Prof. Dr. Sarma VSN Rachakonda M.D., M.Sc., (Canada), FCGP, FIMSA, FRCP (Glasgow), FCCP (USA)., Senior Consultant Physician, Cardio-metabolic & Chest Specialist, Visiting Professor of Internal Medicine, SBMC, FLL, iDRF, Chennai

The Outline of the Presentation Burden, Diagnostic criteria Who should be screened Significance Prediabetes Evidence from research studies Risk Scores - Application Primary prevention of T2DM

How Big is the Problem? CDC. National Diabetes Fact Sheet: National estimates and general information on diabetes and Prediabetes in the United States, % of adults over 20 years50% of those over 65 years79 million Americans in 2010Double the number in India

Years of T2DM Obesity IGT * Diabetes Uncontrolled Hyperglycemia Obesity IGT * Diabetes Uncontrolled Hyperglycemia Relative  -Cell Function 100 (%) Plasma Glucose Insulin Resistance Insulin Level 120 (mg/dL) Fasting Glucose Post-meal Glucose Natural History of T2D Endocrinol Metab Clin North Am.1997;26: ;

ADA Diagnostic Criteria for Diabetes Clinical Practice Recommendations 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 Points Category FPG (mg/dL) 2h 75g OGTT A1C Normal < 100 < 140 < 5.7 Prediabetes Diabetes > 126** > 200 ** > 6.5 Or patients with classic hyperglycaemic symptoms with plasma glucose >200 Diabetes Care 34:Supplement 1, 2011

How is Prediabetes Diagnosed ? Categories of increased risk for diabetes Impaired Fasting Glucose [IFG] FPG of 100–125 mg/dl Impaired Glucose Tolerance [IGT]: 2-hour Plasma Glucose on the 75-g Oral Glucose Tolerance Test 140–199 mg/dl A1C 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) Overnight fast 75g OGTT Overnight fast 75g OGTT Fasting >92 mg/dl Fasting >92 mg/dl 1 h post glucose>180 mg/dl 1 h post glucose>180 mg/dl 2 h post glucose >153 mg/dl 2 h post glucose >153 mg/dl Any ONE abnormal value is adequate Diabetes Care 34:Supplement 1, 2011 Diabetes Care 2010; 33: 676–682

Age 45 or older Age 45 or older Overweight – BMI >25 Overweight – BMI >25 Physical Inactivity Physical Inactivity Asian or African ethnicity Asian or African ethnicity Family H/o of Diabetes Family H/o of Diabetes Excess abdominal fat Excess abdominal fat HT and/or on Rx for HT HT and/or on Rx for HT Previous Prediabetes Previous Prediabetes TG > 200, HDL 200, HDL < 35 Acanthosis Nigricans Acanthosis Nigricans PCOS, IR, Waist Circum PCOS, IR, Waist Circum H/o GDM, CVD H/o GDM, CVD Had macrosomic baby Had macrosomic baby Risk Factors for the Development of Prediabetes and Type 2 Diabetes

Modifiable Risk Factors for T2DM Obesity, Body fat distribution Obesity, Body fat distribution Increased waist circumference Increased waist circumference Physical inactivity Physical inactivity Elevated fasting and 2 hr glucose levels Elevated fasting and 2 hr glucose levels Dyslipidemia and Hypertension Dyslipidemia and Hypertension Smoking and Alcohol Smoking and Alcohol

Physical Inactivity and TV watching Hu et al. Arch Intern Med. 2001;161: >  3.5  <10.0 Quartiles of MET - hours per week Quartiles of no. of hours watching TV per week RR

Natural History of IGT 25% IGT 25% Normal 50% T2DM IGT - after 10 years

Does Prediabetes Predict Diabetes? Progression of IGT/IFG to DM in11year follow up Stephen Twigg. Pre diabetes Symposium ADS & ADEA Annual Scientific Meeting Sydney 2004 Persons with IGTPersons with IFG

Risk of Cardiovascular Disease is elevated prior to diagnosis of T2DM % with CVD Adapted from: Hu F, et al. Diabetes Care. 2002;25: CVD Risk 3.2 higher adjusting for all CVD risk factors

$ spent on fast food Diabetes Prevalence of obesity, increased by 61% since % of US adults are overweight BMI and weight gain major risk factors for diabetes The Prevalence of T2DM & Obesity Prevalence (%) Mean body weight kg Year (70) (110) JAMA.1999;282: & JAMA.2001;286:

What are the Health Risks Associated with Prediabetes? Progression to diabetes: 11% of people with pre-diabetes develop T2DM each year (DPP) Progression to diabetes: 11% of people with pre-diabetes develop T2DM each year (DPP) Other studies: majority with Prediabetes develop T2DM in 10 years Other studies: majority with Prediabetes develop T2DM in 10 years Microvascular complications at onset of DM Microvascular complications at onset of DM 50% higher risk of CVD, CAD and Stroke 50% higher risk of CVD, CAD and Stroke

There is a long period of glucose intolerance that precedes the development of diabetes There is a long period of glucose intolerance that 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 diabetes Predicts high risk for development of diabetes Predicts high risk for development of atherosclerotic vascular disease Predicts high risk for development of atherosclerotic vascular disease There are safe, potentially effective interventions that can prevent the above modifiable risk factors such as lifestyle and pharmacologic interventions There are safe, potentially effective interventions that can prevent the above modifiable risk factors such as lifestyle and pharmacologic interventions Feasibility of Preventing T2DM

Diabetes Prevention Program DPP Progression to Type 2 Diabetes PlaceboMetforminIntensive lifestyle Cases/100 person-years 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 Activity Placebo Metformin Lifestyle The DPP Research Group, NEJM 346: ,2002

Placebo Metformin Lifestyle Mean Weight Change The DPP Research Group, NEJM 346: , 2002

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 DPP Risk reduction 31% by metformin 58% by lifestyle The DPP Research Group, NEJM 346: , 2002

Mean Change in HbA 1c Placebo Metformin Lifestyle The DPP Research Group, NEJM 346: , 2002

A Decade Later….DPPOS The Lancet, Oct 2009 At end of DPP: participants 16-session program of intensive TLC At end of DPP: participants 16-session program of intensive TLC Lifestyle group: 34% reduction in diabetes risk maintained Lifestyle group: 34% reduction in diabetes risk maintained More favorable CV risk factors: BP and TG’s, despite fewer drugs More favorable CV risk factors: BP and TG’s, despite fewer drugs Benefits more pronounced in elderly: 50% reduction in age >60 Benefits more pronounced in elderly: 50% reduction in age >60 ParameterPlacebo Metformin 850 mg bid TLC: MNT, PA Weight Loss<2 lbs5 lbs Diabetes at 2.8 yrs11%7.8%4.8% Diabetes at 10 yrs5-6% Percent reduction-1834 Delay in diabetes-2 yrs4 yrs

The Finnish Diabetes Prevention Study Lifestyle Modifications 522 overweight individuals with IGT randomized to 522 overweight individuals with IGT randomized to – Control: diet instruction at the onset of study – Individualized advice given 7 times in the first year and every 3 months thereafter with goals of » Weight loss  5% » Reducing fat intake to <30% of energy consumption » Increasing fiber intake to  15 g/1000 kcal » Exercising at a moderate level for 30 min/d Primary end point: Prevention of diabetes, assessed by OGTT Primary end point: Prevention of diabetes, assessed by OGTT Tuomilehto et al. N Engl J Med. 2001;344:1343.

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

Cumulative Incidence of Diabetes Ramachandran et al, IDDP-1, Diabetologia (2006) 49: 289–297. Low BMI High IR High incidence of DM

The Finnish Diabetes Prevention Study Lifestyle Modifications (cont’d) Incidence of diabetes (cases/1000 person-years) Tuomilehto et al. N Engl J Med. 2001;344:1343.  58%

Cumulative incidence of diabetes at 6 years Da Qing Chinese Study Data from: Pan et al, Diabetes Care, 1997; 20:

NAVIGATOR Study Effect of Nateglinide & Valsartan on Incidence of T2DM and CV Events persons with IGT, CVD or CV risk followed for 5 years Nateglinide: A postprandial glucose-lowering approach; incidence of diabetes 36% vs. 34%; composite CV outcome 14.2% vs. 15.2%; increased the risk of hypoglycemia Nateglinide: A postprandial glucose-lowering approach; incidence of diabetes 36% vs. 34%; composite CV outcome 14.2% vs. 15.2%; increased the risk of hypoglycemia Valsartan: incidence of diabetes 33.1% vs. 36.8% (RR 14%); 38 fewer cases per 1000 pts treated for 5 years; no reduction in rate of CV events Valsartan: incidence of diabetes 33.1% vs. 36.8% (RR 14%); 38 fewer cases per 1000 pts treated for 5 years; no reduction in rate of CV events NEJM online, March 14, 2010

Prevention Studies in People with IGT Downstream strategies Lifestyle interventions Lifestyle interventions – Da Qing :Diet and Exercise – Malmo study : Diet and exercise – Finish Diabetes Prevention Study Lifestyle – DPP (Diabetes Prevention Study) Lifestyle, MF (Glitazone) Lifestyle interventions with pharmacological agents Lifestyle interventions with pharmacological agents – FHS (Fasting Hyperglycaemia Study) Healthy Living & SU – EDIT (Early Diabetes Intervention Study): Acarbose and MF – STOP NIDDM : Acarbose

How to Ascertain the Risk ? Low Risk - 3 to 9 points Low Risk - 3 to 9 points Maintain healthy wt. Maintain healthy wt. Regular exercise Regular exercise Keep it up regularly Keep it up regularly High Risk 10+ points High Risk 10+ points High risk for diabetes High risk for diabetes Medical evaluation Medical evaluation Take steps to improve score Take steps to improve score

VariablePoints Fasting glucose level mg/dL10 BMI BMI >30.05 HDL-C level <40 mg Men, <50 mg Women 5 Parental H/o of Diabetes Mellitus3 Triglyceride level >150 mg/dL3 Blood pressure >130/85 mm or on Rx.2 Points8 yr. Risk% ≤10< ≥25>35 Framingham DM Risk Score Prediction of Incident DM in Adults Wilson, P. W. F., J. B. Meigs, et al. (2007). Arch Intern Med 167(10):

ParameterScore Age in years < ≥ 5030 Abdominal obesity Waist <80 cm (F), <90 (M)0 Waist cm (F), (M)10 Waist.>90 cm (F), >100 (M)20 Physical Activity Exercise (regular) + strenuous work0 Exercise (regular) or strenuous work20 No exercise and sedentary work30 Family History of DM No family history0 One parent10 Both parents20 Indian Diabetes Risk Score (IDRS) Based on CUREs study Chennai

A1c Level and Future Risk of T2DM A1C Risk of Diabetes <5.0%0.1% %5.4% %9 - 25% > % % Meta-analysis of 16 studies Meta-analysis of 16 studies 44,203 participants 44,203 participants Follow-up 5.6 years Follow-up 5.6 years Zhang, X., E. W. Gregg, et al. (2010). Diabetes Care 33(7):

Prediabetes and Risk of CVD Meta-analysis of 18 studies Meta-analysis of 18 studies 175,152 participants 175,152 participants Ford, E. S., G. Zhao, et al. (2010). J Am Coll Cardiol 55(13): Definition of Pre-diabetes Risk of CVD IFG ( mg/dl)1.18 IFG ( mg/dl)1.20 IGT1.20

ADA Consensus Statement Preventive treatment in high risk individuals with Prediabetes In addition to lifestyle modification, the following individuals should be considered for treatment with metformin: In addition to lifestyle modification, the following individuals should be considered for treatment with metformin: – those who have both IFG and IGT, and – at least one additional risk factor (age 6% Diabetes Care 2007

Prevention of Diabetes Recommendations to reduce risk of type 2 diabetes – Regular physical activity – Interventions to reduce obesity » Waist circumference, » body weight and body mass index (BMI) » identify individuals for weight management program – Individuals at risk should have dietary intake assessed and receive individualised dietary advice and continued diet advice Evidence Based Guideline for the Prevention of Type 2 Diabetes. Australian Government NHMRC

Prevention of Diabetes Recommendations to reduce risk of type 2 diabetes – Identification of women with GDM would allow: » Postnatal clinical interventions in those with diabetes » Option to use preventive methods to  the risk of DM – Diet and exercise education in children should include » Parental involvement » Behavioral techniques Evidence Based Guideline for the Prevention of Type 2 Diabetes. Australian Government NHMRC

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