Advance in Glycemic Control:

Benefit for Diabetics in Terms

of Cardiovascular Outcomes
Sarwono Waspadji
Diabetes and Lipid Center,
Div. Endocrinology and Metabolism, Dept. of Medicine,
School of Medicine, University of Indonesia,
Salemba 6, Jakarta

T2DM, hyperglycemia and cardiovascular outcomes

T2DM, hypoglycemia and cardiovascular outcomes
Glycemic variabilities and cardiovascular outcomes
Long terms-Hard Cardiovascular outcomes in T2DM
Implications as seen in the Latest Recommendation
for Optimal Glycemic control

Natural History of Disease Progression

Aggressive treatment of established cardiovascular risk factors

Macrovascular
complications
Microvascular
complications

Aggressive glycemic control

-cell function

Insulin
resistance
Blood
glucose

10

Prevention
IGT/IF
G of IGT
Prevention

0
Diagnosis

Treatment

10

Years

Type 2
diabetes

Prevention of progression of IGT to Type 2 DM

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In

the multivariable adjusted hazard of

various chronic
consequences of diabetes
7

Amputation or
death for PAD

6
Retinal or renal
disease

Hazard Ratio

5
4

Cataract extraction
Heart failure
Myocardial infarction
Stroke

3
2
1
0
5.5

6.5

Gerstein HC. Circulation. 2009;119:773-5

7.5

8.5

9.5

10.5 HbA1c (%)

Landmarks Studies on DM
And Its Complications

UKPDS
PTM 2007
ACCORD
2008
VADT
2008
Advance
on

Observasional case series

Incidence per 1000 Person Years (%)

Incidence Rates of MI and Microvascular Endpoints by

Mean Hemoglobin A1c: UKPDS

Myocardial
Infarction

Microvascular
Endpoints
5

10

Updated Mean Hemoglobin A1c Concentration (%)

Adjusted for age, sex, and ethnic group

Stratton IM et al. BMJ. 2000;321:405-12.

11

T2DM, hyperglycemia and cardiovascular outcomes

T2DM, hypoglycemia and cardiovascular outcomes
Glycemic variabilities and cardiovascular outcomes
Long terms-Hard Cardiovascular outcomes in T2DM
Implications as seen in the Latest Recommendation
for Optimal Glycemic control

Lessons from the large trials

ACCORD, ADVANCE and VADT
ACCORD
Number (N)
Length of Study
% with major CVD
Diff. of HbA1c

ADVANCE

10. 251
10 yrs

11. 140
8 yrs

35 %
6.4 vs. 7.5

32 %
6.5 vs. 7.3

Renal end-point Red. 21 % (p=0.005)

32 % (p=0.0013)
Primary CV outcome - 10 % ns
Mortality (overall)

+ 22 % (p=0.04)

CV mortality

+ 39 % (p=0.02)

21 % (p=0.006)

VADT
1. 791
11.5 yrs
40 %
6.9 vs. 8.4
33 % (p=0.001)

ns

-13% ns

- 12 %

+ 6.5 % ns
+ 25 % ns

Riddle MC, Karl DM. Practical lessons from ACCORD etc. Diabetes Care. 2012:35;2100-7

Lessons from the large trials

ACCORD, ADVANCE and VADT
ACCORD
Number (N)
Length of Study
% with major CVD
Diff. of HbA1c

ADVANCE

10. 251
10 yrs

11. 140
8 yrs

35 %
6.4 vs. 7.5

32 %
6.5 vs. 7.3

Renal end-point Red. 21 % (p=0.005)

32 % (p=0.0013)
Primary CV outcome - 10 % ns
Mortality (overall)

+ 22 % (p=0.04)

CV mortality

+ 39 % (p=0.02)

21 % (p=0.006)

VADT
1. 791
11.5 yrs
40 %
6.9 vs. 8.4
33 % (p=0.001)

ns

-13% ns

- 12 %

+ 6.5 % ns
+ 25 % ns

Riddle MC, Karl DM. Practical lessons from ACCORD etc. Diabetes Care. 2012:35;2100-7

Landmark clinical trials in diabetes

VADT

ACCORD
ADVANCE

VADT

Severe hypoglycemia and risk of CVD and

death
Number (%) of patients with event
Severe .
Hypoglycemia

No Severe
Hypoglycemia

(n=231)

(n=10909)

Major
macrovascular

33 (15.9%)

1114 (10.2%)

3.53 (2.41-5.17)

Major
microvascular

24 (11.5%)

1107 (10.1%)

2.19 (1.40-3.45)

All cause deaths

45 (19.5%)

986 (9.0%)

3.27 (2.29-4.65)

CVD death

22 (9.5%)

520 (4.8%)

3.79 (2.36-6.08)

Events

0.1

Hazard ratio (95%CI)

1.0

10.0

Zoungas S et al.
NEJM
2010;363:1410

Mixed Meta-Analysis ACCORD, ADVANCE, VADT and UKPDS

Intensive Treatment vs. Conventional Treatment
Reduction of major CV events

9%

HR 0.91 , CI 0.84 0.99

All-cause mortality

HR 1.04, CI 0.90 1.20

CV mortality

HR 1.10, CI 0.84 1.42

Reduction of fatal or non fatal MCI

15 %

Severe Hypoglycemia

HR

HR

0.85 CI 0.76 0.94

2.48

Other Methods of Meta-analysis (Kelly TN et al. Ann Intern Med 2009:151;304-403)

Reduction of major CV events

10 %

RR 0.90 , CI 0.83 0.98

All-cause mortality

RR 0.97 CI 0.76 1.24

CV mortality

RR

0.98, CI 0.84 1.15

Reduction of fatal or non fatal MCI

Severe Hypoglycemia

15 %

RR

0.85 CI 0.76 0.9

RR 2.43

Riddle MC, Karl DM. Practical lessons from ACCORD etc. Diabetes Care. 2012:35;2100-7

T2DM, hyperglycemia and cardiovascular outcomes

T2DM, hypoglycemia and cardiovascular outcomes
Glycemic variabilities and cardiovascular outcomes
Long terms-Hard Cardiovascular outcomes in T2DM
Implications as seen in the Latest Recommendation
for Optimal Glycemic control

J Diabetes Sci Technol. 2008 ;2 (6 ):1094-100

Glycemic Variability: The Third Component of the

Dysglycemia in Diabetes. Is it Important? How to Measure it?
Louis Monnier, M.D.1, Claude Colette, Ph.D.1, David R. Owens, M.D.2

The dysglycemia of diabetes includes two components:

(1)sustained chronic hyperglycemia that exerts its effects
through both excessive protein glycation and activation of
oxidative stress and
(2) acute glucose fluctuations.
Glycemic variability seems to have more deleterious effects than
sustained hyperglycemia in the development of diabetic
complications as both upward (postprandial glucose increments)
and downward (interprandial glucose decrements) changes

activate the oxidative stress.

Arguments for and against the Role of Glucose Variability

in the Development of Diabetes Complications
Eric S. Kilpatrick, M.D.
Journal of Diabetes Science and Technology.2009;3 (4)
Diabetes Technology Society

Glucose Variability and Microvascular Complications

the original analyses of the DCCT data set.

the rate of complications at a given value of HbA1c

was apparently higher in the conventionally treated
patients in the trial than in those treated intensively.

the urinary excretion rate of 8-iso-PGF2, a

reliable marker of oxidative stress,
was found to be strongly, positively
correlated (r = 0.86, p < .001) with glycemic
variability assessed from the mean
amplitude of glycemic excursions (MAGE)
as estimated by continuous glucose
monitoring systems (CGMS).

Correlatiom Between MAGE and HbA1c

Clinical Characteristics

MAGE

HbA1c

Gensini Score

r=0.42, p<0.01 r=0.16, p< 0.05

NLRs on admission
r=0.48, p<0.01 p= NS
Peak HsCRP ng/mL
L-FABP ug/g creatinine
PLU, platelet Reactivity
RHI, endothelial function

r=0.41, p<0.01
r=0.85, p<0.01
r=0.45, p<0.01
r=0.38, p<0.1

p=NS
p=NS
r=0.36, p<0.01
r=0.16, p=0.08.

R = Neutrophyl/Lymphocyte Ratio
HsCRP = high sensitive C Preactive Protein
ABP=Urinary Liver Type Fatty Acid Binding Protein marker chronic kidney disea
U = P2y12 reaction Unit
I = Reaction Hyperemia Index

Intensive Care Med. 2011; 37(4): 58393.

Published online Jan 29, 2011. doi: 10.1007/s00134-010-2129-5
PMCID: PMC3058514

Glucose variability measures and their effect on mortality:

a systematic review
Saeid Eslami,

1 Zhila Taherzadeh,2 Marcus J. Schultz,3,4,5

and Ameen Abu-Hanna1

Glucose variability has been quantified in

many different ways, and in each study at
least one of them appeared to be associated
with mortality.

Diabetes Care.2013;36(4):1026-32
Impact of admission glycemic variability, glucose,
and glycosylated hemoglobin on major adverse
cardiac events after acute myocardial infarction
Gong Su, Shu-hua Mi, Hong Tao, Zhao Li, Hong-Xia Yang, Hong Zheng, Yun
Zhou, and
Lei Tian,

CONCLUSIONS: Elevated admission GV appears

more important than admission

glucose and prior

long-term abnormal glycometabolic status
predicting 1-year MACE in patients with AMI.

in

Treatment Strategies
Glucose Triad

The treatment strategy should target all three components.

HbA1c

FPG

PPG

Ceriello A, Colagiuri S. Diabet Med. 2008;25(10):1151-1156.

To get Maximal benefit for

Cardiovascular Prevention

GLYCEMIC CONTROL TETRAD:

Triad + GLUCOSE VARIABILITY
Standard Deviation of Mean Glucose - Gold Standard

MAGE: Mean Amplitude of Glycemic

Excursion

Continous Glucose Monitoring System

the arithmetic mean of differences between consecutive
peaks and nadirs, provided that the differences be greater
than the SD around the mean values.

T2DM, hyperglycemia and cardiovascular outcomes

T2DM, hypoglycemia and cardiovascular outcomes
Glycemic variabilities and cardiovascular outcomes
Long terms-Hard Cardiovascular outcomes in T2DM
Implications as seen in the Latest Recommendation
for Optimal Glycemic control

Glycemic Variability
Should we and can we prevent it?
Louis Monnier, Claude Colette,
Diabetes Care.2008 ; 31 (Supplement 2 ):S150-S154

There are many reasons to think that both upward (postprandial)

and downward (interprandial) acute fluctuations of glucose around
a mean value activate the oxidative stress.
As a consequence, it is strongly suggested that a global
antidiabetic strategy should be aimed at reducing to a minimum
the different components of dysglycemia (i.e., A1C, fasting and
postprandial glucose, as well as glucose variability).
All the therapeutic agents that act on postprandial glucose
excursions seem of particular interest for reducing the latter
parameter (i.e., the glucose instability).
Particular attention should be paid to such emerging therapeutic
agents as the glucagon-like peptide 1 agonists and the dipeptidyl
peptidase (DPP)-IV inhibitors that act through the incretin
pathway.

The long term follow up

ADVANCE-ON

Post trial effect of intensive glucose lowering over a 5 year period in

ADVANCE patients worldwide.

2 primary outcomes :
- Death from any cause
- Major cardiovascular events

Glycemic Indices Over Time

Composite of cardiovascular
death,
myocardial infarction, or ischemic
stroke

White et al. NEJM 369(2013)1327-35

Glycemic Indices Over Time

Worldwide
Orientation
Plan 2013-2014
White
et al. NEJM
369(2013)1327-35

Glycemic Variabilities ?

T2DM, hyperglycemia and cardiovascular outcomes

T2DM, hypoglycemia and cardiovascular outcomes
Glycemic variabilities and cardiovascular outcomes
Long terms-Hard Cardiovascular outcomes in T2DM
Implications as seen in the Latest
recommendation for Optimal Glycemic control

AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):331

ADA/EASD. Diabetes Care. 2012;35(6):1364-79

Risk factors for severe

hypoglycaemia
The independent risk factors for severe

hypoglycaemia were:
increased age, duration of diabetes and creatinine

level
lower BMI and cognitive function
use of 2 oral glucose lowering drugs
history of smoking
history of microvascular disease
allocation to intensive glucose control (all p<0.05)

Relative Risk (%)

Hypoglycaemia with different Sulfonylureas

Severe hypoglycemia*
Gliclazide
n/1000 person years0.85

Glipizide
8.70

GlimepirideTolbutamide
ChlorpropamidGlyburide
0.86
3.50
e
16.00
16.00

*<50 mg/dL.

Tayek J. Diabetes Obes Metab

ADA/EASD. Diabetes Care. 2012;35(6):1364-79

AACE Comprehensive Diabetes Management Algorithm. Endocrine Practice. 2013;10(2):332

Hatur Nuhuu