Low Hdl Hyper Tg

Hypertriglyceridemia and Low HDL:
Is it Linked with Increased Cardiovascular Risk?

Iris Thiele C. Isip Tan MD, FPCP, FPSEM
Ma. Luz Vicenta Guanzon MD, FPCP, FPSEM
Herbert Ho MD, FPCP, FPSEM

The Case

45/F comes in for a physical
Premenopausal
Nonsmoker
Sedentary
Cholecystitis at age 36
No medication

http://www.lipidsonline.org/clinical-cases

Family History

Both parents, ages 70 and
72: type 2 diabetes
Father: coronary heart
disease at age 60
Mother: stroke at age 66
Mother currently on
dialysis


Family History

2 of 3 brothers
have T2DM
All of her 3 children
obese
Daughter, age 16,
has “pre-diabetes”


Initial PE
BP 134/80 mm Hg
HR 76 bpm
Wt 200 lb Ht 5’4”
BMI 34.4 kg/m2
Waist 41”
Heart exam: normal
Abdomen: obese with RUQ scar


Initial Labs

FBS 118 mg/dL

TC 236 mg/dL

TG 200 mg/dL

LDL-C 140 mg/dL

HDL-C 46 mg/dL


Is this a high-
risk patient?

TC 236 mg/dL
TG 200 mg/dL
LDL-C 140 mg/dL
HDL-C 46 mg/dL

She has none of the
ATP-III risk factors

Cigarette smoking

Hypertension (BP >140/90 mm Hg
or on medication)

Low HDL cholesterol (<40 mg/dL)

Family history of premature CHD
(CHD in male ﬁrst degree relative
<55 y; CHD in female ﬁrst degree
relative <65 y)

Age (men >45 y; women >55 y)

NCEP-ATP III 2001

Life-habit
risk factors

Obesity

Physical inactivity

Atherogenic diet

NCEP-ATP III 2001

“The life-habit risk factors are direct targets for
clinical intervention, but are not used to set a
lower LDL cholesterol goal of therapy.”

NCEP-ATP III 2001

NCEP-ATP III
2001

Emerging
risk factors
Lp(a)
Homocysteine Impaired fasting glucose
Prothrombotic and Evidence of subclinical
proinﬂammatory factors atherosclerotic disease

“The emerging risk factors do not categorically
modify LDL-C goals ... utility in selected persons
to guide intensity of risk-reduction therapy.”

NCEP-ATP III 2001

NCEP-ATP III

Patient is low-risk

How will you
address the
patient’s
dyslipidemia?

Table 5: LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle
Changes (TLC) and Drug Therapy in Different Risk Categories.

Risk Category LDL Goal LDL Level LDL Level
at Which to Initiate at Which to
Therapeutic Lifestyle Consider Drug
Changes (TLC) Therapy
CHD or CHD Risk <100 mg/dL !100 mg/dL !130 mg/dL
Equivalents (100-129 mg/dL:
(10-year risk >20%) drug optional)*

10-year risk 10-20 %:
2+ Risk Factors <130 mg/dL !130 mg/dL !130 mg/dL
(10-year risk quot;20%) 10-year risk <10 %:
!160 mg/dL

0-1 Risk Factor† <160 mg/dL !160 mg/dL !190 mg/dL
(160-189 mg/dL:
LDL-lowering drug
optional)
* Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL
cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify tri-
glycerides and HDL, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy
in this subcategory.
† Almost all people with 0-1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in people with
0-1 risk factor is not necessary. NCEP-ATP III 2001

Table 5: LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle
Changes (TLC) and Drug Therapy in Different Risk Categories.

Risk Category LDL Goal LDL Level LDL Level
at Which to Initiate at Which to
Therapeutic Lifestyle Consider Drug
Changes (TLC) Therapy
CHD or CHD Risk <100 mg/dL !100 mg/dL !130 mg/dL
Equivalents (100-129 mg/dL:
(10-year risk >20%) drug optional)*

10-year risk 10-20 %:
2+ Risk Factors <130 mg/dL !130 mg/dL !130 mg/dL
(10-year risk quot;20%) 10-year risk <10 %:
!160 mg/dL

0-1 Risk Factor† <160 mg/dL !160 mg/dL !190 mg/dL
(160-189 mg/dL:
LDL 140 mg/dL: She is not a LDL-lowering drug
candidate for drug therapy! optional)
* Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL
cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify tri-
glycerides and HDL, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy
in this subcategory.
† Almost all people with 0-1 risk factor have a 10-year risk <10%, thus 10-year risk assessment in people with
0-1 risk factor is not necessary. NCEP-ATP III 2001

Figure IV.2–4. Therapeutic approaches to persons with 0–1 risk factor

The LDL cholesterol goal is <160 mg/dL. Drug therapy can be considered if the LDL cholesterol level is !190 mg/dL after a
trial of TLC. If LDL cholesterol is 160–189 mg/dL, drug therapy is optional depending on clinical judgment.

LDL Public Health M essages
<130 on Healthy Lif e Habits
Reevaluation: 5 Years

Public Health M essages
LDL
on Healthy Lif e Habits
130–159
Reevaluation: 1 Year

0–1 Risk Factor
(10-year risk
usually <10 %) LDL Continue
<160 TLC

LDL 3 mos
!160 TLC

Continue TLC &
LDL LDL-Lo w ering Drugs
160–189 O ptional*

Reinforce healthy life habits. LDL Continue TLC &

Re-evaluate after 1 year. !190 Consider A dding
LDL-Lo w ering Drugs

* Factors favoring drug use are a severe single risk factor, a family history of premature CHD, and/or underlying or emerging risk factors in addition
to a single major risk factor.

NCEP-ATP III 2002

Philippine Dyslipidemia
Guideline (2005) • Hypertension
• Familial
hypercholesterolemia
For low-risk patients • LVH
without evidence of • Smoking
atherosclerosis, drug • Family history of
therapy is not premature CAD
recommended, • Male sex
regardless of lipid levels • Age >55 years
• Proteinuria/
Low risk: <3 risk factors albuminuria
• BMI >25

For purposes of ATP III, the diagnosis of the metabolic syndrome i
when three or more of the risk determinants shown in Table 8 are
These determinants include a combination of categorical and bord
She has the Metabolic Syndrome
factors that can be readily measured in clinical practice.

Table 8. Clinical Identification of the Metabolic Syndrome

Risk Factor Defining Level
Abdominal Obesity* Waist Circumference †
Men >102 cm (>40 in)
Women 41 cm >88 cm (>35 in)
Triglycerides 200 mg/dL !150 mg/dL
HDL cholesterol
Men <40 mg/dL
Women 46 mg/dL <50 mg/dL
Blood pressure 134/80 mm Hg !130/!85 mmHg
Fasting glucose 118 mg/dL !110 mg/dL

NCEP-ATP III 2001
* Overweight and obesity are associated with insulin resistance and the metabolic syndrome. How

Metabolic syndrome confers intermediate risk

Same as NCEP-ATP III deﬁnition except cut-off for
abdominal obesity should geographic region-speciﬁc

LDL-C target for intermediate-risk: <130 mg/dL

High-risk <100 mg/dL and lower-to moderate-risk
patients <160 mg/dL

At all stages of dietary therapy, physicians are encouraged to refer patients
to registered dietitians or other qualified nutritionists for medical nutrition
therapy, which is the term for the nutritional intervention and guidance

Start TLC provided by a nutrition professional.

Figure 1. A Model of Steps in Therapeutic Lifestyle Changes (TLC)

Visit 1 Visit 2 Visit 3 Visit N
6 wks 6 wks Q 4-6 mos
Begin Lifestyle Evaluate LDL Evaluate LDL Monitor
Therapies response response Adherence to
TLC
LDL If LDL goal not
achieved, intensify
If LDL goal not
achieved, consider
140 mg/dL LDL-lowering Tx adding drug Tx

! Emphasize ! Reinforce
reduction in reduction in
saturated fat and saturated fat and ! Initiate Tx for
cholesterol cholesterol Metabolic
! Encourage ! Consider adding Syndrome
moderate physical plant stanols/sterols ! Intensify weight
activity ! Increase fiber intake management and
! Consider referral ! Consider referral physical activity
to dietitian to dietitian ! Consider refer-
Goal LDL ral to dietitian
<130 mg/dL NCEP-ATP III 2001

! Therapeutic options for enhancing LDL lowering such as plant
stanols/sterols (2 g/day) and increased viscous (soluble) fiber (10-25 g/day)
Weight reduction

Enforce TLC diet
!

! Increased physical activity

Table 6. Nutrient Composition of the TLC Diet

Nutrient Recommended Intake
Saturated fat* Less than 7 % of total calories
Polyunsaturated fat Up to 10 % of total calories
Monounsaturated fat Up to 20 % of total calories
Total fat 25-35 % of total calories
Carbohydrate † 50-60 % of total calories
Fiber 20-30 g/day
Protein Approximately 15 % of total calories
Cholesterol Less than 200 mg/day
Total calories (energy)‡ Balance energy intake and expenditure to
maintain desirable body weight/prevent
weight gain NCEP-ATP III 2001
* Trans fatty acids are another LDL-raising fat that should be kept at a low intake.
† Carbohydrate should be derived predominantly from foods rich in complex carbohydrates including grains,
especially whole grains, fruits, and vegetables.
‡ Daily energy expenditure should include at least moderate physical activity (contributing approximately
200 Kcal per day).

based on the literature. Although cumulative responses Because of th
have not been documented by clinical trial, a sizable long-term w
summed response from the multiple components of tion should b
LDL-Clikely. can be achieved with diet
TLC is goal individuals t
medical nutr
Table V.5–2. Approximate and Cumulative LDL Cholesterol
Reduction Achievable By Dietary Modification
A second ele
Dietary Dietary Approximate LDL drome is to
Component Change Reduction should provi
Major activity depe
Saturated fat <7 % of calories 8–10 % and social ci
Dietary cholesterol <200 mg/day 3–5 % given to refe
Weight reduction Lose 10 lbs 5–8 % if this resour
Other LDL-lowering options cise can caus
Viscous fiber 5–10 g/day 3–5 % for CHD. Ex
Plant sterol/ 2g/day 6–15 % that may be
stanol esters V.2–6 and V
Cumulative estimate 20–30 % should be pr
amounts of v
NCEP-ATP III 2002
Adapted From Jenkins et al. 768

American Heart Jour
ari et al July 20

Proportion and projected number of US adults
in 2007 with high LDL-C, TG and low HDL-C

nd projected number of US adults in 2007 (N = 212 million) with combinations of high LDL-C, triglycerides, and low HDL-C.
Ghandehari et al Am Heart J 2008

NNHES 2003: Mean Lipid Levels of Filipinos

Male Female
Total cholesterol 178.9 (0.98) 190.3 (1.13)
LDL-C 112.4 (0.89) 126.8 (1.03)
HDL-C 40.3 (0.24) 42.6 (0.24)
Triglyceride 130.5 (2.3) 104.6 (1.4)

Dans et al PJIM 2005

NNHES 2003: Prevalence of Abnormal Lipid Levels

Male (%) Female (%)
TC >240 mg/dL 5.8 (1.0) 11.5 (1.0)
LDL-C >190 mg/dL 2.0 (0.0) 5.4 (1.0)
HDL-C <40 mg/dL 60.2 (2.2) 47.7 (1.0)
TG 200-399 mg/dL 11.8 (1.0) 5.3 (1.0)

Dans et al PJIM 2005

HDL-C 46 mg/dL:
Is that low?

NCEP-ATP III
deﬁnes low
HDL as <40
mg/dL

NCEP-ATP III 2001

HDL-C 46 mg/dL:
Is that low?

NCEP-ATP III
deﬁnition of
Metabolic Syndrome:
HDL <50 mg/dL in
women

NCEP-ATP III 2001

High TG

TG Classiﬁcation:
Normal <150 mg/dL
Borderline-high 150-199 mg/dL
High 200-499 mg/dL
TC 236 mg/dL Very high >500 mg/dL
TG 200 mg/dL
LDL-C 140 mg/dL
HDL-C 46 mg/dL

NCEP-ATP III 2001

Is this a high-
risk patient?
Does the patient’s low
HDL-C and high TG
confer additional risk
over and above that
TC 236 mg/dL conferred by LDL-C
TG 200 mg/dL level?
LDL-C 140 mg/dL
HDL-C 46 mg/dL

when LDL-cholesterol is normal, or near-normal.22,23 onary heart disease, compared with those who do not.28
Other epidemiological evaluations have conﬁrmed these Data from the Health Survey for England show that HDL-
ﬁndings. The Atherosclerosis Risk in Communities study cholesterol ,0.9 mmol/L (35 mg/dL) is more common
(ARIC) followed 12 339 middle-aged subjects without cor- (P , 0.001) in men with cardiovascular disease (23%)
onary heart disease at baseline for 10 years.24 The risk of compared with men without cardiovascular disease
ARIC study: Cardiovascular risk increase
developing coronary heart disease was strongly related
to HDL-cholesterol in women and in men (Figure 1 ).
(16%).29 A similar association was found for women
(8 vs. 5%, respectively, P , 0.001). In men or women

as serum HDL-C decreases

N = 12 ,339 middle-aged subjects without coronary heart disease at
Figure 1 Relationship between HDL-cholesterol at baseline and cardiovascular risk in the Atherosclerosis Risk in Communities Study (ARIC). Adapted
with permission from Sharrett, Ballantyne, and Coady et al. 24
baseline; 10-y follow-up
Chapman J. Eur Heart J 2005

population. cholesterol at baseline (Figure 2 ). These findings are
consistent with the status of low HDL-cholesterol as an
independent risk factor for cardiovascular disease, as
atins eliminate the elevated coronary defined in epidemiological studies and described earlier.
Incidence of CV events in statin trials
y disease risk associated with low
cholesterol at baseline
Treatment with a statin provided similar absolute
reduction in cardiovascular risk at all levels of HDL-
inversely proportional to baseline HDL-C
ervention trials? cholesterol, as the curves for active treatment and
placebo in Figure 2 were, in general, roughly parallel.
rom some of the major intervention trials with Thus, a similar relationship between the levels of HDL-
have been stratified for HDL-cholesterol at cholesterol and cardiovascular risk holds in patients

Treatment with statin provided similar absolute
reduction in CV risk at all levels of HDL-C


greater predictive potential in women compared
36,37
with men (Figure 2). More recently, the Lipid
Research Clinics’ Follow-Up Study also demon-
Risk of Coronary Heart Disease Increases as
strated that both HDL-C and triglycerides were
Triglyceride Increases (Framingham Data)
TG and HDL-C levels may have greater predictive
potential in women than in men.

Adapted from Castelli WP. Am J Cardiol 1992

PROCAM scoring
scheme includes
triglycerides as major
independent risk factor.

Metabolic Syndrome increases CV risk
Multifactorial Causes of CHD in Metabolic Syndrome

Hyperglycemia
Hypertension Impaired
fibrinolysis
Atherogenic
dyslipidemia Insulin resistance Inflammatory
Hyperinsulinemia profile
Abdominal obesity

Ceska R. Diabetes Vasc Dis Res 2007

Anti-atherogenic action of HDL
Chapman MJ et al. Curr Med Res Opin 2004

Reverse Anti-
cholesterol inﬂammatory
transport activity Anti-
Anti-
infectious oxidative
activity
HDL activity
Anti- Anti-
thrombotic apoptotic
activity activity

CETP Inhibition (D): diminished heteroexchange of CE and TG between
HDL and TG-rich proteins with normalization of HDL-particle turnover

Torcetrapib: CETP Inhibitor

CETP inhibitors: most potent HDL-raising
agents available
Enhance reverse cholesterol transport from
peripheral tissues to liver
Correct HDL functional defects
High CETP activity in T2DM and MetSyn: enriches
TG content of HDL particles

Kontush et al. Nat Clin Pract Cardiovasc Med 2007

Are all types of HDL-C-raising dangerous? Is the speciﬁc
HDL-C-raising mechanism of Torcetrapib dangerous?

Investigation of Lipid Level Management to Understand
its Impact in Atherosclerotic Events (ILLUMINATE)
prematurely terminated Dec 2006: excess mortality
15,000 high CV-risk patients on atorvastatin randomized
to 60 mg torcetrapib or placebo (median 550 d)
HDL-C ↑72%, LDL-C ↓25%

CV mortality ↑40%, CV events ↑25%, non-CV death ↑100%

Kontush et al. Nat Clin Pract Cardiovasc Med 2007

TC 236 mg/dL
TG 200 mg/dL
LDL140 mg/dL

Will raising her
HDL-C reduce HDL
46 mg/dL
cardiovascular
risk?

Helsinki Heart Study:
Primary Prevention Every 1% increase
in HDL-C

34% reduction in coronary events
Raise HDL-C by 11%
3% decrease in
Reduce triglycerides by 35%
coronary events
Reduce LDL-C by 11%
Greatest beneﬁt for independent of
changes in
HDL-C <42 mg/dL (1.09 mmol/L)
triglycerides and
TG >200 mg/dL (2.20 mmol/L) LDL-C

Manninen V et al. JAMA 1988

Effect of various drug classes on coronary
stenosis progression or regression, as related to
in-treatment changes in LDL-C and HDL-C
Brown et al Should HDL-C and LDL-C be lipid therapy targets? 91
Brown et al J Clin Lipidology 2007
Change from baseline in mean

∆%S = 3.0 - 0.076 (%∆HDL-C) +0.06 (%∆LDL-C) R2=0.96; P<0.004
4 Placebo (6)
proximal % stenosis

Fibrates (1)
3 Statins (6)
Statin+Resin (1)
2
(∆%S)

Niacin Combos (4)

1
↑Progression
0
↓Regression
-1

-2
0 25 50 75
%∆ HDL-C minus %∆ LDL-C, in Rx
Placebo-adjusted (%)
Figure 1 Effect of various drug classes on coronary stenosis progression, or regression, as related to in-treatment changes in low-density

Effect of various drug classes on trial
primary clinical event rate, plotted against
in-treatment changes in LDL-C and HDL-C
92 Journal of Clinical Lipidology, Vol 1, No 1, March 2007
Brown et al J Clin Lipidology 2007

%Event Red’n = - 1.28(%∆HDL-C) + 0.97 (%∆LDL-C) R2=0.93; P<0.0001
0 Placebo(23)
Fibrates (3)
%∆ 1ry Event Rate

Statins (11)
-20 Statin+Resin (1)
Niacin (1)
Niacin Combos(5)
-40
(%)

Ileal Bypass (1)

-60

-80
0 25 50 75

%∆ HDL-C minus %∆ LDL-C, in Rx
Placebo-adjusted (%)

NCEP-ATP III recommendations
for the management
of Metabolic Syndrome

Reduce underlying causes (i.e.
obesity and physical inactivity)

Treat associated nonlipid and lipid
risk factors

Treatment of hypertension
Aspirin in patients with CHD to
reduce prothrombotic state
Treatment of elevated TG and low
HDL-C
NCEP-ATP III 2001

NCEP-ATP III:
Non-HDL cholesterol as secondary target of
therapy in those with high triglycerides
Table 9. Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals for
Three Risk Categories

Risk Category LDL Goal (mg/dL) Non-HDL-C Goal (mg/dL)
CHD and CHD Risk Equivalent <100 <130
(10-year risk for CHD >20 %)
Multiple (2+) Risk Factors and <130 <160
10-year risk quot;20 %
0-1 Risk Factor <160 236 - 46 = 190 <190

target of therapy. Aside from weight reduction and increased physical activi-
ty, drug therapy can be considered in high-risk persons to achieve the non-
HDL cholesterol goal. There are two approaches to drug therapy. First, the
NCEP-ATP III 2001

Approaches to reaching the
non-HDL-C goal

Intensify therapy with an LDL-lowering drug

Add nicotinic acid or ﬁbrate

NCEP-ATP III 2001

TC 236 mg/dL
HDL 46 mg/dL
LDL140 mg/dL

Will lowering
TG
her TG improve 200
cardiovascular mg/dL

outcomes?

Crucial Findings from Major Trials of Fibrate Therapy
Study Drug and Lipid Levels
Trial Duration (y) Population Daily Dose (% change) Outcomes
CHD: ↓9% (NS)
Men, secondary Clofibrate
CDP ~5 TC ~8; TG ~ -25 Total mortality: no change
prevention 1.6 g
↑cholelithiasis with clofibrate
Nonfatal MI: ↓25%
Men, primary Clofibrate Total mortality: ↑ with clofibrate
WHO 5.3 TC -9
prevention 1.6 g ↑ cholelithiasis and cholecystectomy
with clofibrate
Men, primary Gemfibrozil TC -11; LDL -10 CHD: ↓34%; Nonfatal MI: ↓37%;
HHS 5
prevention 200 mg TG -43; HDL +10 Total mortality: No change
Men, secondary Gemfibrozil TC -4; LDL 0; CHD death and nonfatal MI: ↓22%;
VA-HIT 5.1 TG -31; HDL +6
prevention 200 mg Total mortality: no change
Fatal and nonfatal MI and sudden
Men and women, Bezafibrate TC -4.5; LDL -6.5
BIP 6.2 death: ↓9% (NS);
secondary prev 400 mg TG -21; HDL +18
Total mortality: no change
CHD death and nonfatal MI: ↓11%
Men and women
Fenofibrate TC -11; LDL -12; (NS); Total CV events ↓11%;
FIELD 5 with diabetes
200 mg TG -29; HDL +5 total mortality: ↑19% with
mellitus
fenofibrate (NS)
CDP=Coronary Drug Project; WHO=World Health Organization; HHS=Helsinki Heart Study; VA-HIT=Veterans Affairs HDL
Intervention Trial; BIP=Bezafibrate Infarction Prevention; FIELD=Fenofibrate Intervention and Event Lowering in Diabetes
Backes et al Pharmacotherapy 2006

Mixed Results of Fibrate Trials?
Fibrate was not always the best choice of drug
therapy for patients enrolled in the trials
Primary lipid abnormalities were ↑LDL and TC

Study TC (mg/dL) HDL (mg/dL) LDL (mg/dL) TG (mg/dL)
CDP 251 NR NR NR
WHO 249 NR NR NR
HHS 270 47 189 175
VA-HIT 175 32 111 161
BIP 212 35 148 145
FIELD 195 43 119 154


Should we start a fibrate despite mixed results?

Trial data show 2 major subpopulations
that appear to receive the greatest clinical
benefit from fibrates
Mixed dyslipidemia: low HDL-C and elevated
triglycerides and/or
Impaired glucose homeostasis (T2DM,
prediabetes, metabolic syndrome)


Should we start a ﬁbrate despite mixed results?

Fibrates have demonstrated reductions in
some of the emerging CV risk factors
associated with mixed dyslipidemia and
metabolic syndrome
CRP level, ﬁbrinogen concentration, small dense
LDL particles


Would the
management
change if the
TC 236 mg/dL
patient was
TG 200 mg/dL diabetic?
LDL-C 140 mg/dL
HDL-C 46 mg/dL

Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD) Study

9, 795 T2DM patients in Australia and Finland
Low-risk population; lipid profile more usually treated
with a statin

Randomized to fenofibrate 200 mg or placebo and
co-prescription of other lipid-lowering agents (94%
statins) was allowed
Little information on combination: unequal statin drop-in

11% reduction in fatal and non-fatal coronary events
(p=0.16)
Wierzbicki W. Diab Vasc Res 2006

Start statin ADA 2008 Guideline
Statin + lifestyle
LDL-C goal in individuals therapy regardless of
without overt CVD: <100 mg/dL baseline lipid levels
(2.6 mmol/L) for diabetic patients
with
Alternative therapeutic goal in
overt CVD
those on maximal tolerated
statin therapy: ~40% reduction without CVD, >40
from baseline years and have one
or more other risk
TG level <150 mg/dL (1.7 mmol/ factors
L) and HDL-C >40 mg/dL (1.0
mmol/L) in men and >50 mg/dL
(1.3 mmol/L) in women

Philippine Dyslipidemia
Guideline 2005

Statement 6:
For diabetic patients without
evidence of atherosclerosis and with
TC >190 mg/dL or LDL >100 mg/
dL, statins are recommended.
Statement 7:
Fibrates may be recommended as an
alternative to statin in diabetic
patients with HDL <35 mg/dL and
LDL <90 mg/dL.

Statins: limited ability to raise HDL
HDL level by atorvastatin dose (STELLAR trial)
HDL Increase
Atorvastatin Dose
(mg/dL + SEM)
10 mg 2.9 + 0.05
20 mg 2.4 + 0.05
30 mg 2.2 + 0.04
40 mg 1.1 + 0.02
As dose of atorvastatin doubles, the effect upon HDL
elevation declines, and the change across all doses is modest

Choi et al Mt. Sinai J Med 2006

Safety concern with statin-fibrate combination

Potential increased risk for myopathy and
rhabdomyolysis
Originally observed with gemfibrozil + lovastatin
Gemfibrozil + cerivastatin; cerivastatin pulled out of the
market

Gemfibrozil ↑ blood concentrations of most statins:
partial inhibition of statin acid byproducts
Fenofibrate is safe: does not use this metabolic pathway

Miller M. Medscape Family Medicine 2007

Recognize predisposing factors for myopathy

Advanced age (>65 years)
Impaired renal function (GFR <30 ml/min)
Hepatic disease
Hypothyroidism
Small muscle mass
Female gender
Use low/starting dose of statin with fenoﬁbrate and titrate upward.

TC 236 mg/dL
HDL 46 mg/dL
LDL140 mg/dL

What are the
TG
beneﬁts of 200
combined statin mg/dL

and ﬁbrates?

HHS: Fibrate Most Beneﬁcial for High TG and Low HDL-C

Slide from Ballantyne C. Medscape CME

High “Residual Risk” of CVD in High TG Patient on Statin

HPS Collaborative Group. Lancet 2002;360:7-22
Sacks FM et al. Circulation 2000;102:1893-900


Low HDL-C is a Risk Factor in Statin-treated Patients:
A Meta-analysis of 14 Trials


Simvastatin Plus Fenoﬁbrate for Combined
Hyperlipidemia (SAFARI ) Trial
Grundy et al. Am J Cardiol 2005;95:462-8

Patients 21-68 y with combined hyperlipidemia (fasting
TG levels >150 and <500 mg/dL, and LDL-C >130 mg/dL
Slide from Dayspring T. Medscape CME

Therapies for Dyslipidemia
Evidence of reduction
Therapy ∆ LDL-C ∆ HDL-C ∆ TG of CV events
Statin ↓18-55% ↑5-15% ↓7-30% ↑↑↑
Niacin ↓5-25% ↑15-35% ↓20-50% ↑↑
Fibrate ↓5-20% ↑10-35% ↓20-50% ↑↑
Bile-acid No effect or
↓15-30% ↑3-5% ↑↑
sequestrant increase
Rx omega-3
↑45% ↑9% ↓45% ↑↑↑
fatty acid
Ezetimibe ↓18% ↑1% ↓8% None


Therapeutic strategies for HDL-raising across a
wide range of low HDL-C phenotypes

Monotherapy (%) Combination therapy (%)
Up to 10
Statins Nicotinic acid + statin +30 (HATS)
(CARE, HPS, ASCOT-LLA)
Up to 10 +37 (CLAS-I)
Fibrates Nicotinic acid + BAS
(VA-HIT, DAIS, HHS) +43 (FATS)

Nicotinic acid Up to 35 Statin + ﬁbrate Up to 25

Statin + BAS Up to 15

ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial (lipid-lowering arm); BAS, blie acid sequestrant; DAIS, Diabetes
Atherosclerosis Intervention Study; HHS, Helsinki Heart Study; HPS, Heart Protection Study;VA-HIT,Veterans Affairs HDL
Intervention Trial


TC 236 mg/dL
TG 200 mg/dL
LDL140 mg/dL

What are the
beneﬁts of HDL
combined statin 46 mg/dL
and nicotinic
acid?

ol, with iﬁes low HDL-cholesterol as an important and indepen-
atin and dent risk factor for adverse cardiovascular outcomes
in HDL- (aforementioned), these guidelines tend to regard low
Combination treatment simultaneouslyas a
olesterol HDL-cholesterol more as a marker of risk, and
outcome reducing LDL-C data package required for global
component of the and increasing HDL-C
nt Study cardiovascular risk calculators. For example, those
eatment more effective in CV risk reduction
Athero- Chapman J. Eur Heart J 2005
on regi-
a statin
reducing
bination
d reduce
greater
eatment
ces LDL-
ast, the
as been
ﬂushing.
h the use
ing with
earance
formu-

The Safety and EfﬁcAcy of a COmbination of
NiAcin ER with SimvasTatin in Patients with
Dyslipidemia: A Dose-Ranging Study

highly atherogenic lipid profile. A wo
Long-term efficacy of USA reached similar conclusions reg
ance of low HDL-cholesterol as a t
Discussion
Niaspan combined and recommended ‘more frequent an
intervention to correct low HDL-chole
Substantial, and growing, epidemiological evidence has
associated lowa statin
with HDL-cholesterol with an increased risk of The improvements in the measurem
Eligible patients
of low HDL-cholesterol implicit in thes
will support the future recognition of l
TG <9.0 mmol/L (<800
alongside raised LDL-cholesterol as a
mg/dL)
target for intervention. Indeed, corr
One of the following
cholesterol should appear in mana
in its own right. Given the likely
CAD or DM with LDL-C
>3.4 mmol/L (>130 mg/
dL)
Table 2 CAD or DM to the position pap
No Contributors but
European Consensus Panel on HDL-choles
other coronary risk
factors with LDL-C >4.1 Thomas F
Gerd Assmann
(Germany) (>160 mg/dL)
mmol/L (Switze
D John Betteridge DM,
No CAD or (UK) Luis Masa
Eric Bruckert (France) Rodolfo P
maximum of 1 coronary
M John Chapman (France) Bernhard
risk factor with LDL-C Terje R P
Eduardo de Teresa (Spain)
Figure 4 Long-term efficacy of Niaspanw combined with a statin.55
Figures in parentheses are numbers of patients. Eligible patients had
>4.9 mmol/L (>190 mg/ James Sh
Jean-Charles Fruchart
serum triglycerides 9.0 mmol/L (800 mg/dL) and satisfied one of dL)
(France)
three further enrolment criteria: (a) positive history of coronary artery Andreas Hamann (Germany) Cesare Si
disease or diabetes together with serum LDL-cholesterol 3.4 mmol/L Markolf Hanefeld (Germany) Luc Van G
(130 mg/dL); (b) no history of coronary artery disease or diabetes,
Francis Heller (Belgium) Eur Heart J 2005 W
Chapman J. Anthony
but with other coronary risk factors together with serum LDL-

COMBination of Prescription
Omega-3s with Simvastatin: COMBOS

Adapted from Davidson MH et al Clin Ther 2007;29:1354-1367

Summary
45/F with Met Syn
Low-risk if individual risk
factors assessed: TLC
Intermediate risk if Met Syn:
TLC, may consider ﬁbrates
If patient were T2DM: statin
Limited studies for
combination therapy

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