MANAGING HIDDEN

CARDIOVASCULAR RISK IN
DIABETES MELLITUS

Agus Yuwono

1
DM – Strongest RF for CVD

Risk Equivalent
 ACS and Diabetes – Up to 1
Year
25
P<0.0001
No Diabetes
20 21.3
N = 3429
% of patients

Diabetes P<0.0001
15 N = 1149
14.4 14.1
P=0.035
10
8.9 7.9
P<0.0001 7.
5 1
3.9
1.8
0
In-Hospital Non-fatal MI 1-y All-Cause 1-y
Mortality Mortality Mortality/MI

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

Duration of T2DM and CVD
48%

29%
24%
21%
15%

≤2 3-5 6-9 10-14 15+

Years after DM Diagnosis

Harris, S et al.; Type 2 Diabetes and Associated Complications in Primary Care in

Canada: The Impact of Duration of Disease on Morbidity Load. CDA 2003.
 Duration of DM - CV
Mortality
4 p for trend <0.001
3.5
Relative Risk

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 / MICRO-HOPE. Lancet 2000;355:253.

OASIS Study: Total Mortality
0.25
Diabetes/CVD +, (n = 1148)
RR = 2.88 (2.37-3.49)
Diabetes/CVD -, (n = 569)
0.20 No Diabetes/CVD +, (n = 3503)
No Diabetes/CVD -, (n = 2796)
Event rate

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 6 9 12 15 18 21 24

Malmberg K, et al. Circulation 2000;102:1014–1019.

 CVD: PREDOMINANT CAUSE OF DEATH
AMONG PEOPLE WITH DIABETES
Men Women

22% 20%
All others All others

8% 54% 49%
Renal Cardiovascular 14% Cardiovascular
Renal

3% 14%
Diabetes
Cancer
14%
3% Cancer
Diabetes

Adapted from Morrish NJ, et al. Diabetologia. 2001; 44 (suppl 2): S14–S21.
 CARDIOVASCULAR RISK IN DIABETES
MELLITUS
Three major risk factors:

Hyperglycemia, focus on A1C (A)

Blood pressure (B)
Cholesterol-LDL (C)
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 CVD
Glucose control remains a major focus 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

 GLYCEMIC RECOMMENDATION
FOR ADULTS (NON-PREGNANT)
Summary of glycemic reccommendations for nonpregnant
adults with diabetes
A1C <7.0%*
Preprandial capillary
plasma glucose 80 - 130 mg/dL* (4.4 – 7.2 mmol/L)
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 1–2 h after the beginning of the
meal, generally peak levels in patients with diabetes.
COMPREHENSIVE MEDICAL
EVALUATION
 ANTIDIABTIC AGENTS

OLD agents:
Metfromin, Sulfonilurea, a-glucosidase inhibi-
tor, TZDs/Piogtazone

NEW agents:
DPP-4 inhibitors, SGLT2 inhibitors, GLP-1recep-
tor agonist, insulin analog

The implementation strategies: ADA-EASD 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 efficacy, 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 93
90
80
71

Prevalence of
hypertension
(%) 50

0 n=323 n=151 n=75 n=54

Hypertension defined as ³140/90 mm Hg.

UAE = urinary albumin excretion Tarnow L et al. Diabetes Care 1994;17:1247-1251
CV mortality rate/ 10.000 person-years 250

225
Without diabetes
200
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.
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 non-fatal 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

Paradigm shift from:

Treat - to -Target
to
Intensive Statin Therapy
(Gupta A: Endocrinol Metab Clin N Am 2014;43:869-892)
 Today’s 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 LDL goal LDL level at LDL level at which
(mg/dL) which to initiate to consider drug
therapeutic life therapy (mg/dL)
style changes
(mg/dL)
0-1 risk factor < 160 > 160 > 190 (160-189:
LDL-lowering
drug optional)

2+ risk factors < 130 > 130 10-y risk

(10-y risk < 20%) 10%-20%: 130
10-y risk
< 10%: 160

CHD or CHD risk < 100 > 100 > 100 (100-129:
equivalents drug optional)
(10-y risk > 20%)

Gupta A, et al. Endocrinology and metabolism clinics of North America 2014; 869-912
 The ACC/AHA Guidelines,
November 2013

ACC, American College of Cardiology

AHA, American Heart Association
27
 ACC/AHA GUIDELINES, THE 4 STATIN BENEFIT GROUPS

Group 1 Group 2

Clinical ASCVD LDL-C ≥190 mg/dL

CHD, stroke, and
(~5 mmol/L)
peripheral arterial
disease, all of
presumed
atherosclerotic origin

Group 3 Group 4

Diabetes mellitus ASCVD risk ≥7.5%

+ age of 40–75 years No diabetes

+ LDL-C 70–189 mg/dL + age of 40–75 years
(1.8–4.9 mmol/L) + LDL-C 70–189 mg/dL
(1.8–4.9 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 Age 40-75 Age > 75
(mg/dl)
10-year CV risk 10-year CV risk
< 7.5% ≥ 7.5%

≥190 High High High High

intensity* intensity* intensity* intensity*
70-189 Discuss Moderate High- Discuss
intensity** intensity*

<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
(mg/dl)

≥190 High intensity* Moderate** or high

intensity*
70-189 High intensity* Moderate** or high
intensity*
<70 High intensity* Moderate** or high
intensity*

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 ≈30–50%)
High-intensity therapy* Moderate-intensity therapy†
Atorvastatin 40–80 mg Atorvastatin 10–20 mg Pravastatin 40–80 mg Pitavastatin 2–4 mg
Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg Lovastatin 40 mg
Simvastatin 20–40 mg Fluvastatin 40-80 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) 5 10 20 40 80
• 1 = 20–30% reduction in LDL-C:
Fluvastatin – – 21%1 27%1 33%2 low-intensity statin
Pravastatin – 20%1 24%1 29%1 – • 2 = 31–40% reduction in LDL-C:
medium-intensity statin
Simvastatin – 27%1 32%2 37%2 42%3§ • 3 = >40% reduction in LDL-C:
Atorvastatin – 37%2 43%3 49%3 55%3 high-intensity statin
Rosuvastatin 38%2 43%3 48%3 53%3 –
National Institute for Health and Care Excellence Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181
31
The information used to make the table is from Law MR et al BMJ 2003;326:142
 Group 3. Diabetes, age 40–75 years, LDL-C 70–189 mg/dL
High- or moderate-intensity statin recommended

Type 1 or 2 diabetes

No Consider statin
Age 40–75 years
individually
Yes

Estimate 10-year ASCVD risk

with Pooled Cohort Equations

ASCVD risk ≥7.5% ASCVD risk <7.5%

Moderate-intensity
High-intensity statin*
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 2016 REVISED STANDARD
OF CARE
Age Risk factors Recommended Monitoring with
statin dose* lipid panel
< 40 years None None Annually or as needed
CVD risk factor (s)** Moderate or high to monitor
Overt CVD*** High
40-75 years None Moderate
Diabetes Care Volume 39, Supplement 1, As needed to monitor
CVD risk factors
January 2016 High adherence
Overt CVD High
> 75 years None Moderate As needed to monitor
CVD risk factors Moderate or high adherence
Overt CVD High

* In addition to lifestyle therapy.

** CVD risk factors include LDL cholesterol >100 mg/dL (2.6 mmol/L), high blood pressure, smoking, and
overweight and obesity
*** Overt CVD includes those with previous cardiovascular events or acute coronary syndromes

Diabetes Care 2016; 38 (Suppl 1): S64

 ADA lipid guidelines: non-
statin drugs
• The addition of ezetimibe to moderate-intensity statin therapy has
been shown to provide additional cardiovascular benefit compared
with moderate-intensity statin therapy alone (IMPROVE-IT)
• Combination therapy (statin/fibrate) has not been shown to improve
atherosclerotic cardiovascular disease outcomes and is generally
not recommended.
• A However, therapy with statin and fenofibrate 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 Acute coronary

interactions Atorvastatin syndrome
High risk of AEs Angina, MI, CHF
80 mg
Patient preference TIA, Stroke,
PAD

National Institute for Health and Care Excellence

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

Consider lower Do not delay

dose 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 Type 1 diabetes

(No established CVD) (No CVD)

Do not use a risk

QRISK2 assessment* assessment tool

Age >40 yr
Diabetes for >10 yr
Established nephropathy
10-year CVD risk ≥10% Other CVD risk factors

Offer Offer statin

atorvastatin 20 mg 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
15 Placebo (n=1410); final LDL-C=121 mg/dL Fatal/non-
Stroke fatal MI
Atorvastatin 10 mg (n=1428); final LDL-C=82 mg/dL
Cumulative incidence (%)

37% 48% 42%

Significant Relative Risk Reduction
10
RRR
95% CI
RRR
95% CI
RRR
95% CI
0.17–0.52 0.31–0.89 0.39–0.86
(p=0.001) 1 (p=0.016) 2 (p=0.007) 3

5 ARR=3.2% ARR=1.3% ARR=1.9%

0 //
2.0 0.0
3.0 1.0
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, 685–96., Copyright (2004),
with 2007;24(12):1313–1321;
1. Colhoun HM, et al. Lancet. 2004;364(9435):685–696; 2. Hitman GA, et al. Diabet Med. permission from Elsevier
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 Placebo
%
(n=1428) (n=1410)

Withdrawals due to muscle-related AEs 0.5 0.6

Myopathy
Non Significant
0.1
AEs 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 0 0

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal
Colhoun HM et al. Lancet. 2004;364:685–696
44
 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 difficult
target