Pleiotropic effects of the HMG-CoA reductase inhibitors

Figures & data

Table 1 Proposed mechanisms of statin pleiotropy

Upregulation of endothelial nitric oxide synthase and improved pathophysiologic response, including inhibition of vasoconstriction and promotion of re-endothelialization Antioxidant effects via the inhibition of nicotinamide adenine dinucleotide phosphate oxidase and thus reactive oxidant species Anti-inflammatory properties, including reduction in C-reactive protein, interleukin 6, tumor necrosis factor alpha, and nuclear factor-k B levels Downregulation of cytokines and chemokines Stabilization of atherosclerotic plaques and inhibition of plaque inflammation Decreased activation of the blood coagulation cascade Inhibition of platelet aggregation Normalization of sympathetic tract outflow Induction of autophagy and inhibition of angiogenesis in cancer cells Neuroprotection and support of blood–brain barrier function

Table 2 Overview of statin pleiotropy and medical disorders

System	Disorder
Cardiology	Heart failure
	Atrial fibrillation
	Ventricular arrhythmias
	Acute coronary syndrome and percutaneous coronary intervention
	Aortic stenosis
Pulmonology	Asthma
	Chronic obstructive lung disease
Hematology/oncology	Prostate cancer
	Colon cancer
	Lung cancer
	Pancreatic cancer
	Renal cancer
Neurology	Stroke
	Intracranial hemorrhage
	Multiple sclerosis
	Alzheimer’s disease
	Parkinson’s disease
Nephrology	Glomerulonephritis
	Renal failure
	Renal transplantation
	Contrast-induced nephropathy
Rheumatology	Rheumatoid arthritis
	Osteoarthritis
	Osteoporosis
	Systemic sclerosis
Miscellaneous	Venous thromboembolism
	Polycystic ovary syndrome
	Macular degeneration
	Influenza
	Infection and sepsis

Table 3 Major trials and studies exhibiting statin pleiotropy

Trial/study	Design	Outcomes with statin treatment
Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA)^Citation7,Citation9	5011 patients with heart failure, reduced left ventricular function, and ischemic heart disease randomly assigned to 10 mg/day rosuvastatin or placebo	Patients with NT-proBNP < 103 pmol/L had 35% reduction in atherothrombotic events or sudden death Patients with hs-CRP > 2 mg/L had better outcomes, decreased all-cause mortality and coronary events, less hospitalizations
Global Registry of Acute Coronary Events (GRACE)^Citation17	64,679 patients hospitalized for ACS in 1999–2007 were prospectively analyzed in an observational study	Patients taking statins prior to hospital admission had a significantly lower risk of atrial fibrillation, VT/VF, cardiac arrest, and death
Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II)^Citation19	654 patients receiving an ICD were analyzed based on the percentage of days statins were taken during follow-up	≥90% statin usage was associated with a reduced risk of VT/VF or cardiac death
Efficacy of high-dose atorvastatin loading before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: The STATIN STEMI trial^Citation20	171 STEMI patients randomized to 600 mg Plavix^® plus either 80 mg or 10 mg atorvastatin pre-PCI, with all patients treated with 10 mg atorvastatin post-PCI	High-dose atorvastatin pre-PCI was associated with immediate improvement of coronary flow and microvascular myocardial perfusion when compared with low-dose atorvastatin
Atorvastatin for Reduction of Myocardial Damage during Angioplasty trial (ARMYDA)^Citation21	153 statin-naïve patients with chronic stable angina undergoing elective PCI randomized to atorvastatin or placebo seven days prior to intervention	Significant reduction in procedural myocardial injury
Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 trial (PROVE IT-TIMI 22)^Citation24	3745 ACS patients randomized to either 40 mg pravastatin or 80 mg atorvastatin daily	High-dose statin therapy superior in aggressive reduction of both LDL-C and CRP levels, leading to lower risk of recurrent myocardial infarction or vascular death
Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 [PROVE IT-TIMI 22] Substudy (PCI-PROVE IT)^Citation25	2868 ACS patients who underwent PCI prior to enrollment in PROVE IT-TIMI 22, which randomized patients to 80 mg atorvastatin or 40 mg pravastatin daily	Reduction in major adverse cardiovascular events, as well as target and nontarget vessel revascularization with intensive statin therapy
Efficacy of atorvastatin reload in patients on chronic statin therapy undergoing percutaneous coronary intervention: results of the ARMYDA-RECAPTURE randomized trial^Citation26	383 long-term statin users with stable angina or NSTEMI undergoing PCI were randomized to atorvastatin reload or placebo pre-PCI, with all patients treated with atorvastatin post-PCI	Decreased 30-day incidence of major adverse cardiovascular events, as well as postprocedural myocardial injury, in patients receiving high-dose pre-PCI atorvastatin reload
Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)^Citation50	17,802 patients with normal LDL-C and elevated CRP randomly assigned to 20 mg/day rosuvastatin or placebo	Reduced the incidence of stroke by more than 50%; reduction in nonfatal MI and cardiovascular death

Abbreviations: NT-proBNP, N-terminal fragment brain natriuretic peptide; hs-CRP, high-sensitivity C-reactive protein; ACS, acute coronary syndrome; VT, ventricular tachycardia; VF, ventricular fibrillation; ICD, implantable cardioverter defibrillator; STEMI, ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; LDL-C, low density lipoprotein cholesterol; NSTEMI, non-ST-segment elevation myocardial infarction; MI, myocardial infarction.

Table 4 Pleiotropic effects of statins in cardiovascular disorders

Heart failure^Citation7^–^Citation10	↓ risk of coronary events and cardiovascular death ↓ all-cause mortality ↓ hospitalizations for cardiovascular reasons or worsening heart failure Prevent further decompensation of cardiac function
Atrial fibrillation^Citation13^–^Citation17	↓ duration of atrial fibrillation 59% ↓ incidence in stable coronary artery disease 10% ↓ incidence after myocardial infarction or coronary revascularization ↓ recurrence after electric cardioversion ↓ incidence after acute coronary syndrome ↓ incidence and duration in postoperative cardiac patients
Ventricular arrhythmias^Citation18,Citation19	↓ incidence of ICD shocks and 35% ↓ risk of sudden cardiac death in patients with ICD and ischemic cardiomyopathy
Percutaneous coronary intervention and acute coronary syndrome^Citation21^–^Citation26	Significantly reduced risk of myocardial injury in elective PCI in statin-naïve patients 50% ↓ risk of major adverse cardiac events in statin users reloaded with statin prior to PCI Superior concomitant reduction in LDL-C and CRP with high-dose statin therapy
Aortic stenosis^Citation27^–^Citation30	Significantly slower reduction of AV area Slower increase of AV peak systolic gradient

Abbreviations: ICD, implantable cardioverter defibrillator; PCI, percutaneous coronary intervention; LDL-C, low-density lipoprotein cholesterol; CRP, C-reactive protein; AV, aortic valve.

Table 5 Pleiotropic effects of statins in malignancies

Prostate cancer^Citation38^–^Citation40	↓ all-cause mortality ↑ relapse-free survival ↓ risk of intratumoral inflammation ↓ biochemical failure and androgen deprivation therapy
Colon cancer^Citation44^–^Citation46	50% ↓ risk of colorectal cancer after 5 years ↓ rate of stage IV carcinomas ↓ colon polyp size, number, and progression rate
Lung cancer^Citation47	50% ↓ incidence after 6 months of therapy
Pancreatic cancer^Citation48	67% ↓ incidence after 6 months, 80% ↓ after four years

Table 6 Pleiotropic effects of statins in miscellaneous disorders

Venous thromboembolism^Citation92,Citation93	32% ↓ in noncancer patients 67% ↓ in those with solid organ tumors 41% ↓ risk of deep vein thrombosis 30% ↓ risk of pulmonary embolism
Polycystic ovary syndrome^Citation96,Citation97	↓ testosterone levels, free androgen index, insulin resistance, and incidence of hirsutism Increases therapeutic effects of oral contraceptives
Macular degeneration^Citation98^–^Citation101	70% ↓ of age-related macular degeneration 67% ↓ drusen formation 49% ↓ choroidal neovascularization
Influenza^Citation102^–^Citation104	8% ↓ risk of hospitalization ↓ risk of pneumonia, or influenza-related death
Infection and sepsis^Citation105^–^Citation108	↓ 30-day, inhospital, bacteremia, sepsis, and mixed infection-related mortality 35% ↓ incidence of severe sepsis in intensive care unit patients ↓ risk of Candida infections in hospitalized diabetics

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