Guideline Directed Lipid Lowering Therapy for Cardiovascular Disease Risk Reduction

          In 2013, the ACC/AHA published guidelines on the treatment of blood cholesterol to reduce the risk of cardiovascular diseases. The guidelines focused on statin therapy for cholesterol management. The decision to use non-statin therapy was left to the clinicians. In absence of data to support the use of non-statin therapy, non-statin therapy was being underutilized. This created a gap in the care of patients who could not be managed adequately with statins.  In order to address this, the ACC convened a panel of experts to address this gap. The panel published an expert consensus document addressing the appropriate use of non-statin drugs for cholesterol lowering to reduce the risk of cardiovascular diseases.

         In addition, the WHO / Fredrickson classification of dyslipidemia is impractical for regular clinical use. So classification of dyslipidemia into one of the four broad categories allows directed workup and treatment for specific causes of dyslipidemia. I have combined the dyslipidemia classification, recommendations from the ACC/AHA guidelines (2013) and the ACC expert consensus panel to create a step-by-step guide drug therapy guide for the management of blood cholesterol.

Step 1: Classify dyslipidemia into one of the four broad categories

A. Hypertriglyceridemia (Triglycerides > 200 mg/dL)

B. Pure Hypercholesterolemia (Total cholesterol > 200 mg/dL)

C. Mixed Hypercholesterolemia (Total cholesterol and triglycerides > 200 mg/dL)

D. Low HDL (HDL-C < 50 mg/dL)

Step 2: Workup for secondary causes


(TG > 200 mg/dL)

Pure Hypercholesterolemia

(TC > 200 mg/dL)

Mixed Hypercholesterolemia

(TC and TG > 200 mg/dL)


(HDL < 50 mg/dL)

Primary Causes
LPL deficiency Familial hypercholesterolemia Familial combined hyperlipidemia Familial hypoalphalipoproteinemia
ApoCII deficiency Familial defective apoB100 Dysbetalipoproteinemia ApoAI mutations
Familial hypertriglyceridemia Polygenic hypercholesterolemia LCAT deficiency
Dysbetalipoproteinemia Sitosterolemia ABCA1 deficiency
Secondary Causes
Diabetes mellitus Hypothyroidism Diabetes mellitus Anabolic steroids
Hypothyroidism Obstructive liver disease Hypothyroidism Retinoids
High-carbohydrate diets Nephrotic syndrome Glucocorticoids HIV infection
Renal failure Thiazides Immunosuppressives Hepatitis C infection
Obesity/insulin resistance Protease inhibitors
Estrogens Nephrotic syndrome
Ethanol Lipodystrophies
Beta blockers
Protease inhibitors
Bile acid–binding resins

Step 3: Suggest therapy based on groups that are likely to benefit with lipid management

Patient Population




Desired LDL – C reduction (%)


Desired LDL-C and

non-HDL (mg/dL)

Clinical ASCVD
Without comorbidities 1. High-intensity statin

2. Ezetimibe

3. PCSK9 inhibitor

 ≥ 50 %  LDL – C < 100 mg/dL
With comorbidities¹ 1. High-intensity statin

2. Ezetimibe

3. PCSK9 inhibitor

 ≥ 50 %  LDL – C < 70 mg/dL

non-HDL – C < 100 mg/dL

And baseline LDL-C ≥ 190 mg/dL  1. High-intensity statin

2. Ezetimibe or PCSK9 inhibitor

3. Bile acid sequestrants

 ≥ 50 %  LDL – C < 70 mg/dL
Baseline LDL-C ≥ 190 mg/dL (without ASCVD)
1. High-intensity statin

2. Ezetimibe or PCSK9 inhibitor

3. Bile acid sequestrants

≥ 50 %  LDL – C < 100 mg/dL
With diabetes mellitus + age 40 – 75 years (without ASCVD or baseline LDL-C ≥ 190 mg/dL)
1. Moderate or high-intensity statin

2. Ezetimibe

3. Bile acid sequestrants

 ≥ 50 %  LDL – C < 100 mg/dL

non-HDL – C < 130 mg/dL

With 10 year ASCVD risk ≥ 7.5 %   + age 40 – 75 years (without ASCVD or baseline LDL-C ≥ 190 mg/dL)
Without high risk markers 1. Moderate intensity statin

2. Ezetimibe

3. Bile acid sequestrants

 30 – 49 %  LDL – C < 100 mg/dL
 With high risk markers² 1. Moderate or high-intensity statin

2. Ezetimibe

3. Bile acid sequestrants

 ≥ 50 % LDL – C < 100 mg/dL
With 10 year ASCVD risk ≥ 5 to 7.5 %   + age 40 – 75 years
1. Moderate intensity statin
Special populations
Heart failure 1. High-intensity statin  Beneficial only in ischemic heart disease
 CKD 1. No benefit with statin despite high all-cause mortality
 Pregnancy  1. Bile acid sequestrants  1.Statins contraindicated during pregnancy and breastfeeding.

2. Premenopausal  patient should be on contraceptives

Pure hypertriglyceridemia
 For TG > 500 mg/dL 1. Fenofibrate, ω-3 fatty acids or niacin

2. High-intensity statins

For TG 200 – 500 mg/dL 1. High-intensity statins

2. Fenofibrate, ω-3 fatty acids or niacin

 In patients with CKD Prefer fenofibric acid to fibrates

¹Comorbidities were defined as diabetes mellitus, recent (<3 months) ASCVD event, ASCVD event while already taking statin therapy, baseline LDL-C ≥190 mg/dL not due to secondary causes, poorly controlled other major ASCVD risk factors, elevated lipoprotein(a), or chronic kidney disease (CKD)

²10-year ASCVD risk ≥20%; primary LDL-C ≥160 mg /dL at baseline; other major ASCVD risk factor(s) that are poorly controlled; family history of premature ASCVD with or without elevated lipoprotein(a); evidence of accelerated subclinical atherosclerosis (e.g., coronary artery calcification); elevated hs-CRP; and other risk-modifying conditions, such as CKD, HIV, and chronic inflammatory disorders

– ASCVD: Atherosclerotic cardiovascular disease, LDL-C: LDL cholesterol, HDL-C: HDL cholesterol

Step 4: Shared decision making using Mayo Clinic’s shared decision-making tool

Step 5: Monitor adherence and response to therapy

  • A fasting lipid panel 4 to 12 weeks after treatment initiation or modification to determine a patient’s response and adherence.

  • Thereafter, a fasting lipid panel should be performed every 3 to 12 months as clinically indicated.

  • Triglycerides > 200 mg/dL can result in underestimation of LDL-C by ~ 30 mg/dL. In this case, prefer measured LDL-C (ref)

Step 6: Intensify lifestyle modifications, consider adding phytosterols and refer to registered dietician

Step 7: Evaluate for statin intolerance

Step 8: Consider referral to lipid specialist if the patient has significant statin intolerance

Recommended additional reading:


Ref: 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents