminotransferase (AST) >3 times upper limit of normal, necessitating withdrawal of therapy;
rhabdomyolysis—no dose effect; occurs in patients with risk factors for rhabdomyolysis (eg, elderly; small body
frame; renal disease; multiple medications; susceptible to shock; certain drugs [fibrates; antifungals; macrolide antibiotics;
protease inhibitors]); may need to lower statin dose or discontinue
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| Triglycerides and HDL: patients with CHD typically have same LDL levels as those without CHD; more often triglycerides
high and HDL low; statins alone reduce risk only 30% to 40%
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| Hypertriglyceridemia: when triglycerides >200 mg/dL; aim for non–HDL-cholesterol (non–HDL-C) level 30 mg/
dL above LDL-C; for HDL <40 mg/dL in high-risk patients, consider therapy to raise HDL-C; calculation of
non–HDL-C—total cholesterol minus HDL-C, ie, cholesterol in LDL, lipoprotein (LP) (a), and very low-density
lipoprotein (VLDL) cholesterol (VLDL-C); examples—in patient with high total cholesterol, non–HDL-C increased
because LDL increased (small amount from cholesterol in triglyceride-rich particles); in patient with hypertriglyceridemia,
cholesterol from triglyceride-rich particles elevates non–HDL-C; Framingham data show
risk for CHD increases as non–HDL-C increases; lowering LDL and VLDL results in lowering of non–HDL-C
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| HDL and statin therapy: higher HDL corresponds with lower risk, and range ≥4-fold; raising HDL adds to benefit of
lowering LDL; complications—although HDL plays role in reverse cholesterol transport and as antioxidant in oxidized
LDL, unknown whether raising HDL enhances these benefits; may actually increase inflammation in plaque because
as HDL reverses oxidation in LDL, HDL becomes proinflammatory; means of raising HDL—while clinical
trial evidence shows combination therapy with statin, fibrate, and niacin significantly raises HDL and lowers LDL and
non–HDL-C, therapy to raise HDL not currently recommended
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| POLYPHARMACY: WHEN LESS IS MORE —Paul D. Snyder Jr, MD, Assistant Professor of Medicine,
Mayo Clinic College of Medicine, Scottsdale, AZ
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| Introduction: patients—often taking multiple medications and do not know purpose of each one; do not take prescription
drugs as prescribed, but in bunches in morning or evening; often take prescription drugs with vitamins
and other nonprescription drugs; label—should state not only dosage, but reason for medication
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| Definition of polypharmacy: more medications than clinically indicated for patient’s problems
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| Risks and consequences: adverse drug reactions (ADRs); drug-to-drug interactions; noncompliance; increased risk
for hospitalization due to ADRs or medication errors; increased cost
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| Patients misunderstand: according to Danish study of 348 elderly patients—disagreement on general drug information,
ie, did not know purpose of drug (22%); disagreement on dosing, ie, not taking drug as prescribed (71%); disagreement
on prescribing regimens, ie, did not know when to take drug (66%); 24% not following prescribing
regimen; only 60% knew purpose of medicaton; only 21% knew consequences of missed doses; <6% understood
toxicity and side effects of potential drug interactions; associated with noncompliance—increased dosing frequency;
>3 drugs; prescriptions from >1 physician; probability of dementia
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| Findings on ADRs: meta-analysis of 39 prospective studies found ADRs fourth-to-sixth leading cause of death in
United States; elderly patients taking ≥5 drugs have ≈35% chance of ADR; ADRs increase from 10 per 10 000 in
second decade of life to >60 per 10,000 in eighth decade; 36% of reported ADRs involve elderly patients; 28% of
hospitalizations of older adults due to ADRs (17% from ADR, 11% from noncompliance); ≈32,000 hip fractures
annually due to ADRs
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| Aging and drug absorption: bioavailability not changed; serum concentrations may be lower and delayed (except for
drugs with extensive first-pass effect; less drug extracted by smaller liver, increasing bioavailability); factors affecting
absorption—route of administration; ingestion with other drugs; comorbid illnesses; concomitant use of calcium,
magnesium, and iron; increased gastric pH; enteral feedings; altered gastrointestinal (GI) motility; volume of
distribution—lowered for hydrophilic drugs by decreased body water; increased for lipophilic drugs by increased
body fat; higher percentage of unbound drug due to decreased plasma albumin (more active drug present); metabolism
and aging—decreased clearance by liver (smaller mass, size, and blood flow); drugs with phase II metabolism
(to inactive metabolite) may be better for elderly; affected by sex, hepatic congestion (eg, heart failure), and smoking;
kidney and aging—decreased size, blood flow, number of nephrons, and tubular secretion; results in decreased
glomerular filtration rate and drug excretion
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| Drugs to avoid in elderly: anticholinergics (cardiac dysrhythmias; dry mouth and eyes; urinary retention); tricyclic
antidepressants (anticholinergic effects; cardiac toxicity; orthostatic hypotension [at usual doses]); first- and second-
generation antipsychotics (extrapyramidal and anticholinergic effects; tardive dyskinesia); barbiturates (respiratory
depression; falls and hip fractures; may be unavoidable for seizures); long-acting benzodiazepines (major
role in falls and hip fractures; basis for most data on hip fractures); first-generation antihistamines, eg, diphenhydramine
(Benadryl; excessive sedation; idiosyncratic hyperactivity); propoxyphene (central nervous system [CNS]
impairment; fall risk); meperidine (CNS impairment); dipyridamole (orthostatic hypotension; fall risk); long-acting
sulfonylureas (overly long action may cause hypoglycemia)
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| Reducing polypharmacy: specify indication on bottle; evaluate all medications (prescriptions; over-the-counter
drugs; nutritional supplements); have patient maintain up-to-date medication list for physician; check dosing
(start with lowest dose possible); educate patients, caregivers, and staff; document all ADRs; monitor compliance
(hospital records; caregiver; pharmacy); decrease number and strength of doses as appropriate; eliminate
unnecessary drugs; consider nonpharmacologic therapies (eg, for bladder dysfunction, vestibular dysfunction);
avoid medication errors during transition periods (hospital to home; home to nursing home and back)
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| DRUGS mnemonic: Discontinue medications; Reassess clinical effect after period; Understand reason for removing
and adding drugs; Give feedback; Start over with next medication
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| Every drug an experiment: reaction of patient unknown
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| For each drug prescribed: identify reason for initial prescription (explain verbally and in writing on label); look at
evidence for continuation; assess intended effect on symptoms; monitor interaction with other drugs; consider
whether drug cause of current symptoms (eg, symptoms of dementia)
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| Medication removal: start with least useful and most detrimental; allow adequate time to assess results (removing
one drug at time); continue until all unnecessary drugs eliminated
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| Adding new drug: one at a time; start low and go slow; offer rational and realistic expectations for benefit
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| Principles of rational prescribing: get rid of unnecessary drugs first; try nonpharmacologic management (eg, behavioral
therapy, physical therapy); one drug at time; start low and go slow (probably most important for elderly); every
drug is experiment; establish rational therapeutic expectations; do not stop trying
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| Questions and answers: PRN dosing in nursing home—pick drugs with least offensive side effects; approach to
guidelines—cannot persist with recommended dosage if side effects intolerable (seek alternative therapy)
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Suggested Reading
Asztalos BF et al: Comparison of the effects of high doses of rosuvastatin versus atorvastatin on the subpopulations of
high-density lipoproteins. Am J Cardiol 99:681, 2007; Castelli WP et al: Lipids and risk of coronary heart disease. The
Framingham Study. Ann Epidemiol 2:23, 1992; Genest JJ Jr et al: Familial lipoprotein disorders in patients with premature
coronary artery disease. Circulation 85:2025, 1992; Grundy SM et al: Implications of recent clinical trials for the
National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110:227, 2004; Hogan DB et
al: Patient sheet: tips for avoiding problems with polypharmacy. CMAJ 175:876, 2006; Jacobson TA et al: Combination
therapy with fluvastatin and niacin in hypercholesterolemia: a preliminary report on safety. Am J Cardiol 73:25D, 1994;
Kannel WB: High-density lipoproteins: epidemiologic profile and risks of coronary artery disease. Am J Cardiol 52:9B,
1983; McKenney JM et al: Effect of niacin and atorvastatin on lipoprotein subclasses in patients with atherogenic dyslipidemia.
Am J Cardiol 88:270, 2001; Meadows M: Medication use and older adults. FDA Consum 40:20, 2006; Reid
JL: Fall and rise of polypharmacy? Hypertension 49:266, 2007; Schaefer EJ et al: Comparisons of effects of statins
(atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with
coronary heart disease versus control subjects. Am J Cardiol 93:31, 2004; Thompson PD et al: Statin-associated myopathy.
JAMA 289:1681, 2003; Violi F et al: MRC/BHF Heart Protection Study. Lancet 360:1782, 2002.
Educational Objectives
| The goal of this program is to improve the treatment ofhyperlipidemia and to optimize the managemet of polypharmacy.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Assess risk factors for coronary heart disease to establish optimal treatment goals.
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| 2. Evaluate the evidence for recent recommendations for treating hyperlipidemia.
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| 3. Manage statin therapy to reduce risks in patients with hyperlipidemia.
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| 4. Recognize polypharmacy.
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| 5. Limit prescribed medications to those indicated for a patient’s problems.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Goldberg—Lilly/
Takeda (speaker; consultant board); Novo Nordisk (research grant); Pfizer (speaker; research grant; consultant
board); Merck (speaker; research grant; consultant board); Merck/Sheering Plough (speaker); KOS (speaker; research
grant); AstraZeneca (speaker; research grant; consultant board); Abbott (speaker; consultant board); Sangyo (research
grant)
Acknowledgements
Dr. Goldberg was recorded at University of Miami Miller School of Medicine’s 42nd Annual Advances in Medicine,
held in Miami, FL, January 21-26, 2007; Dr. Snyder at 9th Annual Mayo Clinic Internal Medicine Update: Sedona in
Sedona, AZ, October 4-8, 2006. The Audio-Digest Foundation thanks Drs. Goldberg and Snyder, and the University
of Miami Miller School of Medicine and Mayo Clinic College of Medicine for their cooperation in the production
of this program.
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