1. A Discussion of Statin Drugs in COPD and Associated Diseases to Improve Outcomes 2014 Donald M. Pell MD, FCCP

2. Incidence CDC data 7/2012 CDC data 7/2012 COPD is now 3 rd leading cause of death COPD is now 3 rd leading cause of death 2008 141,075 2008 141,075 46.4 men@100,000 46.4 men@100,000 34.2 women@100,000 34.2 women@100,000

3. Incidence Male mortality is down from 49@100,000 Male mortality is down from 49@100,000 Female mortality unchanged from 2007 Female mortality unchanged from 2007 75% of patients with COPD are between 40 and 65 75% of patients with COPD are between 40 and 65 There are an estimated 24,000,000 US patients. There are an estimated 24,000,000 US patients. More women die annually. More women die annually.

4. Proposed Pathophysiology of COPD Young, Euro Resp Rev, 2009

5. Pathophysiology of COPD Cigarette smoking, inhaled aerosols, genetic predisposition Cigarette smoking, inhaled aerosols, genetic predisposition Inflammatory process in bronchial lumen release IL-8, sequester polys Inflammatory process in bronchial lumen release IL-8, sequester polys Macrophages plus IL-8 cause poly elastace release Macrophages plus IL-8 cause poly elastace release Elastin is destroyed, tissue protective protease destroyed Elastin is destroyed, tissue protective protease destroyed Young, Euro Resp Rev, 2009

6. Pathophysiology of COPD CD-8 and T lymphocytes migrate CD-8 and T lymphocytes migrate Oxidative load crosses back into vascular endothelium Oxidative load crosses back into vascular endothelium Combines with circulating cytokines Combines with circulating cytokines Systemic vascular damage and endothelial dysfunction occurs Systemic vascular damage and endothelial dysfunction occurs Young, Euro Resp Rev, 2009

7. Pathophysiology of COPD Nicotine releases fibronectin causing increased focal airway fibrosis and collagen release damaging injury repair. Nicotine releases fibronectin causing increased focal airway fibrosis and collagen release damaging injury repair. Cellular apoptosis is diminished prolonging cell life of polys and macros leading to further cell mediated injury. Cellular apoptosis is diminished prolonging cell life of polys and macros leading to further cell mediated injury.

8. Pathophysiology Reactive Oxidative species “spill over” into circulation and cause systemic effects Reactive Oxidative species “spill over” into circulation and cause systemic effects Muscle wasting, weakness, anemia, weight loss, osteoporosis, and premature aging of the lungs Muscle wasting, weakness, anemia, weight loss, osteoporosis, and premature aging of the lungs

9. Relationship between COPD and Lung Cancer 60-90% of lung cancers develop in patients w/COPD 60-90% of lung cancers develop in patients w/COPD May share common inflammatory pathways May share common inflammatory pathways Increased levels of guanine triphosphate, growth factor and epithelial mesenchymal transition may lead to DNA changes and Cancer Increased levels of guanine triphosphate, growth factor and epithelial mesenchymal transition may lead to DNA changes and Cancer

10. Epidemiology of COPD Only 20-30% of people develop COPD despite same exposure. Only 20-30% of people develop COPD despite same exposure. Genetic predisposition heavily affects the results. Genetic predisposition heavily affects the results. After 40 pack years, FEV1/FVC ratio will be 70% or less and will progressively decline in this susceptible population. After 40 pack years, FEV1/FVC ratio will be 70% or less and will progressively decline in this susceptible population.

11. FEV1 decline defines this subset Increased incidence compared with smokers with normal PFT’s Increased incidence compared with smokers with normal PFT’s Coronary artery disease Coronary artery disease Stroke Stroke Lung cancer Lung cancer

12. FEV1 decline and all cause CV mortality is related Increased levels IL6 Increased levels IL6 Increased levels CRP Increased levels CRP Increased levels TNF Increased levels TNF Once FEV1 and FEV1/FCC decline disease is progressive and no current approved treatment alters this course. Once FEV1 and FEV1/FCC decline disease is progressive and no current approved treatment alters this course. Studies now focused on suppressing inflammation. Studies now focused on suppressing inflammation.

13. Decreased Lung Function and the effects of statins Normal lung aging starting at age 25 is loss 0f 18 cc FEV1/year Normal lung aging starting at age 25 is loss 0f 18 cc FEV1/year Burrows (NEJM 1969) showed COPD patients loss 80 cc FEV1/year Burrows (NEJM 1969) showed COPD patients loss 80 cc FEV1/year Exacerbations increase loss 2-7cc more/year Exacerbations increase loss 2-7cc more/year Progression so far not preventable Progression so far not preventable

14. Lung function decline and the Effect of Statins Alexeff 803 elderly men w/o COPD 23.9 v 10.9 Alexeff 803 elderly men w/o COPD 23.9 v 10.9 Keddissi in 210 w COPD 85 cc v 5 cc Keddissi in 210 w COPD 85 cc v 5 cc Mannino in non statin users higher decline higher mortality 171 v 62 cc loss Mannino in non statin users higher decline higher mortality 171 v 62 cc loss Johnson 200 double lung or heart lung transplants Johnson 200 double lung or heart lung transplants

15. Johnson Continued One half on statins One half on statins FEV1’s at 87%=/-2 predicted v. 70%+/-1 FEV1’s at 87%=/-2 predicted v. 70%+/-1 Slower decline over time Slower decline over time Episodes of grade 3 or 4 rejections reduced from 13% to4% Episodes of grade 3 or 4 rejections reduced from 13% to4% Severe rejections 8% v.2% Severe rejections 8% v.2% 6 year survival 91% v. 54% 6 year survival 91% v. 54% Johnson Amer Res Crit Care 2003 vol167,p1271

16. Mortality Outcomes in COPD Observational Studies Soyseth severe COPD 1.9 year study 43% less deaths in statin group Soyseth severe COPD 1.9 year study 43% less deaths in statin group Frost 77,322 patients over 11 years 38% death reduction in all doses, 81% reduction in moderate dose. Frost 77,322 patients over 11 years 38% death reduction in all doses, 81% reduction in moderate dose. Mortenson 46% risk of death reduction following pneumonia hospitalization Mortenson 46% risk of death reduction following pneumonia hospitalization

17. Mortenson, continued Mortenson, Euro Resp Jour, 2008, vol 31, 611-17

18. Proposed Pathogenesis of Lung Cancer Young, Euro Resp Rev, 2009

19. Statins Effects on Lung Cancers /All Cancers Khurana 488,733 VAH over 6 years found 7280 lung cancers only 1/3 on statins Khurana 488,733 VAH over 6 years found 7280 lung cancers only 1/3 on statins Farwell cancer risk reduction of 55% if on statins for 6 months, same as above Farwell cancer risk reduction of 55% if on statins for 6 months, same as above Karp 30,076 7 years post MI for lung cancer admission 30% red risk on statins Karp 30,076 7 years post MI for lung cancer admission 30% red risk on statins

20. Karp continued Karp, Am J Med vol131, p1282-8

21. Karp continued Difference in lipophilic (FLAS) group did not induce angiogenesis Difference in lipophilic (FLAS) group did not induce angiogenesis Hydrophilic (PR) group did Hydrophilic (PR) group did Did this affect earlier study outcomes? Did this affect earlier study outcomes? Death from any cancer reduced in all 3 of his groups 13.9 in high dose, 17 in low dose v. 26 in control group/100 patient years Death from any cancer reduced in all 3 of his groups 13.9 in high dose, 17 in low dose v. 26 in control group/100 patient years Karp Am J Med 2008, vol100, p302-9

22. Statins in Community Acquired Pneumonia All showed decreased ICU transfer, decreased death and improved outcomes All showed decreased ICU transfer, decreased death and improved outcomes Some studies showed COPD patients some did not Some studies showed COPD patients some did not Statins must be maintained during hospitalization Statins must be maintained during hospitalization Improved outcomes occurred also if statins were started on admission Improved outcomes occurred also if statins were started on admission

23. Conclusion Role of inflammation is increasingly recognized in many disease states. Role of inflammation is increasingly recognized in many disease states. Statins effects on COPD exacerbations, outcomes in infections, and on companion diseases of Cancer, CAD and Strokes were discussed. Statins effects on COPD exacerbations, outcomes in infections, and on companion diseases of Cancer, CAD and Strokes were discussed. While pathophysiology is further studied, better outcomes are available now. While pathophysiology is further studied, better outcomes are available now.

24. Pell’s Pearl If I can just get you to think, gosh darn it, you might amount to something. Emphasis on if, gosh darn it and might. If I can just get you to think, gosh darn it, you might amount to something. Emphasis on if, gosh darn it and might. John B. Hickam MD John B. Hickam MD Indianapolis 1968 Indianapolis 1968