Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes

Nizar ALBACHE

Aleppo University- Diabetes Research Unit

President of Syrian Endocrine Society

Vice President of Mediterranean Group for Study of Diabetes

Blood glucose: is lower better for diabetic patients?

Miracle of insulin

Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset

4

Hyperglycaemia

Chronic complications of hyperglycemia

??

Glycemic Control on Diabetic Microvascular Complications

Type 2

UKPDS

8 7%

17-21%

24-33%

-

HbA1c

Retinopathy

Nephropathy

Neuropathy

Type 1

DCCT

9 7%

76%

54%

60%

Type 2

Kumamoto

9 7%

69%

70%

-

DCCT Research Group, NEJM 1993, Ohkubo et al., Diab Res Clin Pract 1995, UKPDS Group, Lancet 1998

UKPDS:Intensive glycemic control reduces microvascular complications

All microvascular

endpoints

Cataract extraction

Retinopathy Microalbuminuria

25% 24% 21% 33%

P = 0.0099 P = 0.046

P = 0.015

P = 0.000054

Rationale for near-normoglycemia Lessons from UKPDS: Better control means fewer complications

EVERY 1% reduction in HBA1C

REDUCED RISK*

1%

Deaths from diabetes

Heartattacks

Microvascular complications

Peripheral vascular disorders

UKPDS 35. BMJ 2000; 321: 405-12

-37%

-43%

*p<0.0001

-14%

-21%

Hyperglycaemia

chronic complications of hyperglycemia

??

Seven-year incidence in a Finnish-based cohort*P < 0.001 vs no prior MI†P < 0.001 vs no diabetes

Risk of myocardial infarction is increased in type 2 diabetes

0%

20%

40%

Ris

k o

f fa

tal

or

no

n-f

atal

m

yoca

rdia

l in

farc

tio

n

No prior myocardial infarction

Prior myocardial infarction

Adapted from Haffner SM. New Engl J Med 1998; 339:229–234.

Non diabetic subjects Type 2 diabetic subjects

*

*

n = 1,30469 890 169

†

†

60%

Recent Studies Evaluating Effect of Glycemic Control on CVD

• ACCORD• ADVANCE• VADT

ACCORD: Action to Control Cardiovascular Risk in Diabetes

– 10,251 Enrollees• 60% male 40%

female• Mean age 62.2• Baseline HgA1c 8.1%• BMI - 32

• 30% macrovascular dx

• Duration DM: 10 years

• Majority of intensive group on 3-5 oral agents plus insulin

• Hypoglycemia 3 times greater in intensive group

ACCORD: Treatment effects on glucose control

ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

A1C (%)

Time (years)

Standard therapy

Intensive therapy

6

9.0

8.5

8.0

7.5

7.0

6.5

6.00

0 1 2 3 4 5

ACCORD: Treatment effect on primary outcome


25

0

20

15

10

5

01 2 3 4 5 6

Standard therapy

Intensive therapy

Patients with events

(%)

Time (years)

HR 0.90 (0.78-1.04)P = 0.16

Primary Outcome: NFMI, NF Stroke or CVD Death

Intensive glycaemic control arm terminated in 3.5 years (instead of 5.6 years as planned for)

February 7, 2008

ADVANCETreatment effect on primary macrovascular outcome

ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

CV death, MI stroke

Cumulative incidence (%)

Follow-up (months)

25

20

15

10

5

00 6 12 18 24 30 36 42 48 54 60 66

HR 0.94 (0.84-1.06)P = 0.32 Standard

control

Intensive control

VADT - Veterans Administration Diabetes Trial

• Primary Endpoint: no difference in CVD outcomes– Standard: 29.3% (predicted – 40%)– Intensive: 27.4% (predicted – 31.6%)

The intensive approach led toconfusion over the best approach

• It does not result in a significantly lower number of major CVA after 5 y

• It led to more death

• Reasons for the higher mortality in the intensive-therapy group are unknowns

• Many factors could be implicated :


• Many factors could be implicated :– The severe hypoglycemia ?– The degree of reduction in A1c ?– The relatively short intervention period (3.7 years) ?– The observed The role of various drugs, drug combinations

or drug interactions; weight gain ?– interaction between the blood-pressure and hyperlipidemia

and glycemia trials with respect to mortality ?

It led to more death

The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001282

Lipid Values

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus

The ACCORD Study Group. N Engl J Med 2010;10.1056/NEJMoa1001286

Mean Systolic Blood-Pressure Levels at Each Study Visit

Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus

Survival as a function of HbA1c

in people with type 2 diabetes

Currie CJ, Peters JR, Tynan A et al.:Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375: 481–89

The Truth Is Not So Sweet

Cardiovascular safety of diabetes drugs

• The goal of marely lowering blood glucose levels in diabetes is too simplistic

• With respect to CVD it appears important how you lower blood sugar as well as how much

• Diabetes drugs, even within the same “class” may yield dramatically different CV outcomes

http://www.escardio.org/

• The optimal mechanism, speed, and extent of glycated hemoglobin reduction are different for differing populations

• Yes For patients with recently diagnosed diabetes, aggressive

treatment will lower cardiovascular risk

• No :• For patients who have diabetes of more than 15 years’

duration and are older and have other comorbidities, less aggressive treatment is indicated

• And

For all patients, treatment of the dyslipidemia and hypertension that are associated with diabetes further reduces CVD risk

Conclusion: is lower better for diabetic patients?

The Promise Land of diabetes therapy

Thank youMerci� شكرًا

Intensive Group Standard Group# Events

**n % n %

1 400 7.8 130 2.5

2 82 1.6 34 0.7

3 to 5 43 0.8 10 0.2

>5 6 0.1 0 0

**Cumulative number of events

Number of Participants With One or More Severe Hypoglycemia Events

Requiring Medical Assistance (n and %)

The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

Intensive Strategy

Higher Mortality

Higher Rates ofHypoglycemia

Intensive Strategy

Higher Rates ofHypoglycemia

Higher Mortality

Can we blame it all on hypoglycemia?

No!The ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-2559.

ACCORD: Glucose-lowering drugs by treatment strategy

55.477.3Insulin

4.917.8Incretin

5.123.2α-Glucosidase inhibitor

58.391.7Thiazolidinedione

73.886.6Secretagogue

Patients (%)

86.994.7Metformin

Standard therapy(n = 5123)

Intensive therapy(n = 5128)


ACCORD: Study design

ACCORD Study Group. Am J Cardiol. 2007;99(suppl):21i-33i.www.accordtrial.org

*Statin + fibrate vs statin, treatment group assignment blinded until end of trialPrimary outcome: CV death, MI, stroke

Glycemia trial

N = 10,251 with T2DM and existing CVD or additional CV risk factors

1178

1184

1193

1178

1383

1370

1374

1391

5128

5123

2362 2371 2753 2765

SBP <120mg Hg

SBP <140mg Hg

Group A Group B

4733 5518

BP trial (n) Lipid trial* (n)

A1C <6%

A1C7.0%-7.9%

A1c Levels at Baseline, at the Intensive-Therapy Group's Transition to Standard Therapy, and After the Transition in the ACCORD Trial

Time of A1c assessment Intensive therapy, n=5128 (%)

Standard therapy, n=5123 (%)

Baseline 8.3 8.3

At transition 6.6 7.7

After transition 7.4 7.8

mortality

Tight glycemic control

Any benefits

Any Diabetes-related Endpoint:legacy effect

Intervention TrialMedian follow-up 10.0 years

Intervention Trial + Post-trial monitoringMedian follow-up 16.8 years

RR=0.88 (0.79-0.99)P=0.029

Conventional

Sulfonylurea/Insulin

Conventional

Sulfonylurea/Insulin

DCCT/EDIC; Memory effect

Metabolic Results

DCCT Intervention

S t u d y Y e a rDCCT

1 2 3 4 5 6 7 8 9

EDIC ObservationTraining

EDIC

ConventionalEDIC mean 8.2%

IntensiveEDIC mean 8.0%

DCCT/EDIC Study Research Group, NEJM 2005

Outcomes • Primary

– First occurrence of nonfatal MI, nonfatal Stroke, or death from CV disease.

• Secondary– Death from any cause.– Also measured the effect of the intervention on

microvascular disease, hypoglycemia, cognition, and quality of life.


Observations

Targeting HbAIC levels below 6.0% increased the rate of death from any cause after a mean of 3.5 years

Magnitude of reductionSpeed of reductionRate of hypoglycaemiaAdverse drug interactions at high doses



• Many factors could be implicated :– The patients selection ?


• Many factors could be implicated :– The patients selection ?– The severe hypoglycemia ?


• Many factors could be implicated :– The patients selection ?– The severe hypoglycemia ?– The degree of reduction in A1c ?

ACCORD: Treatment effects on glucose control


A1C (%)

Time (years)

Standard therapy

Intensive therapy

6

9.0

8.5

8.0

7.5

7.0

6.5

6.00

0 1 2 3 4 5


• Many factors could be implicated :– The patients selection ?– The severe hypoglycemia ?– The degree of reduction in A1c ?– The relatively short intervention period (3.7 years) ?


• Many factors could be implicated :– The patients selection ?– The severe hypoglycemia ?– The degree of reduction in A1c ?– The relatively short intervention period (3.7 years) ?– The observed The role of various drugs, drug

combinations, or drug interactions; weight gain ?– to

ADVANCE: Action in Diabetes and Vascular Disease

•11,140 Enrollees•60% male 40% female•Mean age 66

•50% macrovascular dx•10% microvascular

Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazide combination in >55 y/o Type 2 DM

Baseline HgA1c: 7.51%“standard” : 7.30% Intensive: 6.53%

ADVANCETreatment effect on glucose control

ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72.

Mean A1C (%)

Follow-up (months)

Standard control

Intensive control

10.0

9.0

8.0

7.0

6.0

5.0

0.00 6 12 18 24 30 36 42 48 54 60 66

P < 0.001

ADVANCE

• 11,140 Patients, Age ~66, With Type 2 DM, And High CV Risk

• Intensive (A1c 6.4%) vs Conventional (A1c 7.3%)

• Benefit with regard to microvascular complications

• No Excess Mortality In Intensive Group

VADT - Veterans Administration Diabetes Trial

•1742 Enrollees•97% male•Mean age 60.4

•BMI 31.3•Majority had multiple CV risk factors

•72% HTN•40% macrovascular dx•62% retinopathy•43% neuropathy

confusion over the best approach to cardiovascular risk reduction

Documents

Nizar ALBACHE Aleppo University- Diabetes Research Unit President of Syrian Endocrine Society Vice President of Mediterranean Group for Study of Diabetes