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The Issue of Treating Cholesterol in the Elderly

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Presentation on theme: "The Issue of Treating Cholesterol in the Elderly"— Presentation transcript:

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

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 “I’m Old But I’m Not Dead Yet”
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 A-Fib on diltiazem and coumadin 2 children in the area LDL= HDL=60 TG= 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 proliferative, thrombotic Atherosclerosis Is an inflammatory,
disease that occurs in response to risk factor activation of the endothelium. Cholesterol and specifically oxidized LDL forms the bulk of the plaque

7 proliferative, thrombotic Fibrinogen PAI Nitrous Oxide anti-oxidants
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 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 Lipid Core Thin fibrous cap Inflammatory cell infiltrates: proteolytic activity Lipid-rich plaque Fibrous Cap 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: 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  204  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
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 1) One of the body’s most highly regulated enzymes
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 tetrameric complex Tetramic complex

18 statins treatment in the elderly

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

20 All the Players Good cholesterol = HDL Bad cholesterol = 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 Bad fat Good fat omega-3
cold water fish SMASH plant, Olive , Canola unsaturated short chains animal 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 Players To 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 CHD death, Nonfatal MI, Fatal or Nonfatal Stroke
Primary Endpoint CHD death, Nonfatal MI, Fatal or Nonfatal Stroke 20 Placebo Events = 473/2913 (16.2%) 15% RRR (P = 0.014) 15 % With Event 10 Pravastatin Events = 408/2891 (14.1%) NNT = 48 PROSPER: Primary Endpoint Kaplan-Meier curves for the primary endpoint of CHD death, non-fatal MI, fatal or non-fatal stroke are shown. At 3.2 years pravastatin reduced the risk of the primary endpoint by 15% with a significant p value of In high risk elderly patients, pravastatin 40 mg significantly reduces the incidence of coronary events. PROSPER shows that the benefit of pravastatin 40 mg observed in previous clinical trials of middle-aged people was observed in this older population. 5 1 2 3 Years PROSPER Study Group. Lancet. 2002; 360: 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 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 statins treatment in the elderly

29 Pravachol and Aspirin = Pravigard
combination -- more than additive Fatal or Non-Fatal MI 0.100 Placebo (158/1460) ASA (626/5833) Prava+ASA (445/5888) Prava (125/1436) 31%* RRR 0.075 Cumulative Proportion of Events 0.050 0.025 Results of the meta-analysis: As you can see from the illustrated graph, there was a 31% greater risk reduction of MI with the combined use of pravastatin and aspirin versus aspirin alone. These results were additive and incremental to those seen with aspirin alone. Aspirin alone has been shown to reduce the risk of MI. Results of this meta-analysis support these findings. Pravigard PAC demonstrated an additional 31% on top of the benefits already derived from aspirin alone in this meat-analysis. 0.000 1 2 3 4 5 *Relative Risk Reduction Year Meta-analysis statins treatment in the elderly

30 statins treatment in the elderly

31 Pharmacokinetics of HMG-CoA Reductase Inhibitors
Octanol/H2O Coefficient Increased Conc. With Inhibitors HMG-CoA CYP450 Yes Simvastatin 65.0 3A4/2D6 Yes Lovastatin 16.0 3A4 No Pravastatin 0.2 Yes Atorvastatin 15.0 3A4 Yes Fluvastatin 22.0 2C9 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 Verapamil Itraconazole Erythromycin * Area under the concentration-time curve (AUC) of active simvastatin acid Kantola T et al. Clin Pharmacol Ther. 1998;64: Neuvonen PJ et al. Clin Pharmacol Ther. 1998;63: 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 for elderly known risk factors include: 1) age 2) muscle mass
MYOPATHY lipid solubility 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 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 lab 1) Circulation 2003; 107: ) Circulation 2003; 107: 32-37 3) Euro Heart J 24 (19) October 2003, ) Circulation 2003;108: 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 thrombosis, inflammation, nitrous oxide production
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 Side effects 2. Potency for lipids 3. Potency for Plieotropic effects 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 130/80 fixed income, never smoked, A-Fib on diltiaziem & coumadin weighs 110 2 children in the area LDL= TC=260 HDL=60 TG= 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
Risk Factor Points Age 13 Total C 0 HDL-C 1 BP 2 Smoking 0 Point Total 16 Point Total 10-Year CHD Risk (%) <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 With the score sheet, the patient in this example had a total point score of 16, which gives him a 10-year CHD risk estimate of 25% and places him in the high-risk category. Once risk assessment has been addressed, the next step involves determining the type of intervention required and the level of aggressiveness needed to manage a patient’s dyslipidemia. Moderate High statins treatment in the elderly

51 Pros and Cons of a Statin in Elderly
PRO: Clinically Demonstrated  osteoporosis FX  dementia  diabetes  similar all tertiles of LDL (even low LDL levels benefited)  transplant rejection 19%  MI 15%  all key vascular events # to treat for benefit < 50  CRP benefit seen by year 1 statins treatment in the elderly

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

53 Pros and Cons of a Statin in Elderly
Adverse drug-drug rxn Cost One more pill Muscle problem  T killer cells Liver / kidney insufficiency Quality of life > 1 year see benefit Overall death rate = Life expectancy statins treatment in the elderly

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

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

57 Prevention always the best treatment
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) statins treatment in the elderly


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