Dyslipidemia &

Residual Risk

1
 Global Burden of Cardiovascular disease

No 1 Cause of death worldwide

17.9 Million People die each year from CVD

31 % % of death due to CVD worldwide

85 % % of death due to heart attack and stroke

https://www.who.int/en/newsroom/factsheets/detail/cardiovascular-diseases-(cvds) CVD: cardiovascular Disease, No :Number

 Cardiovascular Disease and Dyslipidemia in the Gulf
In the Gulf CVD is the most Patients that present with heart
common cause of deaths attack in the Middle East are 10
accounting for up to 45% of all 45 % 12 to 12 years younger than those
mortalities1 in western countries2

The increasing prevalence of Dyslipidemia: an abnormally high

obesity is directly associated with concentration of lipids in the
the increase in lipid disorders blood, is one of the main risk
and type 2 diabetes factors for the development and
progression of CVD

1-Al Rasadi K et al, Oman Med Journal, 2015 Nov; 30(6): 403–405
2-Al Rasadi et al, Atherosclerosis 252 (2016) 182e187

CVD: cardiovascular Disease

 Dyslipidemia of Type 2 Diabetes and Metabolic
Syndrome (Atherogenic Lipid Profile)

Non-HDL-C
Triglycerides
VLDL
High TG
Chylomicrons
TG-rich lipoprotein remnants
Small dense LDL

Small,
Low HDL-
dense LDL C
particles

Most Common Lipid Profile in Patients with Coronary Artery Disease (60%)

Jellinger PS Endocr Pract. 2012; 18(suppl 1);1-78

 MACROvascular residual risk in patients with type 2
diabetes Coronary risk reduction
Events
Diabetic
Prevention not
Study Treatment populatio
type Overall avoided
n Diabetic population (p)
population (%)

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

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.
 While LDL-C lowering with statins reduces CV risk, a
substantial residual risk remains

CTT meta-analysis
• A meta-analysis of 21
randomized clinical trials
100% CV risk reduction
following statin
revealed that statin treatment
22%
80%
treatment
leaves 78% of the risk of a major
Relative risk of major

vascular event unaddressed

vascular events

60% 78%
Residual risk of
40%
major vascular • A high-dose statin further
event in statin-
treated patients reduced the absolute risk of CV
20%
events by only 0.8%
0%
6

CTT Collaboration. Lancet. 2010;376:1670-81.

 Aggressive LDL-C lowering with maximal doses of statins does
not eliminate residual CV risk
Even intensive LDL-C lowering with 80 mg of atorvastatin reduces absolute CV risk
by only 2.2% compared to atorvastatin 10 mg

15%
5-yr risk major CV event rate TNT

10%
2.2%8.7%
absolute
10.9% risk reduction

8.7%

5%
Residual risk

0%
10 mg 80 mg
(n=5,006) (n=4,995) 7
Atorvastatin dose

LaRosa JC. N Engl J Med. 2005;352;1425-35.

Non-HDL Cholesterol

8
 Patients reaching the LDL-C but not the Non-HD-C target have a
32% significant higher cardiovascular risk
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

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
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
 LDL and Non-HDL goal attainment declined at higher TG levels
While the proportion of individuals meeting non-HDL-C goal appeared to be continuously and inversely
associated with TG concentrations, the relationship with LDL-C achievement appeared to plateau at TG
levels of around 2.5 mmol/L in 2,674 patients with Diabetes and CVD from Hungary

Non-HDL-C goal attainment was suboptimal

in people with diabetes and co-existing
CVD. This was most marked at higher
triglyceride levels, possibly due to higher
levels of TRL

This study assessed the proportion of individuals with diabetes and CVD who attain a non-HDL-C goal of <2.6 mmol/L, the extent to which triglycerides influence this goal
attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL). 2,674 individuals with diabetes (99.7% with type 2) having a prior history of CVD event taking
LLT for at least one month during the 2009-2011 MULTI-GAP surveys, and having available fasting blood lipid profiles were included.

Laszlo M., Antonio J. V., Istvan R. et al. Non-HDL cholesterol goal attainment and its relationship with triglyceride concentrations among diabetic subjects with cardiovascular disease: A nationwide survey of 2674
individuals in Hungary, Atherosclerosis 241 (2015) 62-68
 Non-HDL-cholesterol
Advantages as a target for treatment

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-c 2 11

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.
 Non-HDL-cholesterol
Advantages as a target for treatment

• 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)

12

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.
 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

LDL* = (TC) - (HDL-C) - (TG/5)

*Valid only when concentrations of triglycerides are less than 4.5 mmol/L (400 mg/dL)

Friedewald equation

 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)

AACE 2017
Guidelines on dyslipidemia
 Guidelines with Targets
Risk Group AACE 2020 NLA ESC/EAS 2019 CCS 2018 IAS
Extreme LDL-C < 55 mg/dl
Secondary Prevention

NON-HDL-C < 80
mg/dl

Very high LDL-C < 70 mg/dl

NON-HDL-C < 100
LDL-C < 70 mg/dl
NON-HDL-C < 100
LDL-C < 55 mg/dl
(< 1.4 mmol/l)
LDL-C < 2.0
mmol/l).Non-HDL <
LDL-C < 70 mg/dl
NON-HDL-C < 100
mg/dl mg/dl NON-HDL < 80 mg/dl 2.6 mmol/l mg/dl
(< 2.2 mmol/l)

High LDL-C < 100 mg/dl

NON-HDL-C < 130
LDL-C < 100 mg/dl
NON-HDL-C < 130
LDL-C < 70 mg/dl
(< 1.8 mmol/l)
LDL-C < 2.0
mmol/l).Non-HDL <
LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl mg/dl NON-HDL < 100 mg/dl 2.6 mmol/l mg/dl
(<2.6 mmol/l)

Moderate LDL-C< 100 mg/dl

NON-HDL-C < 130
LDL-C < 100 mg/dl
NON-HDL-C < 130
LDL-C < 100 mg/dl
(< 2.6 mmol/l)
LDL-C < 2.0
mmol/l).Non-HDL <
LDL-C < 100 mg/dl
NON-HDL-C < 130
mg/dl mg/dl NON-HDL < 130 mg/dl 2.6 mmol/l mg/dl
(< 3.4 mmol/l)
Primary Prevention

Low LDL-C< 130 mg/dl

NON-HDL-C < 160
LDL-C < 100 mg/dl
NON-HDL-C < 130
LDL-C < 116 mg/dl
(< 3 mmol/l)
mg/dl mg/dl
 ESC Guidelines 2019 Treatm
ent goa
IIb-A l for LD
• SCORE <1%
L-C
LDL-c goal
IIa-A
• Young patients (T1DM <35 yrs, T2DM <50 yrs) with
3.0 mmol/L DM duration <10 yrs without other risk factors
(116 mg/dL) Low • SCORE ≥1% and <5%
I-A
2.6 mmol/L • Markedly elevated single risk factor (TC >310, LDL-c >190 or BP ≥180/110)
(100 mg/dL) Moderate • FH without other major risk factors
• DM without TOD, with duration ≥10 yrs or an additional risk factor
• Moderate CKD (GFR 30-59)
• SCORE ≥5% and <10%

• ASCVD (clinical/imaging) (I-A)

1.8 mmol/L
& ≥50% (70 mg/dL) High • DM with TOD or ≥3 major risk factors (I-C)
• Early onset T1DM of long duration (>20 yrs) (I-C)
reduction • Severe CKD (GFR <30) (I-C)
from • SCORE ≥10% (I-C)
baseline 1.4 mmol/L • FH with ASCVD or another major risk factor (IIa-C)
(55 mg/dL) Very High
• LDL-c goal 1.0 mmol/L (55 mg/dL) if 2nd
ASCVD event ≤2 yrs on maximally
tolerated statin-based therapy (IIb-B)
16
Low Moderate High Very high CVD Risk

Mach F et al. Eur Heart J 2019 Aug 31.

Non-HDL-cholesterol ESC/EAS guidelines

17
 Non-HDL-cholesterol ESC/EAS guidelines

18

Mach F et al. Eur Heart J 2019 Aug 31.

 Non HDL Cholesterol 2020 AACE Guidelines
• 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 23
chylomicron remnants and Lp(a).
Lipid Management Algorithm, Endocr Pract. 2020;26(No. 10)
 Non HDL Cholesterol 2020 AACE Guidelines1

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
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
 Consensus Clinical Recommendations for the management of Plasma lipid
disorders in the Middle East

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
 Consensus Clinical Recommendations for the management of Plasma lipid
disorders in the Middle East

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