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

Hypertriglyceridemia (TG > 200 mg/dL)	Pure Hypercholesterolemia (TC > 200 mg/dL)	Mixed Hypercholesterolemia (TC and TG > 200 mg/dL)	Low HDL (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
Glucocorticoids
Retinoids
Bile acid–binding resins
Antipsychotics
Lipodystrophies
Thiazides

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

Patient Population	Recommendation	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

High and moderate intensity statins

Additional details about non-statin agents for management of LDL-Related ASCVD Risk

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)