Does Tight Glycemic Control Improve CV Diabetic Complications?

Khalifa AbdallahProf. of Internal Medicine

Diabetes, Metabolism & Lipidology UnitAlexandria 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 groupError bars = 95% CI Adapted from Stratton IM, et al. BMJ 2000; 321:405–412.

20

40

60

80

Incidence per1,000 patient-years

5 6 7 8 9 10 11

Myocardialinfarction

Microvasculardisease

Updated mean HbA1c (%)

00

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

00 3 6 9 12 15

}0.9%

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

UKPDSUKPDS

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 glucosecontrol control % Risk

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

Macrovascular events

• MI17.4 14.7 16 0.052

• Stroke 5.0 5.6 –11NS

• PVD 1.6 1.1 35NS

• Diabetes-related death 11.5 10.4 10NS

• All-cause mortality 18.9 17.9 6NS

Microvascular events 11.4 8.6 250.0099

All events** 46.0 40.9 120.029

57% risk reduction in non-fatal MI, stroke or CVD death*(P = 0.02; 95% CI: 12–79%)

Cu

mu

lati

ve i

nci

de

nce

o

f n

on

-fat

al M

I, s

tro

ke o

r d

eath

fro

m C

VD

Conventionaltreatment

Intensivetreatment

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

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

A1

C (

%)

9

8

2 3 4 5 7 8 9

Conventional treatment

Intensive treatment

11 12 13 14 15 16 1710

*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

5 731 9

8

9

10

7Hb

A1

c (%

)

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 resultspresented

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

2,118Sulfonylurea/Insulin

279 Metformin

1997# in survivor cohort

2002

Clinic

Clinic

Clinic

Questionnaire

Questionnaire

Questionnaire

2007# with final year data

379 Conventional

1,010Sulfonylurea/Insulin

136 Metformin

P

P

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

Mean age62±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

00 3 6 9 12 15

}0.9%

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

UKPDSUKPDS

Median A1c Conventional : 7.9 %Intensive : 7%

Key insights from the latest randomised trials

ACCORD ADVANCE and VADT- No Significant ACCORD ADVANCE and VADT- No Significant Effect on Macro or Micro Vascular OutcomesEffect on Macro or Micro Vascular Outcomes

ACCORDACCORD ADVANCEADVANCE VADTVADT

No. of participants No. of participants 10,251 10,251 11,140 11,140 1791 1791

Participant age ,years Participant age ,years 62 62 66 66 60 60

Duration of diabetes at Duration of diabetes at study entry, years study entry, years

1010 88 11.511.5

HbA1C at Baseline, % HbA1C at Baseline, % 8.18.1 7.57.5 9.49.4

Participants with prior Participants with prior cardiovascular event, cardiovascular event, % %

3535 3232 4040

Duration of follow-up, Duration of follow-up, years years

3.43.4 5.05.0 66

Summary of ACCORD, ADVANCE and VADTSummary of ACCORD, ADVANCE and VADT

ACCORDACCORD ADVANCEADVANCE VADTVADTNo. of participants No. of participants 10,251 10,251 11,140 11,140 1791 1791

Participant Participant age ,years age ,years

62 62 66 66 60 60

HbA1C at Baseline, HbA1C at Baseline, % %

8.18.1 7.57.5 9.49.4

Significant Effect on Significant Effect on Macrovascular Macrovascular Outcomes?Outcomes?

NoNo NoNo NoNo

Significant Effect on Significant Effect on Microvascular Microvascular Outcomes?Outcomes?

NANA Significant for Significant for nephropathy, nephropathy,

not retinopathynot retinopathy

NoNo

Rosiglitazone use, Rosiglitazone use, (intensive vs. (intensive vs. standard)standard)

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

Duration of follow-Duration of follow-up, years up, years

3.43.4 5.05.0 66

Summary of ACCORD, ADVANCE and VADTSummary of ACCORD, ADVANCE and VADT

ACCORDACCORD ADVANCEADVANCE VADTVADTNo. of participants No. of participants 10,251 10,251 11,140 11,140 1791 1791

Participant Participant age ,years age ,years

62 62 66 66 60 60

HbA1C at Baseline, HbA1C at Baseline, % %

8.18.1 7.57.5 9.49.4

Significant Effect on Significant Effect on Microvascular Microvascular Outcomes?Outcomes?

NANA Significant for Significant for nephropathy, nephropathy,

not retinopathynot retinopathy

NoNo

Rosiglitazone use, Rosiglitazone use, (intensive vs. (intensive vs. standard)standard)

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

Duration of follow-Duration of follow-up, years up, years

3.43.4 5.05.0 66Significant Effect on Significant Effect on Macrovascular Macrovascular OutcomesOutcomes??

No No No

Summary of ACCORD, ADVANCE and VADTSummary of ACCORD, ADVANCE and VADTIncidence of Severe Hypoglycemia (%)Incidence of Severe Hypoglycemia (%)

ACCORDACCORD ADVANCEADVANCE VADTVADT

Intensive armIntensive arm 16.216.2 2.72.7 21.221.2

Standard armStandard arm 5.15.1 1.5 1.5 9.99.9

A1cA1c && HypoglycemiaHypoglycemiaIncrease incidence of HypoglycemiaIncrease incidence of Hypoglycemia

HbA1c (%)

5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0

ComplicationsHypoglycaemia

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

Patie

nts,

%

Type 2diabetes

55.762.5

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 clamp2 weeks afterglibenclamide withdrawal(n=13)

0

360

370

380

390

400

410

420

430

440

450

Mea

n Q

T in

terv

al,

ms

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.

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