Dyslipidemia Management in Diabetic

Patient

Putu Moda Arsana

FKUB, Malang, 2016
 Diabetes is a “CHD Risk Equivalent”
Fatal and nonfatal MI in subjects with and without type 2 diabetes mellitus
P<0.001
50 No Diabetes 45
45 Diabetes
40
Incidence*, %

35 P<0.001
30
25 20.2 18.8
20
15
10
5 3.5
0
(n=1304) (n=890) (n=69) (n=169)
No Prior MI Prior MI

CHD = coronary heart disease; MI = myocardial infarction

*7-year incidence of fatal and nonfatal MI in 1373 nondiabetic and 1059 diabetic subjects
Adapted from Haffner SM, et al. N Engl J Med. 1998;339:229–234.
 Cardiovascular mortality is associated with
serum Cholesterol Concentration in Diabetes
Deaths per 10,000 Person-years

150 No diabetes 130.43

Diabetes

91.99
100 84.79

61.72

46.12
50
29.02
13.84 20.19

0
(n=62,448) (n=1105) (n=75,122) (n=1038) (n=40,090) (n=529) (n=17,604) (n=353)

<180 mg/dL 200–219 mg/dL 240–259 mg/dL 280 mg/dL

Cholesterol Level
Adapted from Stamler J, et al. Diabetes Care. 1993;16:434–444.
 Lipid-Lowering Therapy Accounted for Over 70%
of Cardiovascular Risk Reduction in Patients
With Diabetes*
Risk Reduction in CVD Events

80
Percent of Total Calculated

60

40

20

0
Lipids HbA1c Systolic
Blood Pressure
*Analysis of Steno-2 data based on United Kingdom Prospective Diabetes Study risk engine
Adapted from Gaede P, Pedersen O. Diabetes. 2004;53 (suppl 3):S39–S47.
 LDL-C Levels in Patients
With Diabetes is more atherogenic
• Small, dense LDL-C particles are more atherogenic
No Diabetes Diabetes

LDL particles LDL particles

Apolipoprotein B
LDL-C

“Normal” LDL-C level “Normal” LDL-C level, however:

 Number of LDL particles
 Concentration of apolipoprotein B

Lower CHD risk Higher

Adapted from Chahil TJ, et al. Endocrinol Metab Clin North Am. 2006;35:491–510; Walldius G, Jungner I. Eur Heart J. 2005;26:210–212.
 LDL Cholesterol is The Primary
Target in Dyslipidemia Treatment

NCEP ATP III 2003/ NCEP ATP III Update 2004

ADA/ACC Guideline Update for Secondary Prevention 2006
ESC/EAS Guidelines for the management of Dyslipidemias 2011
AACE Guidelines 2012 for the Management of Dyslipidemia and Prevention
of Atherosclerosis
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults
Standards of Medical Care in Diabetes 2015
AHA/ADA Scientific Statements 2015
 Statin for type-2 DM (ACC/AHA 2013)

• Individuals from 40 to 75 years of age with diabetes and LDL-

C from 70 to 189 mg/dL
Clinical vignette: A 45- year-old man with a 5-year history of
type 2 diabetes and microalbuminuria

Factors that increase his ASCVD risk

• score to ≥7.5% are as follows:
• A 5-year history of diabetes
• A history of micoralbuminuria

Assessing the ASCVD risk will change

the management dosage of statins

Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63:2889-934
 Guideline ACC/AHA 2013

Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63 : 2889-934
 High, Moderate and Low-Intensity
Statin Therapy
High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin Therapy
Therapy Therapy
Daily dose lowers LDL–C on Daily dose lowers LDL–C on Daily dose lowers LDL–C on
average, by approximately average, by approximately 30% to average, by <30%
≥50% <50%

Atorvastatin (40†)–80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg

Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 10–20 mg
Simvastatin 20–40 mg‡ Lovastatin 20 mg
Pravastatin 40 (80) mg Fluvastatin 20–40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2–4 mg
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (47).
‡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.

Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63 : 2889-934
Stone NJ, Robinson, Lichtenstein AH, et al. J Am Coll Cardiol 2014 ; 63 : 2889-934
Studies supported guidelines of
ACC/AHA and ADA
 ANDROMEDA
Change in lipids and lipoproteins (%)
Adjusted percentage change from baseline
8 weeks 16 weeks
Lipid parameter RSV ATV p-value RSV ATV p-value
10 mg 10 mg 20 mg 20 mg
LDL-C –51 –39 <0.001 –57 –46 <0.001
TC –36 –29 <0.001 –40 –33 <0.001
TG –22 –17 0.032 –23 –20 0.184
Non-HDL-C –46 –37 <0.001 –51 –42 <0.001
HDL-C +2.0 +3.6 0.170 +1.9 +2.2 0.794

A raNdomised, Double blind, double dummy, multicentre phase IIIb parallel group study to compare the
efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atOrvastatin (10 Mg and 20 mg) in patiEnts
with type II DiAbetes mellitus
Betteridge DJ, Gibson M Sager PT. Am J cardiol 2007;100 : 1245-1248.
 MERCURY I – Change in Lipid Profile at 8 Weeks
in Patients with Elevated LDL-C and Type 2 Diabetes
20
RSV 10 mg (n=140)
ATV 10 mg (n=142)
ATV 20 mg (n=265)
10
SIM 20 mg (n=141) 9.2 6.8 5.7 8.0 7.6
PRA 40 mg (n=142)
0

LSM
–10
change
–15.9 –10.5
from –20 –13.5
–18.9 –18.3
baseline
(% –30
–31
–35.4 ***
–40 –37.2
***
***
–43.7
–50 –47
LDL-C HDL-C TG
MERCURY=Measuring Effective Reductions in Cholesterol Using Rosuvastatin TherapY; LSM=least-squares mean;
RSV=rosuvastatin; ATV=atorvastatin; SIM=simvastatin; PRA=pravastatin; LDL-C=low-density lipoprotein cholesterol;
HDL-C=high-density lipoprotein cholesterol; TG=triglycerides
***p<0.0001 vs RSV 10 mg
Schuster H et al. am Heart J 2004; 147:705-12
 CORALL – Reduction in LDL-C
6 weeks 12 weeks 18 weeks
RSV ATV RSV ATV RSV ATV
10 mg 20 mg 20 mg 40 mg 20 mg 80 mg
0
n=130
n=130 n=132
n=132 n=130
n=130 n=132
n=132 n=130
n=130 n=132
n=132

–10

–20
Mean
change
from –30
baseline
(%) –40
–41
–50 –46 –46
–48
* –51
–60 * –54
**
CORALL=COmpare the effect of Rosuvastatin with Atorvastatin on ApoB/ApoA-I ratio in patients
with type 2 diabetes meLLitus and dyslipidaemia; LDL-C=low-density lipoprotein cholesterol;
RSV=rosuvastatin; ATV=atorvastatin
*p<0.05, **p<0.01 vs ATV at same time point
Wolffenbuttel BHR et al. J Int Med 2005; 257: 531–539
 SUBARU study
• 427 patients randomized
• Primary endpoint: achievement of LDL-C
• Secondary end point : percent changes of lipids and other
parameters
Atorvastatin 10 mg/d

Atorvastatin 10 mg/d

Rosuvastatin 5 mg/d

At least 4 weeks 8 weeks

Kurabayashi M, et al. J Atheroscler Thrombosis 2008;15:314-323

 LDL-C, LDL/HDL-C ratio and fasting plasma glucose
showed significant difference* and
in favor to Rosuvastatin

LDL-C changes LDL-C/HDL-C changes Fasting glucose changes

mg/dL mg/dL mg/dL
115.0 2.00 1.94
126.0
124.4
109.3
110.0 1.90 1.94
1.84
124.0
105.0 106.7 102.9 1.80 122.0 121.4
120.6
100.0 1.70 120.0 119.0
1.7
95.0 95.3 1.60 118.0
90.0 1.50 116.0
atorva 10 rosuva 5
atorva 10 rosuva 5
85.0 mg/day mg/day
mg/day mg/day
atorva 10 rosuva 5
mg/day mg/day LDL-C/HDL-C ratio baseline Fasting glucose plasma baseline
LDL-C baseline LDL-C 8 weeks LDL-C/HDL-C ratio 8 weeks Fasting glucose plasma 8 weeks

*P<0.01

Kurabayashi M, et al. J Atheroscler Thrombosis 2008;15:314-323

 Lipophilicity of Statin1
Pravastatin
More hydrophilic
CRESTOR

atorvastatin

Fluvastatin More lipophilic

Simvastatin Hydrophilic compounds may have limited access to

nonhepatic cells because of low passive diffusion, but
could be avidly taken up into liver cells via selective
Cerivastatin organic anion transport processes.
CRESTOR exhibits high potency with respect to HMGCoA
reductase inhibition in hepatocytes and selectivity
for the liver.2

1. Sirtori CR, Pharmacological Research 2014;88:3-11

2. McTaggart F et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3- hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;
87(Suppl): 28B–32B;
PHARMACOKINETIC PROPERTIES OF STATINS

• Hydrophilic statins exhibit greater hepatoselectivity.

• A recent study : the uptake of rosuvastatin and

pravastatin by rat hepatocytes, demonstrated that
rosuvastatin and pravastatin are taken up by
hepatocytes by a high-affinity process, with the
transport efficiency for rosuvastatin higher than that
of pravastatin.

Schachter M. Fundamental & Clinical Pharmacology. 2004; 19 : 117-125

 EFFICACY AND SAFETY OF STATINS

The effect of atorvastatin, cerivastatin, fluvastatin, pravastatin,

rosuvastatin and simvastatin on inhibition of cholesterol synthesis has
been compared in primary rat hepatocytes.
Rosuvastatin exhibited a 50% inhibitory concentration (IC50) of 0.16
nM and was significantly more potent than the other statins
investigated, with IC50s ranging from 1.16 nM (atorvastatin) to 6.93
nM (pravastatin)

The more potent inhibition of hepatic cholesterol

synthesis by rosuvastatin explains its greater
efficacy for lowering LDL-C.

Schachter M. Fundamental & Clinical Pharmacology 2004 ; 19:117-125

 Step 1 : Problems identification
 Step 2 : CV Risk calculation, classification,
treatment and treatment Choices
 Step 3 : Patients Education
 Step 4 : Monitoring and evaluation
 By Clinical Process
 Patient problem:
 CVD related problem
 ATP III : Coronary heart disease, carotid artery disease,
peripheral artery disease and abdominal aorta aneurysma
 ACC/AHA 2013 : ACS, history of AMI, stable/unstable
angina, history of coronary revascularization, stroke and
PAD
 CVD risk related problem :
 Age (male ≥ 45 yo, female ≥ 55 yo) Smoking,
hypertension, dyslipidemia, family history of early CVD
 Non CVD related problem.
 Anamnesis, Physical
examination and
Laboratory Exam

CVD Non CVD

related Problems Related
problem Problems

ATP III

ACC/AHA
2013
Step 2 : CV Risk calculation, classification and treatment
choices (ACC/AHA 2013)
 Tujuan : meminta partisipasi pasien dan
keluarganya pada pengelolaan masalah pasien.
 Dimulai sewaktu konsultasi pertama kali.
 Materi yang diberikan
 masalah yang didapatkan pada pasien,
 kemungkinan penyebabnya,
 Langkah pengelolaan yang diambil
 kemungkinan efek samping obat yang diberikan,
 Pengelolaan terhadap efek samping tersebut
 Keberhasilan terapi terutama LDL
 Possibility of complication
 Increasing AST/ALT
 sebelum dan sesudah 3 bulan setelah pemberian statin atau asam
fibrat karena gangguan abnormalitas lipid terjadi kebanyakan pada
3 bulan setelah inisiasi terapi.
 Monitoring dilakukan apabila ada adanya perubahan dosis,
perubahan jenis obat maupun penggunaan obat kombinasi
 Creatinine Phospokinase (CPK).
 apabila pasien mengeluhkan nyeri otot atau mengalami kelemahan
otot.
 Beberapa keadaan dimana evaluasi dan pemantauan
status lipid diperlukan dalam frekuensi lebih sering yaitu
:
 Kendali glukosa darah yang memburuk
 Adanya penggunaan obat lain yang ditenggarai mengganggu
kadar lipid
 Progresivitas dari penyakit aterotrombosis
 Adanya penambahan berat badan
 Adanya perubahan yang tidak terduga dari status lipid pasien
THANK YOU