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Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO The Issue of Treating Cholesterol in the Elderly.

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Presentation on theme: "Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO The Issue of Treating Cholesterol in the Elderly."— Presentation transcript:

1 Steven D. Atwood, M.D., FACP Internal Medicine, Springfield, MO The Issue of Treating Cholesterol in the Elderly

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

3 statins treatment in the elderly 3 Clipped From the Headlines

4 statins treatment in the elderly 4 The Real World 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= years on a statin vs. the cost of losing 2 years of good life to a nursing home Im Old But Im Not Dead Yet

5 statins treatment in the elderly 5 Todays Goal Should I Treat Why Which Statin

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 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 CRP Myeloperoxidase Fibrinogen PAI Nitrous Oxide anti-oxidants

8 statins treatment in the elderly 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

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

10 statins treatment in the elderly 10

11 statins treatment in the elderly 11

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

13 statins treatment in the elderly 13 Lower Cholesterol Levels Associated With Lower CHD Risk Castelli WP. Am J Med. 1984;76:4-12. CHD Incidence per 1000 Serum Cholesterol (mg/100 mL) The Framingham Heart Study

14 statins treatment in the elderly 14

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

16 statins treatment in the elderly 16 Statin Biochemistry

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

18 statins treatment in the elderly 18

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

20 20 All the Players Cholesterol cant 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 LDL Good cholesterol = HDL Bad cholesterol = LDL A good (apoA) B bad (apoB) Big good Small / dense bad

21 statins treatment in the elderly 21 All the Players Cholesterol cant 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 omega-3 cold water fish SMASH plant, Olive, Canola unsaturated short chains animal fat = bad trans fat

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

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

24 statins treatment in the elderly 24

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

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

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

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

29 statins treatment in the elderly 29 Fatal or Non-Fatal MI Placebo (158/1460) Cumulative Proportion of Events Year Prava (125/1436) ASA (626/5833) Prava+ASA (445/5888) 31%* RRR * Relative Risk Reduction Meta-analysis Pravachol and Aspirin = Pravigard combination -- more than additive

30 statins treatment in the elderly 30

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

32 statins treatment in the elderly 32

33 statins treatment in the elderly 33

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

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

36 statins treatment in the elderly 36

37 statins treatment in the elderly 37

38 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.

39 statins treatment in the elderly 39 MYOPATHY 1)lipid solubility 2)increase serum levels via 3A4 up to 20 x increase e.g.. 5x with verapamil )damage to the needed cholesterol, ubiquinone prenalated proteins myopathy muscle cell death 1) for elderly known risk factors include: 1) age 2) muscle mass 3) obesity 4) female 5) impaired renal status

40 statins treatment in the elderly 40 Plavix pro-drug activated by 3A4 Lipitor may diminish Plavixs antiplatelet effect at least in the lab 1) Circulation 2003; 107: ) Circulation 2003; 107: ) Euro Heart J 24 (19) October 2003, ) Circulation 2003;108:

41 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)

42 statins treatment in the elderly 42 Statin Pleiotropic Effects or non-Cholesterol Effects 1.Decrease inflammation– decrease CRP 2.Decrease lipid oxidation 3.Decrease thrombosis 4.Decrease transplant rejection (routinely use with transplants) 5.Increase endothelial medial vasodilation increased nitrous oxide production 6.Increased osteoblastic activity (reduced hip fx)

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

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

45 statins treatment in the elderly 45 Prescription Options list 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

46 statins treatment in the elderly 46 Issues of Crestor in Elderly 1.lack of data 2.long half life 3.rhabdomyolysis 4.trouble clearing FDA 5.triple level in Asians 6.proteinuria 7. hematuria 8. to much suppression 9.2C9 10. superpower in most fragile

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

48 statins treatment in the elderly 48

49 statins treatment in the elderly 49

50 statins treatment in the elderly 50 Risk Assessment: FHS Score for Men <0< Point Total 10-Year CHD Risk (%) Low Moderate High Risk FactorPoints 1)Age13 2)Total C 0 3)HDL-C 1 4)BP2 5)Smoking0 Point Total16

51 statins treatment in the elderly 51 PRO: Clinically Demonstrated Pros and Cons of a Statin in Elderly 1.19% MI 2.15% all key vascular events 3. # to treat for benefit < CRP 5.benefit seen by year 1 7. osteoporosis FX 8. dementia 9. diabetes 10. similar all tertiles of LDL (even low LDL levels benefited) 11. transplant rejection

52 statins treatment in the elderly 52 PRO : Demonstrated in Lab Pros and Cons of a Statin in Elderly 1. thrombosis 2. endothelial function 3. osteoblasts clasts 4.Stabilize plaque 7.Inhibit PAI-1 which is primary inhibitor of fibrinolysis 8. Vasodilation NO

53 statins treatment in the elderly 53 CON Pros and Cons of a Statin in Elderly 1. Adverse drug-drug rxn 2. Cost 3.One more pill 4.Muscle problem 5. T killer cells 6.Liver / kidney insufficiency 7. Quality of life 8. > 1 year see benefit 9.Overall death rate = 10.Life expectancy

54 Probably the most important single pathological process underlying disability in old age is atherosclerosis JC Brocklehurst. The Atlas of Geriatric Medicine

55 statins treatment in the elderly 55 Prevent Heart Disease Prevent Stroke Increase length of life Improve quality of life Goals of Treating the Elderly

56 statins treatment in the elderly 56 Clinical example RX age 80 Less time in nursing home ($57k / yr) VS Cost & supervision Selection: drug-drug / proven / cost

57 statins treatment in the elderly 57 Superior doctors prevent the disease. Mediocre doctors treat the disease before evident. Inferior doctors treat the full-blown disease. --Huang Lee Nai-Ching ( 2600 BC, First Chinese Medical Text) Prevention always the best treatment


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