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Dyslipidemia Management in very high risk patient (type

2 diabetes mellitus)– Practical strategies for healthcare physicians

ID 376506/Dec 19
The Size Of The Problem

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 Cardiovascular disease is a significant
problem
7.4
million
due to
CHD

31% due
to CVD 6.7
million
due to
stroke

Total global deaths in

2012 ~56 million1

1. WHO. CVD Fact sheet N°317, Jan 2015. http://www.who.int/mediacentre/factsheets/fs317/en/#/last accessed 07 Nov 16

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Natural History of Disease Progression

Aggressive treatment of established cardiovascular risk factors

Macrovascular complications

Microvascular complications

Aggressive glycemic control

b-cell function

Insulin
resistance
Blood
glucose

–10 Prevention 0 Treatment 10 Years

Diagnosis
IGT/IFG Type 2 diabetes
Prevention of IGT
Prevention of progression of IGT to Type 2 DM

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In Endocrinology. 4th What Science Can Do
ed. 2001.
 The continuum of CV risk in T2DM

1. Adapted from ADA diabetes care 2003; 26:3160-3167.

2. 2. Tsao PS et al 1998;18:947-953.
3. Hsueh et al 1998. 105:1:4S-14S What Science Can Do
Increasing prevalence of T2DM & CVD

• Globally, 387 million people are • T2DM approximately doubles the

living with diabetes1 risk of death2

Relative risk for

1.85 all-cause mortality

Relative risk for

1.76 CV mortality

1 1.5 2.0

• Diabetes caused 4.9 million

deaths in 20141
• CVD is the principal cause of
• Rising to 592 million by 20351 death in T2DM2
Represents 2 million people.
Diabetes is mostly (85–95%) T2D.1

1. IDF Diabetes Atlas, 2014. 6th Edition. http://www.idf.org/diabetesatlas. Last accessed 07 Nov 16
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2. Nwaneri et al. Br J Diabetes Vasc Dis 2013;13:192–207.
 T2DM associated with serious
complications

Macro-vascular

Micro-vascular

1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 3The Hypertension in Diabetes Study
Group. J Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672–676.
6Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 7King’s Fund. Counting the cost. The real

impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996. 8Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

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 Pathophysiology of CV in T2DM

Insulin resistance

Hyperinsulinemia Impaired Hypertriglyceridemia Essential

glucose Decreased HDL-C hypertension
tolerance

Clinical diabetes

Accelerated atherosclerosis

Adapted from the ADA. Diabetes Care. 1998;21:310-314;

Pradhan AD et al. JAMA. 2001;286:327-334. What Science Can Do
Endothelial dysfunction drives atherosclerotic
progression

Atherosclerosis is accelerated in T2D by hyperglycaemia, insulin resistance,

inflammation and diabetic dyslipidaemia2
1.Figure adapted from Libby. Circulation 2001;104:365‒72
2. Jenny E Kanter. Letter to the editor

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Atherosclerosis in Diabetes
• ~80% of all diabetic mortality
– 75% from coronary atherosclerosis
– 25% from cerebral or peripheral vascular
disease
• >75% of all hospitalizations for diabetic
complications
• >50% of patients with newly diagnosed
type 2 diabetes have CHD

National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995. What Science Can Do
Type 2 DM is a major risk factor for CV

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MRFIT: T2DM & Cardiovascular mortality

160
10.000 person years

140
CV mortality per

Diabetes (man)
No diabetes (man)
120
100
80
60
40
20
0
< 4.7 4.7-5.1 5.2-5.7 5.8-6.2 6.3-6.7 6.8-7.2  7.3 mmol/l
<180 180-199 200-219 220-239 240-259 260-279  Mg/dl

total cholesterol

Adapted from Stamler J et al. Diabetes Care 16(2): 434 - 444, 1993 What Science Can Do
 Diabetes doubles the risk of vascular events
By 2 Folds
Number
Outcome of cases HR (95% CI)

Coronary heart disease 26,505 2.00 (1.83–2.19)

Coronary death 11,556 2.31 (2.05–2.60)

Non-fatal MI 14,741 1.82 (1.64–2.03)

Cerebrovascular disease

Ischaemic stroke 3799 2.27 (1.95–2.65)

Haemorrhagic stroke 1183 1.56 (1.19–2.05)

Unclassified stroke 4973 1.84 (1.59–2.13)

Other vascular deaths 3826 1.73 (1.51–1.98)

2 1 2 4
Hazard ratio (diabetes vs no diabetes)

Adapted from Sarwar et al. Lancet 2010;375(9733):2215–2222.

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T2DM is a CVD risk equivalent

No diabetes, no prior MI Diabetes, no prior MI

No diabetes, prior MI Diabetes, prior MI
50
Incidence of CV events (%)

45
40
35
30
25
20
15
10
5
0
MI Stroke CV Death
P<0.001 for all subjects for prior MI vs. no prior MI, and for diabetes vs. no diabetes
Adapted from Haffner et al. N Engl J Med 1998;339:229–34.

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Evidence from large population study supports that
diabetes and prior MI carry similar CV risk

Men Women
250 250
Diabetes
No diabetes + no prior MI
CV mortality event rate/1000

200 200 Diabetes + prior MI

Prior MI
person-years

150 150

100 100

50 50

0 0
30–39 40–49 50–59 60–69 70–79 80–89 30–39 40–49 50–59 60–69 70–79 80–89
Age Age

Adapted from Schramm et al. Circulation 2008;117:1945–54.

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Prevalence of Dyslipidaemia is high in type 2
diabetes mellitus

Lipid profile Men With Women with

Diabetes, % Diabetes, %
LDL-C
> 100 mg/dL 71 78.9

HDL-C mean
< 40 mg/dL (men)
41.8 46.9
< 50 mg/dL (women)

Triglycerides
> 150 mg/dL 59.1 64.6

N = 498 adults (projected to 13.4 million) aged > or = 18 years with diabetes representative
of the US population and surveyed within the cross-sectional National Health and
Nutrition Examination Survey 1999-2000. Adapted from Diabetes Res Clin Pract;70:263-269.2005

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Lipid pattern in T2DM – UKPDS 1997

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Lipid pattern in T2DM – UKPDS 1997

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Lipid summary in T2DM

T2DM is associated with a lipid profile that

increases CV risk:
– Low levels of (protective) HDL-cholesterol1
– Elevated triglycerides1
– Raised concentrations of FFAs1
– Increased small, dense, more atherogenic 1
LDL particles1
– Total LDL levels remain relatively unchanged1
– Raised total cholesterol:HDL-cholesterol ratio1

1 Adapted from UKPDS 1997.70;20;1663

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Dyslipidemia Management Strategies in
T2DM

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Hyperlipidaemia Management in T2DM

2. How should
1. Whom should we
dyslipidaemia be
treat?
managed?

3. What are the target 4. What are the treatment

levels? strategies?

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1. Whom should we treat?
Focus on 4 Statin benefit groups

LDL-C level
Clinical ASCVD†
≥190 mg/dL

Patient with Diabetes, Estimated 10-year

and LDL-C 70-189 risk of ASCVD of
mg/dL (age 40-75 yo) ≥7.5%,‡ 40-75 years of
with or without clinical age, and with
ASCVD LDL-C 70-189 mg/dL

† Clinical ASCVD defined as acute coronary syndromes, history of MI, stable or unstable angina, coronary or arterial
revascularization, stroke, transient ischemic attacks, or peripheral artery disease
‡ Estimated using Pooled Cohort Risk Assessment Equations

Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002.. What Science Can Do
 How should dyslipidaemia be managed&
the target levels?

Adapted from Handelsman Y et al. Endocr Pract. 2015 Apr;21 Suppl 1:1-87.. What Science Can Do
 How should dyslipidaemia be managed&
the target levels?
AACE 2015 Lipid targets
Treatment Goal
Parameter
Moderate risk High risk
Primary Goals
LDL-C, mg/dL <100 <70
Non–HDL-C, mg/dL <130 <100
Triglycerides, mg/dL <150 <150
TC/HDL-C ratio <3.5 <3.0
Secondary Goals
ApoB, mg/dL <90 <80
LDL particles <1,200 <1,000
 Moderate risk = diabetes or prediabetes with no ASCVD or major CV risk factors
 High risk = established ASCVD or ≥1 major CV risk factor
 CV risk factors
 Hypertension  Low HDL-C
 Family history  Smoking

ApoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; HDL-C = high density lipoprotein
cholesterol; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol.

Adapted from Handelsman Y et al. Endocr Pract. 2015 Apr;21 Suppl 1:1-87.. What Science Can Do
How should dyslipidaemia be managed & the
target levels?
Recommendation for statin in people with diabetes “ADA 2016”
Age Risk Factors Recommended statin
intensity*
< 40 years old None None
ASCVD risk factor (s)** Moderate or high
ASCVD High
40-75 years old None Moderate
ASCVD risk factor High
ASCVD High
ACS and Cholesterol >50 mg/dl (1.3 mmol/L) in Moderate plus ezetimibe
patients who cannot tolerate high dose statins
> 75 years old None Moderate
ASCVD risk factor Moderate or high
ASCVD High
ACS and Cholesterol >50 mg/dl (1.3 mmol/L) in Moderate plus ezetimibe
patients who cannot tolerate high dose statins
*In addition to life style 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
Adapted from Diabetes Care 2016;39(Suppl. 1):S60–S71. DOI: 10.2337/dc16-S011

*; ADA = American Diabetes Association; ADA Standards of Medical Care in Diabetes 2016 What Science Can Do
How should dyslipidaemia be managed & the
target levels?

Recommendation for statin in people with diabetes “ADA 2016”

High Intensity and Moderate-intensity statin theraphy*

High-Intensity Statin Therapy Moderate-Intensity Stain Therapy

Lower LDL cholesterol by ≥50% Lower LDL cholesterol by 30% to <50%

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

Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg
Simvastatin 20–40 mg‡
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
*Once daily dosing Pitavastatin 2–4 mg
Adapted from Diabetes Care 2016;39(Suppl. 1):S60–S71. DOI: 10.2337/dc16-S011

*; ADA = American Diabetes Association; ADA Standards of Medical Care in Diabetes 2016 What Science Can Do
What are the treatment strategies?
• Type 2 diabetes requires a multifactorial approach for the management of
glucose levels, blood pressure, and lipids to reduce complications1
• Recommendations for type 2 diabetes:

Dyslipidemia: Dyslipidemia
Lifestyle
Hypertension LDL LDL (Very high HbA1c Goal
Modification
(High Risk) Risk)

Moderate
High Intensity
Target Intensity Statin
ADA 20161 <140/90 mmHg ↓ LDL 30% -
Statin ↓ LDL > <7%
50%
<50%

Target
ACE 20152 <130/80 mmHg
< 100 mg/Dl < 70 mg/Dl ≤6.5%

*High risk patients are those with acute coronary syndromes or previous cardiovascular events.
AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ADA = American Diabetes
Association; EASD = European Association for the Study of Diabetes; HDL = high-density lipoprotein; LDL = low-density lipoprotein.
1. Adapted from Diabetes Care 2016;39(Suppl. 1):S60–S71. DOI: 10.2337/dc16-S011
2. Adapted from Handelsman Y et al. Endocr Pract. 2015 Apr;21 Suppl 1:1-87

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STENO 2 Study
Estimated impact of single risk factor interventional to reduce
CVD in patients with T2DM

Per 5/2 mmHg Per 0.6 mmol/L Per 0.9%

Aspirin
lower SBP1 lower LDL-C1 lower HbA1c1,2
0
Relative risk reduction (%)

-5

-10 -9

-15 -13

-20

-25
-25
-27
-30

*Non-fatal MI, CHD, stroke and all-cause mortality.

1 STENO 2

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Statin therapy has a pivotal role in reducing CV
risk, yet risk remains
Non-diabetes Diabetes Combined
Secondary prevention High risk Primary prevention
Trial 4S1,2 LIPID1,2 CARE1,2 TNT3 HPS1,2 WOSCOPS4 AFCAPS/ JUPITER6
TexCAPS5
0
RR reduction or hazard ratio (%)

-10

-20 -19 -18

-23 -22
-24 -25 -24 -25
-30
-32 -31
-40
-42
-44
-50

-60
N 4444 9014 4159 10,001 20,536 6595 6605 17,802

1. Ryden et al. Eur Heart J 2007;28:88–136. 2. Libby. J Am Coll Cardiol 2005;46:1225–8. 3. LaRosa et al. N Engl J Med
2005;352:1425–35. 4. Shepherd et al. N Engl J Med 1995;333:1301–8. 5. Downs et al. JAMA 1998;279:1615–22.
6. Ridker et al. N Engl J Med 2008;359:2195.

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Role of Crestor in diabetic dyslipidaemia

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Crestor GALAXY Programme

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 Effect on LDL-C of Crestor, Atorvastatin and
Simvastatin in Patients with Diabetes
Crestor reduces LDL-C from 39% to 55%
Dose (log scale)
0
5 mg 10 mg 20 mg 40 mg 80 mg

-10
Change in LDL-C from
baseline (LSM %)

-20 Simvastatin
Atorvastatin
Rosuvastatin
-30 -27
(n=165)

-33
(n=2929)
-36
-40 -39 (n= 7837) -39 -45
(n=670) (n=548) (n=479)
-41
(n=3908)
-44 -46
-50 (n=11 690) (n=1324)
-50 -50
(n=3554) (n=2072)
-55
-60 (n=2983)

Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

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 Greater reduction of LDL-C level with Crestor Vs.
Atorvastatin in patients with diabetes
URANUS1 ANDROMEDA2 CORALL3
4 weeks 16 weeks 8 weeks 16 weeks 6 weeks 12 weeks 18 weeks
RSV ATV RSV ATV RSV ATV RSV ATV RSV ATV RSV ATV RSV ATV
10 mg 10 mg 10-40 10-80 10 mg 10 mg 20 mg 20 mg 10 mg 20 mg 20 mg 40 mg 40 mg 80 mg
0 mg mg

n=131
n=240

n=240

n=227

n=229
n=220
n=232

n=221

n=131

n=128

n=131

n=128
n=232

n=128
-10

LSM
change -20
from
baseline
in LDL-C -30
(%)
-40 –39 –39
–41

–46 –46 –46 –46

-50 –48 ‡ –48
* –51 –50
–52 ‡
† –52
*
–57 ‡‡
-60 †

*p<0.0001 vs ATV; †p≤0.001 RSV 10 mg vs ATV 10 mg, and RSV 20 mg vs ATV 20 mg;
‡p<0.05 vs ATV; ‡‡p<0.01 vs ATV
Adapted from:
1. Berne C, Siewert-Delle A. Cardiovasc Diabetol 2005; 4: 7
2. Betteridge DJ et al. Diabet Med 2007; 24: 541–549
3. Wolffenbuttel B et al. J Intern Med 2005; 257: 531–539
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 The magnitude of HDL-C increase varied between
statins, with the greater increase seen with
Crestor – result from Voyager

10 Simvastatin
7.9
(n=2983)
Atorvastatin
Change in HDL-C from

8 7.0 Rosuvastatin
baseline (LSM %)

(n=3554)
6.1
(n=11 690)
5.5
6 (n=670)

4.5 5.3
(n=7837) 5.0 5.0 (n=479)

4 (n=2929) (n=548)

4.2
(n=165)
3.5
(n=3908)
2 2.4 2.3
(n=1324) (n=2072)

0
5 mg 10 mg 20 mg 40 mg 80 mg

Dose (log scale)

HDL-C=high-density lipoprotein cholesterol;
LSM=least-squares mean
Note: No p values have been published for this parameter

Adapted from Barter PJ et al. J Lipid Res 2010; 51: 1546–1553 What Science Can Do
Change in Triglyceride level between statin–
result from Voyager

Rosuvastatin Atorvastatin Simvastatin

Dose (mg) 5 10 20 40 10 20 40 80 10 20 40 80
0

-5
LSM % change (SE)

-10

-15

-20

-25

-30

Crestor 10‒40 mg significantly superior to equal and double doses of

simvastatin (p<0.01)

Adapted from Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76 What Science Can Do
 Summary

• There is a continuum of CV risk in T2DM. Accelerated

atherosclerosis might link to cause of CVD in T2DM

• T2DM patients is CHD risk equivalent and need to have aggressive

LDL target

• Major international guidelines recommends to use moderate-to-

high intensity statin in T2DM.Statin therapy plays a pivotal role in
reducing CV events

• Start with Crestor 10 or 20 mg for your diabetic patients that

provide greater LDL-C reduction (44% to 55%)1 compare to other
statin

1. Adapted frorm Nicholls SJ et al. Am J Cardiol 2010; 105: 69–76

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 Take Home Message

1 mmol/L (39
mg/dl) reduction
0.03 mmol/L
in LDL-C reduces
increase in HDL-C
CHD risk by
associated with 1.1%
22%1
reduction in CHD
risk2

1. CTT Collaborators et al. Lancet. 2010; 376: 1670–1676

2. Barter P et al. NEJM 2007; 357: 1301‒1310

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“ Speed & Strength
You Can Trust”

Listed in In-health
CRESTOR 10 & 20 mg

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Thank you

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