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The Issue of Treating Cholesterol in the Elderly

The Issue of Treating Cholesterol in the Elderly. Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO satwood@pol.net. Clipped From the Headlines. Statin therapy associated with reduced mortality across all age groups, including very elderly

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The Issue of Treating Cholesterol in the Elderly

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  1. The Issue of Treating Cholesterol in the Elderly Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MOsatwood@pol.net

  2. Clipped From the Headlines • Statin therapy associated with reduced mortality across all age groups, including very elderly • Statin therapy in the elderly—the evidence mounts • Statins safe for elderly patients. New findings offer reassurance about cholesterol drugs statins treatment in the elderly

  3. Clipped From the Headlines statins treatment in the elderly

  4. The Real World “I’m Old But I’m Not Dead Yet” 80 y/o woman drives to office for yearly checkup controlled hypertension, fixed income, weighs 110 A-Fib on diltiazem and coumadin 2 children in the area LDL=190 HDL=60 TG=18010 years on a statin vs. the cost of losing 2 years of good life to a nursing home statins treatment in the elderly

  5. Today’s Goal • Should I Treat • Why • Which Statin statins treatment in the elderly

  6. Atherosclerosis Is an inflammatory, proliferative, thrombotic disease that occurs in response to risk factor activation of the endothelium.Cholesterol and specifically oxidized LDL forms the bulk of the plaque

  7. Atherosclerosis CRPMyeloperoxidase Is an inflammatory, proliferative, thrombotic disease that occurs in response to risk factor activation of the endothelium.Cholesterol and specifically oxidized LDL forms the bulk of the plaque FibrinogenPAI Nitrous Oxide anti-oxidants

  8. Normal Arterial Wall Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cells Elastic/collagen fibers External elastic membrane statins treatment in the elderly

  9. Development of Atherosclerotic Plaques Fatty streak Normal Lipid-rich plaque Foam cells Fibrous cap Lipid core Thrombus statins treatment in the elderly

  10. statins treatment in the elderly

  11. statins treatment in the elderly

  12. Vulnerable vs. Stable Atherosclerotic Plaques Like Diabetic Vulnerable Plaque Lumen LipidCore • Thin fibrous cap • Inflammatory cell infiltrates: • proteolytic activity • Lipid-rich plaque FibrousCap Enhanced by statins Stable Plaque Lumen • Thick fibrous cap • Smooth muscle cells: • more extracellular matrix • Lipid-poor plaque Lipid Core Fibrous Cap Lot of Plaque before occlude lumen Libby P. Circulation. 1995;91:2844-2850. statins treatment in the elderly

  13. Lower Cholesterol Levels Associated With Lower CHD Risk The Framingham Heart Study 150 125 100 CHD Incidence per 1000 75 50 25 0 265-294  204 205-234 235-264  295 Serum Cholesterol (mg/100 mL) Castelli WP. Am J Med. 1984;76:4-12. statins treatment in the elderly

  14. statins treatment in the elderly

  15. What is the molecular basis for use of a statin?How is the statin working? statins treatment in the elderly

  16. Statin Biochemistry statins treatment in the elderly

  17. HMG-CoA Reductase HMG CoA binding domain Zoomed in view active site 1) One of the body’s most highly regulated enzymes 2) All statins are false substrates positive hole hydrophobic binding site Tetramic complex tetrameric complex

  18. statins treatment in the elderly

  19. You are what you eatBe Afraid, Be Very AfraidFirst step of therapy is always diet statins treatment in the elderly

  20. All the Players LDL • Cholesterol can’t dissolve in water (blood) • Cholesterol only comes from animals– none in plants • To dissolve and move Lipoproteins 5 complexes 4 key protein groups • Good cholesterol = HDL • Bad cholesterol = LDL • A good (apoA) B bad (apoB) • Big good Small / dense bad • Good cholesterol = HDL • Bad cholesterol = LDL • A good (apoA) B bad (apoB) • Big good Small / dense bad

  21. All the Players omega-3 cold water fish SMASH plant, Olive , Canola unsaturated short chainsanimal fat = bad trans fat • Cholesterol can’t dissolve in blood • Cholesterol only comes from animals– none in plants • To dissolve and move Lipoproteins 5 complexes 4 key protein groups • Good cholesterol Bad cholesterol • A good B bad • Big good Small / dense bad • Bad fat Good fat statins treatment in the elderly

  22. All the PlayersTo dissolve and move Lipoproteins 5 complexes 4 key proteins groups apo-proteins A BCE B statins treatment in the elderly

  23. statins benefited ~30% A lot of studies in elderly, statins treatment in the elderly

  24. statins treatment in the elderly

  25. Benefit seen by 1 year statins treatment in the elderly

  26. Primary Endpoint CHD death, Nonfatal MI, Fatal or Nonfatal Stroke 20 15% RRR (P = 0.014) Placebo Events = 473/2913 (16.2%) 15 % With Event 10 NNT = 48 Pravastatin Events = 408/2891 (14.1%) 5 0 0 1 2 3 Years PROSPER Study Group. Lancet. 2002; 360:1623-30. statins treatment in the elderly

  27. Prosper The benefit of treatment in the elderly was the same as the benefit in the young statins treatment in the elderly

  28. Improvement at all levels of LDL • If divide patients byhigh, medium, and low LDLEvent reduction similar for each group • Seen in Prosper • Seen in ALLHAT • ALSO TREAT THE LOW LDL PATIENT ASCOT TRIAL statins treatment in the elderly

  29. ASA (626/5833) 31%* RRR Prava (125/1436) Prava+ASA (445/5888) Pravachol and Aspirin = Pravigard combination -- more than additive Fatal or Non-Fatal MI 0.100 Placebo (158/1460) 0.075 0.050 Cumulative Proportion of Events 0.025 0.000 0 1 2 3 4 5 *RelativeRisk Reduction Year Meta-analysis statins treatment in the elderly

  30. statins treatment in the elderly

  31. Simvastatin 65.0 3A4/2D6 Yes Lovastatin 16.0 3A4 Yes Pravastatin 0.2 No No Atorvastatin 15.0 3A4 Yes Fluvastatin 22.0 2C9 Yes Pharmacokinetics of HMG-CoA Reductase Inhibitors Octanol/H2O Coefficient Increased Conc. With Inhibitors HMG-CoA CYP450 statins treatment in the elderly

  32. statins treatment in the elderly

  33. statins treatment in the elderly

  34. (cardiziem)(sporanox) statins treatment in the elderly

  35. Effects of CYP 3A4 Inhibitors on Statin Serum Concentrations Simvastatin 15 10 x Elevations in Serum Concentrations Versus Placebo* 10 5.0 x 3.9 x 5 0 Verapamil Itraconazole Erythromycin * Area under the concentration-time curve (AUC) of active simvastatin acid Kantola T et al. Clin Pharmacol Ther. 1998;64:177-182. Neuvonen PJ et al. Clin Pharmacol Ther. 1998;63:322-341. statins treatment in the elderly

  36. statins treatment in the elderly

  37. statins treatment in the elderly

  38. Effects of Advancing Age on Drug Distribution and Metabolism • Decreased protein binding • Increased volume of distribution for lipophilic drugs • Decreased phase 1 (CPY 450) oxidation Mayersohn M. Special Pharmacokinetic Considerations in the Elderly in: Evans WE et.al. Eds. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 2nd edition. statins treatment in the elderly

  39. MYOPATHY • lipid solubility • increase serum levels via 3A4up to 20 x increase e.g.. 5x with verapamil 5 125 • damage to the needed cholesterol, ubiquinone prenalated proteins myopathy muscle cell death • for elderly known risk factors include: 1) age 2) muscle mass 3) obesity 4) female 5) impaired renal status statins treatment in the elderly

  40. Plavix pro-drug activated by 3A4 Lipitor may diminish Plavix’s antiplatelet effect at least in the lab1)Circulation 2003; 107: 1568-1569 2) Circulation 2003; 107: 32-37 3) Euro Heart J 24 (19) October 2003, 1744-1749 4) Circulation 2003;108:921-924 statins treatment in the elderly

  41. Pleiotropic Effects or non-Cholesterol effects 1. Unstable angina (stabilize plaque) 2. DM 30% less (Pravachol woscops ) 3. Osteoporosis (reduced hip fractures) 4. Stroke (Vasodilation -  NO) 5. Less dementia (maybe-conflicting data) statins treatment in the elderly

  42. Statin Pleiotropic Effects or non-Cholesterol Effects • Decrease inflammation– decrease CRP • Decrease lipid oxidation • Decrease thrombosis • Decrease transplant rejection (routinely use with transplants) • Increase endothelial medial vasodilation increased nitrous oxide production • Increased osteoblastic activity (reduced hip fx) statins treatment in the elderly

  43. Statin Biochemistry GTP enzyme anchors cell signaling proliferation production cytokines thrombosis, inflammation, nitrous oxide production statins treatment in the elderly

  44. So Many Choices, So Little Time 6 types options for present statins 39 ■ statins treatment in the elderly

  45. Prescription Options list • 39 statin combinations • Statins vary by 1. Side effects 2. Potency for lipids 3. Potency for Plieotropic effects 4. Cost • Geriatric– side effects may be the major issue how is it metabolized does it have the best pleiotropic effect cost is the statin proven to help in the elderly statins treatment in the elderly

  46. Issues of Crestor in Elderly • lack of data • long half life • rhabdomyolysis • trouble clearing FDA • triple level in Asians • proteinuria • hematuria • to much suppression • 2C9 • superpower in most fragile statins treatment in the elderly

  47. The Real World 80 y/o woman drives to office for yearly checkup controlled hypertension on med, BP 130/80fixed income, never smoked, A-Fib on diltiaziem & coumadinweighs 110 2 children in the area LDL=190 TC=260 HDL=60 TG=18010 years on a statin vs. the cost of losing 2 years of good life to a nursing home statins treatment in the elderly

  48. statins treatment in the elderly

  49. statins treatment in the elderly

  50. Risk Assessment: FHS Score for Men Point Total 10-Year CHD Risk (%) Risk Factor Points • Age 13 • Total C 0 • HDL-C 1 • BP 2 • Smoking 0 Point Total 16 <0 <1 0 1 1 1 2 1 3 1 4 1 5 2 6 2 7 3 8 4 9 5 10 6 11 8 12 10 13 12 14 16 15 20 16 25 17 30 Low Moderate www.nhlbi.nih.gov High statins treatment in the elderly

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