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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).,
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
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.
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.
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
• 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
– 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