Does Tight Glycemic Control

Improve CV Diabetic Complications?

Khalifa Abdallah

Prof. of Internal Medicine

Diabetes, Metabolism & Lipidology Unit

Alexandria Faculty of Medicine

No

UKPDS: elevated blood glucose levels increase the risk of diabetic complications

Study population: White, Asian Indian and Afro-Caribbean UKPDS patients (n = 4,585)

Adjusted for age, sex and ethnic group

Error bars = 95% CI Adapted from Stratton IM, et al. BMJ 2000; 321:405–412.

20

40

60

80

Incidence per

1,000 patient-years

5 6 7 8 9 10 11

Myocardial

infarction

Microvascular

disease

Updated mean HbA1c (%)

0 0

HbA1c

6.5%

Intensive vs. conventional management

Time from randomization (years)

Media

n A

1C (

%)

Conventional Treatment (n=1138)

Intensive Treatment (n=2729)

9

8

7

6

0 0 3 6 9 12 15

} 0.9%

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

UKPDS

NS = not significant; PVD = peripheral vascular disease.

*Per 1000 patient-years.

**Combined microvascular and macrovascular events.

Adapted from United Kingdom Prospective Diabetes Study Group (UKPDS) Lancet 1998;352:837-853.

Intensive Glucose Control Significantly Reduced Microvascular Disease

Rate* Conventional Intensive

glucose glucose control control % Risk

(n=2729) (n=1138) reduction p

Macrovascular events

• MI 17.4 14.7 16 0.052

• Stroke 5.0 5.6 –11 NS

• PVD 1.6 1.1 35 NS

• Diabetes-related death 11.5 10.4 10 NS

• All-cause mortality 18.9 17.9 6 NS

Microvascular events 11.4 8.6 25 0.0099

All events** 46.0 40.9 12 0.029

57% risk reduction

in non-fatal MI, stroke or CVD death*

(P = 0.02; 95% CI: 12–79%)

Cu

mu

lati

ve in

cid

en

ce o

f

no

n-f

ata

l M

I, s

tro

ke

or

de

ath

fro

m C

VD

Conventional

treatment

Intensive

treatment

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Years

0.06

0.04

0.02

0.00

Adapted from DCCT. N Engl J Med 1993; 329:977–986. DCCT/EDIC. JAMA 2002; 287:2563–2569.

DCCT/EDIC. N Engl J Med 2005; 353:2643–2653.

DCCT/EDIC: glycaemic control reduces the risk of non-fatal MI, stroke or death from CVD in type 1 diabetes

0

7

1 6

Hb

A1C (

%)

9

8

2 3 4 5 7 8 9

Conventional treatment

Intensive treatment

11 12 13 14 15 16 17 10

*Intensive vs conventional treatment

DCCT (intervention period EDIC (observational follow-up)

DCCT (intervention period) EDIC (observational follow-up)

Years

A1c Reduction With Intensive & Conventional Management

0 2 4 6 8 10

Years from randomization

5 7 3 1 9

8

9

10

7 HbA

1c (%

)

6

0

Intensive

Conventional

DCCT Research Group. N.Eng.J.Med. 1993;329:977–986.

9.1%

7.2%

UKPDS: Post-Trial Changes in HbA1c

UKPDS results

presented

Mean (95%CI)

UKPDS 80. N Eng J Med 2008; 359

After median 8.5 years post-trial follow-up

Aggregate Endpoint 1997 2007

Any diabetes related endpoint RRR: 12% 9%

P: 0.029 0.040

Microvascular disease RRR: 25% 24%

P: 0.0099 0.001

Myocardial infarction RRR: 16% 15%

P: 0.052 0.014

All-cause mortality RRR: 6% 13%

P: 0.44 0.007

RRR = Relative Risk Reduction, P = Log Rank

UKPDS: Legacy Effect of Earlier Glucose Control

N Eng J Med 2008

UKPDS: Post-Trial Monitoring: Patients

880

Conventional

2,118

Sulfonylurea/Insulin

279

Metformin

1997

# in survivor cohort

2002

Clinic

Clinic

Clinic

Questionnaire

Questionnaire

Questionnaire

2007

# with final year data

379

Conventional

1,010

Sulfonylurea/Insulin

136

Metformin

P

P

Mortality 44% (1,852) Lost-to-follow-up 3.5% (146)

Mean age

62±8 years

N Eng J Med 2008

Intensive vs. conventional management

Time from randomization (years)

Media

n A

1C (

%)

Conventional Treatment (n=1138)

Intensive Treatment (n=2729)

9

8

7

6

0 0 3 6 9 12 15

} 0.9%

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

UKPDS

Median A1c

Conventional : 7.9 %

Intensive : 7%

Key insights from the latest

randomised trials

ACCORD ADVANCE and VADT- No Significant Effect

on Macro or Micro Vascular Outcomes

ACCORD ADVANCE VADT

No. of participants 10,251 11,140 1791

Participant age ,years 62 66 60

Duration of diabetes at study entry, years

10

8

11.5

HbA1C at Baseline, % 8.1 7.5 9.4

Participants with prior cardiovascular event, %

35

32

40

Duration of follow-up, years

3.4 5.0

6

Summary of ACCORD, ADVANCE and VADT

ACCORD ADVANCE VADT

No. of participants 10,251 11,140 1791

Participant age ,years 62 66 60

HbA1C at Baseline, % 8.1 7.5 9.4

Significant Effect on Macrovascular Outcomes?

No No No

Significant Effect on Microvascular Outcomes?

NA Significant for nephropathy, not

retinopathy

No

Rosiglitazone use, (intensive vs. standard)

90% vs. 58% 17% vs. 11% 85% vs. 78%

Duration of follow-up, years

3.4

5.0

6

Summary of ACCORD, ADVANCE and VADT

ACCORD ADVANCE VADT

No. of participants 10,251 11,140 1791

Participant age ,years 62 66 60

HbA1C at Baseline, % 8.1 7.5 9.4

Significant Effect on Microvascular Outcomes?

NA Significant for nephropathy, not

retinopathy

No

Rosiglitazone use, (intensive vs. standard)

90% vs. 58% 17% vs. 11% 85% vs. 78%

Duration of follow-up, years

3.4

5.0

6

No

No

No

Significant Effect on Macrovascular Outcomes?

Summary of ACCORD, ADVANCE and VADT

Incidence of Severe Hypoglycemia (%)

ACCORD ADVANCE VADT

Intensive arm 16.2 2.7 21.2

Standard arm 5.1 1.5 9.9

A1c & Hypoglycemia Increase incidence of Hypoglycemia

HbA1c (%)

5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0

Complications

Hypoglycaemia

10.5

DCCT Research Group. N.Eng.J.Med. 1993;329:977–986.

Asymptomatic Episodes of Hypoglycemia May Go Unreported

• In a cohort of patients

with diabetes, more than

50% had asymptomatic

(unrecognized)

hypoglycemia, as

identified by continuous

glucose monitoring1

• Other researchers have

reported similar

findings2,3

1. Copyright © 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Reprinted with permission from the American Diabetes Association.

2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494. 3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.

0

25

50

75

100

All patients

with diabetes

Type 1

diabetes

Pat

ient

s, %

Type 2

diabetes

55.7 62.5

46.6

Patients With ≥1 Unrecognized

Hypoglycemic Event, %

n=70 n=40 n=30

Severe Hypoglycemia Causes QTc Prolongation

P=NS

P=0.0003

Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.

Euglycemic clamp (n=8)

Hypoglycemic clamp

2 weeks after glibenclamide withdrawal (n=13)

0

360

370

380

390

400

410

420

430

440

450

Me

an

QT

in

terv

al, m

s

Baseline (t=0)

End of clamp (t=150 min) ACCORD?

Significant QTc prolongation

during

hypoglycemia

Conclusions

• Although observational trials demonstrated

that the relationship between glycemic control

and CV diabetic complications was log-linear

and extended down to the normal A1c with no

threshold, yet randomized clinical trials failed

to confirm this hypothesis

• There is no solid evidence that tight glycemic

control ( A1c <6.5 %) has clear benefit on

reducing CV outcome in type 2 diabetic

individuals but there is definite evidence that

tight glycemic control increases the risk of

severe hypoglycemia

•Older patients with long standing

diabetes and existing co-morbidities do

not benefit from intensive glycemic

control

•Controlling nonglycemic risk factors

(hypertension, dyslipidemia, obesity, …)

with standard glycemic control (A1c <

7%) is still the recommended strategy to

prevent CV diabetic complications)

Conclusions-Cont.

Thank you