Dyslipidemia 2016

Updates in themanagement of dyslipidemia 2016

Prescribe statin up to the
highest recommended
dose, or highest
tolerable dose to reach
the target level

Risk Levels
 Very High Risk:
 A calculated SCORE ≥10%
 Documented CVD by invasive or non-invasive testing
 Type 2 diabetes, type 1 diabetes with target organ damage
 Moderate to severe CKD
ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2011 Jul;32(14):1769-818.

Risk Levels
 High Risk:
 A calculated SCORE ≥5 to <10%
 Markedly elevated single risk factors
 Moderate Risk:
 A calculated SCORE ≥1 to <5%
 Low Risk:
 A calculated SCORE <1%

VERY HIGH RISK: LDL-C< 1.8 mmol/L (<70mg%) and/or ≥ 50% LDL –C
reduction(IA)
HIGH RISK: LDL-C< 2.5 mmol/L (<100mg%) (IIa A)
MODERATE RISK:LDL-C< 3 mmol/L (<115mg%) (IIa C)
Recommendations for treatment targets for LDL-C

3. M. Bucci, A. Mezzetti, per conto della SISA sezione Abruzzo
1. Grundy SM et al. Circulation 2004; 110:227-239
2. Smith S. et al. J.Am. Coll. Cardiol. 2006; 2130-2139
Baseline LDL-C LDL-C reduction to reach target
> 200 > 50%
180-200 45-50%
160-180 40-45%
140-160 30-40%
120-140 20-30%
TARGET LDL-C < 100 (2.6)

Baseline LDL-C LDL-C reduction to reach target
> 200 > 50%
180-200 > 50%
160-180 > 50%
140-160 > 50%
120-140 40-50%
3. M. Bucci, A. Mezzetti, per conto della SISA sezione Abruzzo
1. Grundy SM et al. Circulation 2004; 110:227-239
2. Smith S. et al. J.Am. Coll. Cardiol. 2006; 2130-2139
TARGET LDL-C < 70 (1.8)

ROSUVA 20 mg
ROSUVA 40 mg
Average LDL-C Reduction from baseline (%)
-20 -25 -30 -35 -40 -45 -50 -55 -60
ROSUVA 10 mg
ATORVA 20 mg
ATORVA 40 mg
ATORVA 80 mg
ATORVA 10 mg
SIMVA 20 mg
SIMVA 40 mg
SIMVA 10 mg
FLUVA 80 mg
PRAVA 40 mg
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160
Statin ?

• If non-HDL-C is used, the targets should be;
<2.6 mmol/L (<~100 mg/dL) in those at VERY HIGH CV risk and
<3.3 mmol/L (<~130 mg/dL) in those at HIGH CV risk
(class IIa B)
• If apo B is available, the targets are;
<80 mg/dL in those at VERY HIGH CV risk and
<100 mg/dL in those at HIGH CV risk
(class IIa B)
Treatment Targets Other Than LDL-C

Moderate to Severe Chronic Kidney Disease
 Statins→beneficial effect on
pathological proteinuria (>300 mg/day);
considered in stage 2-4 CKD patients
(class IIa B)
 Statins (as monotherapy or in
combination with other
drugs)→considered to achieve LDL-C
<1.8 mmol/L (<~70 mg/dL)(class IIa C)

Familial Hypercholesterolaemia
 FH is suspected in subjects with
 CVD aged <50 years (♂) or <60 years (♀),
 relatives with premature CVD,
 known FH in the family.
 Confirm the diagnosis with clinical criteria or with DNA analysis.
 Family screening is indicated when a patient with HeFH is
diagnosed.

If TG are 200–499 mg/dL, non-HDL-C should
be <130 mg/dL
Lipid Management in high TG:
Recommendation
l lla llb lll
B
l lla llb lll
B
Further reduction of non-HDL-C to <100 mg/dL is reasonable
Therapeutic options to reduce non-HDL-C:
More intense LDL-C–lowering therapy I (B) or
Niacin (after LDL-C–lowering therapy) IIa (B) or
Fibrate (after LDL-C–lowering therapy) IIa (B)
l lla llb lll
C
If TG are >500 mg/dL, therapeutic options to prevent
pancreatitis are fibrate or niacin before LDL lowering
therapy; and treat LDL-C to goal after TG-lowering therapy,
Achieve non-HDL-C <130 mg/dL, if possible
TG=Triglycerides; HDL-C=high-density lipoprotein cholesterol
Smith SC Jr et al. Circulation 2006;113:2363–2372.

Management of Lipids in Adults with Diabetes Mellitus
Goal Borderline risk High risk
Treatment decisions based on LDL cholesterol levels in adults with diabetes mellitus
Patients without:
• Cardiovascular Heart Disease (CHD)
• Peripheral Vascular Disease (PVD)
• Cerebrovascular Disease (CVD)
LDL < 100
At Goal
(recheck yearly)
Initiate Lifestyle
intervention, including
Medical Nutrition
Therapy (MNT) and
Drug Therapy
At Goal
(recheck yearly)
LDL 100-129 LDL  130
Yes No Yes No
Initiate
Lifestyle
Intervention,
MNT & Drug
Therapy
Initiate
MNT
Treatment options for diabetic patients without CHD,
PVD, or CVD with LDL 100-129 mg/dl
Initiate/intensify lifestyle
and/or drug therapies specifically
to lower LDL for 3-6 months
Emphasize weight reduction and increase
physical activity in persons with the
metabolic syndrome
Recheck LDL in 3-6 months; if not at goal,
consider drug treatment with a statin
Patients with:
• Cardiovascular Heart Disease (CHD)
• Peripheral Vascular Disease (PVD)
• Cerebrovascular Disease (CVD)
Or
Adapted from: Diabetes Care, vol. 36,
Supplement 1, January 2013
*ADA 2013 Update:
In people with diabetes over the age
of 40 without CVD who have one or
more other CVD risk factors, statin
therapy to achieve LDL reduction of
approximately 30% may be
appropriate, regardless of baseline
levels.
LDL < 70 is an option
Statin Therapy is
contraindicated
in pregnancy
LDL cholesterol < 100 mg/dl 100-129 mg/dl *  130 mg/dl
HDL cholesterol
> 40 mg/dl (men)
> 50 mg/dl (women)
35-45 mg/dl < 35 mg/dl
Triglycerides < 150 mg/dl 200-399 mg/dl  400 mg/dl
Non-HDL cholesterol (Total Chol – HDL) treatment goal = 30 mg/dl above LDL treatment target.
In the absence of severe hypertriglyceridemia
(>1,000 mg/dl), therapy targeting low HDL and/or
elevated triglycerides lacks the strong evidence
base of statin therapy to lower LDL cholesterol.

Reduction in Total (First and
Recurrent) Cardiovascular Events
with Ezetimibe/Simvastatin
compared with Simvastatin Alone
post ACS in the IMPROVE-IT Trial
Sabina A. Murphy, Christopher Cannon, Robert Giugliano, Michael
Blazing, Thomas Musliner, Andrew Tershakovec, Jennifer White, Kelly Im,
Naveen Deenadayalu, Haral Darius, Witold Ruzyllo, Andrew Tonkin, Uma
Kher, Robert Califf, Eugene Braunwald
On behalf of the IMPROVE IT Investigators

Patients stabilized post ACS ≤ 10 days:
LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
Simvastatin
40 mg
Duration: Minimum 2 ½-year follow-up (5314 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Study Design
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

The Statin Decade:
For LDL: “Lower is Better”
0
5
10
15
20
25
30
R² = 0.9029
p < 0.0001
LDL Cholesterol (mg/dl)
CHDEvents(%)
Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.
30 50 70 90 110 130 150 170 190 210
4S
CARE
LIPID
HPS
PROVE IT –TIMI 22
IMPROVE IT66
52
TNT

Downloaded from www.ezetrol.ae
Ezetimibe Coadministered with
Atorvastatin in Patients with
Hypercholesterolemia and
Coronary Heart Disease
Results of Two Randomized, Double-Blind, Placebo-
Controlled Trials

Downloaded from www.ezetrol.ae
Summary and Conclusions
• Ezetimibe coadministered with atorvastatin 10 or 20 mg
was significantly* more effective than atorvastatin in
CHD patients
 More patients achieved LDL-C goal (≤2.60 mmol/L)
 Greater reduction in LDL-C
 Improved lipid profile—TC, TG, HDL-C,** cholesterol ratios
• Ezetimibe coadministered with atorvastatin was well tolerated
 Similar to atorvastatin alone
• Treating two sources (production and absorption) of cholesterol
ensured more patients achieve their lipid lowering goals
*p≤0.001; **p=0.021

Reference
Age Risk Factors Statin Intensity*
<40 years
None None
ASCVD risk factor(s)** Moderate or high
ASCVD High
40–75 years
None Moderate
ASCVD risk factors High
ACS & LDL >50 who can’t
tolerate high dose statin
Moderate + ezetimibe
>75 years
None Moderate
ASCVD risk factors Moderate or high
ASCVD High
ACS & LDL >50 who can’t
tolerate high dose statin
Moderate + ezetimibe
Recommendations for Statin
Treatment in People with Diabetes
* In addition to lifestyle therapy. ** ASCVD risk factors include LDL cholesterol ≥100 mg/dL (2.6 mmol/L),
high blood pressure, smoking, overweight and obesity, and family history of premature ASCVD.
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular
disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

Reference
● Combination therapy (statin/fibrate)
doesn’t improve ASCVD outcomes and is
generally not recommended A. Consider
therapy with statin and fenofibrate for men
with both trigs ≥204 mg/dL (2.3 mmol/L)
and HDL ≤34 mg/dL (0.9 mmol/L). B
● Combination therapy (statin/niacin) hasn’t
demonstrated additional CV benefit over
statins alone, may raise risk of stroke & is
not generally recommended. A
● Statin therapy is contraindicated in
pregnancy. B
Recommendations:
Lipid Management
American Diabetes Association Standards of Medical Care in Diabetes. Cardiovascular
disease and risk management. Diabetes Care 2016; 39 (Suppl. 1): S60-S71

2013 ACC/AHA Guideline on the Treatment of Blood
Cholesterol to Reduce Atherosclerotic Cardiovascular
Risk in Adults
ATP IV

Summary of Statin Initiation Recommendations to
Reduce ASCVD Risk

Clinical ASCVD: Initiating Statin Therapy
*Fasting lipid panel preferred.
In a nonfasting individual, a
nonfasting non-HDL–C ≥220
mg/dL may indicate genetic
hypercholesterolemia that
requires further evaluation or a
secondary etiology. If
nonfasting triglycerides are
≥500 mg/dL, a fasting lipid
panel is required.
†It is reasonable to evaluate
the potential for ASCVD
benefits and for adverse
effects, and to consider patient
preferences, in initiating or
continuing a moderate- or high-
intensity statin, in individuals
with ASCVD >75 years of age.

Intensity of Statin Therapy
*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice.
There might be a biologic basis for a less-than-average response.
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is
not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis.

What about individuals of
“intermediate risk” (<7.5% ASCVD
risk)?
• Optional additional risk measurement tools
to refine predicted risk
– Family history of premature ASCVD?
– High-sensitivity CRP
– Coronary artery calcium
– Ankle brachial Indices (ABI)

Individuals Not in a Statin Benefit Group
• In those for whom a risk decision is uncertain, these
factors may inform clinical decision making:
• Family history of premature ASCVD
• Elevated lifetime risk of ASCVD
• LDL-C ≥160 mg/dL
• hs-CRP ≥2.0 mg/L
• CAC score ≥300 Agaston units
• ABI <0.9
• Statin use still requires discussion between clinician
and patient

Is the Patient at High Risk of ASCVD?
High-risk defined as ≥1 of the following:
• Clinically established coronary heart disease
• Cerebrovascular disease
• Peripheral arterial disease
• Abdominal aortic aneurysm
• Diabetes mellitus
• Chronic kidney disease
• 10-year predicted ASCVD risk ≥7.5% by
Pooled Cohort Equation

Yes: Patient is at High-Risk of ASCVD
Implement treatment recommendations:
• A – Aspirin / Antiplatelet therapy
• B – Blood pressure control
• C – Cholesterol control /Cigarette smoking
cessation
• D – Diet and weight management / Diabetes
and blood sugar control
• E – Exercise

Yes: Patient is at Intermediate Risk
of ASCVD
Consider additional testing to further assess risk:
• CT scan for coronary artery calcium (CAC)
score
• Measure high-sensitivity C-reactive protein
(hsCRP)
Do additional tests indicate that patient may
benefit from treatment because they are really at
higher risk?

Evolution of NCEP ATP III to ACC/AHA- ATPIV
III
2013 Guideline
NCEP ATP III AHA/ACC
Year
introduced
2001 (updated in 2004) 2013
Focus • Reducing risk of coronary heart disease
(CHD)
• Reducing risk of atherosclerotic CV disease (ASCVD),
which includes CHD events as well as stroke/TIA,
peripheral arterial disease or revascularization
Risk
Assessment
• Risk categories / major risk factors that
modify LDL-C goals
• Framingham 10-year Risk Score (CHD death
+ nonfatal MI)
• Pooled Cohort Equations (Fatal and nonfatal CHD +
fatal and nonfatal stroke)
Risk
Categories
• 3 main risk categories : CHD or CHD risk
equivalent, 2+ risk factors with 10-yr CHD
risk ≤20%, 0-1 risk factor + 10-yr risk
<10%
• CHD risk equivalent: diabetes, clinical CHD,
symptomatic carotid artery disease,
peripheral artery disease
• 4 statin benefit groups: Clinical ASCVD, Primary
elevations of LDL–C ≥190 mg/dL (≥4.9 mmol/L),
Diabetes without clinical ASCVD, No diabetes or CVD
with 10-year ASCVD risk ≥7.5%
Treatment
Targets
• LDL-C = primary target
• CHD or CHD risk equivalents: <100 mg/dL
(<2.6 mmol/L) (option < 70 mg/dL [<1.8
mmol/L] in very high risk patients)
• 2+ risk factors with 10-yr CHD risk ≤20%:
<130 mg/dL (<3.4 mmol/L) (Option <100
mg/dL [<2.6 mmol/L] if 10-20% risk), 0-1
risk factor + 10-yr risk <10%: <160 mg/dL
(<4.1 mmol/L)
• Intensity of statin therapy
• High intensity statin therapy (LDL-C reduction
>50%) recommended for most patients in 4 statin
benefit groups:
• Atorvastatin 40 or 80 mg
• Rosuvastatin 20-40 mg
Treatment
Recommendati
ons
• Statin (or bile acid sequestrant or nicotinic
acid) to achieve LDL-C goal
• Maximally tolerated statin first-line to reduce risk of
ASCVD events

Statin Treatment: Heart Failure
and Hemodialysis
The Expert Panel makes no
recommendations regarding the initiation or
discontinuation of statins in patients with
NYHA class II–IV ischemic systolic heart
failure or in patients on maintenance
hemodialysis.
No
recommendation

Nonstatin Safety: Fibrates
Renal status should be evaluated before
fenofibrate initiation, within 3 months after
initiation, and every 6 months thereafter. Assess
renal safety with both a serum creatinine level
and an eGFR based on creatinine.

Nonstatin Safety: Fibrates (cont.)
Harm
 Fenofibrate should not be used if moderate or
severe renal impairment, defined as eGFR <30
mL/min per 1.73 m2, is present.
 If eGFR is between 30 and 59 mL/min per 1.73 m2,
the dose of fenofibrate should not exceed 54
mg/day*.
 If, during follow-up, the eGFR decreases
persistently to ≤30 mL/min per 1.73 m2, fenofibrate
should be discontinued.
*Consult the manufacturer's prescribing information as there are
several forms of fenofibrate available.

Take Home Message
1. Rather than LDL–C or non-HDL– C targets, new guideline
uses the intensity of statin therapy as the goal of
treatment.
2. Know the 4 Statin Benefit Groups:
I. Individuals with clinical ASCVD
II. Individuals with primary elevations of LDL–C ≥190 mg/dL
III. Individuals 40 to 75 years of age with diabetes and LDL–C 70
to189 mg/dL without clinical ASCVD
IV. Individuals without clinical ASCVD or diabetes who are 40 to 75
years of age with LDL–C 70 to 189 mg/dL and have an estimated
10-year ASCVD risk of 7.5% or higher. (using the Pooled Cohort
Equations for ASCVD risk prediction)

Goals
LDL-C Non–HDL-C Apo B
Highest-Risk Patients <70 mg/dL <100 mg/dL <80 mg/dL
• Known cardiovascular disease (CVD)
• Diabetes plus ≥1 additional major CVD risk factor
High-Risk Patients <100 mg/dL <130 mg/dL <90 mg/dL
• No diabetes or known CVD but ≥2 major CVD risk factors
• Diabetes but no other major CVD risk factors
“In individuals on statin therapy who continue to have low HDL-C or elevated non–HDL-C,
especially if Apo B levels remain elevated, combination therapy is recommended.
The preferred agent to use in combination with a statin is nicotinic acid…”
Reprinted from Brunzell JD, et al. J Am Coll Cardiol.
2008;51:1512–1524, with permission from Elsevier.
Treatment Goals for Patients With
Cardiometabolic Risk and Lipoprotein Abnormalities

Dyslipidemia 2016

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