Slide Himawan Liphantyl Febr 2021

Strategies in Non-HDL-C
Management to reduce
Cardiovascular risk
Focus on Diabetic Patients
HIMAWAN SANUSI
D I V I S I O N O F E N D O C R I N E A N D M E TA B O L I S M , D E PA RT M E N T O F
I N T E R N A L M E D I C I N E FA C U LT Y O F M E D I C I N E H A S A N U D D I N
U N I V E R S I T Y / R S U P D R . WA H I D I N S U D I R O H U S O D O / R S . P T N U N H A S
MAKASSAR
Proprietary and confidential – do not distribute 2021 Date of preparation: January 2018; GLCHO170108
Diabetes and CVD
• Patients with DM are at higher risk for cardiovascular
(CV) events, including ACS & stroke
Patients with T2D have

twice to fourfold the risk
of CV disease compared with
the general population1
2-4x
2
Current management of CVD
Blood < 140 / 90 mHg

Pressure
CV risk in
T2 DM
Cholesterol
Blood
Glucose
FPG 80 – 130 mg/dL
LDL < 100
PPG < 180 mmg/dL
mg/dL
HbA1c < 7 %
Current management of CVD
Proprietary and confidential – do not distribute Date of preparation: January 2018; GLCHO170108
Management of Dyslipidemia in diabetic patients
Do We Need More Guidelines?
 Reduction of LDL-C has been one of

the cornerstones of CVD prevention
therapy over the past 2 decades.
 LDL-C lowering with standard statin The cornerstone of treatment is

regimens reduces the risk of CV events statin therapy.1
in a wide range of individuals.
 Further reduction in LDL-C with more

intensive regimens produce further
reductions in the incidence of CV
events.
Residual vascular risk
• A meta-analysis of studies investigating statin-treated patients with diabetes
showed that Statins led to a 21% reduction in the number of major vascular
events for every mmol/L reduction in LDL-C.1
• BUT, residual risk remains:
– 1 in 7 statin-treated patients still experienced CV events across 5 years. 1
– Many diabetic dyslipidaemic patients still develop microvascular and
macrovascular complications despite optimal treatment.2
• Definition of residual risk according to the Residual Risk Reduction
initiative:3
“Residual CV risk is defined as the risk of CV events that

persists in people despite achievement of treatment goals
for LDL cholesterol, blood pressure, and glycaemia
according to current standards of care.”
1. Judge EP, Phelan D, O’Shea D. Beyond statin therapy: a review of the management of residual risk in diabetes mellitus.
J R Soc Med 2010; 103: 357–362.
2. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in
dyslipidaemic patient. Diab Vasc Dis Res 2008; 5: 319–335.
3. Fruchart
Proprietary JC, Davignon
and confidential J, Hermans
– do not distributeMP et al. Residual macrovascular risk in 2013: what have weoflearned?
Date Cardiovasc
preparation: Diabetol
January 2018; 2014; 13: 26.
GLCHO170108
Residual vascular risk
Residual risk is
illustrated in this graph
(adapted from
Fruchart et al. 20082),
which shows that even
after reducing the risk
of CV events by
increasing the statin
dose,there is still a risk
of CV events (i.e
residual risk).
Key: CHD: coronary heart disease; HR: hazard ratio. Major cardiovascular events were defined as a composite of
coronary heart disease death, non-fatal myocardial infarction, resuscitation after cardiac arrest, and fatal/non-fatal
stroke.
dyslipidaemic
Proprietary and confidentialpatient.
– do not Diab Vasc Dis Res 2008; 5: 319–335.
distribute Date of preparation: January 2018; GLCHO170108
Current risk management
• LDL-C is currently the primary
treatment target for
dyslipidaemia management.4
• Patients treated with
medication targeting LDL-C (for
example, statins ) still have
residual
CV risk.1,2
For this reason, other targets are being considered,
including non-high-density lipoprotein cholesterol
(Non-HDL-C).5
1. Judge EP, Phelan D, O’Shea D. Beyond statin therapy: a review of the management of residual risk in diabetes mellitus.
J R Soc Med 2010; 103: 357–362.
dyslipidaemic patient. Diab Vasc Dis Res 2008; 5: 319–335.
4. Virani SS. Non-HDL cholesterol as a metric of good quality of care. Opportunities and challenges. Tex Heart Inst J 2011; 38(2): 160–162.
5. Hirsch GA, Vaid N, Blumenthal RS. The significance of measuring non-HDL-cholesterol. Date
Proprietary and confidential – do not distribute
2002. Available at:
of preparation: January 2018; GLCHO170108
https://www.medscape.com/viewarticle/438773 (accessed Jan 2018).
Non-HDL-C
Non-HDL-C comprises all

atherogenic lipoproteins,
representing all cholesterol
except for HDL-C:6
There are several components of Non-HDL-C, including:5

Low-density lipoprotein cholesterol (LDL-C)
Very low-density lipoprotein cholesterol (VLDL-C)
Intermediate-density lipoprotein (IDL)
Triglycerides (TG)
5. Hirsch GA, Vaid N, Blumenthal RS. The significance of measuring non-HDL-cholesterol. 2002. Available at:
6. Heart UK. Cholesterol tests – know your numbers. Available at:
https://heartuk.org.uk/health-and-high-cholesterol/cholesterol-tests---know-your-number (accessed Jan 2018).
Non-HDL-C
• Plasma Non-HDL-C concentrations are positively correlated with TG and
LDL-C concentrations, while less significant correlations are observed
between LDL-C and TG.7
• LDL-C is estimated with the Friedwald equation :5
LDL-C = TC – HDL-C – (TG / 5) mg/dL
• This estimate requires measurement of TC, TG and HDL-C. However,

estimations of LDL-C become less accurate as TG levels increase (for
example in patients with diabetes).5
• Therefore, Non-HDL-C can provide a more accurate screening

tool, particularly in patients with higher TG, as it requires
measurement of only TC and HDL-C.5
5. Hirsch GA, Vaid N, Blumenthal RS. The significance of measuring non-HDL-cholesterol. 2002. Available at:
7. Sugimoto K, Isobe K, Kawakami Y et al. The relationship between non-HDL cholesterol and other lipid parameters in Japanese subjects. J
Atheroscler Thromb 2004; 12(2):107–110.
Non-HDL-C and CVD risk
• Given that residual risk
remains even after successful
LDL-C lowering, Non-HDL-C
remains an underused and
undertreated secondary target.
This is despite evidence that
Non-HDL-C may predict CV
risk better than LDL-C.8
• Several studies have

reported evidence for a link
between Non-HDL-C and
CVD risk. The major studies
are presented in the
following slides.
8. Puri R, Nissen SE, Shao M et al. Non-HDL cholesterol and triglycerides. Implications for coronary atheroma progression and clinical
events. Thromb Vasc Biol 2016; 36: 2220–2228.
Cui et al. 20019
Objective: to determine whether Non-HDL-C level predicts CVD mortality,
and compare the predictive value of Non-HDL-C and LDL-C levels.
Results: LDL-C was associated with CVD death during follow-up. As lipid
biomarkers increased by 0.78 mmol/L (30 mg/dL), the risk of CVD increased by 19%
(Non-HDL-C), 16% (TC) and (LDL-C) 11% in men, and of 15% (Non-HDL-C), 10%
(TC) and 8% (LDL-C) in women, respectively.
Relative risk associated with a 0.78 mmol/L (30 mg/dL) increase in biomarker
Biomarker
Men (n = 2,406) Women (n = 2.056)
LDL-C 1.11 1.08
HDL-C 0.77 0.77
Non-HDL-C 1.19 1.15
TC 1.16 1.10
9. Cui Y, Blumenthal RS, Flaws JA et al. Non-high-density lipoprotein cholesterol level as aDate
predictor of cardiovascular disease mortality.
of preparation: January 2018; GLCHO170108
Arch Intern Med 2001; 161: 1413–1419.
Bittner et al. 200210
Objective: to investigate whether Non-HDL-C relates to prognosis among

patients with coronary heart disease (CHD).
Methods:
1,514 patients (mean age 61 years), with multivessel coronary artery disease
(CAD) followed for 5 years.
Outcomes during follow up were death and nonfatal myocardial infarction.
Results:
A 0.26 mmol/L (10 mg/dL) increase in Non-HDL-C was associated with a 4.9%
increase in risk for non-fatal myocardial infarction and angina pectoris. The
same increase in TC, LDL-C and TG was associated with an increased risk of
4.3%, 3.3% and 1.6%, respectively.
10. Bittner V, Hardison R, Kelsey SF et al. Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass
Angioplasty Revascularization Investigation (BARI). Circulation 2002; 106: 2537–2542.
Lu et al. 200311
Objective: to determine whether Non-HDL-C is a predictor of CVD in patients

with diabetes.
Methods:
2,108 participants (aged 45–74 years) with diabetes but with no CVD at baseline.
Fasting blood samples were taken for lipid analysis and fatal/nonfatal CVD was
recorded during an average 9 year follow up.
Results:
Compared with the lowest Non-HDL-C levels (<127 mg/dL), individuals with the
highest levels (>161 mg/dL) were almost twice as likely to experience CVD.
Moreover, over three times as many individuals with the highest compared with
the lowest Non-HDL-C level experienced myocardial infarction.
Conclusion: Non-HDL-C is a strong predictor of CVD in men and women

with diabetes, and stronger than LDL-C.
11. Lu W, Resnick HE, Jablonski KA et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes. Diabetes Care
Proprietary and confidential
2003; 26: 16–23.– do not distribute Date of preparation: January 2018; GLCHO170108
Ridker et al. 200512
Objective: to compare the clinical utility of several lipid biomarkers as predictors of

CV events in women.
Methods:
Cohort of 15,632 healthy women (>45 years) followed for 10 years for the occurrence
of CV events (nonfatal myocardial infarction or stroke, coronary revascularisation
procedures or CV-related death).
Participants were divided in quintiles for TC, HDL-C, LDL-C and apolipoprotein
B100/A-I levels, and hazard ratios (HRs) for future CV events were calculated by
comparing quintiles 2–5 with quintile 1 (referent).
Results: All biomarkers were strongly associated with risk of future CV events. Apart
from total cholesterol, Non-HDL-C had the strongest association (those with the
highest levels were 2.5 times more likely to experience a CV event than those with the
lowest levels).
12. Ridker PM, Rifai N, Cook NR et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as
risk factors for cardiovascular disease in women. JAMA 2005; 294(3): 326–333.
Arsenault et al. 201013
Objective: to test whether lipid parameters are associated with an increased
risk of coronary heart disease (CHD).
Methods:
21,448 participants (aged 45–79 years) without diabetes or CHD were recruited
and followed up for 11 years.
Blood samples were processed for levels of TC, LDL-C, HDL-C and TG, and Non-
HDL-C was calculated from these measures.
CHD and death from CHD were recorded from hospital admissions and death
certificates. HRs were calculated for the risk of future CHD in prespecified
categories of LDL-C, Non-HDL-C and TG.
13. Arsenault BJ, Rana JS, Stroes ESG et al. Beyond low-density lipoprotein cholesterol. J Am Coll Cardiol 2010; 55(1): 35–41.
Puri et al. 20168
Objective: to investigate the associations between Non-HDL-C or TG levels and

changes in coronary atheroma volume (CAV).
Methods:
4,957 patients with coronary disease undergoing serial intravascular ultrasonography
to assess changes in CAV.
The effects of lower and higher Non-HDL-C or TG levels on CAV were assessed.
Results:
Non-HDL-C levels were linearly associated with changes in CAV. Lower
(on-treatment) Non-HDL-C and TG levels associated with significant regression
of CAV across all levels of LDL-C.
Conclusion: Changes in CAV were more strongly influenced by changes in

Non-HDL-C than changes in LDL-C.
Guidelines: current recommendations
• Most guidelines for management of dyslipidaemia recommend
LDL-C lowering as the primary means of reducing cardiovascular events. 8,14
• Given the evidence for the predictive association between Non-HDL-C and
CVD outcomes, recent guidelines have recognised the importance of Non-
HDL-C in management of dyslipidaemia and associated CVD risk.
14. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016; 37(39):
2999–3058.
Guidelines: non-HDL-C
Adult Treatment Panel III and National Cholesterol Education Program,
200215
• The ATPIII NCEP guidelines suggest that in people with high TG (≥ 200
mg/dL), Non-HDL-C should be a secondary target of therapy representing
atherogenic cholesterol.
International Atherosclerosis Society, 201316
• The IAS recognises that research shows Non-HDL-C is more strongly related
to CVD risk than LDL-C and argue the former is a preferred target for patients
with dyslipidaemia :
“These findings favor the use of Non-HDL-C over LDL-C as targets of therapy.
Other reasons to place primacy on Non-HDL-C are that it is less expensive to
measure than apoB and does not require fasting as does LDL-C.”
15. ATPIII NCEP. Third Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high
blood cholesterol in adults (Adult Treatment Panel III). Final report. National Institutes of Health,
Maryland, 2002.
16. International Atherosclerosis Society. An International Atherosclerosis Society position paper: global recommendations for the
Proprietary management
and confidentialof–dyslipidaemia.
do not distributeJ Clin Lipidol 2014; 8(1): 29–60. Date of preparation: January 2018; GLCHO170108
NICE, 201417
• NICE in the UK have also provided guidance highlighting the importance of

Non-HDL-C in managing CVD.
• Instead of recommending Non-HDL-C as a secondary target, NICE
recommend the use of Non-HDL-C instead of LDL-C:
“Non-high density lipoprotein (Non-HDL) cholesterol is seen to be a better

cardiovascular disease (CVD) risk indicator than low-density
lipoprotein (LDL) cholesterol. It is more accurate, more practical and
cost effective.”
• Before starting therapy for CVD prevention, NICE recommend taking a
lipid sample, including TC, HDL-C, Non-HDL-C and TG levels.
• They recommend monitoring these levels again after 3 months of treatment
with statin therapy, aiming for a reduction of greater than 40% in
Non-HDL-C.
17. NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification. 2014. Available at:
https://www.nice.org.uk/guidance/cg181/ (accessed Jan 2019).
National Lipid Association, 201518
• The NLA place Non-HDL-C and LDL-C as primary targets of therapy,

recognising that evidence is accumulating that Non-HDL-C is more strongly
related to CVD risk in those with and without hypertriglyceridaemia.
ESC, 201614
• The ESC suggests LDL-C should be the primary target. However, Non-
HDL-C is a secondary target with the following aims:
Very high-risk individuals • < 2.6 mmol/L (100 mg/dL)
High-risk individuals • < 3.4 mmol/L (130 mg/dL)
Moderate-risk individuals • < 3.8 mmol/L (145 mg/dL)
2999–3058.
18. Jacobsen TA, Ito MK, Maki KC et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part
I – Full Report. J Clin Lipidol 2015; 9: 129–169.
American College of Cardiology, ACC, 201619
• The ACC suggests that in patients with diabetes non-HDL-C levels are
frequently elevated despite having near normal LDL-C levels. For this
reason, non-HDL-C thresholds are included for such high-risk patients
(<100 mg/dL).
American Association of Clinical Endocrinologists, 2017 20

• Those with normal LDL-C may still have increased TG, low HDL-C or high
VLDL-C, such that LDL-C alone cannot adequately assess risk for CVD, so
Non-HDL-C should be used in risk stratification for those with moderately
elevated TG (200–500 mg/dL), diabetes and/or established CVD.
19. Jellinger PS, Handelsman Y, Rosenblit PD et al. American Association of Clinical Endocrinologists and American College of Endocrinology
guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocrine Pract 2017; 23(2): 1–87.
20. Lloyd-Jones DM, Morris PB, Ballantyne CM et al. 2016 ACC Expert Consensus Decision Pathway on the role of non-
statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report
of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016; 68(1):
92–125.
New approaches to CVD prevention
• Effective prediction of CVD is only meaningful if it can also
determine effective treatment (that is, treatments that lower non-
HDL-C).21
• While statin therapy has long been the cornerstone of CVD

prevention to lower LDL-C, recently combination therapies have
been explored to further improve the effectiveness of therapy.22
• Therapy targeting LDL-C only cannot address other lipid

abnormalities such as TG, which can contribute to residual CV
risk.22
21. Hsia SH. Non-HDL cholesterol: into the spotlight. Diabetes Care 2003; 26(1): 240–242.
22. Ferrari R, Aguiar C, Alegria E et al. Current practice in identifying and treating cardiovascular risk, with a focus on residual risk associated
with atherogenic dyslipidaemia. Eur Heart J 2016; 18(suppl C): C2–C12.
Untreated dyslipidaemias
Jones et al. 201223
Objective: to estimate the proportion of high-risk statin-treated patients
achieving ATP III-recommended targets for both LDL-C and Non-HDL-C.
Results: 67–77% of patients

achieved LDL-C <100 mg/dL
and 20–26% patients achieved
LDL-C <70 mg/dL.
However, only 46–70% of

patients achieved both LDL-C
<100 mg/dL and Non-HDL-C
<130 mg/dL, while just 13.5–
19% achieved both LDL-C < 70
mg/dL and Non-HDL-C 100
mg/dL.
Conclusion: A significant number of statin-treated patients continue to have

additional dyslipidaemias.
23. Jones
Proprietary andPH, Nair R, Thakker
confidential KM. Prevalence of dyslipidemia and lipid goal attainment in statin-treated
– do not distribute subjectsJanuary
Date of preparation: from 32018;
data GLCHO170108
sources: a
retrospective analysis. J Am Heart Assoc 2012; 1: e001800.
New approaches to CVD prevention
• Furthermore, monitoring and managing Non-HDL-C
may be of particular value where there is residual
vascular risk even once LDL-C is controlled by statin
therapy.22
• Dual therapy with statin and fenofibrate is one approach
that has been investigated in several of studies, including
the ACCORD study.
• Some guidelines recommend the combination of a statin
and fenofibrate in the management of dyslipidaemia for
appropriate patients, including the ESC14 and American
Heart Association (AHA).24
2999–3058.
24. Wiggins BS, Saseen JJ, Page RL et al. Recommendations for management of clinically significant drug-drug interactions with statins and
select agents used in patients with cardiovascular disease; a scientific statement from Date of preparation: January 2018; GLCHO170108
the American Heart Association. Circulation 2016;
Medical Treatment (Based on the
Guidelines)
• Primary Goal (LDL-C goals): Usually statins first.

• Secondary Goal (Non- HDL-C goals) : Will usually
necessitate combination tx [Statin + fenofibrate &/or
ezetimibe – preferred]
– For high TG (200-499 mg/dl), non-HDL is the secondary target of therapy
• Increase statin dose
OR
• Add fibrates/nicotinic acid
• For HDL < 40 mg/dl drugs such as nicotinic acid or fibrates have
to be considered
ACCORD-Lipid25
• In an ACCORD substudy, the effects of dual therapy on CVD risk was
investigated in patients with type 2 diabetes.
• Patients were originally on statin monotherapy, and were then randomly
assigned to treatment with fenofibrate or placebo for a mean follow up of
4.7 years.
• The results suggested that specific subgroups of patients may benefit from
such combination therapy (that is, a statin for LDL-C lowering and
fenofibrate to reduce TG)
– Patients with atherogenic dyslipidaemia (HDL-C <34 mg/dL and TG
>204 mg/dL) had increased risk of CV events despite low LDL-C.
– Among these patients, increased risk was reduced by adding fenofibrate
to simvastatin treatment (12.4% of patients had CV outcomes after
addition of fenofibrate, compared with 17.3% in the placebo group).
• Several other studies have investigated the effects of adding fenofibrate to

statin therapy on Non-HDL-C.
25. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362(17): 1563–1574.
Combination treatment and non-HDL-C
Vega et al. 200626
Objective: to investigate whether addition of fenofibrate or nicotinic acid to

statin treatment improves lipid profiles of patients with diabetic dyslipidaemia.
Methods:
An open-label, crossover study of 20 patients with type 2 diabetes was
conducted, with patients receiving statin followed by the addition of fenofibrate
then nicotinic acid.
Simvastatin 20 mg for 8 Plus fenofibrate 160 mg Plus nicotinic acid 1000

weeks for 8 weeks mg for 8 weeks
Levels of several lipid variables (TC, TG, LDL-C, HDL-C etc.) were monitored.
26. Vega GL, Vajja M, Palacio N et al. Combination of fenofibrate plus low-dose nicotinic acid added to statin treatment in type 2 diabetes:
an open-label, crossover study. Curr Ther Res Clin Exp 2006; 67: 321–333.
Results: Fenofibrate addition led to significant lipid changes, including
reduced non-HDL-C. Similar differences were seen between 3 drug therapy
(statin + fenofibrate + nicotinic acid) compared with statin monotherapy.
Simvastatin Simvastatin +
Biomarker monotherapy fenofibrate Percent change p value
(n = 20) (n = 20)
Total cholesterol (mg/dL) 169 159 -5.9 0.018
Non-HDL-C (mg/dL) 132 120 -9.1 0.004
TG (mg/dL) 209 157 -24.9 0.014
HDL-C (mg/dL) 37 39 +13.5 0.008
NB: Given the lack of significant incremental effect with nicotinic acid, data not shown in above table.
Conclusion: The addition of fenofibrate to statin therapy led to further

improvements in lipid parameters beyond those seen with monotherapy.
Adding nicotinic acid did not increase effects beyond this, suggesting a
non-cumulative effect.
26. Vega GL, Vajja M, Palacio N et al. Combination of fenofibrate plus low-dose nicotinic acid added to statin treatment in type 2 diabetes:
an open-label, crossover study. Curr Ther Res Clin Exp 2006; 67: 321–333.
Ballantyne et al. 201027
Objective: to evaluate the long-term efficacy of combined fenofibrate/statin

therapy in patients who have reached LDL-C goals but have persistent
hypertriglyceridaemia.
Methods:
92 patients with mixed dyslipidaemia were treated with rosuvastatin 20 mg,
simvastatin 40 mg, or atorvastatin 40 mg for 12 weeks. Patients had reached a
LDL-C goal of <100 mg/dL but had TG >200 mg/dL. Fenofibric acid 135 mg was
then added to their treatment for 52 weeks in an open label study.
Percent changes in lipids and the proportion of patients achieving optimal lipid
levels were assessed.
27. Ballantyne CM, Jones PH, Kelly MT et al. Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with
persistent elevated triglycerides. Cardiovasc Drugs Ther 2011; 25: 59–67.
Results: Combined treatment led to significant improvements from baseline
(p<0.001) in several lipid parameters:
Non-
Non- HDL-
HDL-
HDL-
HDL- - 9.0% + 14.9%
C
C
C
C
Apo
Apo B
B - 9.8% TG
TG - 37.6%
Furthermore, a greater proportion of patients had achieved optimal lipid

levels, both individually and as combined targets.
Conclusion: Combination therapy showed further improvements in

lipid profiles in patients who have met LDL-C targets but still additional
dyslipidaemias.
27. Ballantyne CM, Jones PH, Kelly MT et al. Long-term efficacy of adding fenofibric acid to moderate-dose statin therapy in patients with
persistent elevated triglycerides. Cardiovasc Drugs Ther 2011; 25: 59–67.
Farnier et al. 201028
Objective: to evaluate the efficacy and safety of combined fenofibrate/statin therapy

in patients with mixed hyperlipidaemia and high risk of coronary heart disease.
28. Farnier M, Ducobu J, Bryniarski L. Efficacy and safety of adding fenofibrate 160 mg in high-risk patients with mixed hyperlipidemia not
Proprietary and confidential
controlled – do not distribute
by pravastatin 40 mg monotherapy.Am J Cardiol 2010; 106: 787–792. Date of preparation: January 2018; GLCHO170108
Jones et al. 201029
Objective: to evaluate the efficacy and safety of combined fenofibrate/statin

therapy in patients with mixed dyslipidaemia and type 2 diabetes.
Methods:
In a blinded randomised trial, 586 patients were treated with combination or
monotherapy for 12 weeks. Treatment groups were as follows:
Fenofibric acid monotherapy High-dose statin monotherapy

Low-dose statin monotherapy Fenofibric acid + low-dose statin
Moderate-dose statin monotherapy Fenofibric acid + moderate-dose
statin
Mean percent changes in lipids and proportions of patients achieving optimal lipid
levels were assessed.
29. Jones PH, Cusi K, Davidson MH et al. Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients
with mixed dyslipidemia and type 2 diabetes mellitus. Am J Cardiovasc Drugs 2010; 10(2): 73–84.
Results: Not only did combination therapy lead to greater percent
changes in HDL-C and TG than monotherapy, it also led to a 5-fold higher
proportion of patients achieving optimal levels of Non-HDL-C (as well as
LDL-C, HDL-C and TG).
Conclusion:
Combination
therapy showed
greater
improvements in
lipid profiles than
monotherapy
among patients
with mixed
dyslipidaemia and
type 2 diabetes.
29. Jones PH, Cusi K, Davidson MH et al. Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients
with mixed dyslipidemia and type 2 diabetes mellitus. Am J Cardiovasc Drugs 2010; 10(2): 73–84.
Roth et al. 201030
Objective: to evaluate efficacy/safety of rosuvastatin + fenofibric acid fixed dose
combination compared with simvastatin monotherapy in patients with high LDL-C
and TG.
Methods:
Randomised controlled trial of 474 patients with LDL-C ≥160 mg/dL and ≤240 mg/dL,
and TG ≥150 mg/dL and <400 mg/dL.
Patients randomised
for 8 weeks
Simvastatin Rosuvastatin 20 mg +
40 mg fenofibric acid 135 mg
Rosuvastatin 5 mg + Rosuvastatin 10 mg +
fenofibric acid 135 mg fenofibric acid 135 mg
30. Roth EM, McKenney JM, Kelly MT et al. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin
monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs
2010; 10(3): 175–186.
Results: Combination treatment led to significantly larger decreases in
LDL-C compared with monotherapy. Secondary analysis of other lipids showed
that combination therapy also led to significantly larger decreases in Non-HDL-C
than did statin monotherapy.
% change
Simvastatin 40 mg Rosuvastatin 5 mg + Rosuvastatin 10 mg + Rosuvastatin 20 mg +
monotherapy fenofibrate 135 mg fenofibrate fenofibrate
(n = 114) (n = 114) 135 mg 135 mg
(n = 115) (n = 113)
Non-HDL-C -32.6 -40.1 -45.9 -47.2

P value - <0.001 <0.001 <0.001
Conclusion: Combination treatment produced greater improvements in lipid

parameters, including Non-HDL-C, than did statin monotherapy.
30. Roth EM, McKenney JM, Kelly MT et al. Efficacy and safety of rosuvastatin and fenofibric acid combination therapy versus simvastatin
monotherapy in patients with hypercholesterolemia and hypertriglyceridemia: a randomized, double-blind study. Am J Cardiovasc Drugs
2010; 10(3): 175–186.
Farnier et al. 201131
Objective: to compare the efficacy and tolerability of a combination treatment

(fenofibrate 160 mg/pravastatin 40 mg) in patients with type 2 diabetes.
Methods:
Study of 291 patients with type 2 diabetes and mixed hyperlipidaemia (non-HDL-C
≥130 mg/dL or LDL-C ≥100 mg/dL and TG 150–600 mg/dL).
Participants were initially treated for 6 weeks with simvastatin 20 mg monotherapy
but had not reached their lipid goals before randomisation.
Patients randomised for 12 weeks
Fenofibrate 160 mg + Simvastatin 20 mg

pravastatin 40 mg daily daily
The mean percentage change in non-HDL-C was measured after 12 weeks.
31. Farnier M, Steinmetz A, Retterstøl K et al. Fixed-dose combination fenofibrate/pravastatin 160/40 mg versus simvastatin
20 mg monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with simvastatin 20 mg:
a double-blind, randomized comparative study. Clin Ther 2011; 33(1): 1–12.
Results: The combination therapy was associated with significantly
greater reductions in non-HDL-C compared with monotherapy. A larger proportion
of patients also achieved a combined end point of non-HDL-C <130 mg/dL and
LDL-C < 100 mg/dL on combination treatment than on monotherapy.
Percentage change (%)
Biomarker Fenofibrate + pravastatin Simvastatin p value
(n = 144) (n = 145)
Non-HDL-C -12.9 -6.8 0.008
TG -28.6 +5.0 <0.001
LDL-C -5.3 -6.8 0.29
Total cholesterol -8.7 -5.2 0.035
Conclusion: Combined treatment more effectively reduced non-HDL-C levels

than statin monotherapy.
31. Farnier M, Steinmetz A, Retterstøl K et al. Fixed-dose combination fenofibrate/pravastatin 160/40 mg versus simvastatin 20 mg
monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with simvastatin 20 mg: a double-blind, randomized
comparative study. Clin Ther 2011; 33(1): 1–12.
Chen et al. 201332
Objective: to investigate whether increased statin dose is non-inferior to combination

therapy in patients with diabetes/atherosclerosis with metabolic syndrome.
Methods:
112 patients were initially treated with rosuvastatin 5 mg/day for 12 weeks, and then
randomly assigned to either rosvuastatin 10 mg/day (high-dose statin) or fenofibrate
80 mg/day plus rosuvastatin 5 mg/day (combined treatment).
Results:
Both treatments led to similar Non-HDL-C levels (as well as other lipid levels), and
similar changes after 12 weeks (p>0.05, not significantly different).
Conclusion: Combination therapy had similar effects to increasing statin dose on

lipid parameters, including non-HDL-C.
32. Chen YP, Change KC, Tseng WK et al. Increased rosuvastatin dose versus concomitant fenofibrate and rosuvastatin therapy to achieve
lipid goal in patients with diabetes or atherosclerosis with metabolic syndrome. Acta Cardiol Sin 2013; 29: 421–428.
EVALUATION OF CARDIOVASCULAR EVENTS ON KOREAN DYSLIPIDEMIC PATIENTS
WITH FENOFIBRATE TREATMENT IN THE REAL WORLD
ECLIPSE-REAL
Nam Hoon Kim, Ki Hoon Han, Jimi Choi, Juneyoung Lee, Sin Gon Kim
BMJ 2019;366:l5125
Conclusion & Clinical implications
• It is apparent that where patients have mixed dyslipidaemia (for example,
high triglycerides), LDL-C is not necessarily the most appropriate measure
for risk prediction or treatment targets.33
• Given the studies outlined, and the evidence for the relationship between
non-HDL-C and CVD risk, a global approach to CVD prevention has been
proposed, composed of lifestyle optimisation, LDL-C lowering (statin) and
treatment of dyslipidaemia (fenofibrate).22
• Furthermore, a combination of LDL-C and Non-HDL-C measures may be
used to determine appropriate treatment (eg to identify patients who will
likely benefit from combination therapy).
33. Bergmann K. Non-HDL cholesterol and evaluation of cardiovascular disease risk. JIFCC 2010; 21(3): 64–67.
THANK YOU
Date of preparation: January 2018; GLCHO170108

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Strategies in Non-HDL-C

Patients with T2D have

Blood < 140 / 90 mHg

 Reduction of LDL-C has been one of

 LDL-C lowering with standard statin The cornerstone of treatment is

 Further reduction in LDL-C with more

“Residual CV risk is defined as the risk of CV events that

Non-HDL-C comprises all

There are several components of Non-HDL-C, including:5

• LDL-C is estimated with the Friedwald equation :5

LDL-C = TC – HDL-C – (TG / 5) mg/dL

• This estimate requires measurement of TC, TG and HDL-C. However,

• Therefore, Non-HDL-C can provide a more accurate screening

• Several studies have

LDL-C 1.11 1.08

HDL-C 0.77 0.77

Non-HDL-C 1.19 1.15

Objective: to investigate whether Non-HDL-C relates to prognosis among

Objective: to determine whether Non-HDL-C is a predictor of CVD in patients

Conclusion: Non-HDL-C is a strong predictor of CVD in men and women

Objective: to compare the clinical utility of several lipid biomarkers as predictors of

Objective: to investigate the associations between Non-HDL-C or TG levels and

Conclusion: Changes in CAV were more strongly influenced by changes in

• NICE in the UK have also provided guidance highlighting the importance of

“Non-high density lipoprotein (Non-HDL) cholesterol is seen to be a better

• The NLA place Non-HDL-C and LDL-C as primary targets of therapy,

Very high-risk individuals • < 2.6 mmol/L (100 mg/dL)

High-risk individuals • < 3.4 mmol/L (130 mg/dL)

Moderate-risk individuals • < 3.8 mmol/L (145 mg/dL)

American Association of Clinical Endocrinologists, 2017 20

• While statin therapy has long been the cornerstone of CVD

• Therapy targeting LDL-C only cannot address other lipid

Results: 67–77% of patients

However, only 46–70% of

Conclusion: A significant number of statin-treated patients continue to have

• Primary Goal (LDL-C goals): Usually statins first.

• Several other studies have investigated the effects of adding fenofibrate to

Objective: to investigate whether addition of fenofibrate or nicotinic acid to

Simvastatin 20 mg for 8 Plus fenofibrate 160 mg Plus nicotinic acid 1000

Conclusion: The addition of fenofibrate to statin therapy led to further

Objective: to evaluate the long-term efficacy of combined fenofibrate/statin

Furthermore, a greater proportion of patients had achieved optimal lipid

Conclusion: Combination therapy showed further improvements in

Objective: to evaluate the efficacy and safety of combined fenofibrate/statin therapy

Objective: to evaluate the efficacy and safety of combined fenofibrate/statin

Fenofibric acid monotherapy High-dose statin monotherapy

Non-HDL-C -32.6 -40.1 -45.9 -47.2

Conclusion: Combination treatment produced greater improvements in lipid

Objective: to compare the efficacy and tolerability of a combination treatment

Patients randomised for 12 weeks

Fenofibrate 160 mg + Simvastatin 20 mg

The mean percentage change in non-HDL-C was measured after 12 weeks.

Non-HDL-C -12.9 -6.8 0.008

TG -28.6 +5.0 <0.001

LDL-C -5.3 -6.8 0.29

Total cholesterol -8.7 -5.2 0.035

Conclusion: Combined treatment more effectively reduced non-HDL-C levels

Objective: to investigate whether increased statin dose is non-inferior to combination

Conclusion: Combination therapy had similar effects to increasing statin dose on

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