Prevention 2014: Statin Intolerance

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Mahesh J. Patel, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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Prevention 2014: Statin Intolerance

  1. 1. Mahesh J. Patel, MD Assistant Professor of Medicine Statin Intolerance: The Achilles Heel of CVD Prevention
  2. 2. “More Than a Billion People Taking Statins?” “This apparently seasoned integration of data and opinion eventually would lead to massive use of statins at the population level; ie, “statinization.” It is uncertain whether this would be one of the greatest achievements or one of the worst disasters of medical history.” Ioannidis JAMA 2013
  3. 3. 3 Mencina NEJM 2014 12.8 million more statin-eligible patients NHANES 2005 – 2010 ATP III – 43.2 million statin eligible (38% US adults) New guidelines – 56 million statin eligible (49% US adults)
  4. 4. Case Presentation • 58 y/o AA man with PMH CAD s/p 4v CABG (age 36) and multiple subsequent PCI’s who presents to outpt cardiology clinic after NSTEMI and PCI of native LAD and SVG to OM2. • PMH: DM2, familial combined hyperlipidemia, OSA • Meds: aspirin, clopidogrel, insulin, losartan, & metoprolol XL • On no lipid meds. Statin intolerant – h/o myalgias and myositis • In 2010, TC 322, TG 142, HDL-C 26, LDL-C 268 • In 2012, TC 355, TG 208, HDL-C 38, LDL-C 275
  5. 5. Overview • Statin Myopathy • The Management of Statin Intolerance • Statins & the Risk of Diabetes
  6. 6. Statin myopathy definitions • Myopathy – general term referring to any disease of the muscles • Myalgias – muscle ache or weakness w/o CK elevation • Myositis – muscle symptoms with increased CK • Rhabdomyolysis – muscle symptoms with CK > 10x ULN +/- renal disease Pasternak JACC 2002
  7. 7. Epidemiology of Statin Myopathy: Clinical Trials Meta-analysis of 180,000 patients in 21 major statin trials with average follow-up of 3 years • Myalgias Incidence: 1.5 – 3.0% • Myositis Incidence: 11 / 100,000 • Rhabdomyolysis Incidence: 1.6 – 6.5% / 100,000 Law AJC 2000
  8. 8. The PRIMO Study Bruckhert CV Drugs Ther 2005 • PRIMO – Prediction of Muscular Risk in Observation conditions • Observational study of 7924 patients with hyperlipidemia on statin therapy in usual care, outpatient setting in France • Symptoms – Pain 10.5% of total population – Most common lower limbs – 25% tendon pain – More common in more active individuals 10.8% vs 14.7% – Prevention of moderate exertion due to pain in 38% – Bedridden due to pain in 4%
  9. 9. The PRIMO Study Bruckhert CV Drugs Ther 2005 Strongest predictors of muscular symptoms – Hx of muscle pain on another statin OR 10 – Hx of unexplained cramps OR 4 – Hx of CK elevation OR 2
  10. 10. The STOMP Study The Effect of Statins on Skeletal Muscle Function & Performance • 420 healthy statin-naïve patients • RCT of atorvastatin 80 mg vs. placebo x 6 months • No CK increase > 10X ULN • Average CK level increased by 20 U/L with atorvastatin • Higher prevalence of myalgias with atorvastatin (19% vs. 10%; p=0.05) • No change in muscle strength or exercise capacity Parker Circ 2013
  11. 11. Statins impair exercise training adaptations - 37 sedentary adults with >= 2 met syn criteria - Randomized to 12 weeks Ex vs. 12 weeks of Ex + simva 40 mg - Peak VO2 increased by 10% (p < 0.05) after exercise alone, but increased by only 1.5% in statin group - Skeletal muscle citrate synthase activity (a marker of mitochondrial content) increased by (p < 0.05), but decreased by 4.5% in the statin group Mikus JACC 2013 Ex ExEx + statin Ex + statin
  12. 12. Possible statin myopathy mechanisms • A reduction in cholesterol content of skeletal muscle membranes may make them unstable and prone to lysis • A reduction in the synthesis of ubiquinone (coenzyme Q10), an essential element of mitochondria electron transport chain, which potentially reduces ATP biosynthesis • Can unmask or potentiate underlying muscle disorders such as mitochondriopathies or even fibromyalgias • Reduction in small GTP binding proteins which can lead to apoptosis • Increase myocyte degradation of actin and myosin via the atrogin-1 and ubiquitin- proteasome pathway • Activate autoimmune phenomena that promote myocyte injury Pasternak JACC 2002 Thompson JAMA 2013
  13. 13. Clinical Evaluation of Statin Myopathy • History: – Obtain h/o MSK complaints prior to statin initiation – Focus on timing of symptoms in relation to statin initiation/titration – Unusual physical activity or concurrent illness – Diet (daily grapefruit consumption) – Clues to suggest other causes of myopathy • Hypothyroidism • Vitamin D deficiency • Autoimmune disease • Neuromuscular disease • Systemic illness • Medications – Drugs that inhibit cytochrome P450 3A4 (clarithromycin, HIV meds, voriconazole, etc) – Fibrates – Independently cause myopathy (steroids, cyclosporine, etc) • Physical exam – Proximal LE weakness
  14. 14. Statin Selection PRIMO Study Statin Dosage muscular symptoms, % Odds Ratio (95% CI) P-value Pravastatin 40 mg qday 10.9% Fluvastatin 80 mg qday 5.1% 0.33 (0.26- 0.42) < 0.0001 Atorvastatin 40-80 mg qday 14.9% 1.28 (1.02-1.60) < 0.0001 Simvastatin 40-80 mg qday 18.2% 1.78 (1.39- 2.29) 0.035 Bruckhert CV Drugs Ther 2005
  15. 15. Key Properties of Statins • Hydrophilic: Prava, Rosuva, Fluva • Hydrophobic: Lova, Simva, Atorva • CYP 3A4: Simva, Lova, Atorva • CYP 2C9: Rosuva, Fluva
  16. 16. Statin dosing Ruisinger AJC 2009 - 50 statin intolerant pts - Rosuvastatin 2.5-20 mg qweek - 74% tolerated it
  17. 17. 1605 pts referred to a CV prevention clinic 72% of individuals referred were able to tolerate some statin with mean follow up of 31 months - 63% Daily dosing mean LDL lowering of 27.7% - 9% Intermittent dosing = 149/1014 with mean LDL lowering of 21.3% - 27% Persistent intolerant = 441 with mean LDL lowering of 8.3% Trend over 8 years to reduce mortality in the daily/intermittent dosing cohort. Mampuya et al. AHJ 2013 21%8% 28% Statin re-challange: Cleveland Clinic Experience
  18. 18. Statin Combination Therapy Stein AJC 2008 199 statin intolerant pts at mod-high CV risk - Ezetimibe 10 mg - Fluvastatin XL 80 mg vs. - Combination
  19. 19. Statin Combination Therapy Stein AJC 2008 Ezetimibe Fluvastatin XL Combination % at goal, all patients % at goal, highest risk
  20. 20. On the horizon … PCSK9 inhibitors
  21. 21. PCSK9 Inhibitors Sullivan JAMA 2012 - 12 week randomized double blind, placebo and ezetimibe controlled trial of monoclonal antibody to PCSK9 - 160 statin intolerant patients
  22. 22.  Meta- analysis of 5 trials comparing high vs. moderate intensity statin  For every 498 patients treated with high dose statin therapy, there was 1 new-onset diabetes case per year.  For every 155 patients treated with high dose statin therapy, there was 1 CV event reduction per year. Preiss JAMA 2011 Statins & Risk of Diabetes
  23. 23.  Randomized placebo controlled trial of atorvastatin 10, 20, 40, & 80 mg  40 to 44 hypercholesterolemic subjects in each group  Change over 2 months Statins & insulin resistance Koh JACC 2010
  24. 24. Ridker Lancet 2012 JUPITER - 16,603 patients w/o CVD or diabetes - Rosuvastatin 20 mg vs. placebo
  25. 25. Ridker Lancet 2012 JUPITER RF for Diabetes 1) Met syndrome 2) Impaired fasting glucose 3) BMI > 30 kg/m2 4) HbA1c > 6%
  26. 26. Pravastatin and Diabetes Freeman Circulation 2001
  27. 27. Shah Circ 2012 Statin Risk / Benefit Ratio Reducing LDL-C by 40 mg/dL with statins reduces ASCVD risk by 20%
  28. 28. Case Presentation • 58 y/o AA man with PMH CAD s/p 4v CABG (age 36) and multiple subsequent PCI’s who presents to preventive cardiology clinic after NSTEMI and PCI of native LAD and SVG to OM2. • PMH: DM2, familial combined hyperlipidemia, OSA • Meds: aspirin, clopidogrel, insulin, losartan, & metoprolol XL • On NO lipid meds. Statin intolerant – h/o myalgias and myositis • In 2010, TC 322, TG 142, HDL-26, LDL-C 268 • In 2012, TC 355, TG 208, HDL-C 38, LDL-C 275
  29. 29. Case Presentation • TC 322, TG 142, HDL-C 26, LDL-C 268, HbA1c 7.0%, CK 325 U/L – Agreed to try rosuvastatin 2.5 mg , qMWF  tolerated well • TC 317, TG 228, HDL-C 42, LDL-C 230, CK 273 U/L – Titrated up rosuvastatin to 5 mg , qMWF  tolerated well – Titrated up rosuvastatin to 10 mg , qMWF  bilateral thigh pain – Titrated down to rosuvastatin to 5 mg , qMWF  tolerated well • TC 243, TG 190, HDL-C 46, LDL-C 159 – NSTEMI and PCI to native LCX – Added ezetimibe 10 mg – Major dietary changes (decreasing red meat consumption) • TC 181, TG 136, HDL-C 43, LDL-C 111, CK 304 U/L
  30. 30. Conclusions • While side effects can occur with statins, virtually all are reversible and are not life-threatening. • On the other hand, there are major side effects - MI’s and strokes - of not treating with statins in patients at high ASCVD risk. • Presently, one of the best treatment options for statin intolerant is the statin re-challenge.
  31. 31. Conclusions • Careful discussion about ASCVD risks and statin risks/benefits should be had with statin intolerant patients • Consider low dose statin with alternative agents. • New treatment options are on the horizon for statin intolerant patients.

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