Management of DiabetesTreat to Target Approach

(A1c <7%)

by

Professor Dr Intekhab AlamDepartment of Medicine

Postgraduate Medical Institute

Lady Reading Hospital, Peshawar.

Milestones in Diabetes TreatmentMilestones in Diabetes Treatment

Insulin glargine

Insulin Insulin discovereddiscovered First First

sulphonylureassulphonylureas

NPHNPHinsulininsulin

Lente Lente insulinsinsulins

MetforminMetformin

Insulin Insulin pumppump

Rapid-acting Rapid-acting insulininsulin

UKPDSUKPDS

19201920 19401940 19601960 19801980 20002000

A1cA1c DCCTDCCT

DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.

1. Tattersall RB. In: Pickup JC, Williams G, eds. 1. Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of DiabetesTextbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; . 3rd ed. Boston, Mass: Blackwell Science; 2003.2003.

2. US FDA Center for Drug Evaluation and Research. Available at: http://www.fda.gov/cder/da/ddpab96.htm. 2. US FDA Center for Drug Evaluation and Research. Available at: http://www.fda.gov/cder/da/ddpab96.htm. Accessed March 18, 2003.Accessed March 18, 2003.

3. Lantus Consumer Information. Available at: http://www.fda.gov/cder/consumerinfo/druginfo/lantus.htm.3. Lantus Consumer Information. Available at: http://www.fda.gov/cder/consumerinfo/druginfo/lantus.htm. Accessed March 18, 2003.Accessed March 18, 2003.

InsulinResistance

Type 2 Diabetes

-cellDysfunction

InsulinResistance

Hyperglycaem

ia

InsulinConcentration

Insulin Action

Euglycaemia

-cell Failure

Normal IGT ± Obesity Diagnosis oftype 2 diabetes

Progression oftype 2 diabetes

Dual defect of type 2 diabetes: Dual defect of type 2 diabetes: Treating a moving targetTreating a moving target

DeFronzo et al. Diabetes Care 1992;15:318-68

Diet

Metformin

UKPDS Group. Lancet 1998;352:854-65

Med

ian

Hb

A1C

(%

)

Time from randomisation (years)

Sulphonylurea

Insulin

Progressive hyperglycaemia in type 2 diabetesProgressive hyperglycaemia in type 2 diabetes

6

7

8

9

0 2 4 6 8 10

HbA1C 6.5%

(IDF & AACE goal value)

ADA- and AACE/ACE-Recommended Goals for ADA- and AACE/ACE-Recommended Goals for Glycaemic Control: A1c, FPG, and PPGGlycaemic Control: A1c, FPG, and PPG

NormalNormal11 GoalGoal11Biochemical ControlBiochemical Control11

A1cA1c** (%) (%) <6.0<6.0 <7.0<7.0††

FPG (mg/dL)FPG (mg/dL)Average preprandialAverage preprandial <110<110 9090-130-130‡‡

PPG (mg/dL)PPG (mg/dL) <140<140 <180<180§§

*Referenced to the nondiabetic range using a DCCT assay.*Referenced to the nondiabetic range using a DCCT assay.11

††AACE/ACE recommendation: AACE/ACE recommendation: 6.5%.6.5%.22

‡‡AACE/ACE recommendation: <110 mg/dL.AACE/ACE recommendation: <110 mg/dL.22

§§AACE/ACE recommendation: <140 mg/dL.AACE/ACE recommendation: <140 mg/dL.22

ADA, American Diabetes Association; AACE/ACE, American Association of Clinical ADA, American Diabetes Association; AACE/ACE, American Association of Clinical Endocrinologists/American College of Endocrinology; FPG, fasting plasma glucose; PPG, postprandial Endocrinologists/American College of Endocrinology; FPG, fasting plasma glucose; PPG, postprandial glucose; DCCT, Diabetes Control and Complications Trial.glucose; DCCT, Diabetes Control and Complications Trial.

1.1. ADA. ADA. Diabetes CareDiabetes Care. 2003;26(suppl 1):S33-S50.. 2003;26(suppl 1):S33-S50.2.2. AACE/ACE. AACE/ACE. Endocr PractEndocr Pract. 2002;8(suppl 1):40-82.. 2002;8(suppl 1):40-82.

A1c Reflects Overall Glucose ControlA1c Reflects Overall Glucose Control

A1c is the glycated form of the abundant red blood cell protein1

A1c levels provide a 2- to 3-month index of glycaemic control2

The target A1c level for patients with diabetes is <7%1

Overall blood glucose control is best obtained by monitoring A1c3

1. Pickup JC. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.

2. Clark N. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.3. Cefalu WT. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.

0

100

200

300

400

6 7 8 9 10 11 12

A1c (%)

MP

G (

mg

/dL

)

0

100

200

300

400

6 7 8 9 10 11 12

A1c (%)

MP

G (

mg

/dL

)

Relationship of Mean Plasma Relationship of Mean Plasma Glucose and A1cGlucose and A1c

MPG, mean plasma glucose.MPG, mean plasma glucose.

Adapted from Rohlfing CL et al. Adapted from Rohlfing CL et al. Diabetes CareDiabetes Care. 2002;25:275-278.. 2002;25:275-278.

DCCT, Diabetes Control and Complications Trial.DCCT, Diabetes Control and Complications Trial.

1. Adapted from Skyler JS. 1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. Endocrinol Metab Clin North Am. 1996;25:243-254.1996;25:243-254.2. DCCT. 2. DCCT. N Engl J Med.N Engl J Med. 1993;329:977-986. 1993;329:977-986.3. DCCT. 3. DCCT. DiabetesDiabetes. 1995;44:968-983.. 1995;44:968-983.

Re

lati

ve

Ris

kR

ela

tiv

e R

isk

A1c (%)A1c (%)

1515

1313

1111

99

77

55

33

11

66 77 88 99 1010 1111 1212

A1c and Relative Risk of Microvascular A1c and Relative Risk of Microvascular Complications: DCCT Complications: DCCT

RetinopathyRetinopathy

NephropathyNephropathy

NeuropathyNeuropathy

MicroalbuminuriaMicroalbuminuria

2020

*Diet, only.†Insulin or sulphonylurea + diet.UKPDS, United Kingdom Prospective Diabetes Study. Adapted from UKPDS Group. Lancet. 1998;352:837-853.

Cross-sectional median values

Time From Randomisation (years)Time From Randomisation (years)

Conventional Treatment* (n=1138)Conventional Treatment* (n=1138)Intensive TreatmentIntensive Treatment†† (n=2729) (n=2729)

99

88

77

66

0000 33 66 99 1212 1515

Med

ian

A1c

(%

)M

edia

n A

1c (

%)

Type 2 Diabetes Is a ProgressiveType 2 Diabetes Is a ProgressiveDisease: UKPDSDisease: UKPDS

Complications DCCT1,2 Ohkubo3 UKPDS4

of diabetes mellitus (9% 7%) (9% 7%) (8% 7%)

Retinopathy -63% -69% -21%

Nephropathy -54% -70% -34%

Neuropathy -60% – –

Macrovascular disease -41%* – -16%*

Risk reduction by decrease in A1c (%)

Good Glycaemic Control Reduces Good Glycaemic Control Reduces Incidence of ComplicationsIncidence of Complications

*Not statistically significant. *Not statistically significant. DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.

1. DCCT Research Group. 1. DCCT Research Group. N Engl J MedN Engl J Med. 1993;329:977-986. . 1993;329:977-986. 2. DCCT Research Group. 2. DCCT Research Group. DiabetesDiabetes. 1995;44:968-983.. 1995;44:968-983.3. Ohkubo Y et al. 3. Ohkubo Y et al. Diabetes Res Clin PractDiabetes Res Clin Pract. 1995;28:103-117. . 1995;28:103-117. 4. UKPDS Group. 4. UKPDS Group. LancetLancet. 1998;352:837-853.. 1998;352:837-853.

UKPDS, United Kingdom Prospective Diabetes Study; MI, myocardial infarction; UKPDS, United Kingdom Prospective Diabetes Study; MI, myocardial infarction;

PVD, peripheral vascular disease. PVD, peripheral vascular disease.

Stratton IM et al. Stratton IM et al. Br Med JBr Med J. 2000;321:405-412.. 2000;321:405-412.

Correlation of A1c and Correlation of A1c and Complication Risk: UKPDSComplication Risk: UKPDS

Risk reduction in complications per each 1% reduction in mean A1c

0

10

20

30

40

50

0

10

20

30

40

50

Amputation or Amputation or Death From PVDDeath From PVD

3737

2121 2121

1414

4343

Ris

k R

ed

uct

ion

(%

)R

isk

Re

du

ctio

n (

%)

MicrovascularMicrovascular Any Endpoint Any Endpoint Related to DiabetesRelated to Diabetes

Death RelatedDeath Relatedto Diabetesto Diabetes

Fatal and Fatal and Nonfatal MINonfatal MI

Type 2 DMType 2 DM

*1-2 insulin injections and 1 urine/blood glucose test daily.†3 insulin injections/pump treatments daily + SMBG + diet + exercise.EDIC, Epidemiology of Diabetes Interventions and Complications trial; SMBG, self-monitored blood glucose.

DCCT/EDIC Research Group. N Engl J Med. 2000;342:381-389.

Preservation of Benefit: Preservation of Benefit: EDIC Progression of RetinopathyEDIC Progression of Retinopathy

EDIC (year)

Cu

mu

lati

ve In

cid

enc

e (%

)

0.00.0 0.50.5 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 4.04.000

24242222202018181616141412121010

22446688

Conventional Treatment*

Intensive Treatment†

Type 1 DMType 1 DM

Risk of Death Related to A1c LevelsRisk of Death Related to A1c Levels

Note: A1c <5.0% was defined as a relative risk of 1.Note: A1c <5.0% was defined as a relative risk of 1.Adapted from Khaw K-T et al. Adapted from Khaw K-T et al. Br Med J.Br Med J. 2001;322:1-6. 2001;322:1-6.Norfolk cohort of the European Prospective Investigation of cancer and Nutrition, n-4662Norfolk cohort of the European Prospective Investigation of cancer and Nutrition, n-4662

00

22

44

66

CardiovascularCardiovascularDiseaseDisease

Ischaemic Heart Ischaemic Heart DiseaseDisease

All CausesAll Causes

Re

lati

ve

Ris

k (

%)

Re

lati

ve

Ris

k (

%)

A1c 5.0%A1c 5.0%--5.4%5.4%

A1c 5.5%-6.9%A1c 5.5%-6.9%

A1c A1c 7.0%7.0%

A Comprehensive Approach A Comprehensive Approach To Treat to TargetTo Treat to Target

*Composite endpoint = cardiovascular death and amputation (with either therapy), and relative risk for *Composite endpoint = cardiovascular death and amputation (with either therapy), and relative risk for organ damage (with intensive therapy).organ damage (with intensive therapy).Gaede P et al. Gaede P et al. N Engl J MedN Engl J Med. 2003;348:383-393.. 2003;348:383-393.Steno diabetes center,Denmark. n 160.Steno diabetes center,Denmark. n 160.

80808080

72727878

70707474 7171 6666 6363 6161 5959 1919

131341414444505059596363Number at Risk/TreatmentNumber at Risk/Treatment ConventionalConventional

IntensiveIntensive

Pri

mar

y C

om

po

site

P

rim

ary

Co

mp

osi

te

En

dp

oin

t* (

%)

En

dp

oin

t* (

%)

Follow-up (months)Follow-up (months)

6060

5050

4040

3030

2020

1010

00

PP=.007=.007

00 1212 2424 3636 4848 6060 7272 8484 9696

Conventional TreatmentConventional Treatment

Intensive TreatmentIntensive Treatment

Type 2 DMType 2 DM

**PP=.011 sulphonylurea =.011 sulphonylurea insulin vs insulin alone; insulin vs insulin alone; ††PP<.00011 insulin or sulphonylurea <.00011 insulin or sulphonylurea insulin vs insulin vs conventional glucose control policy; conventional glucose control policy; ‡‡PP=.0066 sulphonylurea =.0066 sulphonylurea insulin vs insulin alone. insulin vs insulin alone.SU, sulphonylurea; IQR, interquartile range.SU, sulphonylurea; IQR, interquartile range.

Adapted from Wright A et al. Adapted from Wright A et al. Diabetes CareDiabetes Care. 2002;25:330-336.. 2002;25:330-336.

Pat

ien

ts A

chie

vin

g

A1c

<7%

at

6 Y

ears

(%

)

ConventionalConventionalGlucose ControlGlucose Control

Insulin Alone Insulin Alone SU ± InsulinSU ± Insulin

Intensive Glucose Control (Intensive Glucose Control (FPG < 108 mg%)FPG < 108 mg%)

Median A1c (IQR): 7.6% (6.8-8.7) 7.1% (6.2-8.0)Median A1c (IQR): 7.6% (6.8-8.7) 7.1% (6.2-8.0)† † 6.6% (6.0-7.6)6.6% (6.0-7.6)†‡†‡

2020

3535

4747

00

1010

2020

3030

4040

5050

6060 **

Insulin Helps Achieve ControlInsulin Helps Achieve Control

Type 2 DMType 2 DM

DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.

Treat to Target A1cTreat to Target A1c

A1c is a key marker of diabetes treatment efficacy

A1c levels correlate with a patient’s relative risk of death

and of microvascular and macrovascular complications

The DCCT, UKPDS, and other major trials—as well as

major diabetes organizations—support treatment-to-target

A1c <7%

LDL-C, low-density lipoprotein cholesterol.LDL-C, low-density lipoprotein cholesterol.

Treat to Target A1cTreat to Target A1c

Aggressive therapy is often necessary to achieve control

Treat to target requires a comprehensive approach: control

of blood pressure and control of LDL-c, bolstering a

concerted attack on A1c levels

Treat to target reduces risk of complications and its

associated costs

Pitfalls In HbAPitfalls In HbA1C 1C EstimationEstimation

False high HbA1C:

– Hb F, Acetylated Hb, Cabamoylated Hb. False low HbA1C:

– Hb S or C, Hemolytic anemias, Hemmorhage. Reliability in diagnosing Diabetes:

sensitivity 85%

specificity 91%. Fructosamine levels:

nonenzymatic glycosylation of serum proteins esp Albumin

1.5-2,4 mmol/l with 5gm/dl of Albumin.

The ABC of Diabetes ManagementThe ABC of Diabetes Management

Effective management of diabetes requires

– A – Control of A1c

– B – Control of Blood pressure

– C – Control of Cholesterol

ADA Glycemic TargetsADA Glycemic Targets

American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus.Diabetes Care 1999;22(Suppl):S32-S41.

Normal GoalAction

Level

HbA1c (%) <6 <7>8

Fasting and preprandialblood glucose (mg/dL) <110 80 to 120 >140

ADA Blood Pressure TargetsADA Blood Pressure Targets

American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus.Diabetes Care 1999;22(Suppl):S32-S41.

Goal (mm Hg)

Usual patient <130/85

Isolated systolic hypertension If ≥180 <160 If 160 to 179 Reduce by 20

ADA LDL-Cholesterol Targets (mg/dl)ADA LDL-Cholesterol Targets (mg/dl)

American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus.Diabetes Care 1999;22(Suppl):S32-S41 & S56-S59.

Medical Nutrition Therapy Drug TherapyBegin Rx Goal Begin Rx Goal

With CV disease >100 ≤100 >100 ≤100

No CV disease >100 ≤100 >130 ≤100

European Diabetes Policy Group Desktop GuideEuropean Diabetes Policy Group Desktop Guide

‘Providing a greater emphasis on arterial risk

factor management rather than just good blood

glucose control’

European Diabetes Policy Group (1998–1999)European Diabetes Policy Group (1998–1999)

European Diabetes Policy Group Desktop GuideEuropean Diabetes Policy Group Desktop Guide

At each assessment

– Set individual targets for blood glucose, blood lipid and blood pressure

– Targets should incorporate an assessment of risk and the patient’s needs

– Set realistic objectives within a time period

– Evaluate individual targets at least yearly in the light of past successes and if clinical circumstances change

European Diabetes Policy Group (1998–1999)European Diabetes Policy Group (1998–1999)

European Diabetes Policy Group (1998–1999)European Diabetes Policy Group (1998–1999)

AssessmentAssessment

Measure

– HbA1c every 2-6 months

– blood lipid profile (total, LDL- and HDL-cholesterol, and

triglycerides) every 2-6 months if previously above assessment

levels otherwise annually

– blood pressure at each consultation unless known to be below

assessment levels

European Diabetes Policy Group adviceEuropean Diabetes Policy Group advice

‘Failure to attempt to

reach agreed targets

is inadequate care’

European Diabetes Policy Group (1998–1999)European Diabetes Policy Group (1998–1999)