Lecture at the Diabetes Philippines Vascular Course

1. Glucose lowering for the
prevention of CVD:
Positive, Negative or Neutral
Iris Thiele Isip Tan MD, FPCP, FPSEM
Clinical Associate Professor, University of the Philippines College of Medicine
Section of Endocrinology, Diabetes & Metabolism
Department of Medicine, Philippine General Hospital

2. Who will benefit How do current
from tight therapies for
glycemic control? diabetes compare?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

3. Who will benefit How do current
from tight therapies for
glycemic control? diabetes compare?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

4. Who will benefit
UKPDS
from tight
glycemic control?
Objective
To determine whether
improved glucose control
would prevent complications
Newly diagnosed
type 2 diabetes
(n=3867)
Median age 54 y
UKPDS Group, Lancet 1998;352: 837-53

5. Newly diagnosed diabetes
UKPDS
Newly diagnosed diabetes
FastingFasting plasma glucose >6mmoll
plasma glucose >6 mmol/L –1
‘Prudentdiet’
‘Prudent diet’
for 3–4 months
for
3-4 mos
Design
>6 mmol/L
>6mmoll–1
<6 mmol/L
!6mmoll –1
>6 and <15 mmol/L
>6 and !15mmoll–1 >15 mmol/L
–1
>15mmoll
Diet satisfactory
Diet satisfactory
Main Main
randomization Primary dietfailure
Primary diet failure
randomization
randomization randomization
If ifbecomes
becomes
–1
>6 mmol/L
>6mmoll
Figure adapted from King et al.
Conventional policy
Conventional policy Intensive policy
Intensive policy Br J Clin Pharmacol, 48:643-48
target<15mmoll
target <15 mmol/L target <6 <6mmoll
target mmol/L
–1 –1
Diet only
Diet only Sulphonylurea
Sulphonylurea Insulin
Insulin Metformin
Metformin
(obese patients only)
(obese patients only)
Figure 3 Design of UKPDS.

6. UKPDS
Endpoints
any diabetes-related
endpoint
diabetes-related death
all-cause mortality
UKPDS Group, Lancet 1998;352: 837-53

7. UKPDS Results
0
-12 -25 -33 -21 -16
% Relative Risk Reduction
-10
p=0.03
p=0.052
-20
p=0.02
p<0.01
-30
p<0.01
-40 10-year follow-up median HbA1c
Intensive 7.0% (6.2-8.2%)
Conventional 7.9% (6.9-8.8%)
-50
Any DM endpoint Microvascular complications
Microalbuminuria at 12 yrs Retinopathy
Myocardial Infarction

8. Fatal and non-fatal myocardial infarction Fatal and n
10
Hazard ratio
P<0.0001 P=0.035
1
14% decrease per 1%
reduction in HbA1c
0.5
5 6 7 8 9 10
Microvascular end points Cataract ex
10 Updated mean HbA1c (%)
azard ratio
P<0.0001 P<0.0001
Stratton et al, BMJ 2000; 321:405-12

9. e-
ne 80
Adjusted incidence per 1000 person years (%)
to Myocardial infarction
Myocardial infarction
he Microvascular end points
als
Microvascular end points At near normal A1c
of
he 60
Risk of MI 2-3x
nt that of micro-
ow
he vascular endpoint
est
a
40
%.
g-
an
to
%
20
in Adjusted for age, sex and ethnic
of group, expressed for white men
ce aged 50-54 years at diagnosis
ng and with mean duration of
by diabetes at 10 years
0
a 5 6 7 8 9 10 11
as
Updated mean haemoglobin A1c concentration (%)
rd
on Fig 2 Incidence rates and 95% confidence intervals for myocardial Stratton et al, BMJ 2000; 321:405-12
a infarction and microvascular complications by category of updated

10. Who will benefit
No benefit
from tight in UKPDS?
glycemic control?
Underpowered to detect
reduction in CVD

11. Who will benefit
No benefit
from tight in UKPDS?
glycemic control?
Too late to reverse
macrovascular complications

12. Vascular disease begins early ...
Insulin resistance precedes overt
hyperglycemia or diabetes
LaSalle JR. Hosp Physician 2005
Plante & Nadler, Seminars Cardiothoracic
Vascular Anes 2003; 7(3):295-310

13. Vascular disease begins early ...
Insulin resistance precedes overt
hyperglycemia or diabetes
2-fold increased
risk of CVD in IGT
LaSalle JR. Hosp Physician 2005
Plante & Nadler, Seminars Cardiothoracic
Vascular Anes 2003; 7(3):295-310

14. Vascular disease begins early ...
Insulin resistance precedes overt
hyperglycemia or diabetes
2-fold increased
risk of CVD in IGT
LaSalle JR. Hosp Physician 2005
Plante & Nadler, Seminars Cardiothoracic
Newly-diagnosed diabetics have
Vascular Anes 2003; 7(3):295-310 vascular disease at presentation

15. Fatal and non-fatal myocardial infarction Fatal and non-fatal stroke
Hazard ratio 10
P<0.0001
Macrovascular disease
P=0.035
occurs at a lower
10
glucose threshold;
%)
influenced by
components of MetSyn
1
14% decrease per 1% 12% decrease per 1%
reduction in HbA1c reduction in HbA1c
0.5
Microvascular end points Cataract extraction
10
Hazard ratio
P<0.0001 Microvascular but not
P<0.0001
macrovascular disease
clearly associated with
hyperglycemia
1
k 37% decrease per 1% 19% decrease per 1%
, reduction in HbA1c reduction in HbA1c
0.5
, 5 6 7 8 9 10 Plante & Nadler, Seminars Cardiothoracic
Vascular Anes 2003; 7(3):295-310
n Amputation or death from

16. Who will benefit
No benefit
from tight in UKPDS?
glycemic control?
Cardiovascular disease in
diabetes is multifactorial in origin

17. Dyslipidemia Hypertension
ACE Inhibitors
Angiotensin Receptor Blockers
Statins
!-Blockers
Fibric Acid Derivatives
ATHEROSCLEROSIS Calcium Channel Blockers
Thiazolidinediones?
Diuretics
Hyperglycemia Platelet Activation
Insulin Resistance and Aggregation
Insulin
Metformin
Thiazolidinediones Aspirin
Clopidogrel
Sulfonylureas
Ticlopidine
Nonsulfonylurea
Secretagogues
Beckman et al, JAMA 2002;287:2570-81

18. Steno-2
Multifactorial intervention
and cardiovascular disease
Objective
To compare the effect of a targeted,
intensified, multifactorial intervention
vs conventional treatment of
modifiable CV risk factors
Type 2 diabetes with
microalbuminuria
Mean age 55.1 y
Mean ff-up 7.8 y
(n=160)
Gaede et al, NEJM 2003;348:383-93

19. Steno-2
Endpoint
Composite of CV
death, nonfatal MI,
nonfatal stroke,
revascularization
and amputation
Gaede et al, NEJM 2003;348:383-93

20. Percentage of patients who reached intensive
treatment goals at a mean of 7.8 years
80
P<0.001 P=0.21
70
60 P=0.19
50
Patients (%)
P=0.001
40
Intensive
30
Conventional
20 P=0.06
10
0
Glycosylated Cholesterol Triglycerides Systolic BP Diastolic BP
Hemoglobin <175 mg/dl <150 mg/dl <130 mm Hg <80 mm Hg
<6.5%
Gaede et al, NEJM 2003;348:383-93

21. A
60
P=0.007
Primary Composite End Point (%)
50
Conventional therapy
Conventional therapy
40
30
20
Intensive therapy
Intensive therapy
10
Lower risk of CVD
HR 0.47 (95%CI 0.24,0.73)
0
0 12 24 36 48 60 72 84 96
Months of Follow-up
No. at Risk
Conventional 80 72 70 63 59 50 44 41 13
therapy
Intensive 80 78 74 71 66 63 61 59 19
therapy
Gaede et al, NEJM 2003;348:383-93

22. Who will benefit
No benefit
from tight in UKPDS?
glycemic control?
Treatment was adjusted to
FBG only (not PPBG)

23. Relative contribution of postprandial
and fasting glucose to HbA1c
WHO criteria FPG < 6.0 mmol/L
Postprandial glucose exposure
Fasting hyperglycaemia
100
90 p=0.004 p<0.001
80 69.8
% contribution
70 54.3
60 49.6 50.4 45.7
50
40 30.2
30
20
10
0
< 7.0%
– 7.1%-9.0% > 9.0%
E
HbA1C groups
IN
Peter & Rees, Br J Diabetes Vasc Dis 2008;8:8-14

24. Who will benefit
No benefit
from tight
glycemic control?
in UKPDS?
Treatment was adjusted
to FBG only (not PPBG)
Kumamoto study (n=110)
Intensive insulin regimen vs conventional treatment x 8 years
Titration based on FBG, HbA1c and PPBG
Nonsignificant ~50% reduction in macrovascular complications
Peter & Rees, Br J Diabetes Vasc Dis 2008;8:8-14

25. Who will benefit ACCORD
from tight
glycemic control? Objective
To determine if 3 separate
strategies can reduce CV events
Intensive therapy to target normal
A1c levels (<6.0%) vs standard
therapy to target A1c 7.0-7.9%
Therapy to target SBP <120 mm Hg
Type 2 diabetes vs <140 mm Hg
Mean age 62.2 y Addition of fenofibrate vs placebo in
Median DM duration 10 y patients on statin therapy with
35% had previous CVD
optimal LDL-C
35% already on insulin
(n=10,251)
ACCORD Group, NEJM 2008;358: 2545-59

26. ACCORD
Endpoint
Composite of
nonfatal MI,
nonfatal stroke or
death from CV
causes
ACCORD Group, NEJM 2008;358: 2545-59

27. 25
median HbA1c at 1 y
Standard 7.5%
20 n = 371
Intensive 6.4%
Standard therapy
15
10 HR 0.90 (95%CI 0.78,1.04)
p=0.16 Intensive therapy
n = 352
5
0
0 1 2 3 4 5 6
Intensive therapy 5128 4843 4390 2839 1337 475 448
Standard therapy 5123 4827 4262 2702 1186 440 395
ACCORD Group, NEJM 2008;358: 2545-59

28. Total 10,251 723
Previous cardiovascular event 0.04
No 6,643 330
Yes 3,608 393
Sex 0.74
Female 3,952 212
Male 6,299 511
Age at baseline 0.65
<65 yr 6,779 383
≥65 yr 3,472 340
Glycated hemoglobin at baseline 0.03
≤8.0% 4,868 284
>8.0% 5,360 438
Race 0.29
Nonwhite 3,647 222
White 6,604 501
0.6 1.0 1.4
ACCORD Group, NEJM 2008;358: 2545-59

29. 25
20
15
n = 257
10 HR 1.22 (95%CI 1.01,1.46) Intensive therapy
p=0.04
5 Standard therapy
n = 203
0
0 1 2 3 4 5 6
Intensive therapy 5128 4972 4803 3250 1748 523 506
Standard therapy 5123 4971 4700 3180 1642 499 480
ACCORD Group, NEJM 2008;358: 2545-59

30. Who will benefit
No benefit
from tight in ACCORD?
glycemic control?
Amount of HbA1c reduction
achieved relative to baseline level
Rapidity with which HbA1c was
achieved or actual HbA1c itself
Treatments used or sequence of
treatments used
Presence of unrecognized
hypoglycemia
Cheng & Leiter, Current Diabetes Reports 2009;9: 65-72

31. Who will benefit ADVANCE
from tight
glycemic control? Intensive glucose Standard glucose
control control
(Gliclazide MR-based) Target A1c based
Target A1c <6.5% on local guidelines
Perindopril- Perindopril-
Indapamide-based Indapamide-based
Routine BP lowering Routine BP lowering
Intensive glucose Standard glucose
control control
Type 2 diabetes
(Gliclazide MR-based) Target A1c based
Mean age 66 y
Target A1c <6.5% on local guidelines
Mean DM duration 8 y
37% from Asia Usual BP lowering therapy Usual BP lowering therapy
32% with history of
macrovascular disease
(n=11,140) ADVANCE Collaborative Group, NEJM 2008;358:2560-72

32. ADVANCE
Endpoints
Composites of major
macrovascular and
microvascular events
jointly and separately
Macrovascular events
Death from CV causes, nonfatal MI or nonfatal stroke
ADVANCE Collaborative Group, NEJM 2008;358:2560-72

33. 25
median HbA1c at 5 y
Standard 7.3%
20
Intensive 6.5%
15 Standard
control
10
HR 0.94 Intensive
(95%CI 0.84,1.06) control
5 P=0.32
0
0 6 12 18 24 30 36 42 48 54 60 66
Intensive 5570 5494 5428 5338 5256 5176 5097 5005 4927 4396 2071 486
Standard 5569 5486 5413 5330 5237 5163 5084 4995 4922 4385 2108 509
ADVANCE Collaborative Group, NEJM 2008;358:2560-72

34. HR 0.93
(95%CI 0.83,1.06)
ADVANCE Collaborative Group, NEJM 2008;358:2560-72

35. No benefit
in ADVANCE?
Inadequate statistical power to
detect reduction in macrovascular
Who will benefit events
from tight Annual rate of 2.2% lower than
glycemic control? anticipated rate of 3% (greater use
of statins, BP-lowering drugs and
anti-platelet agents)
ADVANCE Collaborative Group, NEJM 2008;358:2560-72

36. Who will benefit VADT
from tight
glycemic control?
Objective
To determine effects of intensive
glycemic control (target HbA1c
<6%) vs standard control (HbA1c
8% to 9%) on CV outcomes
Type 2 diabetes
Mean age 60 y
Mean DM duration 11.5 y
Mean HbA1c 9.4%
40% had a CV event
(n=1,791)
Duckworth et al NEJM 2009;360:129-39

37. VADT Primary
Time from Endpoint
randomization to
first occurrence of
major CV event*
* Composite of myocardial infarction, stroke,
death from CV causes, CHF, surgery for vascular
disease, inoperable coronary disease and
amputation for ischemic gangrene
Duckworth et al NEJM 2009;360:129-39

38. 1.0 VADT Results
n = 235
0.8 Intensive therapy
0.6 Standard therapy
n = 264
0.4
Intensive group median HbA1c
0.2 HR 0.88 (95%CI 0.74-1.05) Standard 8.4%
P=0.14 Intensive 6.9%
0.0
0 2 4 6 8
Standard therapy 899 770 693 637 570 471 240 55 0
Intensive therapy 892 774 707 639 582 510 252 62 0
Duckworth et al NEJM 2009;360:129-39

39. Who will benefit
No benefit
from tight in VADT?
glycemic control?
Suggests that tight glycemic
control appears to be ineffective
at later stages
Animal model of atherosclerosis
Glucose plays an important role in
lesion initiation
Lipids play a more dominant role in
lesion progression

40. Who will benefit UKPDS
from tight Follow-up
glycemic control?
Objectives
To determine whether the
effects of improved glucose
control on microvascular
disease persisted 10 years
after study completion
UKPDS participants
(n=3277) Whether such therapy had a
Annual visits x 5 years long-term effect on
Questionnaire x 5 more macrovascular outcomes
years assessing outcomes
Holman et al, NEJM 2008;359: 1577-89

41. UKPDS Follow-up
Clinical Outcomes
Any Diabetes-
Myocardial
diabetes- related death Death from
Sudden death or death
infarction
related from MI, stroke, PVD, any cause Fatal or
renal disease, hyper- or nonfatal MI
endpoint * hypoglycemia
Microvascular Glycemic
Stroke PVD disease control at MD’s
Amputation of at Vitreous discretion
Fatal or
least 1 digit or hemorrhage, retinal
nonfatal stroke
death from PVD
Median ff-up
photocoagulation or
renal failure
17 y (range 16-30 y)
* Sudden death, death from hyperglycemia or hypoglycemia, fatal or
nonfatal MI, angina, heart failure, amputation, vitreous hemorrhage, retinal
photocoagulation, blindness in one eye, or cataract extraction
Holman et al, NEJM 2008;359: 1577-89

42. Post-trial risk
1.4
P=0.052 reduction 15% P=0.01
1.2
1.0
0.8
0.6
0.4
Conventional therapy 186 212 239 271 296 319
Sulfonylurea–insulin 387 450 513 573 636 678
Holman et al, NEJM 2008;359: 1577-89

43. 1.0
Legacy Effect
P=0.01
0.8
0.6
Conventional
0.4 therapy
0.2
Sulfonylurea–insulin
0.0
0 5 10 15 20 25
Conventional therapy 1138 1013 857 578 221 20
Sulfonylurea–insulin 2729 2488 2097 1459 577 66
Holman et al, NEJM 2008;359: 1577-89

44. Who will benefit
Meta-analysis
from tight
glycemic control?
Objective
To summarize clinical
benefits and harms of
intensive vs conventional
glucose control for adults
n = 27,802 with type 2 diabetes
UKPDS 33, 1998
UKPDS 34, 1998
ACCORD, 2008
ADVANCE, 2008
VADT, 2009
Kelly et al, Ann Intern Med Jul 2009;151: 394-403

45. Fatal stroke 39/11 591 52/11 591 0.75 (0.49 to 1.14) –1 (–3 to 1)
PAD 374/6463 406/6468 0.92 (0.81 to 1.06) –5 (–9 to –1)
Intensive glucose control reduced 0.5 1.0 2.0
the risk for nonfatal MI Relative Risk (95% CI)
C. All Trials
Event Events/Total, n/n Relative Risk Risk Difference
(95% CI) (95% CI)
Intensive Conventional
Nonfatal MI 611/14 662 598/13 140 0.84 (0.75 to 0.94) –9 (–16 to 3)
Fatal MI 540/14 662 437/13 140 0.94 (0.75 to 1.18) –3 (–10 to 4)
Nonfatal stroke 423/14 662 362/13 140 0.98 (0.82 to 1.17) –3 (–7 to 2)
Fatal stroke 88/14 662 76/13 140 0.87 (0.63 to 1.20) 0 (–2 to 1)
PAD 409/9534 433/8017 0.91 (0.79 to 1.03) –3 (–5 to –1)
0.5 1.0 2.0
Relative Risk (95% CI)
infarction; PAD peripheral artery disease.
Intensive glucose control did not reduce the risk for CV
death or all-cause mortality and increased the risk for
15 September 2009 Annals of Internal Medicine Volume 1
severe hypoglycemia
Kelly et al, Ann Intern Med Jul 2009;151: 394-403

46. ↓ 0.9% HbA1c
over 5 years from
baseline 7.8%
NNT 87
↓ 1 mmol/L ↓ 4 mm Hg
Benefit from glycemic LDL prevents BP prevents
8.2 CV events 12.5 CV
control is modest events
compared to control of
lipids and blood
pressure
Ray et al, Lancet 2009;373:1765-72

47. Who will benefit Summary
from tight
glycemic control?
Glycemic control does play a role
in reducing CV complications ...
Start early in the disease course
Individuals in the ACCORD,
ADVANCE and VADT have had
diabetes 8 to 11 years at start of trial
Cheng & Leiter, Current Diabetes Reports 2009;9: 65-72

48. Who will benefit Summary
from tight
glycemic control?
Glycemic control does play a role
in reducing CV complications ...
Benefit becomes evident only after
a long period of time
Follow-up periods in the ACCORD, ADVANCE
and VADT were between 3.5 to 5 years
Follow-up time required to demonstrate
macrovascular benefit in UKPDS was median
of 17.8 years
Cheng & Leiter, Current Diabetes Reports 2009;9: 65-72

49. Who will benefit How do current
from tight therapies for
glycemic control? diabetes compare?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

50. Who will benefit How do current
from tight therapies for
glycemic control? diabetes compare?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

51. Primary Prevention of CVD in
People with Diabetes Mellitus
A Scientific Statement from AHA & ADA
A1c goal for patients in
general is <7%
A1c goal for the individual
patients is an A1c as close to
What should be normal (<6%) as possible
the target HbA1c? without causing hypoglycemia
Buse, Circulation 2007;115:114-26

52. HbA1c <7% OR <6.5%?
Not enough basis for <7%
Kumamoto study is the only
long-term study with clinical
events as primary outcomes
HbA1c data from UKPDS,
What should be ACCORD, ADVANCE and VADT
the target HbA1c? considered observational
Participants randomized to A1c
target not to the level achieved
Lund & Vaag, Diabetes Care Jul 2009;32(7):e90

53. HbA1c <7% OR <6.5%?
Hypoglycemia
increases
What should be
the target HbA1c?
as HbA1c target
decreases

54. HbA1c <7% OR <6.5%?
A1c target <6.5% might not
increase hypoglycemia per se
ADVANCE intensive group had
2-3% higher hypoglycemia risk
than conventional group
Lower than hypoglycemia risk in
What should be ACCORD/VADT intensive group
the target HbA1c? (~15-20%)
Lower than hypoglycemia risk in
ACCORD/VADT conventional group
(~5-10%)
Lund & Vaag, Diabetes Care Jul 2009;32(7):e90

55. Mortality
Analyses in Hypoglycemia not significantly
related to excess mortality in
ACCORD intensive group
Intensive control increased
mortality irrespective of pre-
existing CVD
In patients with preexisting CVD,
What should be intensive control had no effect on
the target HbA1c? CVD (i.e. no harm)
Hypoglycemia did not explain the
increased mortality
Lund & Vaag, Diabetes Care Jul 2009;32(7):e90

56. Mortality Analyses
in ACCORD
In both arms, patients with
severe hypoglycemia had higher
mortality than those without
Higher mortality in standard arm
among participants with at least
one episode of severe
What should be hypoglycemia
the target HbA1c?
Higher mortality in intensive arm
among participants with no
history of severe hypoglycemia
Skyler et al, J Am Coll Cardiol 2009;53:298-304

57. Intensive Glycemic Control and the Prevention of
Cardiovascular Events: Implications of the ACCORD,
ADVANCE and VA Diabetes Trials
A Position Statement of the ADA and a Scientific Statement of the ACC & AHA
Lower A1c goal if can be achieved
without significant hypoglycemia
Short duration of diabetes
Long life expectancy
No significant CVD
What should be
the target HbA1c?
General A1c goal <7%
Skyler et al, J Am Coll Cardiol 2009;53:298-304

58. Intensive Glycemic Control and the Prevention of
Cardiovascular Events: Implications of the ACCORD,
ADVANCE and VA Diabetes Trials
A Position Statement of the ADA and a Scientific Statement of the ACC & AHA
Less stringent A1c goal
History of severe hypoglycemia
Limited life expectancy
Advanced micro- or macrovascular
complications or extensive comorbid
conditions
Long-standing diabetes which is
difficult to control
What should be
the target HbA1c?
General A1c goal <7%
Skyler et al, J Am Coll Cardiol 2009;53:298-304

59. Who will benefit How do current
from tight therapies for
glycemic control? diabetes compare?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

60. Who will benefit How do current
from tight therapies for
glycemic control? diabetes compare?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

61. UKPDS
Overweight patients on Metformin
↓ MI by 39% (p=0.01)
↓ all-cause mortality by 36% (p=0.01)
How do current
therapies for diabetes
compare?
Holman et al, NEJM 2008;359: 1577-89

62. Legacy Effect
1.0
P=0.005
0.8
0.6 Conventional
therapy
0.4
0.2
Metformin
0.0
0 5 10 15 20 25
Conventional therapy 411 360 311 213 95 4
Metformin 342 317 274 214 106 16
Holman et al, NEJM 2008;359: 1577-89

63. 1.0
Legacy Effect
P=0.01
0.8
0.6
Conventional
0.4 therapy
0.2
Sulfonylurea–insulin
0.0
0 5 10 15 20 25
Conventional therapy 1138 1013 857 578 221 20
Sulfonylurea–insulin 2729 2488 2097 1459 577 66
Holman et al, NEJM 2008;359: 1577-89

64. PROACTIVE
PROspective PioglitAzone Clinical
Trial In macroVascular Events
How do current
therapies for
Objective
diabetes compare?
To determine if treatment
with pioglitazone will
decrease CV events in high-
risk patients with type 2
diabetes
Type 2 diabetes
Evidence of CVD
Continued on current treatment
Randomized to pioglitazone or placebo
Singaram & Pratley, Diabetes Vasc Dis Res 2007; 4:237-40

65. PROACTIVE
Endpoints
Composite of all-cause
mortality, non-fatal MI,
stroke, ACS,
endovascular/surgical
intervention in
coronary/leg arteries or
amputation above the
ankle
Secondary endpoint: composite of all-
cause mortality, non-fatal MI and stroke
Singaram & Pratley, Diabetes Vasc Dis Res 2007; 4:237-40

66. PROACTIVE Primary Endpoint
Dormandy et al, Lancet 2005;366:1279-89

67. PROACTIVE Secondary Endpoint

68. How do current Pioglitazone
therapies for PROACTIVE
diabetes compare?
Unclear whether the effect of
pioglitazone on macrovascular
endpoints is a unique property of the
drug
Slight improvements in SBP, TG and
HDL-C unlikely to get individual
patients to goal
40% higher risk of CHF unsurprising
Singaram & Pratley, Diabetes Vasc Dis Res 2007; 4:237-40

69. Meta-analysis
How do current
therapies for
diabetes compare?
Objective
To systematically examine
the peer-reviewed literature
on the CV risk associated
with oral agents
40 controlled trials that
reported CV events
(primarily MI and stroke)
Selvin et al, Arch Intern Med 2008;168(19):2070-80

70. Meta-analysis
How do current
therapies for
diabetes compare? Results
Metformin ↓ risk of CV mortality
(OR 0.74; 95%CI 0.62-0.89)
Rosiglitazone ↑ risk of CV morbidity
or mortality but not statistically
significant (OR 1.68; 95%CI 0.92-3.06)
No other significant associations for
other oral agents
40 controlled trials that
reported CV events
(primarily MI and stroke)
Selvin et al, Arch Intern Med 2008;168(19):2070-80

71. How do current
therapies for diabetes BARI 2D
compare?
Prompt coronary
Medical Therapy
revascularization Insulin sensitization
Insulin sensitization
therapy
therapy
(Metformin/RSG)
(Metformin/RSG)
Prompt coronary
Medical Therapy
revascularization Insulin provision
Insulin provision
therapy
therapy
(SU/Insulin)
(SU/Insulin)
Type 2 diabetes and heart disease
(n=2,368)
Randomization stratified according
to choice of PCI or CABG BARI 2D Study Group, NEJM 2009;360:2503-15

72. BARI 2D
Endpoints
Death rate
Composite of death,
MI or stroke
BARI 2D Study Group, NEJM 2009;360:2503-15

73. 100 Insulin sensitization
90 88.2
80 87.9
Insulin provision
70
60
50
40 P=0.89
30
20
10
0
0 1 2 3 4 5
2368 2296 2247 2197 1892 1196
BARI 2D Study Group, NEJM 2009;360:2503-15

74. 100
90 Insulin sensitization
80 77.7
70 75.4
Insulin provision
60
P=0.13
50
40
30
Insulin sensitization strategy
20
Fewer severe hypoglycemia, less
10 weight gain and higher HDL-C
0
0 1 2 3 4 5
2368 2094 1984 1807 1459 823
BARI 2D Study Group, NEJM 2009;360:2503-15

75. Who will benefit
from tight
glycemic control?
Cardiovascular Disease Prevention

76. Who will benefit
from tight
glycemic control?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

77. Who will benefit How do current
from tight therapies for
glycemic control? diabetes compare?
What should be
the target
HbA1c?
Cardiovascular Disease Prevention

78. Thank You
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