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TOPICS IN STATIN THERAPY
Audio-Digest Internal Medicine
Volume 60, Issue 13
April 7, 2013

Update on Cholesterol Treatment – Patrick E. McBride, MD, MPH
Statins and Dementia – Marwan N. Sabbagh, MD

  
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The following is an abstracted summary, not a verbatim transcript, of the lectures/discussions on this audio program.

Internal Medicine Program Info  Accreditation InfoCultural & Linguistic Competency Resources

Topics in Statin Therapy

Educational Objectives

The goal of this program is to provide an update on the treatment of abnormal cholesterol and to review the potential role of statin therapy in the treatment of dementia. After hearing and assimilating this program, the clinician will be better able to:

1. Use the C-reactive protein test to determine the approach to management of a patient with elevated cholesterol and indeterminate risk for a cardiovascular (CV) event.

2. Incorporate niacin into the treatment of a patient with elevated triglycerides and low high-density lipoprotein levels.

3. Employ statin therapy to lower a patient’s low-density lipoprotein (LDL) level and risk for CV events.

4. Counsel patients on nutritional strategies and eating plans to reduce elevated levels of triglycerides and LDL.

5. Consider statin therapy as a treatment option for the patient with mild to moderate Alzheimer disease.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee 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: Marwan Sabbagh, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Lilly USA, LLC; AWD Pharma; Eisai Inc.; Piramal Healthcare, Bayer Healthcare Pharmaceuticals. Received grants for clinical research from: GE Healthcare; Baxter; Bristol-Myers Squibb Company; Avid; Lilly USA, LLC; Pfizer Inc; Ortho-McNeil-Janssen Pharmaceuticals, Inc.; Eisai Inc. Dr. McBride and the planning committee reported nothing to disclose. In his lecture, Dr. Sabbagh presents information that is related to the off-label or investigational use of a therapy, product, or device.

Update on Cholesterol Treatment

Patrick E. McBride, MD, MPH, Professor of Medicine and Family Medicine; Associate Director, Preventive Cardiology Program; and Associate Dean for Students, University of Wisconsin School of Medicine and Public Health, Madison

Adult Treatment Panel (ATP) IV guidelines: strictly evidence based (all from randomized controlled trials); will be update rather than comprehensive guide to lipid management; still in development and confidential

Basic approach to lipid therapy: low-density lipoprotein (LDL) — statins; ezetimibe; resins; sterols; triglycerides (TGs) and high-density lipoprotein (HDL) — fibrates; niacin; fish oil; download patient education materials on lipid-lowering agents and treatment protocols from www.healthdecision.org

Effect of lipid-lowering therapy on cardiovascular (CV) events: patients with history of myocardial infarction (MI) or stroke at greater risk for recurrence than persons with no history for initial MI or stroke; studies show patients at greater risk for CV event get greater risk reduction with lipid-lowering therapy; risk reduction not as dramatic in primary prevention trials because patients not at as high risk; consider lifetime risk for patients receiving primary prevention; meta-analysis by Cholesterol Treatment Trialists (CTT) of >90,000 patients found consistent reduction of 25% in overall CV events

Number needed to treat (NNT) for primary prevention: CTT meta-analysis concluded NNT 53 for 5 yr and NNT 29 for 10 yr to prevent major CV event; in patients with regular hypertension (150/95 mm Hg), NNT 100 to 120 for 5 yr to prevent major CV event; in Helsinki Heart Study (patients with TG >200 mg/dL and HDL <40 mg/dL), NNT 7

Heart Protection Study (HPS): conducted in United Kingdom; included diverse population of patients; baseline LDL 131 mg/dL, HDL lower; again, results showed 25% reduction in CV events across board with statin therapy; NNT 19 to prevent one event (for people without previous coronary heart disease [CHD]); risk reduction similar in patients with or without previous CHD

Treating to target: at time of ATP III guidelines, evidence good for treating LDL to targets; however, often difficult to reach exact target in therapy and question has been raised about importance; Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) — study compared treatment with high-dose atorvastatin to standard-dose pravastatin; difference in results showed absolute risk reduction of 4% (rate of CV events 26% with pravastatin compared to 22% with atorvastatin) in favor of more intensive therapy; another study — randomized patients to treatment with atorvastatin dosed at 10 mg or 80 mg daily; LDL reduced to mean of 98 mg/dL during treatment with 10 mg atorvastatin and to mean of 77 mg/dL with 80 mg; difference in total major CV events 10.9 compared to 8.7; study focused on efficacy of high- vs low-dose therapy, not treating to target

Safety: overall, statins extremely safe; challenge to determine whether reports of side effects reflect patients’ concern about medication or real; eg, in HPS (33,000 patients), initial rates of muscle aching with treatment 3% in patients on placebo compared to 2% in those on simvastatin; after public withdrawal of cerivastatin (Baycol) from market due to cases of muscle aching, rate of reports of muscle aches increased to 33% in patients on placebo and 30% in those on simvastatin; studies show rates of discontinuation of statins extremely low

Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER): patients >60 yr of age with low LDL (108 mg/dL at baseline), elevated body mass index, and high levels of C-reactive protein (CRP) randomized to 20 mg rosuvastatin (Crestor) or placebo; on treatment, LDL 55 mg/dL; study stopped after 2 yr; results showed significant difference in CV events between groups; NNT 25 to prevent one event; cost effectiveness dependent on cost of statin

Clinical use of CRP and biomarkers: do test if results will change management significantly; do not use for routine screening; reserve for patients at intermediate risk when undecided whether or not to treat

Ezetimibe: only few studies on use (mainly add-on trials because of baseline effects); shown to lower LDL safely and effectively; however, adequate studies have not been conducted to demonstrate whether ezetimibe reduces CV events; eg, in one study, patient group of 720 too small and follow-up (2 yr) too short to detect difference in primary end point (ie, carotid intima-media thickness)

Fenofibrate: can be combined safely with statins; however, studies done in patients with mixed dyslipidemia (in whom drug ineffective); Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study — average age of patients 62 yr; 22% had CV disease (CVD); many patients put on statin during trial (no use initially); difference nonsignificant in coronary events between patients on fenofibrate compared to placebo; in diabetic patients with mixed dyslipidemia, fenofibrate did not work; no difference in mortality; slight increase in pulmonary embolism and pancreatitis associated with treatment; subgroup analysis found small difference in total CVD events; drug has potential as good medication for cholesterol treatment but good studies (with appropriate patients) not yet done

Niacin: excellent treatment but challenging to use in practice; Atherothrombosis Intervention in Metabolic Syndrome with Low LDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial — niacin added to treatment for patients with LDL lowered to 40 to 80 mg/dL on high-dose simvastatin therapy; study stopped prematurely due to increased number of strokes in combined treatment group; no difference seen in primary end point; HDL-Atherosclerosis Treatment Study (HATS) — simvastatin and niacin combination therapy given to patients with high LDL and TG and low HDL; results showed significant reductions in CV events (effect blunted by addition of antioxidants); Cholesterol Lowering Atherosclerosis (CLAS) I and II studies — showed significant regression in CHD and drop in mortality; sustained-release forms of niacin (vitamin B3) easiest to use (extended-release form [Niaspan] expensive); niacin can be given twice daily; extended-release forms have some problems with gastrointestinal toxicity; most common side effect flushing (avoid by taking with meals, premedicating with aspirin [325 mg], and taking with applesauce [pectin slows flushing]); niacin plus aspirin, water, and food lowers TG by 50% to 80%, raises HDL by 50% to 75%, and lowers LDL by 25%

Patients with diabetes mellitus (DM): glucose interferes with TGs and raises LDL; gemfibrozilin Veterans Affairs HDL Intervention Trial (VA-HIT), patients with and without DM showed 24% relative risk reduction with gemfibrozil; patients with DM also had 8% absolute risk reduction (similar to differences seen in statin studies); both groups also showed significant reductions in CV events (patients had CHD, high TGs, and low HDL)

Lifestyle changes: recommended first-line therapy in patients with high TGs and low HDL; TG levels respond immediately to weight loss and daily exercise; nutritional strategies — decrease calories, fats, simple carbohydrates, and alcohol; consume high doses of fish oil (4 g/day of omega-3 fatty acids reduce TGs by 40%; read labels carefully to determine amount of omega-3 in over-the-counter products); Mediterranean diet — best eating plan; high in fruits, vegetables, calcium, healthy oils, lean meats, fish, complex carbohydrates (eg, whole grains, nuts, legumes); 35% fat; proven effective in reducing all-cause mortality and cardiac death in patients with CHD

Summary of evidence for lipid therapy: LDL — best evidence for statins; second-best evidence for resins; sterols easy way to lower LDL by additional 10% to 12%; TGs and HDL — best evidence for niacin, fish oil, and gemfibrozil; evidence undecided on fenofibrate and ezetimibe

Statins: greatest drop in LDL occurs with initial dose; every subsequent doubling of dose achieves additional decrease of 6%; dose should be based on patient’s required drop in LDL (start at maximum required; do not start low and titrate upwards; side effect profile similar across doses 80 mg, then doubles); potency — pravastatin, lovastatin, and fluvastatin provide 35% maximum reduction in LDL; atorvastatin, rosuvastatin, and simvastatin provide 50% to 60% reduction; side effects — major side effect myopathy (characterized by severe muscle aches across entire body; localized muscle problem [eg, sore shoulder, stiff back, one-sided muscle pain] not induced by statins); elevated liver enzymes (extremely rare; should be checked once after initiating dose but not again unless other medications used; not concern unless 3 times normal and rising; do not monitor creatine kinase routinely); risk for DM — rare (1 in 1000 patients treated); important to remember patients with DM receive significant benefit from statins; mechanism for risk not clear; not reason to avoid initiating statin therapy

Methods for achieving further reductions in LDL: increased adherence to therapeutic lifestyle changes (counsel patient on exercise and nutritional changes; portfolio diet [includes soy, nuts, oat bran, and psyllium] can lower LDL by 30% in patient who will not take statin); consider bile acid sequestrants and plant stanol and sterol esters

Lipid management recommendations: LDL elevated but TG normal — statin, resin, sterol, and ezetimibe; TG >400 mg/dL but LDL normal — fibrate, niacin, fish oil; combined dyslipidemia (LDL and TGs elevated) — combination therapy recommended; best combination statin and niacin; alternative statin and fish oil

Questions and Answers

LDL target in primary prevention: if patient has >7.5% 10-yr risk for CV event, clear benefit from LDL therapy; initiate treatment and do not worry about target level; if 10-yr risk 5.0% to 7.5%, decision to treat based on clinical judgment

Non-HDL as predictor of CV risk: non-HDL (total cholesterol minus HDL) excellent test and better predictor than LDL or HDL; good in adults and children; test inexpensive; recommended cutoff for treatment 30 mg/dL above those for LDL (eg, if LDL >130 mg/dL treated, then treat non-HDL >160 mg/dL); test can be done nonfasting and at any time of day

Simvastatin, 80 mg: speaker does not use 80 mg dose unless patient on drug for long period; even then, would try to change medication because risk for myopathy 4 to 5 times higher than with other agents at that dose

Statins and Dementia

Marwan N. Sabbagh, MD, Director, Banner Sun Health Research Institute; Research Professor of Neurology, University of Arizona College of Medicine, Phoenix

Introductory remarks: disparity between general impression (statins worsen memory) and scientific evidence (statins good for cognition)

Hypercholesterolemia and Alzheimer disease (AD): numerous studies in literature show association between high fat and cholesterol diet, hypercholesterolemia, and increased risk for AD; also evident serum cholesterol levels increase in patients with AD (some suggest increase precedes cognitive decline); mechanism of cholesterol — cholesterol freely crosses blood-brain barrier and key factor for neuronal health; however, also evidence that cholesterol cofactor of amyloid deposition; high cholesterol levels appear to accelerate oxidation and amyloidogenesis; cholesterol levels and risk for AD may not be related — not universally agreed that high cholesterol increases risk for AD; Framingham Heart Study found no identifiable link between AD and cholesterol

Statin use and risk for AD: extremely well researched; some studies suggest use of statins and other lipid-lowering agents reduces risk of developing AD (in some trials by up to 60%-70%); however, others have found statin use does not alter risk (one study attributed study results that show positive benefit of statins to inappropriate statistical methodology)

Statins as treatment for AD: several plausible biologic mechanisms support statins as treatment for AD; statins shown to have anti-inflammatory properties and to decrease risk for CV events; neuropathologic studies show chronic statin use associated with reduced AD pathology

Evidence from clinical trials: AD Cholesterol Treatment Trial (ADCLT; Sparks et al, 2006) — first double-blind, placebo-controlled clinical trial to treat AD using atorvastatin (Lipitor); data from AD Assessment Scale-cognitive subscale and Mini Mental State Examination showed patients taking 80 mg atorvastatin for treatment of AD had no reduction in cognition at 12 mo compared to those on placebo; Cholesterol Lowering Agent to Slow Progression (CLASP) of AD study (Sano et al, 2011) — 400 participants with mild to moderate AD randomized to simvastatin or placebo; results at 18 mo showed no benefit from treatment; Lipitor’s Effect in Alzheimer’s Dementia (LEADE) study — statin therapy for mild to moderate AD over 72 wk did not produce statistically significant difference in end points

Possible reasons for negative results in recent studies: ADCLT included patients with high cholesterol levels, while CLASP study excluded patients with cholesterol high enough to require statin therapy; posthoc analysis of ADCLT found benefit of atorvastatin on cognition seen only in patients with elevated baseline cholesterol, mild AD, and apolipoprotein E carriers; suggests CLASP study may have failed because it excluded patients likely to benefit from treatment (patient selection may have also been factor in LEADE study); blood-brain barrier permeability of statins hypothesized to influence responsiveness

Emerging research: kinesin family member 6 (KIF6) gene polymorphism — studies show patients with KIF6 polymorphism have strong response to statins in terms of cholesterol reduction, while those without polymorphism have no response; influence of KIF6 polymorphism on response to statin therapy for AD not yet studied; 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) — recent data suggest HMGCR polymorphisms may also predict responsiveness to statins; bottom line — these factors have not been investigated (may influence why past studies positive or negative)

Comments: at this time, clinical trial data and epidemiologic evidence disparate (epidemiologic data largely suggest that high cholesterol risk factor for AD and statin therapy reduces risk; animal data largely support epidemiologic data); no randomized controlled trial done to determine whether chronic statin use prevents development of AD over time (only have epidemiologic data on prevention); statins remain appealing therapeutic approach for AD because of safety profile and multiple potential benefits

Acknowledgements

Dr. McBride was recorded at the 35th Annual Eastern Shore Medical Symposium, held on June 18-22, 2012, in Rehoboth Beach, DE, and presented by Jefferson Medical College of Thomas Jefferson University and the University of Delaware. Dr. Sabbagh spoke at the 10th Annual Dr. Roizen’s Preventive and Integrative Medicine Conference, held on December 7-9, 2012, in Las Vegas, NV, and presented by the Cleveland Clinic Foundation Center for Continuing Education. For information about the 36th Annual Eastern Shore Medical Symposium, presented by Jefferson Medical College of Thomas Jefferson University and the University of Delaware and scheduled for June 17-21, 2013, please visit their website at www.jefferson.edu. For information about the 11th Annual Dr. Roizen’s Preventive and Integrative Medicine Conference, presented by the Cleveland Clinic Foundation Center for Continuing Education and scheduled for December 6-8, 2013, their web address is www.clevelandclinicmeded.com. The Audio-Digest Foundation thanks the speakers and their sponsors for their cooperation in the production of this program.

Suggested Reading

Baigent C et al: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005 Oct 8;366(9493):1267-78; Boden WE et al: Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011 Dec 15;365(24):2255-67; Cannon CP et al: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004 Apr 8;350(15):1495-504; Feldman HH et al: Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 2010 Mar 23;74(12):956-64; Ginsberg HN et al: Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010 Apr 29;362(17):1563-74; Gouni-Berthold I, Berthold HK: The Role of Niacin in Lipid-Lowering Treatment: Are we Aiming Too High? Curr Pharm Des 2013 Jan 9 [Epub ahead of print]; Kastelein JJ et al: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008 Apr 3;358(14):1431-43; Katsiki N et al: Ezetimibe Therapy for Dyslipidemia: An Update. Curr Pharm Des 2013 Jan 9. [Epub ahead of print]; Keech A et al: Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005 Nov 26;366(9500):1849-61; LaRosa JC et al: Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005 Apr 7;352(14):1425-35; Ling H et al: Novel strategies for managing dyslipidemia: treatment beyond statins. Postgrad Med 2012 Nov;124(6):43-54; Martin SS et al: Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the meantime, some challenges and recommendations. Am J Cardiol 2012 Jul 15;110(2):307-13; Reitz C: Dyslipidemia and the risk of Alzheimer’s disease. Curr Atheroscler Rep 2013 Mar;15(3):307; Ridker PM et al: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008 Nov 20;359(21):2195-207; Sabbagh MN et al: On cholesterol levels and statins in cognitive decline and Alzheimer disease: progress and setbacks. Alzheimer Dis Assoc Disord 2009 Oct-Dec;23(4):303-5; Sánchez-Ferro A et al: A review of the potential therapeutic role of statins in the treatment of Alzheimer’s disease: current research and opinion. Neuropsychiatr Dis Treat 2013;9:55-63; Sano M et al: A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology 2011 Aug 9;77(6):556-63; Shai I et al: Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N Engl J Med 2008 Jul 17;359(3):229-41; Sparks DL et al: Circulating cholesterol levels, apolipoprotein E genotype and dementia severity influence the benefit of atorvastatin treatment in Alzheimer’s disease: results of the Alzheimer’s Disease Cholesterol-Lowering Treatment (ADCLT) trial. Acta Neurol Scand Suppl 2006;185:3-7; Virani SS et al: Non-high-density lipoprotein cholesterol reporting and goal attainment in primary care. J Clin Lipidol 2012 Nov;6(6):545-552.


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