Resident Editors: Scott Goldberg, MD, Christopher Lee, MD, MSc, MPH

Faculty Editor: Robert B. Baron, MD, MS

BOTTOM LINE ✔ Statin therapy should be instituted in those groups most likely to derive benefit, based on cardiovascular risk and comorbid diseases and not to specific treatment goals ✔ Lifestyle modification is a critical component to reducing cardiovascular risk

Background

1. Cholesterol

• There is a significant relationship between total cholesterol and risk for atherosclerotic cardiovascular disease (ASCVD) including coronary heart disease and stroke
• There is no distinct cutoff to define dyslipidemia; the risk of coronary heart disease (CHD) appears to be continuous and log-linear with total cholesterol, high LDL and low HDL cholesterol
• Testing for lipid abnormalities is one component of assessing overall cardiovascular risk in healthy patients 
• High total cholesterol is most often related to diets high in trans fat, saturated fat, and excess calories, genetics, and severe anorexia

• Hyperlipidemia may be secondary to DM, hypothyroidism, physical inactivity, metabolic syndrome, excessive alcohol intake, nephrotic syndrome, obstructive biliary disease, or medications such as anabolic steroids, progestins, protease inhibitors, diuretics, amiodarone, or corticosteroids
• Familial hyperlipidemia should be considered in the young patient with elevated lipids (LDL > 190) and a personal or family history of early-onset CHD

2. Triglycerides

• Elevated triglyceride levels are independently associated with cardiovascular risk, however, the excess risk is modest and it is uncertain whether lowering triglyceride levels reduces risk
• Most often triglycerides are elevated due to obesity, hyperglycemia and poorly controlled diabetes, and dietary indiscretion
• Be sure to consider secondary causes of hypertriglyceridemia such as hypothyroidism, CKD, familial hyperlipidemia disorders, and estrogen therapy

Evaluation

1. Screening Fasting Lipids (USPSTF 2008)

• Men age 35 and older regardless of risk level, and age 20-35 at increased risk
• Women age 20 and older at increased risk
• The USPSTF makes no recommendation for women not at increased risk
• Increased risk defined as the presence of established CV disease, tobacco use, DM, HTN, obesity, CKD, or family history of premature CHD
• Suspect familial hypercholesterolemia in patients with: 
  • Severe hypercholesterolemia in absence of secondary causes 
  • Family hx of familial hypercholesterolemia with elevated LDL-C
  • Early-onset (<50 years) CAD (particularly premature MI) 
  • Corneal arcus prior to age 45 or presence of xanthomas 
• Patients with elevated LDL (> 190mg/dL) or triglycerides (> 500mg/dL) should be evaluated for secondary causes of hyperlipidemia
  • Rule out secondary causes with A1c, TSH, alk phos (rule out biliary obstruction), and UA (to assess for proteinuria) 
• Assessment of CV risk appears to be similar in fasting and non-fasting patients as long as the TG level is <500 mg/dL

2. Evaluation of Risk for ASCVD (ACC/AHA 2013)

• 2013 guidelines differ from the earlier guidelines in that they evaluate a comprehensive 10-year risk of ASCVD including CHD and stroke (using “Pooled Cohort Equations”), rather the Framingham Risk Score which predicts risk of CHD alone
• The “Pooled Cohort Equations” were derived from several population-based studies to ascertain risk of “hard” ASCVD events: nonfatal MI, CHD death, fatal or nonfatal stroke
• Most studies suggest that these equations overestimate risk
• The equations for risk differ by race
• ASCVD + ACC risk calculator can be found at: http://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/

Treatment

Lifestyle Modifications

• Diet and lifestyle modifications should be made in all patients who would benefit from reduction of LDL or elevation of HDL
• The ACC/AHA recommends exercise 3-4 times per week on average 40 minutes each, at moderate-to-vigorous intensity
• Dietary changes include emphasizing the (1) incorporation of fruits and vegetables, whole grains, low-fat dairy products, poultry, fish, and legumes, (2) limitation of sugar-sweetened beverages, other sweets, and red meats, (3) aim for a dietary pattern of 5-6% of calories from saturated fat, (4) reduce calories from saturated and trans fats

Statin Therapy

• Secondary Prevention 
  • Guidelines differ based on professional society: 
    • ACC/AHA and NICE guidelines de-emphasize target numbers for LDL-C 
    • European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines have specific LDL-C treatment targets for patients with established CV disease, other concomitant medical conditions, and those at risk of first fatal atherosclerotic event 
  • Per ACC/AHA, prescribe statin therapy (with highest recommended or tolerated doses) for high-risk patients where evidence supports substantial reduction in CV events (i.e. patients <75 years old with clinical ASCVD) 
• Primary Prevention 
  • USPSTF and ACC/AHA differ based on when to initiate treatment (10% vs 7.5% 10-year risk) 
  • ACC/AHA guidelines use Pooled Cohort Equations which overestimate risk 
  • USPSTF Grade B recommendation (2016): Adults without a history of cardiovascular disease use a low- to moderate-dose statin for prevention of CVD events and mortality when all of the following are met:
    • Aged 40 to 75
    • 1 or more CVD risk factors (i.e. dyslipidemia, DM, HTN, or smoking) 
    • 10-year risk of a CV event of 10% or greater  
  • Grade I recommendation to initiate in some adults with a 10-year CVD event risk <10% because likelihood of benefit is smaller, because of a lower probability of disease, and uncertainty in individual risk prediction 

NNT for Statins for 5 years:

10-Year Risk of CVD events	5-Year NNT for CVD Events	5-Year NNT for MI	5-year NNT for Stroke	5-Year NNT for Mortality
5%	160	278	910	none
7.5%	108	186	606	none
10%	80	140	456	500
15%	54	94	304	334
20%	40	70	228	250

Intensity of Statin Therapy

High Intensity	Moderate Intensity	Low Intensity
LDL reduction > 50%	LDL reduction 30-50%	LDL reduction < 30%
Atorvastatin 40-80mg Rosuvastatin 20-40mg	Atorvastatin 10-20mg Rosuvastatin 5-10mg Simvastatin* 20-40mg Pravastatin 40-80mg Lovastatin 40mg	Simvastatin 10mg Pravastatin 10-20mg Lovastatin 20mg

*Simvastatin 80mg should not be initiated in any patient due to the risk of rhabdomyolysis, but may be continued in patients who have tolerated this dose; it should be avoided in patients concomitantly on a calcium channel blocker

Safety

• Predisposing characteristics to statin intolerance include impairments in hepatic or renal function, hypothyroidism, history of muscle disorders, age greater than 75 years, unexplained elevation of ALT > 3x the upper limit of normal, concomitant use of drugs affecting statin metabolism, history of hemorrhagic stroke, and Asian ancestry
• Statin toxicities
  • Muscle injury: from diffuse myalgias to myositis to overt rhabdomyolysis
    • Muscle symptoms usually begin within weeks to months after starting statins and can occur in the absence of CK elevation
    • Fluvastatin and pravastatin may be associated with less muscle toxicity than other agents in the class
    • Patients with CKD and hypothyroidism appear to be at higher risk for muscle toxicity
    • CK elevation >10x the upper limit of normal is an indication for discontinuing the statin being used
  • Hepatic dysfunction
    • 0.5-3% occurrence of persistent LFT elevations with statin therapy
    • Primarily occurs during the first three months of therapy and is dose-dependent
    • LFT elevation more than 3x the upper limit of normal is an indication to reduce the dose or change to an alternate statin
  • Diabetes
    • It appears statin therapy confers a small increased risk of developing diabetes
    • Multiple studies suggest that the beneficial effects of statins on cardiovascular events and mortality outweigh any increased risk conferred by promoting the development of diabetes
• Monitoring of statin therapy
  • Fasting lipid profile and LFTs should be checked prior to initiating therapy
  • Evaluation and treatment of unexplained ALT elevation > 3x the upper limit of normal should be undertaken prior to initiating therapy
  • CK need only be checked prior to therapy for patients with a personal or family history of muscle disorder or increased risk of myopathy; otherwise CK should not be checked in the absence of symptoms
  • LFTs do not need to be followed after initiating therapy in the absence of symptoms suggesting liver disease or increased risk of liver disease including concomitant medications
  • Repeat lipid profile can be checked four to six weeks after starting therapy to assess treatment effect

Non-statin medications

• Ezetimibe
  • Consider adding ezetimibe to high-dose statin in patients with h/o ACS. 
    • IMPROVE-IT trial (NEJM 2015) showed that ezetimibe/simvastatin reduced total number of coronary events compared to simvastatin alone in patients with ACS (not for low-risk patients). Valid criticism is that simvastatin is not a high-dose statin.  
• PCSK9 inhibitors (alirocumab and evolocumab)
  • Approved for use in combination with diet and maximally tolerated statin and/or lipid-lowering therapy in adults with familial hypercholesterolemia or in patients with clinical ASCVD who require additional lowering of LDL-C 
  • Very expensive, once-weekly injectable monoclonal antibody 
  • FOURIER trial (NEJM 2017) showed decreased 2-year risk of adverse CV events in patients with ASCVD (NNT 67)
• Niacin
  • Improves HDL but has limited clinical benefit
  • Combination statin + niacin does not decrease CV events or mortality in patients with CHD
  • May be used as monotherapy in patients intolerant to statins 
• Fish oil 
  • Recent meta-analyses have not shown consistent benefit 
  • Evidence argues against routine use of fish oil supplements (Risk and Prevention Study Group, NEJM 2013) 
  • Recommendation is to consume 1-2 servings of oily fish per week 

Treatment of low HDL cholesterol

• Therapies to raise HDL cholesterol have not been shown to affect cardiovascular events or mortality
• Therapy should not be specifically directed at low HDL levels
• Exercise, weight loss, smoking cessation, and decreasing saturated fat intake raise HDL cholesterol and should be recommended to all patients

Hypertriglyceridemia

• Diet and lifestyle modifications are first-line therapy for asymptomatic hypertriglyceridemia
• If pharmacologic therapy is necessary, statins should be considered first and result in a 10-30% reduction in triglycerides
• Other options for pharmacologic therapy include fibrates, niacin, and fish oil
• Gemfibrozil should not be used in conjunction with a statin due to the increased risk of rhabdomyolysis
• Fenofibrate may be used concomitantly with a low- or moderate-intensity statin, but requires baseline and q6 months renal function monitoring and is contraindicated in patients with eGFR<30 mL/min. There is little evidence, however, that adding fibrates to statins leads to improved clinical outcomes.

When to refer

• Consider referral for refractory LDL elevation, management of toxicities of lipid-lowering therapy, or management of a familial syndrome

References

Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new era of lipid lowering therapy. World J Cardiol. 2017 Feb 26;9(2):76-91. doi: 10.4330/wjc.v9.i2.76. Review. [PMID: 28289523]

DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. 114250, Hypercholesterolemia; [updated 2018 Feb 22, cited 2018 April 1]; [about 44 screens]. Available from http://www.dynamed.com/login.aspx?direct=true&site=DynaMed&id=114250. Registration and login required.

Eckel et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. JACC 2014;63(25_PA). 

Muntner P, et al. Validation of the Atherosclerotic Cardiovascular Disease Pooled Cohort Risk Equations. JAMA 2014;311(14):1406-1415

Silverman MG, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA. 2016 Sep 27;316(12):1289-97. doi: 10.1001/jama.2016.13985. Review. [PMID: 27673306]

US Preventive Services Task Force. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults. US Preventive Services Task Force Recommendation Statement. JAMA. 2016;316(19):1997–2007. doi:10.1001/jama.2016.15450

Yusuf S et al; HOPE-3 Investigators. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016 May 26;374(21):2021–31. [PMID: 27040132]