Dyslipidemia Management : Time To Act

Nanang Miftah Fajari

Diabetes And Cardiovascular Disease

• CVD is the major cause of morbidity,

mortality for those with diabetes
– Largest contributor to direct/indirect costs
• Common conditions coexisting with type 2
diabetes (e.g., hypertension, dyslipidemia)
are clear risk factors for CVD
• Benefits observed when individual
cardiovascular risk factors are controlled
to prevent/slow CVD in people with
diabetes

ADA. VI. Prevention, Management of Complications. Diabetes Care 2014;37(suppl 1):S36

Global Burden of Cardiovascular Disease
According to WHO estimates:
• 16.6 million people die of CVD worldwide each year
• CVD contributed to approximately one third of
global deaths

In 2001:
• 7.2 million deaths from CHD
• 5.5 million deaths from stroke

Adapted from International Cardiovascular Disease Statistics 2003; American Heart Association
4
 Risk Factors for Cardiovascular Disease

• Modifiable • Non-modifiable
– Smoking – Personal history of CHD
– Dyslipidaemia – Family history of CHD
– Age
• raised LDL cholesterol – Gender
• low HDL cholesterol
• raised triglycerides
– Raised blood pressure
– Diabetes mellitus
– Obesity
– Dietary factors
– Thrombogenic factors
– Lack of exercise
– Excess alcohol consumption
Multiple risk factors for CHD are usually present in an individual

Hypertension
(SBP >195 mmHg)

x3

x4.5 x9
x16
x1.6 x6 x4
Smoking

Serum cholesterol level

(>8.5 mmol/L, 330 mg/dL)

Adapted from Poulter N et al., 1993

 Cholesterol: A Major Risk Factor
• In the USA, 102 million people have elevated
total cholesterol (>200 mg/dL, 5.2 mmol/L)1
• In EUROASPIRE II, 58% of patients with established CHD
had elevated total cholesterol
(5 mmol/L, 190 mg/dL)2
• 10% reduction in total cholesterol results in:
– 15% reduction in CHD mortality (P<0.001)
– 11% reduction in total mortality (P<0.001)3

• LDL-C is the primary target to prevent CHD

Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II
Study Group. Eur Heart J 2001;22:554–572; 3. Gould AL et al. Circulation 1998;97:946–952.
 Spectrum of CHD Risk – to guide lipid-lowering strategy
Should we treat low HDL?

 HDL-C
­TG
+
LDL-C
Glucose intolerance
Abdominal obesity
 BP

Metabolic
Syndrome

Achieving low LDL/total cholesterol target Lipid-lowering guidelines (JBS-2, NICE type 1 DM)
evidence and young diabetics
how to achieve it? ?role of metabolic syndrome

Expert Panel. JAMA 2001;285:2486-2497.

 Part of the complex approach
to decrease CV RISK
Dyslipidemia
Management
Influence all lipid parameters

LDL-C – The first target

HDL-C,TGs, apoB…

To lower MACROvascular risk

To lower MICROvascular risk

To lower CV morbidity and mortality

 Pleiotropic effects of statins
 Coagulation

 Platelet activation  Endothelial

progenitor cells

 Endothelial function
 NO bioactivity  Effects on collagen
 Reactive oxygen  MMPs
species
Statins

 AT1 receptor
 Macrophages  VSMC proliferation
 Inflammation
 Immunomodulation
 Endothelin

MMPs = matrix metalloproteinases Liao JK. Am J Cardiol. 2005;96(suppl 1):24F-33F.

 HMG-CoA Reductase Inhibitor: Mechanism of Action

Cholesterol VLDL
synthesis
LDL receptor Apo B LDL-R–mediated hepatic
VLDLR
(B–E receptor) uptake of LDL and VLDL
synthesis Apo E
remnants
Intracellular Serum LDL-C
Cholesterol LDL Apo B Serum VLDL remnants
Serum IDL

Hepatocyte Systemic Circulation

The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which
stimulates upregulation of the LDL receptor and increases uptake of non-HDL particles from
the systemic circulation
 Mechanism of Benefit of Statins in
Secondary Prevention
• Regression of atherosclerosis
• Plaque stabilization
• Reduced inflammation
• Decreased thrombogenicity
• Reversal of endothelial dysfunction
• Others
– Reduced monocyte adhesion to endothelium
– Reduced oxidative modification of LDL
– Increased mobilization and differentiation of endothelial
progenitor cells leading to new vessel formation
 How Much of the “Atheroma Volume” Can Be
Mobilized?
Small changes in percent atheroma volume (-1.06%)
may translate into large changes in the plaque lipid content

Necrotic Core
(15%–25%)
Cholesterol
Clefts
(5%–10%)
Potential
for Lipid Macrophage
(10%–20%)
Mobilization

Modified from Virmani R et al. Arterioscler Thromb Vasc Biol. 2000; 20:1262-1275.
 Risk Reduction for CHD Events
As a Function of Changes in TC, LDL-C, and HDL-C

PERCENT CHD EVENT

CHANGE RATE

*4S, CARE, LIPID, WOSCOPS

**HELSINKI, VA-HIT,AFCAPS/TexCAPS
 Meta-analysis of statin treatment in diabetes

Risk reduction of clinical outcomes

reduction in LDL cholesterol
• 21% reduction major vascular events
• 25% reduction in coronary revascularisation
LDL
• 21% reduction in stroke

• 9% reduction in all-cause mortality

• 13% reduction in CVD mortality
• No difference in non-vascular mortality
Independent of baseline LDL or prior CVD

per 40 mg/dL (1.0 mmol/L)

Lancet, 371, 117-25, 2008

 Rosuvastatin

is the most effective statin at lowering LDL-C

and produces a significant increase in HDL-C
Comparation of Statin Drugs

Roberts WC. Am J Cardiolo. 1997;80:106-107.

Stein E et al. J Cardiovasc Rharmacol Therapeu. 1997;2:7-16
 Pharmacologic Therapy:
Statins-Dose Response
Response to Minimum/Maximum Statin Dose
Fluvastatin Pravastatin Lovastatin Simvastatin Atorvastatin Rosuvastatin
20/80 mg 20/80 mg 20/80 mg 20/80 mg 10/80 mg 10/40 mg
% Reduction in LDL-C

31
37*
40
47
55 55
Adapted from Illingworth. Med Clin North Am. 2000;84:23.
*Pravachol® (pravastatin) PI.
*CRESTOR (rosuvastatin) for active control study PI.
 CRESTOR effectively raises HDL-C 1

12

10
LS mean % change from baseline

0
10 20 40 80
Log scale
Dose (mg)
CRESTOR atorvastatin simvastatin pravastatin

STELLAR Study. Am J Cardiol 2003; 92: 152–60.

 Rosuvastatin reduces in Inflammatory Marker
C-Reactive Protein (ANDROMEDA)
8 weeks 16 weeks
RSV ATV RSV ATV
10 mg 10 mg 20 mg 20 mg
0

-5

-10
baseline in hsCRP (%)

-15
Mean change from

-21.2
-20
Rosuvastatin (RSV)
-25 Atorvastatin (ATV)
-30
-34.0 -33.8
-35
-39.8
-40

-45 74th EASC 17-20 April 2004, Seville, Spain

 Rosuvastatin Safety

Safety profile of rosuvastatin, including

effects on liver enzymes and creatine
kinase, compares favorably to those of
other marketed statins from 10–40 mg
daily in all pre-approval studies
• Hydrophilic properties
• Good selectivity for target organ – liver
• Limited metabolism by cytochrome P450
(2C9‚2C19)
 Rosuvastatin – Liver Effects

Persistent ALT >3 × ULN: Frequency by

LDL-C Reduction

Rosuvastatin (10–40 mg)

Atorvastatin (10–80 mg)
3.0 Simvastatin (40–80 mg)
Lovastatin (20–80 mg)
Persistent ALT >3 × ULN (%)

2.5 Fluvastatin (20–80 mg)

2.0

1.5

1.0

0.5

0.0
20 30 40 50 60 70
LDL-C reduction (%)
Persistent elevation is elevation to >3 x ULN on 2 successive occasions

Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

 Decrease of CV RISK

Hypolipidemic treatment
Dyslipidemia
Management LDL-C - main target
of treatment, than RR
as a part of
complex Highers doses
„The Lower The Better“
approach (higher prices)

More patients
(not at desired goal)

„The Earlier The Better“ Longer

treatment

„The Longer The Better“ Longer

treatment

Use therapy which is effective, safe, well tolerated, supported

by EBM data in appropriate dose.
New Guideline: 4 Statin Benefit Goups

Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline

 Optional Statin Therapy

Stone NJ, et al. 2013 ACC/AHA Blood Cholesterol Guideline

ESC 2019 Dyslipidemia Guideline1
New LDL- C target for very high risk (<55 mg/dL)

High-intensity statin is recommended (class IA) to prescribed up to Mach F, et al. European Heart Journal. 2019; 00: 1-78.
the highest tolerated dose to reach the goals
 Treatment Target of LDL-C

Risk level LDL-C target (mg/dl)

Very high ↓≥50% and <55*

High ↓≥50% and <70

Moderate <100

Low <116

* <40 mg/dl may be considered for patients with ASCVD who experience a
second vascular event within 2 years

Mach F, et al. European Heart Journal. 2019; 00: 1-78.

 Initiation of Treatment

Mach F, et al. European Heart Journal. 2019; 00: 1-78.

DISCLAIMER: Crestor has not yet been approved by BPOM RI for primary prevention. The information should under no circumstances be regarded as a
recommendation for use of Crestor in Primary Prevention
 Drugs Choice
High-intensity Moderate-intensity Low-intensity
statin therapy (mg) statin therapy (mg) statin therapy (mg)
Daily dose lowers Daily dose lowers Daily dose lowers
LDL-C on average, LDL-C on average, LDL-C on average,
by approx. ≥50% by approx. 30% to <50% by approx. <30%

Atorvastatin 40-80 Atorvastatin 10-20 Simvastatin 10

Rosuvastatin 20-40 Rosuvastatin 5-10 Pravastatin 10-20
Simvastatin 20-40 Lovastatin 20
Pravastatin 40-80 Fluvastatin 20-40
Lovastatin 40 Pitavastatin 1
Fluvastatin Xl 80
Fluvastatin 40 bid
Pitavastatin 2-4

Donald M. Lloyd-Jones DM, et al. JACC. 2016;68:92-125

LDL-C Reduction With Each Titration of Rosuvastatin, Atorvastatin, Simvastatin, or Pravastatin

Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg)

Mean %
Change
in LDL-C
From
Untreated
Baseline

p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; †p<0.002 vs atorvastatin 20, 40
mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg; ‡p<0.002 vs atorvastatin 40 mg;
simvastatin 40, 80 mg; pravastatin 40 mg

Jones PH et al. Am J Cardiol. 2003;92:152–160

Rosuvastatin : Third Generation Statin1
Most potent statin to reduce LDL-C

Relative efficacy of statin-based therapies in LDL-C reduction2:

Adapted from FDA drug safety communication

1. Kapur Navin K,et al. Vascular Health and Risk Management 2008:4(2) 341–353
2. FDA drug safety communication. Available in https://www.fda.gov/Drugs/DrugSafety/ucm256581.htm 03/12/2018
 Conclusion
• Statin treatment forms the basis of contemporary
drug therapy for atherosclerotic vascular disease.
• Clinical evidence clearly supports the use of
statins in the majority of patients with vascular
disease and elevated, average, or even below
average cholesterol levels.