Prof. Dr. Sarma VSN RachakondaProf. Dr. Sarma VSN RachakondaM.D., M.Sc., (Canada), FCGP, FIMSA, FRCP (Glasgow), M.D., M.Sc., (Canada), FCGP, FIMSA, FRCP (Glasgow), FCCP (USA).,FCCP (USA).,

Senior Consultant Physician, Cardio-metabolic & Chest Senior Consultant Physician, Cardio-metabolic & Chest Specialist, Specialist,

Visiting Professor of Internal Medicine, SBMC, FLL, Visiting Professor of Internal Medicine, SBMC, FLL, iDRF, ChennaiiDRF, Chennai

www.drsarma.in

The Outline of the The Outline of the PresentationPresentation

How Big is the Problem?How Big is the Problem?

CDC. National Diabetes Fact Sheet: National estimates and general information on diabetes and Prediabetes in the United States, 2011.

Years of T2DM

Obesity IGT* Diabetes Uncontrolled Hyperglycemia

Obesity IGT* Diabetes Uncontrolled Hyperglycemia

Relative -Cell Function

100 (%)

-20 -10 0 10 20 30

PlasmaGlucose

Insulin Resistance

Insulin Level

120 (mg/dL)

Fasting Glucose

Post-meal Glucose

Natural History of T2DNatural History of T2D

Endocrinol Metab Clin North Am.1997;26:659-677;

ADA Diagnostic Criteria for ADA Diagnostic Criteria for DiabetesDiabetes

Clinical Practice Recommendations Clinical Practice Recommendations 20102010

1. A1C ≥6.5%. The test should be performed as per NGSP method and standardized to the DCCT assay.* 2. FPG ≥126 mg/dl. – No caloric intake for at least 8 h.*3. 2-h plasma glucose ≥200 mg/dl OGTT performed using 75 anhydrous glucose dissolved in water.* 4. Random plasma glucose ≥200 mg/dl + classic symptoms of hyperglycemia or hyperglycemic crisis.

* In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat testing

Diagnostic Cut PointsDiagnostic Cut PointsCategory FPG (mg/dL) 2h 75g OGTT Category FPG (mg/dL) 2h 75g OGTT A1CA1C

Normal Normal < 100 < 140< 100 < 140 < < 5.75.7

Prediabetes Prediabetes 100 -125 140 -199 100 -125 140 -199 5.7 - 6.45.7 - 6.4

Diabetes Diabetes > > 126126** ** > > 200200 ** ** > 6.5 > 6.5

Or patients with classic hyperglycaemicOr patients with classic hyperglycaemic

symptoms with plasma glucose symptoms with plasma glucose >>200200

Diabetes Care 34:Supplement 1, 2011

How is Prediabetes How is Prediabetes Diagnosed ?Diagnosed ?

Categories of increased risk for Categories of increased risk for diabetesdiabetes

Impaired Fasting Glucose [IFG] FPG of 100–125 mg/dlImpaired Glucose Tolerance [IGT]:2-hour Plasma Glucose on the 75-g Oral Glucose Tolerance Test 140–199 mg/dlA1C 5.7 – 6.4%

For all three tests, risk is continuous, extending below the lower limit of the range and becoming disproportionately greater at higher ends of the range.

Gestational Diabetes (GDM)Gestational Diabetes (GDM)

Overnight fast Overnight fast 75g OGTT75g OGTT

•FastingFasting >>92 mg/dl 92 mg/dl

•1 h post glucose1 h post glucose >>180 mg/dl 180 mg/dl

•2 h post glucose 2 h post glucose >>153 153 mg/dlmg/dl

Any Any ONEONE abnormal value is abnormal value is adequate adequate

Diabetes Care 34:Supplement 1, 2011 Diabetes Care 2010; 33: 676–682

• Age 45 or olderAge 45 or older

• Overweight – BMI >25Overweight – BMI >25

• Physical Inactivity Physical Inactivity

• Asian or African Asian or African

ethnicityethnicity

• Family H/o of Family H/o of

DiabetesDiabetes

• Excess abdominal fatExcess abdominal fat

• HT and/or on Rx for HTHT and/or on Rx for HT

• Previous PrediabetesPrevious Prediabetes

• TG > 200, HDL < 35TG > 200, HDL < 35

• Acanthosis NigricansAcanthosis Nigricans

• PCOS, IR, Waist CircumPCOS, IR, Waist Circum

• H/o GDM, CVDH/o GDM, CVD

• Had macrosomic babyHad macrosomic baby

Risk Factors for the Risk Factors for the Development of Prediabetes Development of Prediabetes

and Type 2 Diabetesand Type 2 Diabetes

Modifiable Risk Factors for Modifiable Risk Factors for T2DMT2DM

• Obesity, Body fat distributionObesity, Body fat distribution

• Increased waist circumferenceIncreased waist circumference

• Physical inactivityPhysical inactivity

• Elevated fasting and 2 hr glucose Elevated fasting and 2 hr glucose

levelslevels

• Dyslipidemia and HypertensionDyslipidemia and Hypertension

• Smoking and AlcoholSmoking and Alcohol

Physical Inactivity and TV watchingPhysical Inactivity and TV watching

Hu et al. Arch Intern Med. 2001;161:1542.

3.0

2.5

2.0

1.5

1.0

0.5

0>15.0

8.1-15.03.6-8.0 3.5

46.0

23.6-45.9

10.0-23.5

<10.0

Quartiles ofMET - hours per week

Quartiles of no. of hourswatching TV per week

RR

Natural History of IGTNatural History of IGT

IGT -after 10

years

Does Prediabetes Predict Does Prediabetes Predict Diabetes?Diabetes?

Progression of IGT/IFG to DM in11year Progression of IGT/IFG to DM in11year follow upfollow up

Stephen Twigg. Pre diabetes Symposium ADS & ADEA Annual Scientific Meeting Sydney 2004

Persons with IGT Persons with IFG

Risk of Cardiovascular Disease is Risk of Cardiovascular Disease is elevated prior to diagnosis of elevated prior to diagnosis of

T2DMT2DM%

wit

h C

VD

Adapted from: Hu F, et al. Diabetes Care. 2002;25:1129-1134.

CVD Risk 3.2 higher adjusting for all CVD risk

factors

$ spent on fast food

4.0

4.5

5.0

5.5

6.0

6.5

7.0

7.5

1990 1992 1994 1996 1998 2000

Diabetes Prevalence of obesity, increased by 61% since 1991

65% of US adults are overweight

BMI and weight gain major risk factors

for diabetes

The Prevalence of T2DM & The Prevalence of T2DM & ObesityObesity

Pre

val

en

ce

(%)

72

73

74

75

76

77

78

Mean body weight

kgYear

(70)

(110)

JAMA.1999;282:1519-1522 & JAMA.2001;286:1195-1200.

What are the Health Risks What are the Health Risks Associated with Prediabetes?Associated with Prediabetes?

• Progression to diabetes: 11% of people Progression to diabetes: 11% of people with pre-diabetes develop T2DM each with pre-diabetes develop T2DM each year (DPP)year (DPP)

• Other studies: majority with Prediabetes Other studies: majority with Prediabetes develop T2DM in 10 yearsdevelop T2DM in 10 years

• Microvascular complications at onset of Microvascular complications at onset of DMDM

• 50% higher risk of CVD, CAD and Stroke50% higher risk of CVD, CAD and Stroke

• There is a long period of glucose intolerance There is a long period of glucose intolerance that precedes the development of diabetesthat precedes the development of diabetes

• Screening tests can identify persons at high risk Screening tests can identify persons at high risk

• Predicts high risk for development of diabetesPredicts high risk for development of diabetes

• Predicts high risk for development of Predicts high risk for development of atherosclerotic vascular diseaseatherosclerotic vascular disease

• There are safe, potentially effective There are safe, potentially effective interventions that can prevent the above interventions that can prevent the above modifiable risk factors such as lifestyle and modifiable risk factors such as lifestyle and pharmacologic interventionspharmacologic interventions

Feasibility of Preventing T2DMFeasibility of Preventing T2DM

Diabetes Prevention Program Diabetes Prevention Program DPPDPP

Progression to Type 2 Progression to Type 2 DiabetesDiabetes

Placebo Metformin Intensivelifestyle

Cas

es/1

00

per

son

-ye

ars

Average follow-up of 2.8 years

31%*

58%*

*All pairwise comparisons significantly different by group;

The Diabetes Prevention Program Research Group. N Eng. J Med. 2002;346:393.

Mean Change in Physical Mean Change in Physical ActivityActivity

0

2

4

6

8

0 1 2 3 4

Years from Randomization

MET

-hou

rs/w

eek

Placebo

Metformin

Lifestyle

The DPP Research Group, NEJM 346:393-403,2002

Placebo

Metformin

Lifestyle

Mean Weight ChangeMean Weight Change

The DPP Research Group, NEJM 346:393-403, 2002

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cum

ulat

ive

inci

denc

e (%

)

Placebo (n=1082)

Metformin (n=1073, p<0.001 vs. Placebo)

Lifestyle (n=1079, p<0.001 vs. Metformin , p<0.001 vs. Placebo)

Incidence of Diabetes in Incidence of Diabetes in DPP DPP

Risk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle

The DPP Research Group, NEJM 346:393-403, 2002

Mean Change in HbAMean Change in HbA1c1c

5.8

5.9

6.0

6.1

0 1 2 3 4

Years from Randomization

HbA

1c (%

)

Placebo

Metformin

Lifestyle

The DPP Research Group, NEJM 346:393-403, 2002

A Decade Later….DPPOSA Decade Later….DPPOSThe Lancet, Oct 2009The Lancet, Oct 2009

• At end of DPP: participants 16-session program of intensive TLCAt end of DPP: participants 16-session program of intensive TLC

• Lifestyle group: 34% reduction in diabetes risk maintainedLifestyle group: 34% reduction in diabetes risk maintained• More favorable CV risk factors: BP and TG’s, despite fewer drugsMore favorable CV risk factors: BP and TG’s, despite fewer drugs• Benefits more pronounced in elderly: 50% reduction in age >60Benefits more pronounced in elderly: 50% reduction in age >60

Parameter PlaceboMetformin 850 mg

bidTLC: MNT, PA

Weight Loss <2 lbs 5 lbs 5 lbs

Diabetes at 2.8 yrs 11% 7.8% 4.8%

Diabetes at 10 yrs 5-6%

Percent reduction - 18 34

Delay in diabetes - 2 yrs 4 yrs

The Finnish Diabetes Prevention The Finnish Diabetes Prevention StudyStudy

Lifestyle ModificationsLifestyle Modifications•522 overweight individuals with IGT randomized to522 overweight individuals with IGT randomized to

– Control: diet instruction at the onset of studyControl: diet instruction at the onset of study

– Individualized advice given 7 times in the first Individualized advice given 7 times in the first year and every 3 months thereafter with goals year and every 3 months thereafter with goals ofof

»Weight loss Weight loss 5% 5%

»Reducing fat intake to <30% of energy Reducing fat intake to <30% of energy consumptionconsumption

» Increasing fiber intake to Increasing fiber intake to 15 g/1000 kcal 15 g/1000 kcal

»Exercising at a moderate level for 30 min/dExercising at a moderate level for 30 min/d

•Primary end point: Prevention of diabetes, Primary end point: Prevention of diabetes, assessed by OGTTassessed by OGTT

Tuomilehto et al. N Engl J Med. 2001;344:1343.

Indian Diabetes Prevention Indian Diabetes Prevention ProgramProgram

Ramachandran et al, IDDP-1, Diabetologia (2006) 49: 289–297.

Cumulative Incidence of Cumulative Incidence of DiabetesDiabetes

Ramachandran et al, IDDP-1, Diabetologia (2006) 49: 289–297.

Low BMIHigh IRHigh incidence of DM

The Finnish Diabetes Prevention StudyThe Finnish Diabetes Prevention StudyLifestyle Modifications (cont’d)Lifestyle Modifications (cont’d)

Inc

ide

nce

of

dia

be

tes

(ca

ses/

100

0 p

ers

on

-ye

ars)

Tuomilehto et al. N Engl J Med. 2001;344:1343.

58% 58%

Cumulative incidence of diabetes Cumulative incidence of diabetes at 6 years Da Qing Chinese at 6 years Da Qing Chinese

StudyStudy

Data from: Pan et al, Diabetes Care, 1997; 20: 537-44

NAVIGATOR StudyNAVIGATOR StudyEffect of Nateglinide & Valsartan on Incidence Effect of Nateglinide & Valsartan on Incidence

of T2DM and CV Events - 9306 persons with of T2DM and CV Events - 9306 persons with IGT, CVD or CV riskIGT, CVD or CV risk followed for 5 yearsfollowed for 5 years

• Nateglinide: Nateglinide: A postprandial glucose-lowering A postprandial glucose-lowering approach; incidence of diabetes 36% vs. approach; incidence of diabetes 36% vs. 34%; composite CV outcome 14.2% vs. 34%; composite CV outcome 14.2% vs. 15.2%; increased the risk of hypoglycemia15.2%; increased the risk of hypoglycemia

• ValsartanValsartan: incidence of diabetes 33.1% vs. : incidence of diabetes 33.1% vs. 36.8% (RR 14%); 38 fewer cases per 1000 36.8% (RR 14%); 38 fewer cases per 1000 pts treated for 5 years; no reduction in rate pts treated for 5 years; no reduction in rate of CV eventsof CV events

NEJM online, March 14, 2010

Prevention Studies in People Prevention Studies in People with IGT with IGT Downstream Downstream

strategiesstrategies• Lifestyle interventions Lifestyle interventions

– Da Qing :Da Qing : Diet and ExerciseDiet and Exercise

– Malmo study : Diet and exerciseMalmo study : Diet and exercise

– Finish Diabetes Prevention Study LifestyleFinish Diabetes Prevention Study Lifestyle

– DPP (Diabetes Prevention Study) Lifestyle, MF (Glitazone)DPP (Diabetes Prevention Study) Lifestyle, MF (Glitazone)

• Lifestyle interventions with pharmacological agentsLifestyle interventions with pharmacological agents

– FHS (Fasting Hyperglycaemia Study) Healthy Living & SUFHS (Fasting Hyperglycaemia Study) Healthy Living & SU

– EDIT (Early Diabetes Intervention Study): Acarbose and EDIT (Early Diabetes Intervention Study): Acarbose and MFMF

– STOP NIDDM : AcarboseSTOP NIDDM : Acarbose

How to Ascertain the Risk ?How to Ascertain the Risk ?

• Low Risk - 3 to 9 Low Risk - 3 to 9

pointspoints

• Maintain healthy wt. Maintain healthy wt.

• Regular exerciseRegular exercise

• Keep it up regularlyKeep it up regularly

• High Risk 10+ pointsHigh Risk 10+ points

• High risk for diabetesHigh risk for diabetes

• Medical evaluationMedical evaluation

• Take steps to improve Take steps to improve

scorescore

VariablePoints

Fasting glucose level 100-126 mg/dL

10

BMI 25.0-29.9 2

BMI >30.0 5

HDL-C level <40 mg Men, <50 mg Women

5

Parental H/o of Diabetes Mellitus 3

Triglyceride level >150 mg/dL 3

Blood pressure >130/85 mm or on Rx.

2

Points8 yr. Risk

%

≤10 <3

11 4

12 4

13 5

14 6

15 7

16 9

17 11

18 13

19 15

20 18

21 21

22 25

23 29

24 33

≥25 >35

Framingham DM Risk Framingham DM Risk ScoreScorePrediction of Incident DM in Prediction of Incident DM in AdultsAdults

Wilson, P. W. F., J. B. Meigs, et al. (2007). Arch Intern Med 167(10): 1068-1074.

Parameter Score

Age in years

< 35 0

35 - 49 20

≥ 50 30

Abdominal obesity

Waist <80 cm (F), <90 (M) 0

Waist 80-89 cm (F), 90-99 (M) 10

Waist .>90 cm (F), >100 (M) 20

Physical Activity

Exercise (regular) + strenuous work

0

Exercise (regular) or strenuous work

20

No exercise and sedentary work

30

Family History of DM

No family history 0

One parent 10

Both parents 20

Ind

ian

Dia

bete

s R

isk S

core

In

dia

n D

iab

ete

s R

isk S

core

(I

DR

S)

(ID

RS

)B

ased

on

CU

REs s

tud

y

Based

on

CU

REs s

tud

y

Ch

en

nai

Ch

en

nai

A1c Level and Future Risk of A1c Level and Future Risk of T2DMT2DM

A1CRisk of

Diabetes

<5.0% 0.1%

5.0 -5.4% 5.4%

5.5-6.0% 9 - 25%

>6.0-6.5%

25 - 50%

• Meta-analysis of 16 Meta-analysis of 16 studiesstudies

• 44,203 participants44,203 participants• Follow-up 5.6 yearsFollow-up 5.6 years

Zhang, X., E. W. Gregg, et al. (2010). Diabetes Care 33(7): 1665-73.

Prediabetes and Risk of CVDPrediabetes and Risk of CVD

• Meta-analysis of 18 studiesMeta-analysis of 18 studies• 175,152 participants175,152 participants

Ford, E. S., G. Zhao, et al. (2010). J Am Coll Cardiol 55(13): 1310-7.

Definition of Pre-diabetes

Risk of CVD

IFG (100-125 mg/dl)

1.18

IFG (110-125 mg/dl)

1.20

IGT 1.20

ADA Consensus StatementADA Consensus Statement Preventive treatment in high risk Preventive treatment in high risk

individuals with Prediabetes individuals with Prediabetes

• In addition to lifestyle modification, the In addition to lifestyle modification, the following individuals should be considered following individuals should be considered for treatment with metformin: for treatment with metformin:

– those who have both IFG and IGT, and those who have both IFG and IGT, and

– at least one additional risk factor (age < 60, at least one additional risk factor (age < 60, BMI ≥35, F H/o of diabetes, BMI ≥35, F H/o of diabetes, TGs, TGs, HDL, or HDL, or A1C > 6%A1C > 6%

Diabetes Care 2007

Prevention of DiabetesPrevention of Diabetes

Recommendations to reduce risk of type 2 Recommendations to reduce risk of type 2 diabetesdiabetes

– Regular physical activityRegular physical activity

– Interventions to reduce obesity Interventions to reduce obesity

»Waist circumference, Waist circumference,

»body weight and body mass index (BMI)body weight and body mass index (BMI)

» identify individuals for weight management programidentify individuals for weight management program

– Individuals at risk should have dietary intake assessed Individuals at risk should have dietary intake assessed and receive individualised dietary advice and and receive individualised dietary advice and continued diet advicecontinued diet advice

Evidence Based Guideline for the Prevention of Type 2 Diabetes. Australian Government NHMRC www.diabetesaustralia.com.au

Prevention of DiabetesPrevention of Diabetes

Recommendations to reduce risk of type 2 diabetesRecommendations to reduce risk of type 2 diabetes

– Identification of women with GDM would allow:Identification of women with GDM would allow:

»Postnatal clinical interventions in those with diabetes Postnatal clinical interventions in those with diabetes

»Option to use preventive methods to Option to use preventive methods to the risk of DM the risk of DM

– Diet and exercise education in children should includeDiet and exercise education in children should include

»Parental involvement Parental involvement

»Behavioral techniquesBehavioral techniques

Evidence Based Guideline for the Prevention of Type 2 Diabetes. Australian Government NHMRC www.diabetesaustralia.com.au

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