A Discussion of Statin Drugs in COPD and Associated

Diseases to Improve Outcomes 2014

Donald M. Pell MD, FCCP

Incidence

• CDC data 7/2012• COPD is now 3rd leading cause of

death• 2008 141,075• 46.4 men@100,000• 34.2 women@100,000

Incidence

• Male mortality is down from 49@100,000

• Female mortality unchanged from 2007

• 75% of patients with COPD are between 40 and 65

• There are an estimated 24,000,000 US patients.

• More women die annually.

Proposed Pathophysiology of COPD

Young, Euro Resp Rev, 2009

Pathophysiology of COPD

• Cigarette smoking, inhaled aerosols, genetic predisposition

• Inflammatory process in bronchial lumen release IL-8, sequester polys

• Macrophages plus IL-8 cause poly elastace release

• Elastin is destroyed, tissue protective protease destroyed

Young, Euro Resp Rev, 2009

Pathophysiology of COPD

• CD-8 and T lymphocytes migrate• Oxidative load crosses back into

vascular endothelium• Combines with circulating cytokines• Systemic vascular damage and

endothelial dysfunction occurs

Young, Euro Resp Rev, 2009

Pathophysiology of COPD

• 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.

Pathophysiology

• Reactive Oxidative species “spill over” into circulation and cause systemic effects

• Muscle wasting, weakness, anemia, weight loss, osteoporosis, and premature aging of the lungs

Relationship between COPD and Lung Cancer• 60-90% of lung cancers develop in

patients w/COPD• May share common inflammatory

pathways• Increased levels of guanine

triphosphate, growth factor and epithelial mesenchymal transition may lead to DNA changes and Cancer

Epidemiology of COPD

• Only 20-30% of people develop COPD despite same exposure.

• 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.

FEV1 decline defines this subset• Increased incidence compared with

smokers with normal PFT’s • Coronary artery disease• Stroke• Lung cancer

FEV1 decline and all cause CV mortality is related • Increased levels IL6• Increased levels CRP• Increased levels TNF• Once FEV1 and FEV1/FCC decline

disease is progressive and no current approved treatment alters this course.

• Studies now focused on suppressing inflammation.

Decreased Lung Function and the effects of statins• 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• Exacerbations increase loss 2-7cc

more/year• Progression so far not preventable

Lung function decline and the Effect of Statins• Alexeff 803 elderly men w/o COPD

23.9 v 10.9• Keddissi in 210 w COPD 85 cc v 5 cc• Mannino in non statin users higher

decline higher mortality 171 v 62 cc loss

• Johnson 200 double lung or heart lung transplants

Johnson Continued

• One half on statins• FEV1’s at 87%=/-2 predicted v. 70%

+/-1• Slower decline over time• Episodes of grade 3 or 4 rejections

reduced from 13% to4%• Severe rejections 8% v.2%• 6 year survival 91% v. 54%

Johnson Amer Res Crit Care 2003 vol167,p1271

Mortality Outcomes in COPDObservational Studies• 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.

• Mortenson 46% risk of death reduction following pneumonia hospitalization

Mortenson, continued

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

Proposed Pathogenesis of Lung Cancer

Young, Euro Resp Rev, 2009

Statins Effects on Lung Cancers /All Cancers• 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

• Karp 30,076 7 years post MI for lung cancer admission 30% red risk on statins

Karp continued

Karp, Am J Med vol131, p1282-8

Karp continued

• Difference in lipophilic (FLAS) group did not induce angiogenesis

• Hydrophilic (PR) group did• 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 yearsKarp Am J Med 2008, vol100,

p302-9

Statins in Community Acquired Pneumonia• All showed decreased ICU transfer,

decreased death and improved outcomes

• Some studies showed COPD patients some did not

• Statins must be maintained during hospitalization

• Improved outcomes occurred also if statins were started on admission

Conclusion

• 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.

• While pathophysiology is further studied, better outcomes are available now.

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.

John B. Hickam MD Indianapolis 1968