Diabetic Dyslipidemia By Dr. Usama Ragab Youssif ISMA CME Activity 2021 In Tolip EL Galala Hotel ----------- Introduction Physiology of lipid metabolism Pathophysiology of diabetic dyslipidemia Statin therapy (+/- ezetimibe) evidence and translation of evidence Residual CV risk: excess TG EPA therapy evidence and translation of evidence

1. Diabetic Dyslipidemia
Usama Ragab Youssif, MD
Lecturer of Medicine
Zagazig University

2. Agenda
• Introduction
• Physiology of lipid metabolism
• Pathophysiology of diabetic dyslipidemia
• Statin therapy (+/- ezetimibe) evidence and
translation of evidence
• Residual CV risk: excess TG
• EPA therapy evidence and translation of
evidence
• Final bottom line

3. Represents 2 million people.
Diabetes is mostly (85–95%) T2D.1
• T2D approximately doubles the risk
of death2
• Diabetes caused 4.9 million deaths
in 20141
• CVD is the principal cause of death
in T2D2,3
1.76
1.85
1 1.5 2.0
T2D is increasingly prevalent and CVD is the leading
cause of death in this population
3
1. IDF Diabetes Atlas, 2019. 9th Edition. http://www.idf.org/diabetesatlas.
2. Nwaneri et al. Br J Diabetes Vasc Dis 2013;13:192–207. 3. Morrish et al. Diabetologia 2001;44(suppl 2):S14–21.
• Globally, 463 million people are living
with diabetes1
• Rising to 700 million by 20451
Relative risk for
all-cause mortality
Relative risk for
CV mortality

4. Key manifestations of CV disease
4
1. World Health Organization 2015: http://www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf?ua=1
2. http://www.heart.org/HEARTORG/Caregiver/Resources/WhatisCardiovascularDisease/What-is-Cardiovascular-Disease_UCM_301852_Article.jsp#
Peripheral arterial
disease
Disease of blood vessels
supplying arms and legs1
Coronary
heart disease
Disease of blood vessels
supplying heart muscle1
Stroke
Caused by disruption of blood
supply to the brain1
Heart failure
Failure of the heart to pump
blood with normal efficiency
(sometimes called congestive
heart failure)2

5. The “common soil” from which type 2
diabetes and cardiovascular disease arise

6. Diabetes is
ASCVD risk
equivalent
N Engl J Med 1998;339:229-34.

7. Modifiable CV risk factors are common in patients
with T2D1,2
7
Almost a third of diabetes patients were current smokers2
1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93.

8. Plasma lipids
Because they are not water soluble, lipids are
transported in the plasma in association with
proteins.
They circulate in complexes known as
lipoproteins.
These consist of a non-polar core of
triglycerides and cholesteryl esters surrounded
by a surface layer of phospholipids, cholesterol
and proteins known as apolipoproteins

9. Lipoproteins
• Lipoproteins are classified by their densities as
demonstrated by their ultracentrifugal separation.
• Density increases from chylomicrons (of lowest
density) through lipoproteins of very-low-density
(VLDL), intermediate density (IDL) and low-density
(LDL), to high-density lipoprotein (HDL)

10. • ApoB lipoprotein (Non HDL)
• ApoA-1 lipoprotein (HDL)

11. Functions of apoproteins
Apolipoproteins Lipoproteins Functions
Apo A-I HDL Activator for LCAT
Structural in HDL
Apo A-II HDL Inhibits HTGL at high concentrations
Structural in HDL
Apo B-48 CM and CM remnants Structural in CM
Legend for CM remnants receptors in liver
Apo B-100 LDL – VLDL – IDL Structural in LDL and VLDL
Legend for LDL receptors
Apo C-II CM – VLDL – HDL Activator of LPL
Apo C-III HDL Inhibit LPL
Inhibit clearance of CM and VLDL remnants
Apo D HDL May act as lipid transfer protein
Apo E CM – CM remnants – VLDL – HDL Binding to LDL and remnants receptors

12. Chylomicrons
= Exogenous
pathway of
the lipid

13. VLDL =
Endogenous
pathway of
the lipid

15. LDL-C

16. HDL-c
HDL’s Atheroprotective role:
• Reverse Cholesterol transport
• Antioxidant properities

17. CHO/LDL/TG
TC = LDL + HDL + VLDL
LDL = TC – HDL – VLDL * VLDL = 20% of all TG
LDL = TC – HDL – TG/5
This is called Friedewald equation
BUT: Valid with TG up to 400 mg/dL

18. What is the
problem?

19. Verschuren WMM et al. JAMA. 1995;274:131-136

20. LDL is causal of atherosclerosis
Evidence from meta-analyses of Mendelian randomization studies,
prospective cohort studies, and randomized controlled trials unequivocally
establishes that LDL causes ASCVD.
Ference BA et al., Eur Heart J. 2017;38(32):2459-2472
Mendelian randomization studies
Median follow-up: 52 years
N=194,427
Prospective cohort studies
Median follow-up: 12 years
N=403,501
Randomized controlled trials
Median follow-up: 5 years
N=196,552

21. Natural history of the condition
should be adequately understood.
No Symptoms + Symptoms
Lesion: Initiation
Ischemic Heart
Disease
Cerebrovascular
Disease
Peripheral Vascular
Disease
Symptoms
Reversible + Reversible Non - Reversible
 Progression  + Stable
Years

22. Endothelial dysfunction drives atherosclerotic
progression
Figure adapted from Libby. Circulation 2001;104:365‒72.
Zeadin et al. Can J Diabetes 2013;37:345e350.
Atherosclerosis is accelerated in T2D by hyperglycaemia, insulin resistance, inflammation
and diabetic dyslipidaemia

23. We Should look for
the risk…

27. ASCVD risk categories

28. Where is the
problem in
diabetes?

29. Hepatic triglyceride (TG) content determines the type of VLDL particles secreted.
Insulin resistance
increased FA and
glucose flux to liver
Increased
VLDL
Insulin resistance
and decreased
apo-B degradation IR impairs
LDLR

30. Overproduction of TG-rich lipoproteins
creates small dense LDL
• Production of VLDL and
chylomicrons (TG-rich
lipoproteins (TRLs)) is stimulated
in individuals with type 2
diabetes.
• The long residence time of TRLs
in circulation promotes
excessive transfer of TG to LDL
and a concomitant transfer of
cholesteryl esters (CE) to TRLs
via the action of CETP.
• Hepatic TG lipase-mediated
hydrolysis of core TG produces
cholesterol-poor LDL particles
(small dense LDL).

31. Lipid
metabolism in
the setting of
insulin
resistance

32. Increased Atherogenicity of sd-LDL
Direct association
• Longer residence time in plasma than
normal sized LDL due to lower binding
affinity to LDL receptors in liver
• Better penetration of arterial wall =
Magic bullet
• Enhanced interaction with scavenger
receptor promoting foam cell
formation
• Weaker resistance to oxidative stress
• Endothelial cell dysfunction
Indirect association
• Inverse relationship with HDL
• Marker for atherogenic TG remnant
accumulation
• Insulin resistance

34. Protect your
patient with
diabetes

37. LDL lowering dugs
• Statin, Ezetimibe, BAS, PCSK9i
• Bempedoic acid
Increase LDL Removal
• MTP inhibitors
• Antisense oligonucleotides
Decrease LDL
Production
• CETP inhibitors
Inhibit Cholesterol
Exchange Between LDL
& HDL

38. Statins therapy

39. Key lessons From
Statin Trials (data
from 170 000
participants in 26
randomised trials)
Reduction of LDL cholesterol
by 2–3 mmol/L would reduce
risk by about 40–50%
Cholesterol Treatment Trialists' (CTT) Collaborators, Lancet. 2012 Aug 11; 380(9841): 581–590.

40. Different
Statins

41. Comparable Efficacy of
Statins
• Rosuvastatin ranked 1st in LDL-
C, ApoB-lowering efficacy and
ApoA1-increasing efficacy.
Cardiovascular therapeutics. 2020 Apr 23;2020.

42. Comparison of low density lipoprotein cholesterol (LDL-C) reduction effects of statins

43. Rosuvastatin for
Primary Prevention of CVD

44. Rosuvastatin 20 mg (N=8901) MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
4-week
run-in
Ridker et al, Circulation 2003;108:2292-2297.
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
JUPITER
Trial Design
Placebo (N=8901)
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela

45. 0
1
2
3
4
5
hsCRP
(mg/L)
0
20
40
60
80
100
120
140
LDL
(mg/dL)
Months
0 12 24 36 48
0
10
20
30
40
50
60
0
20
40
60
80
100
120
140
0 12 24 36 48
TG
(mg/dL)
HDL
(mg/dL) Months
JUPITER
Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP
LDL decrease 50 percent at 12 months
hsCRP decrease 37 percent at 12 months
HDL increase 4 percent at 12 months
TG decrease 17 percent at 12 months

46. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
Cumulative
Incidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

47. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
Placebo 251 / 8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Number Needed to Treat (NNT5) = 25
- 44 %
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
Cumulative
Incidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

48. JUPITER
Myocardial Infarction, Stroke, Cardiovascular Death
Placebo (N = 157)
Rosuvastatin (N = 83)
HR 0.53, 95%CI 0.40-0.69
P < 0.00001
- 47 %
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
Cumulative
Incidence
Number at Risk
Follow-up (years)
Rosuvastatin
Placebo
8,901 8,643 8,437 6,571 3,921 1,979 1,370 998 551 159
8,901 8,633 8,381 6,542 3,918 1,992 1,365 979 550 181

49. JUPITER
Arterial Revascularization / Unstable Angina
Placebo (N = 143)
Rosuvastatin (N = 76)
HR 0.53, 95%CI 0.40-0.70
P < 0.00001
- 47 %
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cumulative
Incidence
Number at Risk
Follow-up (years)
Rosuvastatin
Placebo
8,901 8,640 8,426 6,550 3,905 1,966 1,359 989 547 158
8,901 8,641 8,390 6,542 3,895 1,977 1,346 963 538 176

50. JUPITER
Secondary Endpoint – All Cause Mortality
Placebo 247 / 8901
Rosuvastatin 198 / 8901
HR 0.80, 95%CI 0.67-0.97
P= 0.02
- 20 %
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cumulative
Incidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227
8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

51. What about getting more
benefit?
Rosuvastatin + Ezitimibe
Combo

52. Ezetimibe
Inhibits
Absorption of
Cholesterol
from SI

53. Combination Therapy
Am J Cardiol 2007;99:673–680

54. Figure 1
American Journal of Cardiology 2007 99673-680DOI: (10.1016/j.amjcard.2006.10.022)
Copyright © 2007 Elsevier Inc. Terms and Conditions

55. Figure 2
American Journal of Cardiology 2007 99673-680DOI: (10.1016/j.amjcard.2006.10.022)
Copyright © 2007 Elsevier Inc. Terms and Conditions

56. Combination Therapy
Am J Cardiol 2011;108:523–530

57. Combo Treatment • Attainment of prespecified LDL cholesterol targets or LDL-c
below 70 mg/dL after 6 weeks of therapy.
Am J Cardiol 2011;108:523–530

58. • Co-administration of rosuvastatin 10 or 20 mg plus
ezetimibe achieved significant improvements in
lipid profiles in high-risk patients vs. simvastatin 40
or 80 mg plus ezetimibe.

60. • In the Gravity Study, comparator arms were simvastatin + ezetimibe
40mg/10 mg and 80mg/10mg which reduced LDL-C by 55% and 57%
respectively.

61. • In the Gravity Study, comparator arms were simvastatin + ezetimibe
40mg/10 mg and 80mg/10mg which reduced LDL-C by 55% and 57%
respectively.

62. FDA Approvel for Rosuvastatin +
Ezetimib single pill combination

63. What about this
combo in
atherosclerosis
regression?

65. Less is the best…
There is no too
Low..

66. Even below LDL-c target further LDL-c reduction gives
additional CV benefit
A quarter of a century of
treating LDL-C
0
20
40
60
80
100
120
140
160
180
200
High is bad
Average is not good
Lower is better
Even lower is even better
Lowest is best
1994 1996-2002 2004-2005 2015 2017
TNT
mg/dL

67. Lowering LDL-c to very low levels is safe
Exploratory analysis in FOURIER trial
0
5
10
15
20
25
Serious AE Stopping study drug due to AE
Incidence
(%)
Safety outcomes at 4 weeks
N=504, median [IQR] LDL-c: 0.18 [0.13-0.23] mM, 7 [5-9] mg/dL
>2.6 mM
<0.26 mM (<10 mg/dL)
HR: 0.94
(95%CI: 0.74-1.20)
P=0.61
HR: 1.08
(95%CI: 0.63-1.85)
P=0.78
Giuliano RP et al., Lancet. 2017;390(10106):1962-1971

68. Even below LDL-c target further LDL-c reduction gives
additional CV benefit
1,00
0.71
0.64
0.58 0.56
0.51
0.44
0
0.2
0.4
0.6
0.8
1
>175 150 - 175 125 - 150 100 - 125 75 - 100 50 - 75 < 50
adjusted
HR
(95%CI)*
> 4.52 3.88 - 4.52 3.23 - 3.88 2.58 - 3.23 1.94 - 2.58 1.29 - 1.94 < 1.29
(0,53-0,79)
(0,48-0,69) (0,46-0,67)
(0,42-0,62)
(0,35-0,55)
mg/dL
mmol/L
(Ref.)
(0,56-0,89)
Risk for Major CV Events by Achieved on-Trial LDL-C levels
Boekholdt et al. JACC 2014; 64: 485-494
* Adjusted for sex, age, smoking status, presence of DM, SBP, HDL-C and trial

69. Statin therapy is remarkably safe
Mach F et al., Eur Heart J. 2018;39(27):2526-2539, Collins R et al., Lancet. 2016; 388(10059):2532-2561
NO evidence to support adverse effects of statins on:
Cognitive function, clinically significant renal deterioration, risk of cataract and risk of
haemorrhagic stroke in patients without prior stroke
Typically, treating 10.000 patients for 5 years with a standard statin
regimen, is expected
to prevent:
1000 major vascular events (secondary prevention)
500 major vascular events (primary prevention)
to cause:
5 cases of myopathy
50-100 new cases of diabetes
5-10 hemorrhagic strokes (in those with prior stroke)
50-100 patients may experience symptomatic adverse events such as muscle
pain or weakness. Placebo-controlled randomized trials show that almost all of
these cases are misattributed.

70. The established
CV benefit of
statin therapy far
outweigh the
risk of any such
adverse event
Eur Heart J. 2018 Jul 14; 39(27): 2526–2539.

71. What is the position of
statin and Statin +
Ezetimibe in
guidelines?

72. Primary Prevention

73. Secondary Prevention

77. AACE point of view

80. What about
triglycerides?

81. Triglycerides

82. Triglycerides a Causal Risk Factor?
Adapted with permission from Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J. 2015;36:774-776.
Causal risk factors?
Bystanders?
Triglyceride-rich
lipoproteins
ApoC3
HDL-C
ApoA1

83. The PROVE IT-TIMI 22 trial
TG ≥150 mg/dL Predicts Higher
CHD Risk in Statin patients with
LDL-C <70 mg/dL
(n=4162)
Miller M et al. J Am Coll Cardiol. 2008;51:724-30

84. Most ↑↑↑ in TG is secondary
• Don’t forget primary genetic causes, but rare…
Disease Drugs Diet
Hypothyroidism
Diabetes mellitus
(Poorly controlled)
Central obesity
Renal diseases
Nephrotic syndrome
Autoimmune disorders e.g. SLE
HIV- associated dyslipidemia
Pregnancy (the third trimester)
Beta-blockers (nonselective)
Thiazides
Corticosteroids
Tamoxifen, Raloxifene
Estrogens (oral, not transdermal)
(e.g. COC, HRT)
Protease inhibitors
Sirolimus
Bile acid resins
Phenothiazines
Antipsychotics (second generation)
Immunosuppressants
Alcohol excess
Positive-energy balanced diet with saturated
fat or high glycemic index/load content
Current Cardiology Reviews, 2018, 14, 67-76

85. Don’t Forget
Although patients with diabetes have
higher triglyceride levels compared
with patients without diabetes, LDL
lowering is still the first priority in
treating diabetic dyslipidemia.
Nonpharmacologic interventions (diet
and exercise) are the background for
managing dyslipidemia in diabetes, but
statin therapy is additionally indicated
for all patients with diabetes

87. Hypertriglyceridemia
NCEP ATP III The endocrine society 2010
Borderline
high
150 – 199 mg/dL Mild 150 – 199 mg/dL
High 200 – 499 mg/dL Moderate 200 – 999 mg/dL
Very high ≥500 mg/dL Severe 1000 – 1999 mg/dL
Very severe ≥2000 mg/dL

88. Treatment
Objectives
for Elevated
TGs
TG levels Rationale for therapy
“Very High” TGs ≥500
mg/dL
Prevention of
Pancreatitis
“High” or “Moderate
Hypertriglyceridemia”
200-499 mg/dL
Prevention of CVD

89. Lifestyle and Diet Can
Have Big Impacts on
Hypertriglyceridemia
• 50% Reduction in TG with Lifestyle Interventions
DIET/LIFE STYLE CHANGE LIPID PROFILE CHANGE
Weight loss (5–10%) ↓TG (20%), ↓LDL-C (15%) & ↑HDL-C (10%)
Diet
↑Fruits, vegetables & low-fat dairy; ↓ added
sugar
↓Total carb; ↓Fat (to 33–50% of calories)
↓TG (variable, depends on baseline TG)
Exercise
Brisk 30-min walk, 3x/wk
↓TG (10-20%)
Miller M et al. J Am Coll Cardiol. 2008;51:724-30. Sampson UK et al. Curr Atheroscler Rep. 2012;14:1-10.

91. Efficacy of TG
lowering?

92. Major randomized controlled trials (RCTs) on
fibrates and their outcomes
RCT 1ry end point Therapy N CHD risk reduction
ACCORD-Lipid Nonfatal MI, or
stroke, death
from CV cause
Fenofibrate vs. placebo
(Simvastatin background)
5518
8% (p=0.32)
FIELD CV event rates Fenofibrate vs. placebo 9795 11% (p=0.16)
VA-HIT CV events Gemfibrozil vs. placebo 2531 22% (p<0.006)
BIP Mortality Benzafibrate vs. placebo 3090 7.3 (p=0.26)
HHS CV risk Gemfibrozil vs. placebo 6126 34% (p<0.02)
The impact of fibrate monotherapy on CHD risk reduction in the major randomized clinical trials completed prior to
ACCORD-Lipid was variable, with some trials reporting a significant reduction and others no significant effect overall.

93. VA-HIT
(n= 2531 men)
(25% with diabetes)
(50% with IR)
A double-blind trial comparing gemfibrozil (1200 mg per
day) with placebo in 2531 men with coronary heart disease,
an HDL cholesterol level of 40 mg per deciliter (1.0 mmol
per liter) or less, and an LDL cholesterol level of 140 mg per
deciliter (3.6 mmol per liter) or less. The primary study
outcome was nonfatal myocardial infarction or death from
coronary causes.
N Engl J Med 1999;341:410-8.

94. What about patients
with diabetes
• In men with CHD and a low high-density
lipoprotein cholesterol level, gemfibrozil
use was associated with a reduction in
major cardiovascular events in persons
with diabetes and in nondiabetic subjects
with a high fasting plasma insulin level.
Arch Intern Med. 2002;162(22):2597-2604.

95. www. Clinical trial results.org
Fenofibrate
(200 mg daily)
n=4895
Endpoints:
 Primary – Composite of CHD death or non-fatal MI at 5 year follow-up
 Secondary – Composite of total CV events, CV mortality, total mortality, stroke,
coronary revascularization and all revascularization at 5 year follow-up
FIELD: Design
ESC 2005
Placebo
N=4900
9795 patients, Age 50-75 years, type 2 diabetes diagnosed after age
35 years, no clear indication for cholesterol-lowering therapy at
baseline (total cholesterol 116-251 mg/dL, plus either total cholesterol
to HDL ratio ≥4.0 or triglyceride >88.6 mg/dL

96. www. Clinical trial results.org
FIELD: Primary Endpoint
5.2%
5.9%
0%
2%
4%
6%
Fenofibrate Placebo
• The primary
composite endpoint of
CHD death or non-fatal
MI was not significantly
lower in the fenofibrate
group compared to the
placebo group.
Composite CHD death or nonfatal MI at 5 Years
(% of treatment arm)
AHA 2005
p=0.16

97. www. Clinical trial results.org
FIELD: Secondary Endpoint
2.9%
7.3%
3.2%
2.6%
6.6%
3.6%
0%
2%
4%
6%
8%
CV Mortality Total Mortality Stroke
Fenofibrate Placebo
• CV Mortality, Total
Mortality, and Stroke
were not significantly
different between the
fenofibrate and
placebo groups
Individual Components of Secondary Endpoint
p=0.41
p=0.18
p=0.36
AHA 2005

98. www. Clinical trial results.org
FIELD: Secondary Endpoint
5.9%
7.4%
9.6%
7.8%
0%
5%
10%
Coronary revascularization All Revascularization
Fenofibrate Placebo
• Percentage of
coronary
revascularization and
all revascularization
were significantly
lower in the
fenofibrate group
compared to placebo
Individual Components of Secondary Endpoint
P=0.003
P=0.001
AHA 2005

100. Action to Control Cardiovascular Risk in Diabetes
(ACCORD Study)
Statins + Fenofibrate
Statins + Placebo
Diabetic Patients
LDL 60-180 mg/dl
TG <750 mg/dl with lipid therapy
and <400 without lipid therapy.
(n=5518)
0 5 years
The primary CVD end point
(fatal and nonfatal coronary heart
disease and stroke)
randomized, placebo controlled trial
N Engl J Med 2010;362:1563-74.
NEJM 2010

101. ACCORD Results:
Primary outcome occurred at a rate of :
2.4% per year in the placebo group Vs. 2.2% per year in the fenofibrate group.
hazard ratio: 0.92 which was not significant (P = 0.32).
Secondary outcomes:
( Each component of the primary composite outcome tested individually,
an expanded cardiovascular outcome, major coronary events, and total mortality).
None of these outcomes showed differences that were statistically significant.
N Engl J Med 2010;362:1563-74.
The ACCORD Lipid trial did not confirm its primary hypothesis.

102. Conclusion
• The combination of fenofibrate and statin did not
reduce the rate of fatal cardiovascular events,
nonfatal myocardial infarction or nonfatal stroke as
compared with statin alone.
• These results do not support the routine use of
combination therapy with fenofibrate and statin to
reduce cardiovascular risk in the majority of high-
risk patients with type 2 diabetes.
• Although the ACCORD-Lipid study findings do not
support the wide application of combination
fibrate–statin therapy in patients with T2DM,
subgroup analyses from ACCORD-Lipid and previous
fibrate trials suggest that the presence of
hypertriglyceridemia and low HDL-C identifies a
subgroup of patients in whom CVD events may be
reduced with combination fibrate–statin therapy

103. Omega 3 fatty acid

104. • Description: The goal of the trial was to assess the cardiovascular (CV) and
cancer benefits of n–3 (also called omega-3) fatty acid and vitamin D3
supplementation compared with placebo among healthy participants.
• Study Design: In a 2 x 2 factorial design, healthy participants were randomized in
a 1:1 fashion to either vitamin D3 (at a dose of 2000 IU per day) (n = 12,927) or
placebo (n = 12,944), OR n–3 fatty acids (1 g per day as a fish-oil capsule
containing 840 mg of n–3 fatty acids, including 460 mg of eicosapentaenoic
acid [EPA] and 380 mg of docosahexaenoic acid [DHA]) (n = 12,933) or
matching placebo (n = 12,938).
• Total number of enrollees: 25,871
• Duration of follow-up: 5.3 years
NEJM 2019

105. NEJM 2019

106. Low Dose Omega-3 Mixtures Show
No Significant Cardiovascular Benefit
Adapted with permissionǂ from Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use with
cardiovascular disease risks: Meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234. [ǂhttps://creativecommons.org/licenses.org/by-nc/4.0/]
Source Treatment Control Rate Ratios (CI)
No. of Events (%)
Coronary heart disease
Nonfatal myocardial infarction 1121 (2.9) 1155 (3.0) 0.97 (0.87–1.08)
Coronary heart disease 1301 (3.3) 1394 (3.6) 0.93 (0.83–1.03)
Any 3085 (7.9) 3188 (8.2) 0.96 (0.90–1.01)
P=.12
Stroke
Ischemic 574 (1.9) 554 (1.8) 1.03 (0.88–1.21)
Hemorrhagic 117 (0.4) 109 (0.4) 1.07 (0.76–1.51)
Unclassified/other 142 (0.4) 135 (0.3) 1.05 (0.77–1.43)
Any 870 (2.2) 843 (2.2) 1.03 (0.93–1.13)
P=.60
Revascularization
Coronary 3044 (9.3) 3040 (9.3) 1.00 (0.93–1.07)
Noncoronary 305 (2.7) 330 (2.9) 0.92 (0.75–1.13)
Any 3290 (10.0) 3313 (10.2) 0.99 (0.94–1.04)
P=.60
Any major vascular event 5930 (15.2) 6071 (15.6) 0.97 (0.93–1.01)
P=.10
Favors
Treatment
Favors
Control
2.0
Rate Ratio
1.0
0.5

107. Novel TG Reducing
Agent

108. Marine Trial Anchor Trial
Objective:
investigate the efficacy and safety
of EPA in reducing TG levels in
patients with very high TG (≥500
mg/dl) and evaluate its effect on
other lipid and lipoprotein
parameters.
Objective:
investigate the efficacy and safety of EPA in
reducing TG levels in patients with with
mixed dyslipidemia (TG ≥200 mg/dl and
<500 mg/dL) and evaluate its effect on
other lipid and lipoprotein parameters.
secondary endpoint: LDL‐C non‐inferiority to
Placebo

109. 113
Marine Trial Results
Patients with Very High TGs > 500 mg / dl
Anchor Trial Results
Patients with Mixed Dyslipidemia On Statin
Baseline TGs (200 – 499 mg/dl)
EPA 4g = 33% ↓TGs
EPA 2g = 20% ↓TGs EPA 2g + Statin = 41 % ↓TGs
EPA 4g + Statin = 65 % ↓TGs

110. Icosapent Ethyl (EPA) is indicated as an adjunct to diet to
reduce TGs level in Adults with Severe TGs ≥ 500 mg / dl
Hypertriglyceridemia
114
July 2012

111. Novel TG Reducing
Agents (EPA) role in CVD
risk

112. JELIS Suggests CV Risk Reduction
with EPA in Japanese
Hypercholesterolemic Patients
Total Population
Adapted with permission from Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic
patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090-1098.
Kaplan-Meier Estimates of Incidence of Coronary Events
Secondary Prevention Cohort
Primary Prevention Cohort
7478 7204 7103 6841 6678 6508
7503 7210 7020 6823 6649 6482
1841 1727 1658 1592 1514 1450
1823 1719 1638 1566 1504 1442
Hazard ratio: 0.81 (0.657–0.998)
p=0.048
Hazard ratio: 0.82 (0.63–1.06)
p=0.132
9319 8931 8671 8433 8192 7958
9326 8929 8658 8389 8153 7924
Numbers at risk
Control group
Treatment group
Major
coronary
events
(%)
Hazard ratio: 0.81 (0.69–0.95)
p=0.011
Years
Control
1
2
3
4
0
1 5
0 2 3 4
Years
0.5
1.0
1.5
2.0
0
1 5
0 2 3 4
4.0
8.0
0
1 5
0 2 3 4
Years
EPA*
Control
EPA*
Control
EPA*
*1.8 g/day
18 645 patients
5-year follow-up
1800 mg of EPA daily with
statin
Vs. statin only

113. • Article available at http://doi.org/10.1016/j.jacc.2019.02.032
• Slides available for download at www.lipid.org

114. (REDUCE-IT) Study Design:
2 g of Icosapent Ethyl twice daily
( total 4 g daily)
Placebo
Patients with established
Cardiovascular disease or
diabetes and other risk factors
(n=8179)
0 4.9 years
• Study Sample represents Primary
and secondary prevention
patients.
• Patients from 473 participating
site in 11 countries.
Phase 3b,multi-center, randomized, double-blind,
placebo controlled trial
N Engl J Med 2019; 380:11-22
DOI: 10.1056/NEJMoa1812792

115. Exclusion criteria:
• Severe Heart Failure
• Active Severe Liver
Disease
• HbA1c > 10%
• Planned Coronary
Intervention or Surgery
• History of acute or
chronic pancreatitis
• Hypersensitivity to fish
or ingredients
Inclusion criteria:
• Established
Cardiovascular disease
≥45 years of age or
• Diabetic + at least one
risk factor ≥50 years of
age
• Fasting TG 150–499
mg/dl
• LDL 41–100 mg/dl on
statins for at least 4
weeks before trial
Primary End Point:
Composite of:
• Cardiovascular death.
• nonfatal myocardial
infarction.
• nonfatal stroke.
• coronary
revascularization or
unstable angina .
Secondary End Point:
Composite of:
• Cardiovascular death.
• nonfatal myocardial
infarction.
• nonfatal stroke.
N Engl J Med 2019; 380:11-22
DOI: 10.1056/NEJMoa1812792
(REDUCE-IT) Study Design:

116. Key Baseline Characteristics
Icosapent Ethyl
(N=4089)
Placebo
(N=4090)
Age (years), Median (Q1-Q3) 64.0 (57.0 - 69.0) 64.0 (57.0 - 69.0)
Female, n (%) 1162 (28.4%) 1195 (29.2%)
Non-White, n (%) 398 (9.7%) 401 (9.8%)
Westernized Region, n (%) 2906 (71.1%) 2905 (71.0%)
CV Risk Category, n (%)
Secondary Prevention Cohort 2892 (70.7%) 2893 (70.7%)
Primary Prevention Cohort 1197 (29.3%) 1197 (29.3%)
Ezetimibe Use, n (%) 262 (6.4%) 262 (6.4%)
Statin Intensity, n (%)
Low 254 (6.2%) 267 (6.5%)
Moderate 2533 (61.9%) 2575 (63.0%)
High 1290 (31.5%) 1226 (30.0%)
Type 2 Diabetes, n (%) 2367 (57.9%) 2363 (57.8%)
Triglycerides (mg/dL), Median (Q1-Q3) 216.5 (176.5 - 272.0) 216.0 (175.5 - 274.0)
HDL-C (mg/dL), Median (Q1-Q3) 40.0 (34.5 - 46.0) 40.0 (35.0 - 46.0)
LDL-C (mg/dL), Median (Q1-Q3) 74.5 (62.0 - 88.0) 76.0 (63.0 - 89.0)
Triglycerides Category
<150 mg/dL 412 (10.1%) 429 (10.5%)
150 to <200 mg/dL 1193 (29.2%) 1191 (29.1%)
≥200 mg/dL 2481 (60.7%) 2469 (60.4%)

117. Primary End Point:
CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Placebo
28.3%
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30

118. Primary End Point:
CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Icosapent Ethyl
23.0%
Placebo
28.3%
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30
Hazard Ratio, 0.75
(95% CI, 0.68–0.83)

119. Primary End Point:
CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Icosapent Ethyl
23.0%
Placebo
28.3%
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30
RRR = 24.8%
ARR = 4.8%
NNT = 21 (95% CI, 15–33)
Hazard Ratio, 0.75
(95% CI, 0.68–0.83)

120. Primary End Point:
CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Icosapent Ethyl
23.0%
Placebo
28.3%
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30
P=0.00000001
RRR = 24.8%
ARR = 4.8%
NNT = 21 (95% CI, 15–33)
Hazard Ratio, 0.75
(95% CI, 0.68–0.83)

121. Key Secondary End Point:
CV Death, MI, Stroke
20.0%
Placebo
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30

122. Key Secondary End Point:
CV Death, MI, Stroke
20.0%
16.2%
Icosapent Ethyl
Placebo
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30
Hazard Ratio, 0.74
(95% CI, 0.65–0.83)

123. Key Secondary End Point:
CV Death, MI, Stroke
20.0%
16.2%
Icosapent Ethyl
Placebo
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30
Hazard Ratio, 0.74
(95% CI, 0.65–0.83)
RRR = 26.5%
ARR = 3.6%
NNT = 28 (95% CI, 20–47)

124. 20.0%
16.2%
Icosapent Ethyl
Placebo
Key Secondary End Point:
CV Death, MI, Stroke
Hazard Ratio, 0.74
(95% CI, 0.65–0.83)
RRR = 26.5%
ARR = 3.6%
NNT = 28 (95% CI, 20–47)
P=0.0000006
Years since Randomization
Patients
with
an
Event
(%)
0 1 2 3 4 5
0
10
20
30

125. EPA Effect:
“In addition, icosapent ethyl may have
anti inflammatory,
ant oxidative, plaque-stabilizing, and
membrane-stabilizing properties”
N Engl J Med 2019; 380:11-22
DOI: 10.1056/NEJMoa1812792
“… It is possible that membrane – stabilizing effects
could explain part of the benefit.
Stabilization or regression of coronary plaque
(or both) may also play a part .
. It is also possible that the difference in high-
sensitivity C-reactive protein (hs CRP) level
observed in REDUCE-IT may contribute to the
benefit”

126. Treatment-Emergent Adverse Events
Icosapent Ethyl
(N=4089)
Placebo
(N=4090) P-value
Subjects with at Least One TEAE, n (%) 3343 (81.8%) 3326 (81.3%) 0.63
Serious TEAE 1252 (30.6%) 1254 (30.7%) 0.98
TEAE Leading to Withdrawal of Study
Drug
321 (7.9%) 335 (8.2%) 0.60
Serious TEAE Leading to Withdrawal of
Study Drug
88 (2.2%) 88 (2.2%) 1.00
Serious TEAE Leading to Death 94 (2.3%) 102 (2.5%) 0.61

127. 131
(REDUCE-IT) Safety and Adverse Events:
N Engl J Med 2019; 380:11-22
DOI: 10.1056/NEJMoa1812792
The rate of hospitalization for
atrial fibrillation or flutter was significantly
higher in the icosapent ethyl group
although the rates were low.
The rates of adverse events and serious
adverse events leading to discontinuation
of trial drug were similar in the two
groups

128. Cardiovascular
Death
-12
-100
-150
-200
-50
0
Risk
Difference
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
For Every 1000 Patients Treated with
Icosapent Ethyl for 5 Years:

129. Cardiovascular
Death
-12
Fatal or
Nonfatal MI
-42
-100
-150
-200
-50
0
Risk
Difference
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
For Every 1000 Patients Treated with
Icosapent Ethyl for 5 Years:

130. Cardiovascular
Death
-12
Fatal or
Nonfatal MI
-42 Fatal or
Nonfatal
Stroke
-14
-100
-150
-200
-50
0
Risk
Difference
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
For Every 1000 Patients Treated with
Icosapent Ethyl for 5 Years:

131. Cardiovascular
Death
-12
Fatal or
Nonfatal MI
-42 Fatal or
Nonfatal
Stroke
-14
Coronary
Revascularization
-76
-100
-150
-200
-50
0
Risk
Difference
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
For Every 1000 Patients Treated with
Icosapent Ethyl for 5 Years:

132. Cardiovascular
Death
-12
Fatal or
Nonfatal MI
-42 Fatal or
Nonfatal
Stroke
-14
Coronary
Revascularization
-76
Hospitalization
for Unstable
Angina
-16
-100
-150
-200
-50
0
Risk
Difference
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
For Every 1000 Patients Treated with
Icosapent Ethyl for 5 Years:

133. Primary
Composite
Endpoint
-159
Cardiovascular
Death
-12
Fatal or
Nonfatal MI
-42 Fatal or
Nonfatal
Stroke
-14
Coronary
Revascularization
-76
Hospitalization
for Unstable
Angina
-16
-100
-150
-200
-50
0
Risk
Difference
Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019.
For Every 1000 Patients Treated with
Icosapent Ethyl for 5 Years:

134. TG lowering
using EPA

135. AACE point of view

138. 144
30%
omega 3 Fatty
acids
(300 mg)
EPA 150 mg +
DHA 150 mg
And 70 %
(700 mgs)
of other fats
including 270
mgs of
Saturated Fats
A 30% Fish Oil product
Provides:
Vs.
Highly Purified
Icosapent Ethyl
1 g capsules
Single- Entity active
drug Substance
93%
icosapent ethyl
(EPA ethyl ester)
&No Harmful Saturated
Fats
93%
EPA
7 Capsules
of Regular Omega 3 – capsules are
needed to give 1 gm EPA !

139. Final look

141. Take Home Messages
• LDL lowering is the cornerstone of managing diabetic dyslipidemia because of the robust
clinical data demonstrating benefit, and statin therapy is the mainstay.
• Other LDL-lowering therapies that have also shown benefit are the cholesterol
absorption inhibitor ezetimibe and monoclonal antibodies that inhibit PCSK9.
• As regard elevated triglycerides: Niacin and fibrates have been shown to lower
triglycerides in patients on statin therapy but have not been shown to reduce
cardiovascular risk.
• The two long-chain n-3 FA EPA and DHA are well studied for triglyceride lowering, and
recently an EPA only n-3 FA preparation (icosapent ethyl) showed cardiovascular benefit
in the REDUCE-IT trial.
• To date, no HDL raising strategies have been shown to reduce cardiovascular benefit in
patients on background statin therapy; thus, this strategy is not currently recommended.

142. Final Bottom
line
Lipid-lowering agents of proven benefit for
cardiovascular risk reduction in patients with
type 2 diabetes
• Statins
• Ezetimibe
• PCSK9 inhibitors
• Icosapent ethyl EPA only n-3 FA

143. 149
High Intensity Lipid Lowering Therapy
Single Pill combination
Monthly Cost = 100 LE Monthly Cost = 160 LE

144. Icosapent ethyl 1 gm

145. Thank You