Assessment and management of Non HDL Cholesterol

1. Dyslipidemia &
Residual Risk
1

2. MostCommonLipidProfileinPatientswithCoronaryArteryDisease(60%)
DyslipidemiaofType 2Diabetes andMetabolic
Syndrome(Atherogenic LipidProfile)
Non-HDL-C
Triglycerides
VLDL
Chylomicrons
TG-richlipoproteinremnants
SmalldenseLDL
Jellinger PS Endocr Pract. 2012; 18(suppl 1);1-78
High TG
Small,
dense LDL
particles
Low HDL-C

3. Study
Prevention
type
Treatment
Diabetic
populatio
n
Coronary risk reduction Events
not
avoided
(%)
Overall
population
Diabetic population (p)
AFCAPS/TexCAPS1 I Lovastatin 155 -37% -43% (NS) 56
Post CABG2 II Lovastatin 116 -13%a -47% (NS) 53
CARE3 II Pravastatin 586 -23% -25% (p=0.05) 75
LIPID4 II Pravastatin 782 -24% -19% (NS) 81
PROSPER5 I/II Pravastatin 623 -15% +27% (NS) NA
ALLHAT-LLT6 I/II Pravastatin 3,638 -12% -11% (NS) 89
4S7 II Simvastatin 202 -32% -55% (p=0.002) 57
HPS8 II Simvastatin 3,051 -24% -18% (p<0.0001) 82
HPS8 I Simvastatin 2,912 -24% -33% (p<0.0003) 66
ASCOT-LLA9 I Atorvastatin 2,352 -36% -16% (NS) 84
CARDS10 I Atorvastatin 2,838 -37% -37% (p=0.001) 63
4D11 I/II Atorvastatin 1,255 -18% -18% (p=0.03) 82
Meta-analysis12 I/II Any 18,686 -21% -23% (p=0.001) 77
MACROvascularresidualrisk in patientswithtype2
diabetes
1. Heart Protection Study Collaborative Group. Lancet 2002;360:7-22. 2. Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383-9. 3. Sever PS et al. Lancet 2003;361:1149-58. 4. Colhoun HM et
al. Lancet 2004;364:685-96. 5. LaRosa JC et al. N Engl J Med. 2005;352:1425-35. 6. Shepherd J et al. Diabetes Care 2006;29:1220-6. 7. Wanner C et al. N Engl J Med. 2005;353:238-48. 8. Knopp RH et al.
Diabetes Care 2006;29:1478-1485. 9. ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007. 10. Cholesterol Treatment Trialists’ Collaboration. Lancet 2008;371:117-25.

4. WhileLDL-CloweringwithstatinsreducesCVrisk,a
substantialresidualriskremains
4
• A meta-analysis of 21
randomized clinical trials
revealed that statin treatment
leaves 78% of the risk of a major
vascular event unaddressed
• A high-dose statin further
reduced the absolute risk of CV
events by only 0.8%
78%
22%
0%
20%
40%
60%
80%
100%
CTT meta-analysis
Relative
risk
of
major
vascular
events
Residual risk of
major vascular
event in statin-
treated patients
CV risk reduction
following statin
treatment
CTT Collaboration. Lancet. 2010;376:1670-81.

5. AggressiveLDL-Cloweringwithmaximaldosesofstatinsdoes
noteliminateresidualCVrisk
5
EvenintensiveLDL-Cloweringwith80mgofatorvastatinreducesabsoluteCVriskby
only2.2%comparedtoatorvastatin10mg
10 mg
(n=5,006)
80 mg
(n=4,995)
TNT
0%
5%
10%
15%
5-yr
risk
major
CV
event
rate
Atorvastatin dose
10.9%
8.7%
2.2% absolute
risk reduction
Residual risk
8.7%
LaRosa JC. N Engl J Med. 2005;352;1425-35.

6. Non-HDL Cholesterol
6

7. PatientsreachingtheLDL-CbutnottheNon-HD-Ctargethavea
32%significanthighercardiovascularrisk
A meta-analysis of statins RCTs. Individual patient data were requested and obtained for 62,154 patients
enrolled in 8 trials, published between 1994 and 2008 to study the association of LDL-C, Non-HDL-C and
Apo-B with risk of cardiovascular events among patients treated with statins
Boekholdt et al. Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients
Treated With Statins A Meta-analysis, JAMA, March 28, 2012—Vol 307, No. 12
Among statin-treated patients, on-treatment levels of LDL-C, Non– HDL-C, and Apo-B were each
associated with risk of future major cardiovascular events, but the strength of this association was
greater for non–HDL-C than for LDL-C and Apo-B

8. Non-HDL-cholesterol
Advantagesasatarget fortreatment
1. Aguiar C et al. Atheroscler Suppl 2015;19:1.
2. Sniderman A et al. J Clin Lipidol 2010;4:152. 3. Nordestgaard BG et al. Eur Heart J 2016;37:1944.
8
Non-HDL-c= Total Cholesterol – HDL-c
• Non-HDL-c includes an assessment of all apo B-containing lipoproteins considered
to be atherogenic (good correlation with apo B)1
• VLDL, IDL, LDL, and even Lp(a)
• Non-HDL-c is an indirect estimate of LDL particle number, and LDL particle number
relates more closely to CVD risk than LDL-c2

9. Non-HDL-cholesterol
Advantagesasatarget fortreatment
1. Aguiar C et al. Atheroscler Suppl 2015;19:1.
2. Sniderman A et al. J Clin Lipidol 2010;4:152. 3. Nordestgaard BG et al. Eur Heart J 2016;37:1944.
9
• Non-HDL-c makes no assumption about the relationship between VLDL-c and TGs
• In T2DM, this relationship can be altered, leading to falsely low LDL-c values as calculated
by the Friedewald formula
• Practical advantages
• Does not require fasting3
• Easily calculated (difference between 2 well standardized assays) and inexpensive (vs apo B)
• Can be used in patients with TG >400 mg/dL (4.5 mmol/L)

10. Disadvantage of using LDL-c is the methodologic
limitation of its calculations using Friedewald´s equation,
which cannot be used in the setting of
hypertriglyceridemia
Friedewald equation
*Valid only when concentrations of triglycerides are less than 4.5 mmol/L (400 mg/dL)
LDL* = (TC) - (HDL-C) - (TG/5)
AACE 2017
 This method is valid only for values obtained during the fasting state and
becomes increasingly inaccurate when TG ≥ 200 mg/dl and invalid when
TG ≥ 400 mg/dl, respectively ( Grade C)

11. Guidelines on dyslipidemia

12. Risk Group AACE 2020 NLA ESC/EAS 2019 CCS 2018 IAS
Extreme LDL-C < 55 mg/dl
NON-HDL-C < 80
mg/dl
Very high LDL-C < 70 mg/dl
NON-HDL-C < 100
mg/dl
LDL-C < 70 mg/dl
NON-HDL-C < 100
mg/dl
LDL-C < 55 mg/dl
(< 1.4 mmol/l)
NON-HDL < 80 mg/dl
(< 2.2 mmol/l)
LDL-C < 2.0
mmol/l).Non-HDL <
2.6 mmol/l
LDL-C < 70 mg/dl
NON-HDL-C < 100
mg/dl
High LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl
LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl
LDL-C < 70 mg/dl
(< 1.8 mmol/l)
NON-HDL < 100 mg/dl
(<2.6 mmol/l)
LDL-C < 2.0
mmol/l).Non-HDL <
2.6 mmol/l
LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl
Moderate LDL-C< 100 mg/dl
NON-HDL-C < 130
mg/dl
LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl
LDL-C < 100 mg/dl
(< 2.6 mmol/l)
NON-HDL < 130 mg/dl
(< 3.4 mmol/l)
LDL-C < 2.0
mmol/l).Non-HDL <
2.6 mmol/l
LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl
Low LDL-C< 130 mg/dl
NON-HDL-C < 160
mg/dl
LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl
LDL-C < 116 mg/dl
(< 3 mmol/l)
Guidelines with Targets
Secondary
Prevention
Primary
Prevention

13. Non-HDL-cholesterol ESC/EAS guidelines
13

14. Non-HDL-cholesterol ESC/EAS guidelines
14
Mach F et al. Eur Heart J 2019 Aug 31.

15. • LDL-C has been, and remains, the main focus of efforts to improve
lipid profiles in individuals at risk for ASCVD.
• However, because an isolated focus on LDL-C is not always
sufficient to prevent ASCVD in at-risk individuals or to treat
existing atherosclerosis, goals for non-HDL-C, apo B, and
triglycerides are also included in the risk assessment and goals
• Non-HDL (total cholesterol minus HDL-C) reflects the total
atherogenic burden, including particles contained within very-low-
density lipoproteins (VLDL), intermediate-density lipoproteins
(IDL), and LDL as well as chylomicron remnants and Lp(a). 15
NonHDLCholesterol2020AACEGuidelines
Lipid Management Algorithm, Endocr Pract. 2020;26(No. 10)

16. NonHDLCholesterol2020AACEGuidelines1
1- AACE/ACE MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE ALGORITHMDOI 10.4158/CS-2020-0490
2- Jellinger et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE, NDOCRINE PRACTICE Vol 23 (Suppl 2)
April 2017
The Non-HDL-C (total cholesterol – HDL-C) should be calculated to assist risk stratification in
individuals with moderately elevated TG (200 to 500 mg/dL), Diabetes, and/or
established ASCVD (Grade B, Bel 2)2

17. ConsensusClinicalRecommendationsforthemanagementofPlasma
lipiddisordersintheMiddleEast
Nasreen A. Sayed et al. Consensus clinical recommendations for the management of plasma lipid disorders in the middle East, int J. of Cardio, 15 Dec 2015

18. ConsensusClinicalRecommendationsforthemanagementofPlasma
lipiddisordersintheMiddleEast
Nasreen A. Sayed et al. Consensus clinical recommendations for the management of plasma lipid disorders in the middle East, int J. of Cardio, 15 Dec 2015

19. Triglycerides as an
independent risk factor
19

20. ClassificationofElevatedTriglycerideLevels
TG category TG concentration (mg/dL) TG goal
Normal <150
<150 mg/dL
Borderline high 150-199
High 200-499
Very high ≥500
TG levels that are even moderately elevated (≥150 mg/dL) may identify individuals at
risk for the insulin resistance syndrome. TG levels ≥200 mg/dL may indicate a
substantial increase in ASCVD risk. Hypertriglyceridemia is also commonly associated
with a procoagulant state and hypertension.
Einhorn D, et al. Endocr Pract. 2003;9:237-252; Frick MH, et al. NEJM. 1987;317:1237-1245; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr
Practice. 2017;23(4):479-497; Keech A, et al. Lancet. 2005;366:1849-1861; NHLBI. NIH Publication No. 02-5215. 2002; Tenaknen L, et al. Arch Intern
Med. 2006;166:743-748.
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; TG, triglycerides.

21. 21
Duran et al. JACC VOL. 75, NO. 17, 2020 MAY 5, 2020:2122–35
 TRL-C strongly associates with future
MI and Peripheral Artery Disease
events, whereas sdLDL-C strongly
associates with MI alone.
A prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk
associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). The purpose of this study was to prospectively
evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD)
outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD).

22. TG is independently and significantlyassociated
with CAD
There is a strongly increased risk for
premature familial CAD with elevated
plasma TGs. Importantly, this excess risk
begins at a mild and relatively common
TG elevation of just 200 mg/dl, and is
independent of plasma HDL-cholesterol,
other elements of the metabolic syndrome,
and other CAD risk factors.
22
Summary of (CAD) coronary artery disease risk (odds ratios and 95% confidence intervals) associated with commonly used
cut points. Risks were estimated simultaneously in a multiple logistic regression model adjusting for age, gender, hypertension,
diabetes, serum albumin, bilirubin, creatinine, and low-density lipoprotein cholesterol.
Hopkins PN. Et al. J Am. Coll Cardiology 2005; 45:1003-1012
Aim of the study was to explore contributions of plasma total triglycerides (TGs) and type III hyperlipidemia to the risk of premature familial coronary artery disease (CAD). Lipids
were analyzed by ultracentrifugation in a series of 653 cases with premature familial CAD (myocardial infarction or revascularization by age 55 years in men or age 65 years in
women, with similar onset in at least one other first-degree relative) and in 1,029 control subjects.

23. Fenofibrate in
hypertrigyceridemia
23

24. Fenofibrate: Optimizing CVDoutcomes in T2DM
1. Keech A et al. Lancet 2005;366:1849.
2. Scott R et al. Diabetes Care 2009;32:493. 3. Ginsberg HN et al. N Engl J Med 2010;362:1563.
4. FDA Endocrinologic and Metabolic Drugs Advisory Committee Meeting. 19 May 2011.
24
aPost-hoc analysis of data from the FIELD trial2; bPre-specified subgroup analysis for ACCORD Lipid trial
Trial Patient population Outcomes
FIELD1,2 9795 patients with T2DM
• 22% patients with CVD
All patients
Baseline median TG levels of
1.7 mmol/L
Non-fatal MI + CHD death
RRR 11% (p=0.16)
Patients with TG ≥2.30 mmol/L
and HDL <1.30/1.29 mmol/L
men/womena
Total CV events (CV deaths, MI,
stroke, revascularisation)
RRR 27% (p=0.005)
ACCORD
Lipid3,4
5518 patients with T2DM
• 37% patients with CVD
All patients
Baseline median TG levels of
1.8 mmol/L
CVD death, non-fatal MI +
non-fatal stroke
RRR 8% (p=0.32)
Patients with TG ≥2.3 mmol/L and
HDL-c ≤0.9 mmol/Lb
CVD death, non-fatal MI +
non-fatal stroke
RRR 31% (p=0.032)
NNT5=20
NNT5=23
C, cholesterol. CHD, coronary heart disease. CVD, cardiovascular disease. HDL, high density lipoprotein.
MI, myocardial infarction. NNT5, number needed to treat for 5 years. T2DM, type 2 diabetes mellitus. TG, triglycerides.

25. Astatin with fenofibratereduced therisk ofmajorCV
eventsindyslipidaemia patientswith Type 2Diabetes 1
1- Elam MB et al. JAMA Cardiol 2017;2:370
25
CVD risk reduction in patients with dyslipidaemia and Type 2 Diabetes (Post-trial follow up of ACCORD Lipid
Study)
ACCORDION: 4644 survivors of ACCORD consented to an additional 5 years non treatment, observation-only study
(mean total follow-up 9.0 years). Only 144 ACCORDION participants (4.3%) were continued or started on fibrate
therapy following completion of ACCORD.
0
5
10
15
20
25
30
CVD
events,
%
a
HDL >34 mg/dL (0.9 mmol/L)
TG <204 mg/dL (2.3 mmol/L)
RRR: 27% (Pint=0.05)
All Patients
Fenofibrate–simvastatin
Simvastatin
19.73
18.55 18.15
18.31
20.54
26.65
HDL ≤34 mg/dL
TG ≥204 mg/dL

26. -31 -30
-40
9
-31
-37
-50
-46
22
-41
-60
-50
-40
-30
-20
-10
0
10
20
30 TC TG HDL-c
LDL-c Apo-B
* *
*†
*†
*
*†
*‡
*
*†
* P< 0.0001 vs Baseline
‡P < 0.05 vs. atorvastatin
†P < 0.05 vs. both monotherapies
1-Athyros VG et al. Diabetes Care 2002;25:1198
Combined treatment reduced the 10 year probability for Myocardial Infarction from 21.6to
4.2%
AcombinationofFenofibratewithAtorvastatin
improvedalllipidparameters1
ATHYROS: 120 patients with T2DM and no known CHD, treated with
atorvastatin 20 mg od or micronized fenofibrate 200 mg od or both for 24
weeks.

27. Lessthanonecaseofrhabdomyolysisforfenofibrate
permillionco-prescriptionswithastatin
Number of reports of rhabdomyolysis
per million prescriptions in combination
with statin (excluding cerivastatin)
0.58
8.6
Fenofibrate
Gemfibrozil
Number
of
cases
reported
per
million
prescriptions
0
10
5
1
2
3
4
6
7
8
9
6,641,000
prescriptions
dispensed
3,419,000
prescriptions
dispensed
1- Jones PH and Davidson MH. Am J Cardiol 2005;95:120-2; 2. Kyrklund C et al. Clin Pharmacol Ther 2003;73:538 –544; 3. Kyrklund C et al., Clin Pharmacol Ther 2001;69:340 –345; 4. Backman Jt et al. Clin Pharmacol Ther 2002;72: 685–
691, 5. Schneck DW et al., Clin Pharmacol Ther 2004; 75:455– 463, 6.Evans M et al. Opin Lipidol 2002;13:415–420.7. Davidson et al. Am JCardiol 1997;79:38 – 42; 8.Staffa, N Engl J Med 2002;346:539 –540.
Fenofibrate resulted in a 15 times
lower rhabdomyolysis reporting
rate than did gemfibrozil as
reported in a FDA safety report 1
15 times
lower
Clinical studies on the interactions of statins with
fibrates have shown that gemfibrozil use results in
higher plasma concentrations of Statins. 2-5
Because myotoxicity induced by statins depends on
dose,6-8 inhibition of statin elimination by
gemfibrozil may be expected to increase statin
myotoxicity.

28. SafetyofFenofibrate–StatincombinationintheGuidelines
Francois Mach, Colin Baigent, Alberico L. Catapano et al. European Heart Journal, 2019 ESC/EAS guidelines

29. TheuseofFenofibrateinHypertriglyceridemia,ESC2019
Francois Mach, Colin Baigent, Alberico L. Catapano et al. European Heart Journal, 2019 ESC/EAS guidelines

30. AACE2020-DyslipidemiaAlgorithm
Alan J. Garber, Yehuda Handelsman,, George Grunberger et al. consensus statement by the American Association of Clinical Endocrinologists and American college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2020 executive summary,
ENDOCRINE PRACTICE Vol 26 No. 1 January 2020

31. Prescription Omega-3
EPA+DHA
31

32. Afavorableeffectofthecombinationonthelipidprofile
200 subjects
(97 subjects in the ATOMEGA
group and 103 subjects in the
atorvastatin group) were included
in full analysis set population for
evaluating the efficacy endpoints.
*P<0.05, ** P<0.001
for the difference between ATOMEGA and atorvastatin
group.
Mean
percent
change
after
8
weeks
of
treatment,
%
3.6 4.9 3.8
6.5
2.6
4.9
1
3
-29.8
-10.1
-6.1
-1.9
6.4
-30.1
-3.2 -3.1
-40
-30
-20
-10
0
10
20
30
ATOMEGA
Atorvastatin
LDL-c
Non-HDL-c TC
TG HDL-c ApoB
ApoA-I
VLDL-c
**
**
**
**
* *
The combination has greater effect in reducing TG and Non-HDL-c
Total Cholesterol (TC), High Density Lipoprotein Cholesterol (HDL-C), Very
Change in lipid and lipoprotein levels after 8 weeks of treatment

33. PatientswithDiabetes benefitedfromthecombination
intermsofTGand Non-HDL reduction
Triglycerides (TG), Non-High Density Lipoprotein Cholesterol (Non
C)
TG
*P<0.001
Only the ATOMEGA combination significantly reduced
TG and Non-HDL-C levels in subjects with DM after 8
weeks of treatment, while atorvastatin slightly
increased TG and Non-HDL-C levels compared to
baseline
Non-HDL-C
Atorvastatin
ATOMEGA
6.4% 6.7%
-31.3%
-11.1%
-35%
-30%
-25%
-20%
-15%
-10%
-5%
0%
5%
10%
*
*
Patients With Diabetes
change
%

34. Omega-3–Rosuvastatincombination
1. Kim CH et al. Clin Ther 2018;40:83
34
Change in lipid and lipoprotein levels after 8 weeks of treatment1
ROMANTIC: 201 patients at high Cardiovascular Disease risk with TG 200-499 mg/dL (2.3-5.6 mmol/L)
despite rosuvastatin 20 mg od were randomized to rosuvastatin 20 mg od + 4 g ω-3 od or rosuvastatin 20 mg
od (double-blind)
Mean
percent
change
after
8
weeks
of
treatment,
%
p<0.001
-11.4
-2.2 -1.2
4.3
2.8
-12.2
-0.5
0.3
-26.3
-10.7
-8.1
1.8 0.9
-28.5
-1.5
-3.4
-40
-30
-20
-10
0
10
20
30
ω-3 + rosuvastatin
Rosuvastatin
LDL-c
Non-HDL-c TC
TG HDL-c ApoB ApoA-I
VLDL-c
p<0.001
p=0.001 p=0.004 p=0.009 p=0.049
VLDL -c = Very Low Density Lipoprotein – Cholesterol, ω-3 = Omega-3, LDL-C = Low Density Lipoprotein Choles
HDL-c = High Density Lipoprotein-Cholesterol , TG = Triglycerides, Apo-B(A-I) = Apolipoprotein B (A-I)

35. -9.4
-16.8
-25.4
-29.5
-40
-30
-20
-10
0
10
20
30
p=0.002 p=0.045
Patients with DM
ω-3 + rosuvastatin
Rosuvastatin
TG reduction
Patients without DM
The ROSUMEGA group had a greater
reduction in TG levels after 8 weeks
compared with the rosuvastatin group
regardless of the presence of DM
Hypertriglyceridemia is known as an independent risk factor associated with cardiovascular event 1-3
1- Freiberg JJ,et al. JAMA. 2008;300:2142–2152.
2- Labreuche J et alAtherosclerosis. 2009;203:331–345.
3- Sarwar N et al. Circulation. 2007;115:450–458.
The most important treatment in patients with dyslipidemia is statins, which mainly lowers LDL-C
However, statins do not control TG levels effectively
DM= Diabetes Mellitus, ω-3 = Omega-3, LDL-C = Low Density Lipoprotein Cholesterol, TG = Triglycerides
1. Kim CH et al. Clin Ther 2018;40:83
Omega-3–Rosuvastatincombination

36. -1.6
-3.8
-12.6
-4.3
-20
-10
0
10
20
30
p=0.002 p=0.250
Patients with DM
ω-3 + rosuvastatin
Rosuvastatin
Non-HDL reduction
Patients without DM
In patients with DM, ROSUMEGA had a greater
lowering effect on non–HDL-C than rosuvastatin but
in patients without DM, ROSUMEGA had similar
effects on non-HDL-C as rosuvastatin
Non–HDL-C is a more inclusive measure of all atherogenic Apo B containing lipoproteins :VLDL-C, IDL-C,
chylomicron remnants, lipoprotein A and LDL-C.
It serves as a strong predictor of
cardiovascular disease in patients with
DM*
*Lu W et al. Diabetes Care. 2003;26:16–23.
VLDL -c = Very Low Density Lipoprotein – Cholesterol, ω-3 = Omega-3, LDL-C = Low Density Lipoprotein Cholesterol, DM = Diabete
HDL-c = High Density Lipoprotein-Cholesterol, IDL= Intermediate Density Lipoprotein, Apo-B= Apolipoprotein B
1. Kim CH et al. Clin Ther 2018;40:83
Omega-3–Rosuvastatincombination

37. Supplement fishoilvsPrescription Omega-3
AACE 2017 : Dietary fish oil supplements are not FDA-approved for treatment of hypertriglyceridemia
and generally are not recommended for this purpose. (Grade A, BEL 1).
EPA & DHA as Triacylglycerols
Contains up to 30% EPA & DHA
Rapidly degraded in the duodenum
Short acting
EPA & DHA as Ethyl esters
1 capsule Contains 90% EPA & DHA
Covering 24 hrs
Sustained release, Absorbed more slowly
FDA approved prescription Omega-3
Omega-3 supplements

38. Improved patientprognosispost-MI
In GISSI-Prevenzione a multicenter randomized double blind placebo controlled trial,
Omega-3 (EPA +DHA) was given as an adjuvant treatment in secondary prevention after MI
(within 90 days) in addition to standard therapy (1g per day, n= 11,324 patients)
38
Benefits on cardiovascular outcomes compared with control (% risk reduction)
GISSI-Prevenzione Investigators. Lancet 1999;354:447-455.

39. EPA vs DHA Monotherapy and Triglycerides:
DHA reduces TG significantly more than EPA
Wei MY and Jacobson TA. Curr Athero Reports 2011 (online10/6/11)
Mean Difference in TG
(95%CI)

40. Wei MY and Jacobson TA. Curr Athero Reports 2011 (online10/6/11)
Mean Difference in HDL
(95%CI)
EPA vs DHA Monotherapy and HDL-C:
DHA “Trends” to raise HDL-C more than EPA

41. RxEPA/DHA Rx onLDLParticleSize:
inDiabetic Dyslipidemia
• N=51 T2DM patients
• Persistent fasting TG level (>200 mg/dL) and LDL-C level (>100 mg/dL) ≥6m statin
•Rx either Rx EPA/DHA 4g, 2 g, or no drug for 8 weeks (background statin Rx).
Lee et al. Diabetes Metab J 2013;37:207

42. Combinationtherapywithstatinsandn-3PUFAisassociatedwitha
relevantbenefitintermsofclinicaloutcomesinpatients
dischargedafterMI.
Retrospective cohort study that used linked hospital discharge, prescription databases and vital
statistics containing information on 14,704 patients who were discharged for MI between 1/2003
and 12/2003 in 117 hospitals in Italy.
42
Exploratory AnalysisontheUseof Statins withorwithoutn-3PUFAand
Major Eventsin Patients Discharged forAcuteMyocardial Infarction:An
Observational RetrospectiveStudy
A. Macchia, M. Romero, A. D’Ettorre et al. Exploratory Analysis on the Use of Statins with or without n-3 PUFA and Major Events in Patients Discharged for Acute Myocardial Infarction: An Observational Retrospective Study, Open access PLOS one May 2013 | Volume 8 | Issue 5 | e62772

43. PlasmaPhospholipidLong-ChainOmega-3FattyAcidsandTotalandCause-
SpecificMortalityinOlderAdults: theCardiovascularHealthStudy
•Objective:
To investigate associations of plasma phospholipid EPA, DPA, DHA, and
total ω3-PUFA levels with total and cause-specific mortality among
healthy older adults not receiving supplements.
•Design: Prospective cohort study.
•Participants:
2692 U.S. adults aged 74 years (±5 years) without prevalent coronary
heart disease (CHD), stroke, or heart failure at baseline
•Measurements:
Phospholipid fatty acid levels and cardiovascular risk factors were
measured in 1992. Relationships with total and cause-specific mortality
and incident fatal or nonfatal CHD and stroke through 2008 were
assessed.
Results:
During 30 829 person-years, 1625 deaths (including 570
cardiovascular deaths).
After adjustment, higher plasma levels of ω3-PUFA
biomarkers were associated with lower total mortality,
with extreme-quintile hazard ratios of
• 0.83 for EPA (95% CI, 0.71 to 0.98; P for trend =
0.005),
• 0.77 for DPA (CI, 0.66 to 0.90; P for trend = 0.008),
• 0.80 for DHA (CI, 0.67 to 0.94; P for trend = 0.006), and
• 0.73 for total ω3-PUFAs (CI, 0.61 to 0.86; P for trend <
0.001)
• Lower risk was largely attributable to fewer cardiovascular
than non-cardiovascular deaths
Conclusions— Higher circulating individual and total ω3-PUFA
levels are associated with lower total mortality, especially CHD
Mozaffarian D, Lemaitre RN, et al. Ann Intern Med. 2013 Apr 2;158(7):515-25.
-17% RRR
-20% RRR
-27% RRR
EPA
DHA

44. 44
Skulas-Ray AC et al. Circulation 2019 Aug 19
Prescription n-3 FAs (EPA+DHA or EPA-
only) at a dose of 4 g/d (>3 g/d total
EPA+DHA) are an effective and safe option
for reducing triglycerides as monotherapy or
as an adjunct to other lipid-lowering agents.
All prescription agents appear comparably
effective, but head-to-head comparisons are
lacking
AHAScienceAdvisory
In patients with very high TG treated with prescription EPA
+DHA products LDL-C increased by 15 to 36 %.
However there was no increase in Apo-B suggesting that the
increase in LDL-C may reflect an increase in the average size
of LDL particles rather than an increase in LDL particle
concentration

45. AHA Science Advisory 2019
Concerns have been raised that DHA-containing prescription agents may raise
LDL-C in patients with HTG. We identified 9 trials of patients with HTG that
reported effects on LDL-C with 4 g/d of DHA containing prescription n-3 FA (8
studies of O3AEE and 1 study of O3CA).
In 8 of these 9 studies, there was no change in LDL-C versus placebo (4 of
which used n-3 FA as an adjunct to statin therapy), whereas in 1 study, the
median LDL-C was marginally increased by 3.5% versus placebo (P=0.052).31
This is similar to the change reported in REDUCE-IT, with a median increase in
LDL-C of 3.1% from baseline (P<0.001) for EPA-only.
45
Skulas-Ray AC et al. Circulation 2019 Aug 19

46. 46
Ikizler TA, Burrowes JD, Byham-Gray LD, et al; KDOQI Nutrition in CKD Guideline Work Group. KDOQI clinical practice guideline for nutrition in CKD: 2020 update. Am J Kidney Dis. 2020;76(3)(suppl 1):S1-S107.