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 destroyedYoung, 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