Prof. Khalifa M. AbdallahProf. Khalifa M. AbdallahProfessor of Internal MedicineProfessor of Internal Medicine

Unit of Diabetes & Metabolic DiseasesUnit of Diabetes & Metabolic Diseases

Alexandria Faculty of MedicineAlexandria Faculty of Medicine

Importance of early glycemic control in management of type 2

diabetes

OverviewOverview

The importance of early and The importance of early and sustained glycemic controlsustained glycemic control

The rationale for early insulinizationThe rationale for early insulinization Advantages of basal insulin therapyAdvantages of basal insulin therapy Take home messageTake home message

Diabetes MellitusDiabetes MellitusA Constellation of A Constellation of

ComplicationsComplications

GastropathGastropathyy

Autonomic Autonomic NeuropathyNeuropathy

Renal Renal DiseaseDisease

Peripheral Peripheral NeuropathyNeuropathy

Retinopathy/ Retinopathy/ Macular Macular

EdemaEdema

HypertensionHypertensionCardiovascular Cardiovascular

DiseaseDisease

DyslipidemiaDyslipidemia

Peripheral Peripheral

Vascular Vascular DiseaseDisease

Erectile Erectile DysfunctionDysfunction

DiabetesDiabetes

- A1c & - A1c & MMicrovascular icrovascular CComplicationsomplications60 – 70 % Reduction of Complications60 – 70 % Reduction of Complications

Rel

ativ

e R

isk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

HbA1c (%)

15

13

11

9

7

5

3

16 7 8 9 10 11 12

Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.

Risk Reduction in DCCTR

isk R

ed

uct

ion

DCCT Research Group. N Engl J Med. 1993;329:977-986.

Neuropathy AlbuminuriaRetinopathy

76%

54%60%

54%

39%

Onset

Progression

20

0

40

60

80

albuminuria

Effects of reduction of A1c by 1.9% in intensively Effects of reduction of A1c by 1.9% in intensively treated grouptreated group

P=0.002 P=0.002 P=0.002 P=0.04 P=0.04

UKPDS 35. BMJ 2000; 321: 405-12.

A1c : Myocardial Infarction and A1c : Myocardial Infarction and Microvascular Complication Microvascular Complication

0

20

40

60

80

0 5 6 7 8 9 10 11

Myocardial infarction

Microvasculardisease

Mean HbA1c (%)

Inci

dence

per

100

0 p

ati

ent-

years

UKPDS: Glucose Control Study SummaryUKPDS: Glucose Control Study Summary

The intensive glucose control policy maintained a lower The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in years from diagnosis of type 2 diabetes with reduction in risk of:risk of:

12% for any diabetes related endpoints p=0.02912% for any diabetes related endpoints p=0.029

25% for microvascular endpoints p=0.009925% for microvascular endpoints p=0.0099

16% for myocardial infarction p=0.05216% for myocardial infarction p=0.052

UKPDS: Glucose Control Study SummaryUKPDS: Glucose Control Study Summary

The intensive glucose control policy maintained a lower The intensive glucose control policy maintained a lower HbA1c by a mean of 0.9% over a median follow up of 10 HbA1c by a mean of 0.9% over a median follow up of 10 years from diagnosis of type 2 diabetes with reduction in years from diagnosis of type 2 diabetes with reduction in risk of:risk of:

12% for any diabetes related endpoints p=0.02912% for any diabetes related endpoints p=0.029

25% for microvascular endpoints p=0.009925% for microvascular endpoints p=0.0099

16% for myocardial infarction p=0.05216% for myocardial infarction p=0.052

40

1513 13

10

4 5

0

10

20

30

40

50

Ische

mic

hear

t dise

ase

Other

hea

rt

Other

hea

rt

disea

se

disea

se

Diabet

es

Diabet

es

Mali

gnan

t

Mali

gnan

t

neop

lasm

s

neop

lasm

s

Cereb

rova

scula

r

Cereb

rova

scula

r

disea

se

disea

se

Pneum

onia/

Pneum

onia/

influe

nza

influe

nza

All oth

er

All oth

er

Dea

ths

(%)

Causes of Death in People With DiabetesCauses of Death in People With Diabetes

WHO Report 1997. World Health Organisation. Geneva 1997

of Diabetic Patients Deaths are from CV Causes65%

Can long-term glycemic control Can long-term glycemic control reduce the risk of cardiovascular reduce the risk of cardiovascular

disease? disease?

Summary of ACCORD, ADVANCE and Summary of ACCORD, ADVANCE and VADTVADTACCORDACCORDADVANCEADVANCEVADTVADT

No. 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, % %

8.18.17.57.59.49.4

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

NoNoNoNoNoNo

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

NANASignificant 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

3.43.45.05.066

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

ACCORDACCORDADVANCEADVANCEVADTVADT

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

10108811.511.5

HbA1C at Baseline, % HbA1C at Baseline, % 8.18.17.57.59.49.4

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

353532324040

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

3.43.45.05.066

DCCT / EDIC: majority of patients receive DCCT / EDIC: majority of patients receive intensive therapy and HbAintensive therapy and HbA1C1C levels converge levels converge

DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653

HbA

1c

)%(

YearDCCT

11

10

9

8

7

6

09

ConventionalIntensive

1 2 3 4 5 6 7 8 DCCT end

1 2 3 4 5 6 7

EDIC

Conventional group encouraged to switch

to intensive treatment

HbA

1c

)%(

YearDCCT

11

10

9

8

7

6

09

ConventionalIntensiveConventionalIntensiveIntensive

1 2 3 4 5 6 7 8 DCCT end

1 2 3 4 5 6 7

EDIC

Conventional group encouraged to switch

to intensive treatment

1 2 3 4 5 6 7

EDIC

Conventional group encouraged to switch

to intensive treatment

DCCT / EDIC – incidence of all DCCT / EDIC – incidence of all predefined cardiovascular predefined cardiovascular

outcomeoutcome

Patients previously receiving intensive treatment Patients previously receiving intensive treatment in the DCCT study had a in the DCCT study had a 57%57% reduced incidence reduced incidence of nonfatal myocardial infarction, stroke or death of nonfatal myocardial infarction, stroke or death from cardiovascular diseasefrom cardiovascular disease

DCCT/EDIC: NEJM, 2005;353, No 25: 2643-2653

UKPDS: Post-Trial Changes in UKPDS: Post-Trial Changes in HbAHbA1c1c

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 UKPDS: Legacy Effect of Earlier Glucose ControlControl

N Eng J Med 2008

Can long-term glycemic control Can long-term glycemic control reduce the risk of cardiovascular reduce the risk of cardiovascular

disease? disease?

Yes

If early and sustained glycemic control started before atherosclerosis is established

At present, The question is not At present, The question is not whetherwhether to intensively treat people with type 2 to intensively treat people with type 2 diabetes at onset of the disease to prevent diabetes at onset of the disease to prevent long-term complications. long-term complications.

The question rather is The question rather is howhow to intensively to intensively treat patients with type 2 diabetes to treat patients with type 2 diabetes to consistently keep A1c < 7% all through consistently keep A1c < 7% all through the course of the diseasethe course of the disease

Glycemic control & A1c TargetGlycemic control & A1c Target

ADAADAAACEAACE

A1c (%)A1c (%)<7<7<6.5<6.5

Preprandial Preprandial (mg/dl)(mg/dl)

80-12080-120<110<110

Postprandial Postprandial (mg/dl)(mg/dl)

140-180140-180<140<140

Bedtime (mg/dl)Bedtime (mg/dl)100-140100-140100-140100-140

ADA: American Diabetes AssociationAACE: American Association of Clinical Endocrinologists

Two-thirds of Type 2 Patients are not Achieving Two-thirds of Type 2 Patients are not Achieving Glycemic ControlGlycemic Control

NHANES = National Health and Nutrition Examination Survey.

1Koro et al. Diabetes Care. 2004;27:17-20; 2 “State of Diabetes in America,” American Association of Clinical Endocrinologists, 2003-2004. Available at: http://www.aace.com/public/awareness/stateofdiabetes/ DiabetesAmericaReport.pdf. Accessed January 6, 2006.

A1c 6.5%

AACE survey 2003-20042

N=157,000 type 2 patients

39 US states included

33%33%33%33%

A1c <7%NHANES1

1988-1994N=1215

1999-2000N=372

44.5%44.5%44.5%44.5% 35.8%35.8%35.8%35.8%

Traditional Type 2 Diabetes Traditional Type 2 Diabetes Management: Management:

A “Treat-to-Fail Approach”A “Treat-to-Fail Approach”H

bA

1c G

oal

Duration of Diabetes

OAD monotherapy

Diet andexercise

OAD combination

OAD up-titration

OAD + multiple daily

insulininjections

OAD + basal insulin

6

7

8

9

10

Published Conceptual ApproachMean HbA1c of patients

OAD=oral antihyperglycemic agent.Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631. Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

Conventional stepwise treatment approach

Delays often occur between stepping up Delays often occur between stepping up from monotherapy to combination from monotherapy to combination

therapytherapy

0

5

10

15

20

25

Month

s

Metformin onlyn = 513

14.5 months

Sulfonylurea onlyn = 3394

20.5 months

Length of time between first monotherapy HbA1c > 8.0% and switch/addition in therapy (months)

Brown, JB et al. Diabetes Care 2004; 27:1535–1540.

Brown JB et al. Diabetes Care 2004;27:1535-1540.

0

20

40

60

80

100

%o

f Su

bje

cts

Percentage of subjects advancing when A1C >7% < 8%

Clinical Inertia :Failure to Advance Therapy When Required

Diet

66.6%

Sulfonylurea Metformin

35.3%44.6%

Combination

18.6%

At insulin initiation, the average patient had:• 5 years with A1C > 8%• 10 years with A1C > 7%

Diagnosis

Lifestyle Intervention + Metformin

No Yes

Add Basal Insulin

Add Sulfonylurea

Add DPP-4 inhibitor

Add Glitazone

ADA-EASD-Consensus 2006

Sulphonylureas failed to maintain Sulphonylureas failed to maintain glycemic control glycemic control

0

-1

-2

1

Gliclazide

Tan (n=297)

Glyburide

Hanefeld (n=250)

Chicago (n=230)

GlimpirideGlyburide

Periscope (n=181)

Glibenclamide

ADOPT (n=1441)

1 2 3 4 5 10

Glyburide

UKPDS (n=1573)

HB

A1

c %

Red

ucti

on

Time (years)0

Is

let -

cell

funct

ion %

(of

norm

al by H

OM

A)

HOMA = homeostasis model assessment

Holman RR. Diab Res Clin Pract. 1998;40(suppl):S21-S25;UKPDS. Diabetes. 1995;44:1249-1258

Years

0

20

40

60

80

100

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6

Time of diagnosis

UKPDS: Islet UKPDS: Islet -cell function and the -cell function and the progressive nature of diabetesprogressive nature of diabetes

Pancreatic function =50% of normal

Advantages of insulinAdvantages of insulin

It lowers mean blood glucose in a It lowers mean blood glucose in a predictable dose-dependent mannerpredictable dose-dependent manner

Can be tailored to individual needs Can be tailored to individual needs on a unit-to-unit basison a unit-to-unit basis

It has the longest experience than It has the longest experience than any other drug (90 years)any other drug (90 years)

No contraindications to its useNo contraindications to its use

Insulin is the only drug that directly reduces Insulin is the only drug that directly reduces lipolysis and free fatty acid concentrations lipolysis and free fatty acid concentrations in blood, thus reducing lipotoxicityin blood, thus reducing lipotoxicity

Insulin improves lipoprotein metabolism, Insulin improves lipoprotein metabolism, decreases LDL cholesterol and triglycerides, decreases LDL cholesterol and triglycerides, and increases HDL cholesteroland increases HDL cholesterol

Insulin improves endothelial dysfunctionInsulin improves endothelial dysfunction

Advantages of insulinAdvantages of insulin

thoughts/concerns about thoughts/concerns about starting insulinstarting insulin

Common Fears:Common Fears: NeedlesNeedles HypoglycemiaHypoglycemia Weight gainWeight gain

Common Beliefs:Common Beliefs: Insulin is the last optionInsulin is the last option Insulin causes complicationsInsulin causes complications Insulin is a personal failureInsulin is a personal failure Adverse impact on relationships/lifestyleAdverse impact on relationships/lifestyle

What should I tell people What should I tell people with Type 2 diabetes about with Type 2 diabetes about

insulin?insulin?

‘‘Most people with Type 2 diabetes Most people with Type 2 diabetes eventually need insulin because their eventually need insulin because their

own production of insulin falls off own production of insulin falls off with time and they therefore with time and they therefore

inevitably become insulin deficient’inevitably become insulin deficient’

What should I tell peopleWhat should I tell peoplewith Type 2 diabetes about insulin?with Type 2 diabetes about insulin?

‘‘If you need insulin, it doesn’t mean If you need insulin, it doesn’t mean you failed. Tablets cannot control blood you failed. Tablets cannot control blood

glucose forever, because they don’t glucose forever, because they don’t stop the problem of your own declining stop the problem of your own declining

insulin production getting worse’insulin production getting worse’

Islet Islet -cell dysfunction worsens over -cell dysfunction worsens over time, regardless of therapytime, regardless of therapy

What should I tell the person with What should I tell the person with Type 2 diabetes who needsType 2 diabetes who needs

insulin, but doesn’t want to take it?insulin, but doesn’t want to take it?

‘‘Insulin will not make your diabetes Insulin will not make your diabetes worse. In fact, it will help control your worse. In fact, it will help control your

glucose, so you’ll have fewer glucose, so you’ll have fewer complications and you’ll feel better.’complications and you’ll feel better.’

Strict glycaemic control reduces the Strict glycaemic control reduces the risks of both microvascular and risks of both microvascular and macrovascular complicationsmacrovascular complications

Insulin RegimensInsulin Regimens

1. Basal insulin ( NPH or long-acting 1. Basal insulin ( NPH or long-acting insulin analogue) + OADinsulin analogue) + OAD

2. Total insulin replacement therapy2. Total insulin replacement therapy

- Premixed insulins- Premixed insulins

- Basal-bolus- Basal-bolus

24-hour Plasma Glucose Curve:24-hour Plasma Glucose Curve:Rationale for Adding Basal InsulinRationale for Adding Basal Insulin

Time of Day

400

300

200

100

00600 06001000 1400 1800 2200 0200

Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Glu

cose

(m

g/d

L) Diabetes

Normal

400

300

200

100

00600 06001000 1400 1800 2200 0200

24-hour Plasma Glucose Curve:24-hour Plasma Glucose Curve:Rationale for Adding Basal InsulinRationale for Adding Basal Insulin

Normal

Diabetic

Time of Day

Glu

cose

(m

g/d

L)

Adapted from Polonsky KS et al. N Engl J Med. 1988;318:1231-1239.

Starting With Basal Insulin in DM 2 Starting With Basal Insulin in DM 2 – Advantages– Advantages

1 injection with no mixing1 injection with no mixing Insulin pens for increased acceptanceInsulin pens for increased acceptance Slow, safe, simple titrationSlow, safe, simple titration Low dosageLow dosage Effective improvement in glycemic Effective improvement in glycemic

control control Limited weight gainLimited weight gain

Mean A1C Levels During Study

6

7

8

9

0 4 8 12 16 20 24

Mean A

1C

(%

)

Time (weeks)

Insulin glargine

NPH insulin

Target A1C (%)

Insulin Glargine vs. NPH Insulin Added to Oral Therapy

Riddle MC et al. Diabetes Care. 2003;26:3080-3086.

Mullins P et al. Clin Ther 2007;29:1607−19.

Less Hypoglycemia with Insulin Glargine vs NPH

6 7 8 9 10HbA1c

3500

3000

2500

2000

1500

1000

Hyp

ogly

cem

ia

even

ts p

er 1

00

patie

nt-y

ears

NPH Insulin glargine

200

150

100

50

06 7 8 9 10

HbA1c

Hyp

ogly

cem

ia

even

ts p

er 1

00

patie

nt-y

ears

T1DM

T2DM

p=0.004 between treatments

p=0.021 between treatments

Insulin Glargine vs. NPH InsulinInsulin Glargine vs. NPH InsulinAdded to Oral TherapyAdded to Oral Therapy

Hypoglycemia defined as PG 72 mg/dL, by hour

Glargine

NPH insulin

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

20 22 24 2 4 6 8 10 12 14 16 18

Time of Day (hour)

Even

ts p

er

Pati

ent-

Year

**

**

*

*

Basal insulin

Riddle MC et al. Diabetes Care. 2003;26:3080-3086.

*

Symptomatic Hypoglycemia by Time of Day

*P < 0.05 vs. glargine.

Insulin Glargine Trials Showing Effective Reduction in HbA1c

Hb

A1

c (%

)

APOLLO LAPTOP Triple Therapy

LANMET

10

9

8

7

6

5Treat-To-

TargetINITIATE

7.147.156.96

7.146.80

8.71 8.85 8.809.5

8.808.61

6.96

Baseline Study endpoint

Target: FPG 100 mg/dLSubjects )n=364( were randomly assigned to:

Insulin glargine once daily + continued OADs

Premixed human insulin 70/30 BID

Baseline End PointTime (wk)0 24

Treatment Regimen

*Sulfonylurea + metformin*Sulfonylurea + metforminOAD=oral antidiabetic drugOAD=oral antidiabetic drugJanka HU, et al. Janka HU, et al. Diabetes Care.Diabetes Care. 2005;28:254-259. 2005;28:254-259.

Insulin Glargine Plus OADs vs Insulin Glargine Plus OADs vs Twice-daily Premixed 70/30 Human Twice-daily Premixed 70/30 Human

InsulinInsulin

OADs*

Change in A1C from Baseline to Study End Point*

*Intent-to-treat analysis*Intent-to-treat analysis OAD=oral antidiabetic drugOAD=oral antidiabetic drug

Janka HU, et al. Janka HU, et al. Diabetes Care.Diabetes Care. 2005;28:254-259. 2005;28:254-259.

8.85 8.83

7.157.49

5

6

7

8

9

Insulin glargine + OAD Premixed

P=0.0003

A1C

Insulin Glargine Plus OADs vs Insulin Glargine Plus OADs vs Twice-daily Premixed Human Twice-daily Premixed Human

InsulinInsulin

BaselineBaseline

24 week24 week

LAPTOP: Insulin Glargine Versus 70/30 Premixed Insulin in OHA

Failures

Janka H et al. Diabetes Care 2005;28:254−259.

*Confirmed symptomatic hypoglycaemia (blood glucose <60 mg/dl [<3.3 mmol/l])

N=371 insulin-naïve patientsInsulin glargine + OADs vs twice-daily human NPH insulin (70/30)

Follow-up: 24 weeks

Hypogly

caem

ia*

(even

ts/p

ati

ent

year)

0

1

2

3

4

5

p=0.0009

5

6

7

8

9

HbA

1c

(%)

7.5%7.2%

1.3% 1.7%

p=0.0003

Twice-daily premixed insulin

Insulin glargine + OADs

2.6

5.7

ConclusionsConclusions

Due to declining Due to declining -cell function, insulin -cell function, insulin therapy will be necessary for most therapy will be necessary for most patients with Type 2 diabetespatients with Type 2 diabetes

Insulin therapy should be initiated early Insulin therapy should be initiated early when glycemic control exceeds the when glycemic control exceeds the recommended targetsrecommended targets

Insulin effectively lowers HbAInsulin effectively lowers HbA1c1c, thereby , thereby reducing the risks of both micro- and reducing the risks of both micro- and macrovascular complicationsmacrovascular complications

Insulin glargine when used as a basal Insulin glargine when used as a basal insulin has the following advantages:insulin has the following advantages:It effectively lowers fasting and mean It effectively lowers fasting and mean blood glucoseblood glucoseEasily initiated and titratedEasily initiated and titratedLow risk of hypoglycemiaLow risk of hypoglycemia

Conclusions-cont.Conclusions-cont.

Thank YouThank You

Insulin glargine offers long-term efficacy without the need for intensification

Gordon J, et al. Int J Clin Pract. 2010;64(12):1609-18.  

Insulin glargine provides superior long term efficacy vs. NPH.

52