Dyslipidemia
HDL-C – high density lipoprotein cholesterol (good cholesterol, non-atherogenic)
LDL-C – low density lipoprotein cholesterol (non-HDL, bad cholesterol, most atherogenic)
TG – triglycerides (VLDL chief carrier of TG, atherogenic)
Total-C/TC – total cholesterol (total of atherogenic + non-atherogenic
 Non-HDL – all atherogenic lipoproteins
 using fasting lipid profile (FLP) via venipuncture (not direct measure)
Formula for Calculated LDL-C = TC – HDL – [TG÷5]
- Lab report provides TC, LDL, HDL, TG and non-HDL
-
• “Cannot calculate LDL” appears on report if TG ≥400 mg/dL
• “Direct LDL” test ($$) could be used to check LDL if TG ≥400 mg/dL
Reduce accuracy of LDL calculation if LDL < 70mg/dL
May be less accurate when non-fasting in some individuals
Formula for Calculated Non-HDL-C = [TC] – [HDL]
Cholesterol Screening:
 Routinely check Lipid Profile every 4-6 years to screen healthy adults
o More often if high risk primary ASCVD prevention (e.g., familial)
o This does NOT apply to treatment monitoring (more frequent checks)
o Test generally requires FASTING (nothing to eat/drink ~8-12 hours; water ok)
 Exception for initial assessment ONLY:
Non-fasting okay ONLY if age ≥20
 AND primary prevention (no ASCVD) AND
 AND no family history of premature ASCVD
 AND no genetic hyperlipidemia
o (if TG ≥400mg/dL, redraw as FLP)
 Dyslipidemia
 AKA Hyperlipidemia AKA Hypercholesterolemia
• Etiology can be genetic and/or acquired (diet, drug, disease, disorder)



Traditional CV Risk Factor
o Elevated LDL (and thus, TC) directly related to ASCVD
o High TC 200mg/dL present in ~ 45% of American adults 20YO+
Elevated LDL-Cholesterol – highly atherogenic
o High LDL levels affects ~ 30% of American adults 20YO+
o Dose-dependent log-linear association between LDL and ASCVD risk
o Not all lipid-lowering agents that reduce LDL have resulted in reduction in ASCVD events 
so LDL lowering alone NOT basis for drug choice
Elevated Triglycerides (TG) – atherogenic (+ pancreatitis)
o Hypertriglyceridemia (High TG) affects ~ 33% American adults 20YO+
 Among those 1.7% (~3.4 million Americans) with severe hypertriglyceridemia
Increasing prevalence largely due to growing Obesity & DM rates
o Persistently elevated TG ≥ 175mg/dL may enhance ASCVD risk (debatable)
o Severe elevations in TG ≥ 500mg/dL increases risk of pancreatitis
Elevated LDL
CLINICAL CONCERN: significantly increases risk of ASCVD
• VERY HIGH LDL ≥ 190mg/dL HIGHEST ASCVD RISK
• LDL ≥ 190mg/dL Heterozygous Familial Hypercholesterolemia (HFH)
• LDL ≥ 400mg/dL Homozygous Familial Hypercholesterolemia (HoFH)
• HIGH LDL 160 -189 mg/dL ASCVD Risk Enhancing Factor
• Elevated LDL 70-159mg/dL ASCVD Risk varies (Risk Assessment)
Elevated TG: Hypertriglyceridemia (HTG)
MODERATE HTG: 150 - 499mg/dL
• LAB report: TG 150-199 mg/dL “borderline”; TG 200-499 mg/dL “high”
• CLINICAL CONCERN: TG ≥ 175mg/dL may enhance risk for ASCVD
(direct role of TG in the development of ASCVD remains debatable)
SEVERE HTG: ≥500mg/dL
• LAB report: TG 500 - 2000 mg/dL “very high”
• CLINICAL CONCERN: TG ≥500mg/dL increases risk of pancreatitis
Clinical Presentation:
 High LDL
o Generally asymptomatic
 until ASCVD develops
 rare xanthomas or corneal arcus (familial hypercholesterolemia)
 High TG
o Generally asymptomatic
 Until pancreatitis develops
 acute pancreatitis may cause acute abdominal pain, nausea, vomiting, fever,
tachycardia)
Goals of Tx:
Patient outcomes
Treatment Target
•
Reduce ASCVD risk (primary &
secondary prevention)
Elevated LDL
• Percent reduction from baseline is KEY
• May consider LDL cut-point
• i.e., may Target LDL level less than a certain mg/dL
for higher risk patients
• FYI: Targeting Non-HDL may be considered
after LDL reduction goals are achieved (NOT A LEARNING
OBJECTIVE to assess NON-HDL
•
Reduce ASCVD risk (primary &
secondary prevention)
Reduce Pancreatitis risk with
severe HTG
Elevated TG: Hypertriglyceridemia (HTG)
• “TG Reduction” reasonable to further reduce ASCVD risk (if
higher risk)
• ASCVD risk enhancing factor if persistently TG ≥
175mg/dL
• Target TG < 500mg/dL to reduce pancreatitis risk
•
Component
Surrogate Efficacy Target
(based on evidence supporting drug therapy to improve
patient outcomes related to changes in FLP)
TC
(indirectly – see LDL and TG)
LDL
Yes
LDL reduction with evidence-based therapy lowers ASCVD risk
TG
Maybe
MODERATE HTG: AFTER statin therapy is maximized,
lowering TG MAY reduce ASCVD risk in higher risk persons
**direct role of TG in the development of ASCVD remains debatable
SEVERE HTG: Lower TG to ↓ Pancreatitis risk
HDL
Non-HDL
No
While low HDL contributes to ASCVD it is NOT treatment target due to lack of
evidence supporting improved outcomes
when nonstatin Rx to raise HDL is added to statin therapy
Maybe
(secondary consideration in some patients - NOT a learning objective)
Issue
Approach
(with lifestyle changes after addressing reversible causes)
•
Elevated LDL
• Significantly
increases risk
of ASCVD
Elevated TG
• Moderate HTG:
increases risk
of ASCVD
• Severe HTG:
Increases risk of
pancreatitis
Drug class
•
•
•
TARGET LDL: PERCENT (%) LDL lowering from baseline with
STATIN (intensity of statin LDL lowering will be based on
patient’s ASCVD risk)
THRESHOLD LDL (mg/dL) – above this value consider addition
of evidence-based NON-STATIN to further reduce ASCVD risk
in higher risk patients already maximized on STATIN
TARGET TG “lowering” to reduce ASCVD risk
 Optimize STATIN therapy +lifestyle changes
 if higher ASCVD risk reasonable to add
evidence-based NON-STATIN to lower TG
Treatment success for reducing pancreatitis risk:
TG less than 500mg/dL
Generic (Brand) *module drug list
ASCVD Outcome Data
For TG Lowering
For LDL lowering
Statin (HMG Co-A
reductase inhibitor)
Atorvastatin (Lipitor®)
Lovastatin (Mevacor®)
Pravastatin (Pravachol®)
Rosuvastatin (Crestor®)
Simvastatin (Zocor®)
++++++++ (ROBUST)
significant ASCVD risk reduction in
statin benefit groups; risk reduction
based on level of statin intensity/LDL
lowering
*also has some TG lowering
Cholesterol absorption
inhibitor
ezetimibe (Zetia®)
Ezetimibe + simvastatin (Vytorin®)
+++ (EVIDENT) modest reduction in
ASCVD risk w/ statin
Bile acid sequestrants
(BAS) “resins”
cholestyramine (Questran®)
colesevelam (Welchol®)
colestipol (Colestid®)
+ (LIMITED) modest reduction in
ASCVD risk w/ statin
Proprotein convertase
subtilisin kexin 9 (PCSK9)
inhibitor
alirocumab (Praluent®)
evolocumab (Repatha®)
Adenosine triphosphate –
citrate lyase (ACL) inhibitor
Bempedoic acid (Nexletol®)
Bempedoic acid + ezetimibe (Nexlezet®)
Omega-3 “fish oils”
(2-4 g per day)
ethyl esters (DHA/EPA) – Lovaza®
icosapent ethyl (EPA only) - Vascepa®
+ (LIMITED)
(++ for severe HTG to ↓ pancreatitis
risk)
clinically modest reduction in ASCVD
risk when added to statin (2018
REDUCE-IT)
Fibric acid derivatives
(fibrates)
fenofibrate (Tricor®; Trilipix®)
gemfibrozil (Lopid®)
NO
(+++ for severe HTG to ↓ pancreatitis
risk)
Niacin
(1-3g/day)
niacin extended-release (Niaspan®)
niacin immediate release (Niacor®)
niacin sustained-release (Slo-Niacin/AVOID)
NO
(Lack ASCVD benefit /possible harm if
used for LDL lowering; last line for TG
lowering to reduce pancreatitis only
++ (EVIDENT) modest reduction in
ASCVD risk w/statin +/- ezetimibe
NO
OTC Dietary supplements: not routinely recommended
 Efficacy issues: lack OUTCOME data (unknown impact on ASCVD risk, even if lowers LDL)
 Safety issues: lack of purity, standardization, adverse effect potential, no monitoring
-E.g., Red Yeast Rice supplement (chemically like lovastatin; >120-fold variability in active
ingredient)
-E.g., Omega-3 fish oil OTC supplement low dose (1g per day DHE/EPA –lack outcome data
-E.g., Slo-Niacin (hepatotoxic); No-Flush Niacin (no LDL↓) – lack outcome data
Only safe product w/ limited outcome data: Phytosterols/stanols-e.g., Benecol spread 1g to
3g per day
- Limited utility clinically
Statin Benefit Groups:
Lipid Therapy for ASCVD Reduction:
 Always first address secondary causes
 Guidelines change regularly based on EVIDENCE on patient outcomes
o Only 55% of Americans (~43 million) who could benefit from cholesterol medicine are
currently taking it.
 Mixed dyslipidemia may involve managing LDL and TG
o Primary focus is LDL lowering for ASCVD risk reduction!
Evidence supports
1. Address secondary causes
2. LIFESTYLE modifications
3. Drug therapy
• PRIMARY: LDL lowering
• STATIN – 4 benefit groups
• NON-STATIN – add evidence-based therapy to “maximally tolerated statin” (i.e.,clinical trial data
support further reduction in ASCVD risk with addition of this nonstatin)
 EZETIMIBE –evident data*usually first choice
 PCSK9 INHIBITOR – evident data*may be choice for some patients (COST$$)
 BILE ACID RESIN- limited data *last choice
• SECONDARY: Lower TG
• Emerging data suggest it is reasonable to add RX FISH OIL therapy for “higher risk population“with
moderate HTG
DIET
EXERCISE
LIFESTYLE
Follow dietary pattern (e.g., DASH, USDA, or AHA diet) **adapt to appropriate caloric
requirements, personal/ cultural food preferences and nutrition therapy for other medical conditions
(e.g., Diabetes Mellitus)
 emphasizing intake of vegetables, fruits, whole grains; include low fat dairy products,
poultry, fish, legumes, non-tropical vegetable oils
 limited intake of sweets, sugary beverages, red meats
 reduced intake/calories from saturated fat (5-6% of calories) AND limit trans fat.
 3g to 12 g per day soluble/viscous fiber (diet or may consider OTC psyllium)
Aerobic moderate-to-vigorous physical activity 3-4 sessions/week lasting ~40 min/session
 Weight loss (if obese or overweight)
 Tobacco cessation (if applicable)
Secondary causes of high LDL
Diet
•
•
•
•
Anorexia
Saturated fats intake
Trans fats intake
Weight gain
Drugs
•
•
•
•
•
Amiodarone
Cyclosporine
High-dose Thiazide diuretic
Corticosteroids (Glucocorticoids) – e.g., Prednisone
Anabolic steroids – e.g., testosterone
Conditions
•
Progestins, especially those with androgenic activity (e.g., levonorgestrolcontaining oral contraceptives)
•
•
•
•
•
Biliary Obstruction
Hypothyroidism
Nephrotic syndrome
Obesity
Pregnancy
Statin Benefit Group 1:
 GROUP 1. Clinical ASCVD (Secondary prevention) * see module 2!
 History of ≥2 major ASCVD events, OR
 Major ASCVD event with ≥2 high risk conditions
o Rx Statin; Do not calculate 10-year ASCVD risk score (invalid)
Clinical ASCVD Events:


Coronary Artery Disease (CAD)
AKA Ischemic Heart Disease (IHD)
AKA called Coronary Heart Disease (CHD)
o Chronic Stable Angina
o Myocardial Infarction (MI)
o Acute Coronary Syndrome (ACS) / unstable angina
o Surgical revascularization of Coronary Artery
e.g., Coronary Artery Bypass Graft (CABG) – “bypass surgery”
e.g., Percutaneous Coronary Intervention (PCI) - coronary stent “angioplasty”
Non-Coronary Vessel Disease
o Ischemic stroke - “Cerebrovascular Accident” (CVA)
o Transient Ischemic Attack (TIA) – “mini–stroke”
o Renal artery stenosis
o Mesenteric artery disease -” bowel infarction”
o Abdominal Aortic Aneurysm (AAA) - “triple A”
o Peripheral Vascular Disease (PVD)
e.g., Peripheral Artery Disease (PAD) “intermittent claudication”
o Surgical revascularization of non-coronary artery (E.g., AAA repair)
Statin Benefit Groups 2, 3, 4:
 GROUP 2. Very High LDL (≥190), Primary prevention, Age 20-75
o Rx Statin regardless of 10-year ASCVD risk score
 GROUP 3. DM, Primary prevention, LDL 70-189, Age 40-75
o Rx Statin regardless of 10-year risk score (almost always ≥7.5% due to DM risk);
AGE and ASCVD risk level determines statin intensity
 GROUP 4. No DM, Primary prevention, LDL 70-189, Age 40-75
o 10-year ASCVD risk score begins discussion on statin benefit/risk/preferences
For
group 4
Benefit
Group
Recommended Statin intensity
(use maximum tolerated Statin if not possible)
Group 1
AGE ≤75: Initiate High intensity (to ↓ LDL ≥50% from baseline)
AGE >75: Reasonable to initiate Moderate intensity or High intensity (or continue)
Group 2
AGE 20-75: Initiate High intensity (to ↓ LDL ≥50% from baseline)
Group 3
(age 40-75)
-Initiate at least Moderate intensity
-Reasonable to initiate High intensity (to ↓ LDL ≥50%) if Age 50-75 years
OR multiple ASCVD risk factors (consider 10yr risk; REF; DM-specific risk enhancers)
(exceptions)
Age 75+: reasonable to continue statin OR consider initiation (discuss benefit/risk)
Age 20-39: reasonable to initiate statin after consider DM-specific risk enhancers
Group 4
(age 40-75)
•
•
•
•
HIGH 10yr RISK: initiate High-intensity intensity (to ↓ LDL ≥50% from baseline)
INTERMEDIATE 10yr RISK: REF FAVOR statin initiation/intensification
a. If statin favored, initiate Moderate intensity (to ↓ LDL at least 30%)
b. If would benefit from more aggressive LDL ↓ - may consider High-intensity
c. If statin choice uncertain, may consider measuring Coronary Artery Calcium
 CAC score ≥100 (HIGH): initiate statin
 CAC 1-99: FAVORS initiating statin, especially after age 55
 CAC zero: statin only if smoker or family history of premature ASCVD
BORDERLINE 10yr RISK: consider Moderate intensity if REF present
LOW 10yr RISK: no statin; emphasize lifestyle modifications only
(exceptions)
•
AGE 20-39 + 10yr risk score <5% (Low risk): may consider “statin” if has BOTH
Family History of premature ASCVD AND High LDL (160mg-189mg/dL)
• Reasonable to continue statin if initiated PRIOR to dialysis
8 Risk Enhancing Factors (REF) for Primary Prevention of ASCVD
Family history of premature ASCVD
1st degree relative (parent, child, sibling) had
early age ASCVD (male <55YO or female <65 YO)
High-risk race/ethnicity/ancestry
•
South Asian, American Indian, Puerto Rican
High LDL-Cholesterol (primary)
•
160–189 mg/dL
Elevated biomarker levels
(these may ↑ ASCVD risk; cannot precisely
assess impact)
•
•
•
•
•
Elevated TG - persistently ≥175 mg/dL
Elevated CRP (FYI: risk ≥2.0 mg/L) – C reactive protein
Elevated Lp(a) (FYI: risk ≥50 mg/dL) – Lipoprotein(a)
Elevated ApoB (FYI: risk ≥130 mg/dL) – Apoprotein-B
Low ABI ratio (FYI: <0.9 indicates PAD risk) - Ankle
brachial index (ankle vs. upper arm blood pressure)
Metabolic syndrome
•
FYI: at least 3 of 5 criteria: low HDL cholesterol;
Elevated waist circumference; high triglycerides;
high Blood Pressure; High blood glucose
Chronic Kidney Disease (CKD)
(DO NOT count if dialysis or kidney transplant)
Chronic inflammatory conditions
•
•
•
•
Psoriasis
Rheumatoid Arthritis
Lupus
HIV/AIDS
Premature menopause or pregnancyassociated conditions
•
•
Menopause under age 40
Pre-eclampsia during pregnancy
DM-Specific Risk Enhancer
Any 1 of these enhances ASCVD in persons with Diabetes Mellitus
• Long duration (Type 2 DM ≥ 10years Type 1 DM ≥ 20years)
• Nephropathy (GFR <60; proteinuria)
• Retinopathy
• Neuropathy (FYI - ABI <0.9)
Statin
Benefit
Group
Threshold LDL
(to add nonstatin)
Group 1
Age 20+
≥70mg/dL
or <50%
reduction from
baseline
NON-STATIN Drug to consider
(when Threshold is met on MAXimally tolerated statin)
•
Very High Risk* (see definition)
• 1st reasonable to add ezetimibe
nd
2 consider PCSK9i (if still LDL ≥70 on statin + ezetimibe)
NOT Very high risk - may add ezetimibe
• 1st reasonable to add ezetimibe
• Age 20-75: 2nd consider adding Bile acid resin (AVOID if TG≥300)
• Age 30-75: may add PCSK9I (if still LDL ≥100 on statin + ezetimibe)
Group 2
Age 20-75
≥100mg/dL
or <50%
reduction from
baseline
Group 3
Age 40-75
<50% reduction
from baseline
If 10yr risk ≥20% (HIGH RISK): reasonable to add ezetimibe
Group 4
Age 40-75
n/a
 See criteria
instead
If 10-yr risk score ≥20% (HIGH RISK): If patient would benefit from more aggressive
LDL ↓ with High-intensity but therapy is unacceptable (or not tolerated) may be
reasonable to add Ezetimibe or Bile Acid Resin to moderate intensity statin
therapy
•
High-intensity statin
• Estimated to achieve ≥50% LDL reduction for MOST people
• Estimated to provide ~ 45% relative risk reduction for ASCVD
•
•
•
• Typically initiate therapy at this level when indicated (clinical trial dosing)
Moderate-intensity statin
• Estimated to achieve 30-49% LDL reduction for MOST people
• Estimated to provide ~ 35% relative risk reduction for ASCVD
• Typically initiate therapy at this level when indicated (clinical trial dosing)
Low-intensity statin therapy
• Estimated to achieve <30% LDL reduction for MOST people
• Estimated to provide < 35% relative risk reduction for ASCVD
• primarily for intolerance to higher doses (something better than nothing)
Expected LDL effects may vary in each patient (adherence; administration; PK)
• EACH doubling of statin adds ~6% further ↓ LDL
• With evening meal: lovastatin (50% reduction in absorption if not with food)
• At bedtime: pravastatin; simvastatin (chrono-therapeutics)
• NOTE: atorvastatin OR rosuvastatin any time of day regardless of food
Significant evidence supports statin as FIRST LINE to reduce ASCVD
 Link to LDL lowering (TG lowering is modest as well)
 Pleiotrophic effects? (FYI some clinicians tout benefit on changing small dense LDL  large
fluffy LDL less likely to contribute arterial wall plaque build-up …..stabilize existing
plaque)
 NONSTATIN role is as an ADJUNCT to maximally tolerated statin
 Not all lipid-lowering therapies have translated to reducing ASCVD risk, despite having
favorable effects on FLP including LDL lowering
 Not all lipid-lowering therapies have sufficient TG lowering for severe HTG to reduce
risk of pancreatitis from that condition

Evidence supports
Evidence does NOT support
1. Address secondary causes
2. LIFESTYLE modifications
3. Drug therapy
• PRIMARY: LDL lowering
• STATIN – 4 benefit groups
• NON-STATIN evidence-based therapy
added to “maximally tolerated statin”
 EZETIMIBE - evident
 BILE ACID RESIN- limited
 PCSK9 INHIBITOR - evident
• SECONDARY: Lower TG
• Emerging data suggest reasonable to
add evidence-based RX FISH OIL for
“higher risk population“ with moderate
HTG

FDA prescribing information for each agent warns that
therapy “has not been shown to reduce CV morbidity or
mortality.”
• FIBRATE – studies show lack of clinical
benefit when added to statin therapy
(despite lipid profile improvements)
• NIACIN- studies show lack of clinical
benefit when added to statin therapy
(despite lipid profile improvements)
• BEMPEDOIC ACID - lack outcome data
(only data on lipid profile improvements
so far)
EFFICACY: Lacking ASCVD risk reduction data E.g. AIMHIGH trial - No incremental benefit of
NIASPAN co-administered with simvastatin or lovastatin on cardiovascular morbidity and mortality
over and above that demonstrated for niacin, simvastatin and lovastatin monotherapy, has been
established.
LDL reduction monitoring:
1. Assesses adherence to lifestyle and Rx
2. Check FLP 4-12 weeks after statin initiation or dose adjustment (each)
a. CALCULATE LDL % lowering from baseline
i. E.g. Baseline LDL 140 mg/dL and new LDL is 90mg/dL on statin for at least 4 weeks
a. LDL difference = [140 - 90] = 50 mg/dL (amount of LDL reduction)
b. % LDL reduction = Difference ÷ Baseline (50/140 = 0.35) *100 =
35%
3. Consider intensifying statin therapy if % LDL reduction GOAL not achieved
i. MAY also consider actual “LDL value” as a secondary efficacy factor
ii. If at follow-up LDL goal(s) still not achieved, may consider add-on NONSTATIN
4. 4. Check FLP every 3 to 12 months thereafter to assess adherence (and to monitor safety/tolerability
– more on this later…..)
NON- STATIN
LDL reduction
Cholesterol absorption
Inhibitor
adding ezetimibe to moderateintensity statin ~ same % LDL
lowering as high-intensity statin
ezetimibe (Zetia)
10mg tablets
1 tab po DAILY
Bile acid resin
*Welchol is also FDA approved
for T2DM glycemic control
cholestyramine (Questran)
mix 4g dose QD or BID; MDD 24g
ezetimibe /simvastatin (Vytorin)
available as
10/10, 10/20, 10/40 mg tablets
1 tab po DAILY
colesevelam (Welchol)
625mg tabs 6 P QD (or 3 tab PO BID);
also available as powder or bar
Alone: ~18%
(range 13-20%)
With Statin: ~20 to 25% additional
LDL lowering
~15 to 30%
(dose-related response)
colestipol (Colestid)
PCSK9
Inhibitor
(FDA dosing)
*may up-titrate dose
Self-Inject or
professionally administered
alirocumab (Praluent)
HFH or ASCVD:
*75mg-150mg SQ q2wks
OR 300mg SQ q4wks
evolocumab (Repatha)
HFH or HoFH or ASCVD:
140mg SQ q2wks OR
420mg q4wks if HoFH
43 to 64%
(added to
maximally tolerated statin
+/- ezetimibe)
REDUCE-IT Trial:
 Compared Icosapent ethyl (Vascepa) omega-3 fish oils 4g/d vs. placebo
in persons with
HIGH CV risk on statin (67% on high-; 32% on moderate-intensity)
o Median baseline LDL 75 mg/dL (range 41-100mg/dL)
o Median baseline TG 216 (range up to 499mg/dL) – Moderate HTG
 Followed primary & secondary ASCVD prevention patients x 4.9 years
o 71% secondary ASCVD prevention
o 29% primary ASCVD prevention (age 50+ with DM + 1 other CV risk factor)
 Adding Icosapent ethyl 4g/d showed
o Median TG ↓ was ~20% better than placebo; no significant change LDL
o Significant (4.8% absolute risk reduction) reduction in primary composite endpoints (death,
non-fatal MI or CVA, coronary revascularization, ACS)
o Significant (3.6% absolute risk reduction) reduction in key secondary composite endpoints
(CV death, fatal MI or fatal CVA)
 FIRST well designed multi-center trial to show benefit with High dose FishOil
o LIMITATIONS – e.g, If mineral oil in the placebo affected statin absorption in some patients,
this might have contributed to differences in outcomes between the groups (i.e., reduced
statin efficacy in placebo group) – need more data!
 NOTE: THIS data HAS changed FDA approved indication for use (2019)
o Clinical guidelines not updates yet
o “Reasonable to consider” 4g/day EPA or EPA/DHA in Statin Benefit Group 1 or 3 if patient
clinician discussion agree benefits >> risks for individual
HIGH DOSE Omega-3 Fatty Acids AKA “fish oils”:
 EPA: EicosaPentaenoic Acid
 DHA: DocosaHexanoic Acid
 GENERAL RULE: 1 gram of omega-3 fatty acids lowers triglycerides by 5-10% with greater TG
lowering seen with HIGHER baseline TG levels.
o Moderate HTG at baseline: 20 – 30% reduction in TG level expected
o Severe HTG at baseline: > 30% reduction in TG level expected **
 2 Rx products
o Lovaza (or generic) – EPA/DHA (ethyl esters) – DHA may increase LDL >10% - 40%
o Vascepa – EPA (icosapent ethyl)– NO DHA (no LDL change)
2019 AHA science advisory statement – Rx EPA or EPA/DHA dosed 4g daily are “effective and
safe option” to lower TG as monotherapy or as adjunct to other lipid lowering agents in
management of HTG…..
VASCEPA– new FDA approved indication as adjunct to maximally tolerated statin to reduce risk
of MI, CVA, Coronary Revascularization, and unstable angina requiring hospitalization in adults
with TG ≥150mg/dl AND established ASCVD …..OR…… DM plus 2 other CV risk factor
Secondary Causes of High TG:
Diet
•
•
•
•
•
Excessive alcohol intake
High saturated fat diet
High intake of refined carbohydrates
Very high fat diet
Weight gain
Drugs
•
•
•
•
•
•
•
•
•
Anabolic steroids – e.g., testosterone
Atypical antipsychotics – e.g., olanzapine, risperdone
Beta-blockers (not carvedilol)
Bile acid sequestrants (resins)
Glucocorticoids - e.g., prednisone
High-dose thiazide diuretics - e.g., HCTZ ≥ 50mg PO daily
Immunosuppressants – e.g., tacrolimus, cyclosporine
Oral estrogens; raloxifene; tamoxifen
Protease inhibitors for HIV
Conditions
•
•
•
CKD
Hypothyroidism
Poorly controlled DM -1 in 3 persons with type 2 diabetes has
hypertriglyceridemia
Pregnancy
Obesity~8 out of 10 individuals with high TG are overweight or obese
•
•
Severe HTG tx:
 Moderate to intensive physical activity
o ↓ TG level 20-30% especially combined with calorie reduction
o Weight reduction
 5-10% reduction can reduce TG ~20%
o Improve glycemic control (if have DM)
o Dietary changes: may help reduce TG levels by 20-50%.
o Eliminate TRANS fats (e.g., bakery shortening, stick margarine)
o Moderate carbohydrate intake (< 60% of total calories)
o Restrict fructose
o Increase fiber
o Limit alcohol intake (< 1 ounce daily or complete abstinence)
o If TG > 1000 mg/dL – very low-fat diet, avoid refined carbs, consume omega-3 fish oils,
control blood glucose (if applicable)
Drug
Generic (Brand)
TG lowering
Role in Therapy
Fibric acid
derivatives
(fibrates)
fenofibrate (Tricor; Trilipix)
gemfibrozil (Lopid)
Omega-3 “fish
oils”
(2-4 g per day)
ethyl esters (DHA/EPA) Lovaza
icosapent ethyl (EPA only) Vascepa
Niacin
(1-3g/day)
niacin immediate release (Niacor)
niacin extended-release (Niaspan)
niacin sustained-release (SloNiacin/AVOID)
Statin
See module drug list
Statin CI:
Absolute CI
 Known hypersensitivity
 Active liver disease OR unexplained
persistent transaminase elevations
 AVOID if ALT or AST ≥3XULN
 Pregnancy/Lactation
~30-50%
Standard
First line therapy to lower
severe HTG to reduce
pancreatitis
~30- 50%
Emerging
First line therapy
to lower severe HTG to
reduce pancreatitis
IR: 20-50%
ER: 10-30%
(SR: don’t use)
NOT first line
to lower severe HTG to
reduce pancreatitis
Happens to also lower TG
~10- 30%
Optimize if indicated to
reduce ASCVD risk
Relative CI
 History of liver disease
 may consider if baseline risk
assessed & plan to monitor
 Major drug-drug interactions
 Women of child-bearing age *require
reliable contraception
FROM assigned reading – Guideline 4.5.3 : Special issues in Women
• Women of childbearing age who are treated with statin therapy and are sexually active should be counseled to
use a reliable form of contraception.
• Women of childbearing age with hypercholesterolemia who plan to become pregnant should stop the statin 1
to 2 months before pregnancy is attempted, OR if they become pregnant while on a statin, should have the
statin stopped as soon as the pregnancy is discovered
Statin interaction risks:
 STATIN drug inhibits metabolism/levels of OTHER drug
o -E.g., warfarin (monitor INR for increased effects of same dose of warfarin)
 OTHER drug changes metabolism/levels of STATIN
o Cytochrome P450
 No significant P450 metabolism: PRAVASTATIN
 P450 2C9 : ROSUVASTATIN
 P450 3A4 : SIMVASTATIN (most), LOVASTATIN, ATORVASTATIN (least)
o Transport proteins – see READING Table 5 FYI for detailed information
 P-Glycoprotein (P-Gp)
 Organic Anion-Transporting polypeptide (OATP1B1/B3)
 Concurrent use increases risk of SASE (e.g., muscle, liver)
o FIBRATE: AVOID gemfibrozil; may consider fenofibrate w/ monitoring
o
NIACIN: generally avoid, may consider w/ monitoring
NDA: No Dose Adjustment
Simvastatin: Avoid concomitant use of NEXLETOL with simvastatin greater than 20 mg.
Pravastatin: Avoid concomitant use of NEXLETOL with pravastatin greater than 40 mg
Avoid gemfibrozil
CKD:
RECALL: No data to recommend STATIN initiation if Statin Benefit Group 4
if a DIALYSIS or RENAL TRANSPLANT patient…….
May continue STATIN if initiated before became dialysis or transplant patient
Safety:
 Statin Safety
 Potential for Statin drug interactions
 Potential for Statin-Associated Side Effects (SASE)
o Statin Associated Muscle Symptoms (SAMS)
o Liver
o New Onset Type 2 DM
o Cognition
o Other
 Fact that SASE can be addressed successfully
Statin Associated Muscle Symptoms (SAMS)
 muscle symptoms may include: Muscle pain, aches as well as tenderness, stiffness, cramping,
weakness, or generalized fatigue

Other Possible Etiologies for Muscle Symptoms
o Uncontrolled Hypothyroidism (not euthyroid; TSH WNL ok)
o Vitamin D deficiency
 Two small cohort studies reported that more than 90% of patients who were
previously intolerant to statins and who had low baseline levels of vitamin D were
able to adhere to statins 1 year after vitamin D supplement
o Rheumatologic disorders (e.g., polymyalgia rheumatic; steroid-induced myopathy)
o Primary muscle diseases
o Renal dysfunction
o Hepatic dysfunction
In patients with indication for statin therapy identify potential predisposing factors for SAMS or New Onset
Type 2 DM (before initiation of treatment):
 Check for baseline muscle symptoms
 Assess baseline risk factors for developing New onset Type 2 DM
o Adherence to lifestyle regimen is critical prevention of T2DM
o Side effect occurs most often if many other risk factors exist
o Appears that risk is greater with high- vs. moderate- intensity
 NO increased risk of T1DM reported
 ASCVD reduction benefits outweigh possible DM
 NO data to suggest risk of adverse glucose effects with existing Diabetes Mellitus
Recommendation 5:
In patients with increased risk for new-onset T2DM
it is recommended to continue statin therapy, with added emphasis on adherence, net clinical benefit,
and core principles of
regular moderate-intensity physical activity,
healthy dietary pattern, and modest weight loss.
SASE predisposing factors:
Know CK normal range: 22 to 200 U/L
*ALT [normal range 7-53IU/L]; 3 X ULN is 2 x53 = 159 (see Module 1 – Clinical Basics)
The FDA NO longer recommends “routine” liver function monitoring w/ statin
therapy (reserve for higher risk population)
Recommendation 4:
in patients with SASE that are not severe, it is recommended to reassess
and to rechallenge to achieve maximal LDL lowering with
- by modified dosing regimen (same statin),
- an alternate statin (new regimen) , or
- statin in combination with nonstatin therapy.
•
•
Hydrophilic statin (theoretically less muscle side effects)
• PRAVASTATIN
• ROSUVASTATIN
Pharmacogenomics - East Asian data (Chinese, Japanese, Malay Asian Indian)
• AVOID simvastatin
• use lower dose rosuvastatin initially & caution with up-titration
Assessing & Managing SAMS
 ASSESSMENT – also see https://www.acc.org/statinintoleranceapp
 Obtain patient history of prior/current muscle symptoms at baseline
 Typically bilateral presentation in large, proximal muscles
 Typically see onset 4 to 6 week after drug initiation OR after dose increase
 SAMS may occur later during therapy
 MANAGEMENT
 Identify/manage to prevent progression to very rare rhabdomyolysis
 Important patient education/counseling point
 Stop offending agent and assess for resolution of symptoms (sx)
 Once sx resolved – typically “rechallenge” with new statin regimen
 If severe & patient prefers NOT to retrial statin – may consider NONSTATIN
 Majority of patients safely tolerate a different statin regimen
 Consider “wash out period” (no statin) prior to restarting (new baseline)
 New regimen: new daily regimen of same or different statin intensity
 Consider new regimen(s) until “intolerance” is certain
-
Majority of patients safely tolerate a different statin regimen
2017 ACC expert pathway defines “statin intolerance” as follows AFTER at least 2-3 trials of
different type statin regimens
-
Tried at least 1 statin prescribed at lowest FDA-approved dose
Tried statin with LESS lipophilicity [PRAVASTATIN; ROSUVASTATIN]
Tried statin with different metabolic pathways
Washout period between each trial (assess new baseline before retrial)
 Reasonable to step down to MODERATE-intensity statin therapy in individuals with intolerable statin
muscle side effects who are otherwise recommended to receive HIGH-intensity statin
 If “statin intolerant” may consider alternative (nondaily) statin dosing
• Expert opinion –no randomized controlled trial data (off-label use; last resort)
• E.g., ATORVASTATIN or ROSUVASTATIN three times weekly (or two times weekly)
Recommendation 6:
•
•
If patient has severe SAMS or objective muscle weakness:
measure creatine kinase (CK)
IF there are symptoms suggesting hepatotoxicity on a statin: measure transaminases (AST; ALT);
bilirubin; alkaline phosphatase

Symptoms of hepatoxicity may include but are not limited to jaundice (yellow skin/sclera); pruritis;
abdominal pain; nausea; vomiting; anorexia; rash
Recommendation 7:
patients at increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver
disease), it is reasonable
to use statins (when indicated) after obtaining baseline
LFT measurements and determining a schedule
of monitoring and safety checks.
e.g., check LFT at 6 -12 weeks after starting or increasing statin dose, then periodically thereafter and/or
if new symptoms
NOT useful to routinely measure CK or LFTs except in these populations
Recommendations 8, 9, 10:
In patients at increased ASCVD risk with severe SAMS or
recurrent SAMS despite appropriate statin rechallenge,
it is reasonable to use RCT proven NONSTATIN therapy
that is likely to provide net clinical benefit
If severe or recurrent
SAMS reasonable to
consider RCT proven
NON-STATIN
No co-Q10
No routine LFT or
CK monitoring
Bempedoic acid (Nexletol)
 Adenosine triphosphate – citrate lyase (ACL) inhibitor
Omega-3 “fish oils”
Warnings
•
•
Hypersensitive to fish or shellfish
Pregnancy (category C) and Lactation
Monitoring
•
•
•
•

ALT/AST periodically if hepatic
impaired
DHA/EPA may increase LDL
Reasonable to evaluate the patient for
gastrointestinal disturbances, skin
changes, and bleeding
Potential for more frequent recurrences
of symptomatic atrial fibrillation or
flutter in patients with atrial fibrillation
• Particularly in first
months of use
Reported Side effects (2-4%)
Increased LDL [EPA/DHA product]
GI disturbances - belching; dyspepsia; taste
perversion; constipation
• Peripheral edema
• Pruritis, rash
• May cause arthralgia/joint pain
• May increase bleeding risk
Drug interaction potential:
-Monitor patients taking drugs affecting
platelet (e.g., aspirin) or anticoagulation
*appears safe with concurrent statin, fibrate, or
niacin but more research needed to review
impact on efficacy
High Dose (4g/day)
o 2 US Products are Rx : do not OPEN, Crush, Dissolve, or Chew oral capsules
 Lovaza – 4g EPA/DHA (ethyl esters) per day – may increase LDL >10%+++ (monitor
LDL)
 Vascepa – 4g EPA (icosapent ethyl) per day – contains NO DHA (no LDL change)
o DOSING: Typically 4g/day (range 2-4g PO daily)
 1 g capsules – SIG: Take 4 caps PO per day
 May be administered 4 cap PO QD OR 2 cap PO BID)
REDUCE-IT trial (VASCEPA)
Excluded patients
• severe heart failure, active severe liver disease, poorly controlled DM
• planned coronary intervention or surgery
• history of acute or chronic pancreatitis; or
• known hypersensitivity to fish, shellfish
Common reported adverse events (5% or more) significantly higher rate than placebo
• Atrial Fibrillation (5.3% vs. 3.9% placebo)
• Peripheral edema (6.5% vs. 5.0% placebo)
• Hospitalization for atrial fibrillation or flutter (3.1% vs. 2.1%, P = 0.004)
Overall rates of serious adverse bleeding
• 2.7% vs. 2.1% in the placebo group (P = 0.06) ; none were fatal.
• No significant differences in rates of hemorrhagic stroke, serious central nervous system, bleeding
or gastrointestinal bleeding
Fibrates:
•
Gemfibrozil (Lopid)
•
DOSE: 600mg PO BID 30 min. before meals
•
Nano-crystals (various generics): TRICOR
•
DOSE: 145mg PO DAILY typical (initial)
•
If “renal impaired” initially 48 mg PO daily only
(and do not exceed initial dose if GFR 30 - 59 mL/min )
Delayed release: TRILIPIX
•
•
Fenofibrate – 2 forms on drug list
Adverse effects
• Dyspepsia
• ↑ Serum Creatinine (SCr)
• Cholelithiasis risk *Gall stones
• Myopathy – w/ or w/o statin
• Hepatotoxicity -↑ ALT
Drug interaction potential
•
RESIN - separate dosing
•
WARFARIN–↑ INR
•
EZETIMIBE–↑ cholelithiasis
•
COLCHICINE –↑ myopathy
ABSOLUTE CONTRAINDICATIONS:
o Active gallbladder disease
o Lactation
o Concurrent statin: avoid GEMFIBROZIL
o Active liver disease (e.g., ALT ≥ 3 x ULN)
o Renal impairment/CKD
 AVOID GEMFIBROZIL all levels of renal impairment (expert opinion)
 AVOID fenofibrate if moderate - severe renal impairment (GFR <30 mL/min)
Warnings/Precautions
o Myopathy/rhabdomyolysis risk, especially with statin therapy
 Particularly in elderly, or DM, or CKD, or hypothyroidism
 Significantly less risk w/ fenofibrate (vs gemfibrozil – see above)
o Pregnancy category C
o Renal impairment
o
 If eGFR 30 - 59 mL/min, lower fenofibrate dose (see product info)
Increased cholesterol into bile cholelithiasis risk
Niacin (vitamin B3 -lipid-modifying doses):
 Immediate-release niacin (IR) – Niacor (and generics)
• LOWER risk of dose-related hepatotoxicity (lessthan SR)
• BID to TID dosing causes poor tolerability and adherence concerns
• Requires SLOW & complex dose titration (increase dose weekly as tolerated )
 Sustained-release niacin (SR) - Slo-Niacin® (and generics)
• HIGHER risk of dose-related hepatotoxicity (this is OTC! AVOID!!)
• Once daily dosing (WITH FOOD) improves tolerability & adherence
• Requires SLOW dose titration (increase dose monthly as tolerated)
 Extended-release niacin (ER) NIASPAN (and generic)
• LOWER risk of dose-related hepatotoxicity (less than SR)
• Once daily dosing (WITH FOOD at HS) improves tolerability & adherence
• Requires SLOW dose titration (increase dose monthly as tolerated)
 ADMINISTRATION: Daily at bedtime; take with low-fat snack
 TITRATION: Must initiate at 500 mg PO daily at bedtime
 Increase dose by no more than 500 mg in any 4-week period
 Max daily dose 2000mg (2g) po HS (do not divide dosing BID)
Absolute contraindications:
• Active liver disease or significant
hepatic dysfunction
• ALT or AST ≥ 3 ULN
• Active peptic ulcer
• Unexplained GI symptoms or newonset weight loss
• Arterial bleeding
• Persistent severe skin symptoms
• Persistent hyperglycemia
• Acute gout
• New-onset atrial fibrillation
Relative contraindications:
 Poorly controlled diabetes
 Past Peptic ulcer
 Hyperuricemia
 Chronic Kidney Disease
 Unstable angina or ACS
Adverse effects
•
GI - Dyspepsia, GI pain, Nausea, Diarrhea (take
•
SKIN - Pruritis, rash, Flushing*
w/food)
* avoid hot, spicy food or alcohol drinks w/dose
* ask MD about Aspirin 81mg po QD ~ 30 min before dose
•
•
•
•
MUSCLE (monitor)
Hyperglycemia (may cause or exacerbate DM)
Hyperuricemia (may cause or exacerbate gout)
Hepatotoxicity (incidence 4% SR vs. 1-2% IR or
ER)
•
Monitor ALT at baseline and “periodically”
Drug interactions (examples)
-RESIN: separate dose 4 to 6 hours
-STATIN: May increase of myopathy and/or hepatoxicity
-FIBRATE: May increase of myopathy and/or hepatoxicity