MANAGING HIDDEN

CARDIOVASCULAR RISK IN
DIABETES MELLITUS

Agus Yuwono

DM Strongest RF for CVD

ACS and Diabetes Up to 1

Year
% of patients

25
20
15

21.3

N = 3429

Diabetes

P<0.0001

N = 1149

14.4

P=0.035

10
5

P<0.0001

No Diabetes

P<0.0001
1.8

3.9

In-Hospital
Mortality

7.
1

8.9

14.1

7.9

Non-fatal MI

1-y All-Cause
Mortality

1-y
Mortality/MI

Yan R, et al. Can J Cardiol 2003;19(suppl A):260A.

Duration of T2DM and CVD

48%

29%
21%

24%

15%

3-5

6-9

10-14

15+

Years after DM Diagnosis

Harris,Setal.;Type2DiabetesandAssociatedComplicationsinPrimaryCarein
Canada:TheImpactofDurationofDiseaseonMorbidityLoad.CDA2003.

Duration of DM - CV
Mortality
4

p for trend <0.001

Relative Risk

3.5
3
2.5
2
1.5
1
0.5
0

<5

6 to 10

11 to 15

16 to 25

26 +

Duration of Diabetes (years)

Cho, et al. J Am Coll Card 2002:40:954.

Clinical Outcome for Diabetes

4-year Follow-up
14
12
10

8
6
4
2
0

CV Death

MI

Stroke

Dialysis

HOPE/MICROHOPE.Lancet2000;355:253.

0.25

Event rate

0.20

OASIS Study: Total

Mortality
Diabetes/CVD +, (n = 1148)
Diabetes/CVD -, (n = 569)
No Diabetes/CVD +, (n = 3503)
No Diabetes/CVD -, (n = 2796)

RR = 2.88 (2.37-3.49)

0.15

RR=1.99 (1.52-2.60)

0.10

RR=1.71 (1.44-2.04)

0.05

RR=1.00

0.0

Months 3

12

15

18

21

24

Malmberg K, et al. Circulation 2000;102:10141019.

CVD: PREDOMINANT CAUSE OF DEATH

AMONG PEOPLE WITH DIABETES
Men
22%

20%

All others

All others

54%

8%

Cardiovascular

Renal

3%
Diabetes

Women

14%

Cancer

49%

14%

Cardiovascular

Renal

3%
Diabetes

Adapted from Morrish NJ, et al. Diabetologia.

Diabetologia. 2001; 44 (suppl 2):
S14S21.

14%

Cancer

CARDIOVASCULAR RISK IN DIABETES

MELLITUS
Three major risk factors:
Hyperglycemia,
Blood pressure
Cholesterol-LDL

focus on A1C
(B)
(C)

(A)

These 3 components, the primary

target goals, namely the ABC

goals

DEEP DIVE ON AMERICAN

DIABETES ASSOCIATION
GUIDELINE 2016

(The ABC control for preventing CVD in

diabetic patients)

Information of ABC control from the

new ADA guideline - 2016

A1C (GLYCAEMIC)
CONTROL AND
CVDa major focus
control remains

Glucose
in the
management of patients with type 2 diabetes mellitus.
Studies (UKPDS,Kumamoto,DCCT):
Reducing hyperglycemia decreases onset/ progression
of microvascular complications
BUT for CVD complications remains uncertain
(ACCORD, ADVANCE, VADT)
In older patients, suggested that aggressive glycemic
control may present some risk
The A1C target goal is <7.0%

The new ADAS-EASD statement

G LYCEMIC RECOMMENDATION
FOR ADULTS (NON-PREGNANT)
Summary of glycemic reccommendations
nonpregnant adults with diabetes
A1C

<7.0%*

Preprandial capillary
plasma glucose
mmol/L)

80 - 130 mg/dL* (4.4 7.2

for

Peak postprandial capillary

plasma
glucose
180 mg/dL* (10.0 mmol/L)
*More or less stringent glycemic goals may be appropriate for individual patients.

Goals should be
individualized based on duration of diabetes, age/life expectancy, comorbid
conditions, known CVD
or advanced microvascular complications, hypoglycemia unawareness, and individual
patient
considerations.
Postprandial glucose may be targeted if A1C goals are not met despite reaching
preprandial
glucose goals. Postprandial glucose measurements should be made 12 h after the
beginning of the

COMPREHENSIVE MEDICAL
EVALUATION

ANTIDIABTIC
AGENTS

OLD agents:

Metfromin, Sulfonilurea, a-glucosidase

inhibitor, TZDs/Piogtazone

NEW agents:

DPP-4 inhibitors, SGLT2 inhibitors, GLP1receptor

insulin analog
Theagonist,
implementation
strategies: ADAEASD 2015
A Patient-Centered Approach

ADA EASD
PATIENT CENTERED
Diabetes self-management education
(DSME), diabetes self-management
support
(DSMS), medical nutrition therapy (MNT)

A patient-centered approach should be used to guide the choice of

pharmacological agents. Considerations include efcacy, cost, potential
side effects, weight, comorbidities,hypoglycemia risk, and patient
preferences.

BLOOD PRESSURE (B)

CONTROL AND CVD IN
DIABETIC PATIENTS

PREVALENCE OF HYPERTENSION
IN TYPE 2 DIABETES
Normoalbuminuria (UAE 30 mg/day)

Macroalbuminuria (UAE 300 mg/day)

Microalbuminuria (UAE 30-300 mg/day)

All patients

100

90

93
80

71

Prevalence of
hypertension
50
(%)

n=323

Hypertension defined as 140/90 mm Hg.

UAE = urinary albumin excretion

n=151

n=75

n=54

Tarnow L et al. Diabetes Care 1994;17:1247-1251

CV mortality rate/ 10.000 person-years

250
225
200

Without diabetes
With diabetes

175
150
125
100
75
50
25
0

< 120

120-139

140-159

160-179

180-199

> 200

Systolic blood pressure (mmHg)

Association of systolic blood pressure and CV death
in type 2 diabetes
The Lancet 2000; 36: 1955 - 1964

BLOOD PRESSURE (B) CONTROL ADA

2015
BP should be measured at EVERY routine
visit
The target goals:
Systolic BP
< 140 mmHg
Diastolic BP < 90 mmHg
Lower BP, systolic < 130 mmHg,
diastolic <

80 mmHg

for younger patients,people with albuminuria, one or

more additional ASCVD.
ASCVD
Pharmacologic therapy: either ACE inhibitors or ARB
multiple drug combination is generally reqiured

BLOOD PRESSURE (B) CONTROL ADA

2015

Intensive BP target (upper limit of Syst < 130

and Diast < 80 mmHg) vs Standard BP target
(upper limit Syst 140-160, Diast 85-100 mmHg:
- no significant reduction in mortality or nonfatal MI
BUT statistically reduction in stroke
ACCORD study, SBP < 120 mmHg compared to
SBP 130-140 mmHg, no benefit
ADVANCE study, BP 136/73, 6 yr follow up,
significant reduction of death any cause, and
CVD

CHOLESTEROL LDL (C)

CONTROL AND CVD IN
DIABETIC PATIENTS

shift from:
Treat - to -Target

Paradigm

to

Intensive Statin Therapy

(Gupta A: Endocrinol Metab Clin N Am 2014;43:869-892)

Todays Safer Values

Total Cholesterol < 200
Triglycerides < 150
LDL Cholesterol < 100 preferably <
70
HDL Cholesterol > 40 (for women 50)
Non HDL Cholesterol < 130
Lp(a) values < 20

Bad Cholesterols the lower the better

Good Cholesterols the higher the better

24

LIPID CLINICAL
GUIDELINES

NCEP ATP III LIPID GUIDELINE LDL-C GOALS FOR

DIFFERENT RISK CATEGORIES : TREAT TO TARGET
Risk category
level at which

LDL goal

0-1 risk factor

(160-189:
LDL-lowering
drug optional)

< 160

2+ risk factors
10-y risk
(10-y risk < 20%)
20%: 130

(mg/dL)

< 130

LDL level at

LDL

which to initiate
therapeutic life
style changes
(mg/dL)
> 160

to consider drug
therapy (mg/dL)

> 190

> 130
10%10-y risk
< 10%: 160

CHD or CHD risk

< 100
> 100
> 100
(100-129: Gupta A, et al. Endocrinology and metabolism clinics of North America
2014; 869-912
equivalents
drug optional)

The ACC/AHA Guidelines,

November 2013

27

ACC, American College of Cardiology

AHA, American Heart Association

ACC/AHA GUIDELINES, THE 4 STATIN BENEFIT

GROUPS
Group 1

Group 2

Clinical ASCVD

LDL-C 190 mg/dL

(~5 mmol/L)

CHD, stroke, and

peripheral arterial
disease, all of
presumed
atherosclerotic origin

Group 3

Group 4

Diabetes mellitus

ASCVD risk 7.5%

+ age of 4075 years

+ LDL-C 70189 mg/dL
(1.84.9 mmol/L)

No diabetes
+ age of 4075 years
+ LDL-C 70189 mg/dL
(1.84.9 mmol/L)

ASCVD, atherosclerotic cardiovascular disease

CHD, coronary heart disease
LDL-C, low-density lipoprotein-cholesterol

Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print

AHA guidelines for statin therapy in people with

diabetes
No CVD
LDL-C

Age 21-40

(mg/dl)

Age 40-75
10-year CV risk
< 7.5%

10-year CV risk
7.5%

Age > 75

190

High
intensity*

High
intensity*

High
intensity*

High
intensity*

70-189

Discuss

Moderate
intensity**

Highintensity*

Discuss

<70

Discuss

Discuss

Discuss

Discuss

No recommendations for or against specific LDL or HDL targets

*High intensity- dose that reduces LDL approx 50% or more (e.g. Atorvastatin 40-80mg, Rosuvastatin 20mg)
**Moderate intensity- dose that reduces LDL 30-50% (e.g. Atorvastatin 10mg, Rosuvastatin 10mg, Simvastatin 20-40mg,
Pravastatin 40mg)

Stone et al 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
Circulation 2014; 129: S1-S45

AHA guidelines for statin therapy in people with

diabetes
CVD
LDL-C

Age 21-74

Age > 75

190

High intensity*

Moderate** or high
intensity*

70-189

High intensity*

Moderate** or high
intensity*

<70

High intensity*

Moderate** or high
intensity*

(mg/dl)

No recommendations for or against specific LDL or HDL targets

*High intensity- dose that reduces LDL approx 50% or more (e.g. Atorvastatin 40-80mg, Rosuvastatin 20mg)
**Moderate intensity- dose that reduces LDL 30-50% (e.g. Atorvastatin 10mg, Rosuvastatin 10mg, Simvastatin 20-40mg,
Pravastatin 40mg)

Stone et al 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
Circulation 2014; 129: S1-S45

Intensity of Statin Therapy: ACC/AHA 2013 VS NICE 2014

ACC/AHA 2013 (* LDL-C reduced by 50%; LDL-C reduced 3050%)
High-intensity therapy*

Moderate-intensity therapy

Atorvastatin 4080 mg

Atorvastatin 1020 mg

Pravastatin 4080 mg

Rosuvastatin 2040 mg

Rosuvastatin 510 mg

Lovastatin 40 mg

Simvastatin 2040 mg

Fluvastatin 40-80 mg

Pitavastatin 24 mg

Adapted from Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7.

UK NICE Guidelines 2014

Statin

LDL-cholesterol reduction

Dose
(mg/day)

10

20

Fluvastatin

21% 27% 33%2

1

Pravastatin

80

20% 24% 29%

1

Simvastatin

40

1 = 2030% reduction in LDL-C:

low-intensity statin
2 = 3140% reduction in LDL-C:
medium-intensity statin

3 = >40% reduction in LDL-C:

high-intensity statin

27% 32% 37% 42%3

1

National Institute for Health and Care Excellence Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181
The information
used to make the table is from Law MR et al BMJ 2003;326:142
31

Atorvastat

37% 43% 49% 55%3

Group 3. Diabetes, age 4075 years, LDL-C 70189

mg/dL
High- or moderate-intensity statin recommended
Type 1 or 2 diabetes
No

Age 4075 years

Consider statin
individually

Yes

Estimate 10-year ASCVD risk

with Pooled Cohort Equations

ASCVD risk 7.5%

ASCVD risk <7.5%

High-intensity statin*

Moderate-intensity
statin

*Expected to reduce LDL-C by 50%

Expected to reduce LDL-C by 30 to <50%

Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead

of print

Recommendations for statin treatment in people

with diabetes: THE ADA 201 6 REVISED STANDARD
OF CARE
Age
with

Risk factors

Recommended Monitoring
statin dose*

panel
< 40 years
as needed
monitor

None

Overt CVD***

High

40-75 years
monitor

None

Moderate

adherence

None
CVD risk factor (s)**

CVD risk factors

lipid

Annually or
Moderate or high to

As needed to

High

* In addition to lifestyle
Overt therapy.
CVD
High
** CVD risk factors include LDL cholesterol >100 mg/dL (2.6 mmol/L), high blood pressure,
smoking,
and overweight
75 years
None and obesity
Moderate
As needed to
*** Overt CVD includes those with previous cardiovascular events or acute coronary syndromes

>
monitor

adherence

CVD risk factors

Overt CVD

Moderate or high
High

Diabetes Care 2016; 38 (Suppl 1):

ADA lipid guidelines: nonstatin drugs

The addition of ezetimibe to moderate-intensity statin therapy has

been shown to provide additional cardiovascular benet compared
with moderate-intensity statin therapy alone (IMPROVE-IT)
Combination therapy (statin/brate) has not been shown to improve
atherosclerotic cardiovascular disease outcomes and is generally
not recommended.
A However, therapy with statin and fenobrate may be considered
for men with both triglyceride level >204 mg/dL (2.3 mmol/L) and
HDL cholesterol level <34 mg/dL (0.9 mmol/L).
Combination therapy (statin/niacin) not generally recommended
Statin therapy is contraindicated in pregnancy.

www.drsarma.in

34

UK NICE GUIDELINES

NICE LIPID GUIDELINES: ESTABLIHED

CVD / STROKE
Established
CVD/Stroke

Do not use a risk

assessment tool

Potential drug
interactions
High risk of AEs
Patient preference

Atorvastatin
80 mg

Acute coronary
syndrome
Angina, MI, CHF
TIA, Stroke,
PAD

National Institute for Health and Care Excellence

Lipid modification July 2014
http://www.nice.org.uk/Guidance/CG181

Consider lower
dose

Do not delay
statin

2014 NICE lipid guidelines recommend atorvastatin

in all settings where lipid modification therapy is
indicated

Atorvastatin:

2 prevention: 80 mg
1 prevention (including diabetes and CKD): 20 mg

(Possibility to increase in some situations)

Type 2 diabetes
(No established CVD)

Type 1 diabetes
(No CVD)

QRISK2 assessment*

Do not use a risk

assessment tool

10-year CVD risk 10%

Age >40 yr
Diabetes for >10 yr
Established nephropathy
Other CVD risk factors

Offer
atorvastatin 20 mg

Offer statin
Start with atorvastatin 20 mg
National Institute for Health and Care Excellence
Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181

NICE lipid guidelines: non-statin

drugs
Because there is no evidence of benefit in non-statins:

Do NOT routinely offer fibrates for primary or secondary prevention of

CVD

Do NOT offer nicotinic acid (niacin), a bile acid sequestrant (anion

exchange resin) or omega-3 fatty acid compounds for primary or
secondary prevention of CVD

Do NOT offer the combination of a bile acid sequestrant, fibrate, nicotinic

acid or omega-3 fatty acid compound with a statin for primary or
secondary prevention of CVD

Heterozygous familial and non-familial hypercholesterolemia: consider

ezetimibe

National Institute for Health and Care Excellence

Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181

LIPID CLINICAL GUIDELINES

Apakah perlu ? YA, sebagai pegangan terapi
terutama bagi dokter praktek umum
Guideline is guideline, dokter harus melihat
kepentingan penderita
Saat ini ada 3 jenis:
NCEP ATP III - USA
2004
ACC/AHA USA
2013
NICE - UK
2014
ADA - USA
2016
Pilih yang mana: bukan yang terbaik, TETAPI
mana yang praktis digunakan oleh dokter praktek

I Would like to leave it to the experts The

Endo-crinologist and cardiologist

Research on DM
Dyslipidemia

40

41

CARDS: Efficacy results in patients with

type 2 diabetes

CARDS: Atorvastatin 10 mg provided a significant reduction in CV events in

patients with type 2 diabetes and 1 risk factor compared with placebo
Incidence of major CV events* (primary endpoint
Cumulative incidence
(%)

15

10

Placebo (n=1410); final LDL-C=121

mg/dL
Atorvastatin 10 mg (n=1428); final LDLC=82 mg/dL

Stroke

37% 48% 42%

Significant Relative Risk

Reduction

0
0.0

Fatal/nonfatal MI

RRR
95% CI
0.170.52
(p=0.001) 1

RRR
95% CI
0.310.89
(p=0.016) 2

RRR
95% CI
0.390.86
(p=0.007) 3

ARR=3.2%

ARR=1.3%

ARR=1.9%

//
1.0

2.0
3.0
3.9
Time (years)
CARDS was stopped ~2 years early due to significant CV benefits with atorvastatin
Reprinted from The Lancet, 364, Colhoun HM, Betteridge DJ et al. Primary prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, 68596., Copyright (2004),
with2007;24(12):13131321;
permission from Elsevier
1. Colhoun HM, et al. Lancet. 2004;364(9435):685696; 2. Hitman GA, et al. Diabet Med.
3. Lipitor Highlights of US Prescribing Information, 2013

CARDS: Safety results in patients with

type 2 diabetes
Data from the CARDS study of 2838 patients with type 2 diabetes
%

Atorvastatin 10 mg
(n=1428)

Placebo
(n=1410)

0.5

0.6

Withdrawals due to muscle-related AEs

Myopathy

Non Significant
AEs
0.1

0.1

Myalgia

4.3

5.1

1 ALT elevation >3 x ULN

1.2

1.0

1 AST elevation >3 x ULN

0.4

0.3

Rhabdomyolysis

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal

44

Colhoun HM et al. Lancet. 2004;364:685696

Key Massage
CVD is the most common cause of death among
diabetic patients
For the prevention,
focus on Glycemic (A1C),
Blood pressure (B), and Cholesterol LDL (C)
control
A1C, intensive, ADA combination
Blood pressure, ACE, ARB, mostly combination
Cholesterol LDL, statin (especially atorvastatin) is The
first choice drug to manage dyslipidemia in T2DM first line,
high dose in high risk
From the ABC target goals,
A1C is the most
difcult target