Role of Non-HDL-C in

cardiovascular risk management

Dr. Wirawan Hambali, Sp.PD
Cardiovascular Disease Remain a Major Cause of Health
Loss for All Regions of the World
A study published in 2017 described the global burden of cardiovascular
disease (CVD). Analysis showed that at present, CVDs remain a main cause of
health loss in various regions of the world, and ischaemic heart disease was the
leading cause of CVD health loss globally, as well as in each world region.

Roth GA, Johnson C, Abajobir A, et al. Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll
Cardiol. 2017;70(1):1-25. doi:10.1016/j.jacc.2017.04.052
The Deadly Quartet
Proportion of Dyslipidemia is High in Indonesia
Prevalence of High LDL-C 83%

Shamiri M, Ghanaim MMA,..Santoso A,.. et al Int J Gen Med 2018; 11: 313 - 22
Dyslipidemia and Metabolic Syndrome

Current concept of the metabolic syndrome. Central obesity is the principal abnormality that
predisposes to the development of the metabolic syndrome, which also includes insulin
resistance (hyperglycemia and/or type II diabetes), atherogenic dyslipidemia characterized by
hypertriglyceridemia and decreased high density lipoprotein cholesterol concentrations,
hypertension, along with proinflammatory and prothrombotic states (increased circulating
plasma concentrations of plasminogen activator inhibitor-1, fibrinogen and C-reactive protein).

Lau DC, Yan H, Dhillon B. Metabolic syndrome: a marker of patients at high cardiovascular risk. The Canadian Journal of Cardiology. 2006
Feb;22 Suppl B:85B-90B.
In Diabetic Patients, CV Mortality Increases
Sharply with Serum Cholesterol Concentration

Stamler J et al. Diabetes Care 1993 Feb; 16(2): 434-444.

 Lipid-Lowering Therapy Accounted for Over 70% of
Cardiovascular Risk Reduction in Patients With Diabetes*

Adapted from Gaede P, Pedersen O. Diabetes. 2004;53 (suppl 3):S39–S47.

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 JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014; 13:
26.
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 (ie
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.

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.
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.
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.
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. 2002. Available at:
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:
https://www.medscape.com/viewarticle/438773 (accessed Jan 2018).
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 and CVD risk
Objective: to determine whether Non-HDL-C level predicts CVD mortality, and compare the
predictive value of Non-HDL-C and LDL-C levels.

Methods:
4,462 participants (2,406 men and 2,056 women, aged 40–64 years) were followed up for an
average of 19 years. Fasting blood samples were taken to measure TC, LDL-C, HDL-C and TG, and
to calculate Non-HDL-C. Cause of death was obtained from death certificates, hospital records or
next of kin. Subsequently, relative risk rates for CVD mortality were calculated for each lipid
biomarker.
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

Conclusion: Both LDL-C and Non-HDL-C levels at baseline were significant

predictors of CVD death, but with a stronger relationship for Non-HDL-C.

9. Cui Y, Blumenthal RS, Flaws JA et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001; 161: 1413–1419.
Non-HDL-C and CVD risk
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, Conclusion: Non-HDL-C is a strong independent
LDL-C and TG was associated with
predictor of nonfatal myocardial infarction and
an increased risk of 4.3%, 3.3% and
1.6%, respectively. angina pectoris at five years.

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.
Summary of Studies Using Non-HDL-C as
Predictor of CV Events
Study Sample characteristics Primary outcome Main results

Cui et al. 20019
Bittner et al. 200210
Lu et al. 200311
4,462 participants
aged 40–64 years
1,514 patients with
coronary artery
disease
2,108 patients with
diabetes but no CVD
Cause of death (CVD-
related)
Death/nonfatal
myocardial infarction
Fatal/nonfatal CVD
• Non-HDL-C was the most
significant predictor of CVD
death (RR = 1.19)
• Non-HDL-C strongly predicted
nonfatal myocardial infarction
but not death
• Other lipids did not predict
outcomes
• Non-HDL-C was the strongest
predictor of CVD in diabetes,
and strongly predicted MI.

9. Cui Y, Blumenthal RS, Flaws JA, et al. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality.
Arch Intern Med 2001; 161: 1413–1419.
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.
11. Lu W, Resnick HE, Jablonski KA et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes. Diabetes Care
2003; 26: 16–23.
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
• 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

21. Hsia SH. Diabetes Care 2003; 26(1): 240–242.

22. Ferrari R, Aguiar C, Alegria E et al. Eur Heart J 2016; 18(suppl C): C2–C12.
14. Catapano AL, Graham I, De Backer G et al. Eur Heart J 2016; 37(39): 2999–3058.
22. Ferrari R, Aguiar C, Alegria E et al. Eur Heart J 2016; 18(suppl C): C2–C12.
24. Wiggins BS, Saseen JJ, Page RL et al.. Circulation 2016; 134: e468–495.
Combination treatment and non-HDL-C
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.
Combination treatment and non-HDL-C

Conclusion: Combined therapy showed significant improvements in lipid

profiles of high-risk patients with mixed hyperlipidaemia that was not
controlled with monotherapy.

28. Farnier M, Ducobu J, Bryniarski L. Efficacy and safety of adding fenofibrate 160 mg in high-risk patients with mixed hyperlipidemia not
controlled by pravastatin 40 mg monotherapy. Am J Cardiol 2010; 106: 787–792.
Combination treatment and non-HDL-C
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.
Combination treatment and non-HDL-C
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.
Statin + Fenofibrate combination therapy;
Summary of Findings
Study Sample characteristics/treatment Outcome measures Main results

Jones et al. 586 patients with mixed dyslipidaemia
201029 and type 2 diabetes given combination
therapy (statin + fenofibrate, various
doses) or statin monotherapy
Roth et al. 474 patients with mixed dyslipidaemia
201030 given simvastatin 40 mg or combination
therapy (rosuvastatin + fenofibrate,
various doses)
Farnier et al. 291 patients with type 2 diabetes and
201131 mixed hyperlipidaemia given
simvastatin 20 mg or fenofibrate 160
mg + pravastatin 40 mg
Chen et al. 112 patients with
201332 diabetes/atherosclerosis given
rosuvastatin 10 mg or fenofibrate 80 mg
+ rosuvastatin 5 mg
Proportion of • Combined treatment led
patients achieving to a 5-fold higher proportion of
optimal lipid levels patients achieving optimal
levels of Non-HDL-C
Mean percent change • Combination therapy led to
in Non-HDL-C from significantly larger decreases in
baseline Non-HDL-C than monotherapy
(p < 0.001)
Mean percent • Combined treatment led
change in non-HDL-C to significantly greater
reductions in Non-HDL-C than
monotherapy
(p = 0.018)
Changes in lipid • Combined therapy had
levels a similar effect on Non-HDL-C as
an increased statin dose.
However, combination therapy
was more cost-effective.
 Safety Concerns of Statin + Fenofibrate

• Fibrates are believed to increase the risk of myopathy when combined with
a statin by altering statin catabolism1
• Statins, including simvastatin, atorvastatin, and cerivastatin, have been
found in animal and human studies to undergo extensive glucuronidation.
• Gemfibrozil also undergoes glucuronidation, which interferes with statin
catabolism and thus causes an increase in plasma statin concentrations2
• Not all fibrates have this effect on statin metabolism. A study in human
hepatocytes found that while gemfibrozil inhibited the lactonization and
glucuronidation of simvastatin, fenofibrate did not appreciably affect
any of the metabolic pathways of simvastatin3
• Although fenofibrate also undergoes glucuronidation, the pattern of
isoform selectivity for fenofibrate is different than that for gemfibrozil and
statins, with less potential for interference with statin metabolism.

1. Thompson PD, Clarkson P, Karas RH. Statin‐associated myopathy. JAMA. 2003;289: 1681–1690.
2. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp
Ther. 2002;301: 1042–1051.
3. Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30: 1280–
1287.
Fibrates
Mechanism of Action, Effect on Non-
HDL-C, and CV Outcomes
Fenofibrates
• There are 2 types of fenofibrate in market
Fenofibrate (100 mg, 200 mg, 300 mg, 160 mg, 145 mg)
Fenofibric Acid 135 mg/Choline fibrate (Active form of Fenofibrate)
Keating GM, Ormrod D. Drugs 2002;62:1-35
 Effect of Fenofibrate vs Gemfibrozil on Statin
Plasma Levels

Michael H Davidson (2006) Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions, Expert Opinion on Drug Safety, 5:1,
145- 156, DOI: 10.1517/14740338.5.1.145
 Safety of fenofibric acid in combination with a statin in patients
with mixed dyslipidemia

The primary safety concern of combining fibrates with statins is the potential for increased muscle-
related adverse effects. Although myalgia was commonly reported (3.1%–6.1%), the incidence was the
same or lower in both combination therapy groups compared to any statin monotherapy arm, and
there was no report of rhabdomyolysis

Jones PH et al. Journal of Clinical Lipidology, Vol 3, No 2, April 2009

Evolution of Fenofibrate particles

Fenofibrate is highly lipophilic, virtually insoluble in water, and poorly absorbed. Coadministration
with meals was necessary to maximize bioavailability of early formulations.

Micronized and nanoparticle formulations of fenofibrate with reduced particle sizes were
developed, resulting in greater solubility, improved bioavailability, and ability to be given
irrespective of food. Nanoparticle formulations further reduced particle size, leading to a
significantly increased ratio of surface area to volume and greater bioavailability

Ling H, Luoma JT, Hilleman D. A Review of Currently Available Fenofibrate and Fenofibric Acid Formulations. Cardiol Res.
2013;4(2):47-55. doi:10.4021/cr270w
With nanoparticles fenofibrate 145mg
NFE (no food effect)

45 subjects received in a random order one 145 mg fenofibrate tablet under high-fat fed
(HFF), low-fat fed (LFF) or fasting (reference) conditions. Plasma concentrations of
fenofibric acid were determined up to 120 hours post-dose. Comparisons were
made between test (HFF and LFF) and reference conditions (fasting).

Sauron et al. International Journal of Clinical Pharmacology and Therapeu tics, Vol. 44 – No. 2/2006 (64-70)
Thank You