Prevention Of Diabetes “A Dream” Or “A Reality”
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Transcript of Prevention Of Diabetes “A Dream” Or “A Reality”
Prevention Of Diabetes
“A Dream” Or “A Reality”By
Professor
Dr Intekhab AlamDepartment of Medicine
Postgraduate Medical Institute,Lady Reading Hospital, Peshawar
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2000 2010 2025
The worldwide pandemic oftype 2 diabetes
International Diabetes Federation Diabetes Atlas 2000; Amos et al. Diabet Med 1997;14 (Suppl 5):S1-S85.
Estimated Growth in the Prevalence of Diabetes 1994-2010
Estimated Growth in the Prevalence of Diabetes 1994-2010
0
50
100
150
200
250
300
Africa Asia Russia L. Amer. Europe Pacific N.Amer.
Per
cen
t In
crea
se
McCarty, Zimmet 1994
25-34 0 2.3
35-44 0.7 4.9
45-54 3.0 6.3
55-64 4.012.5
65-74 6.110.7
» Newcastle Unwin et al
Association of Age & Diabetes
Age distribution Caucasians S.Asian
WPR-IDF, Beijing May 2002
Reduction in life expectancy in type 2 diabetes
Age atDiagnosis
10/1515-1920-2930-3940-4950-5960-6970+
Marks & Krall1971
(17)16-1712-1410-11
8-96-74-5-
Goodkin1975
272316111065-
Panzram &Zabel-Langhennig
1981
----
7-85-63-43
Panzram G. Diabetologia 1987;30:123-31
Preclinical state
Normal IGT
Clinical disease
Type 2Diabetes
Disability Death
Complications
Complications
Primaryprevention
Secondaryintervention
Tertiaryintervention
The continuum of glucose intolerance
2-h plasma glucose (mmol/L)
FP
G (
mm
ol/L
)
7.8 11.1
6.1
7.0
NGT
IFG
IGT
IGT/IFG
Type 2 Diabetes
Classification of glucose intolerance
approximately 1 in 7 people aged over 40 years have impaired glucose tolerance (IGT)
IFG IGT IFG + IGTType 2
diabetes
Normal glucose tolerance
1.3 3.9 0.5 0.6
IFG - 3.7 6.5 2.4
IGT - - 0.9 2.7
IFG + IGT - - - 9.9
Progression to type 2 diabetes
Annual rates of progression to moresevere forms of glucose intolerance
Koehler et al. Diabetologia 2001;44 Suppl 1:A108
Harris. Consultant. 1997;37 Suppl:S9
IGT
Undiagnosedtype 2 diabetes
Diagnosedtype 2 diabetes
504540353025201510
5020-44 45-54 55-64 65
Age (years)
% o
f p
op
ula
tio
n
IGT is driving the worldwide diabetes pandemic
OBESITY is the driving force behind IGT
Prevalence of OBESITY is reaching epidemic proportions worldwide. In USA 50% of the population is overweight while 20-22% is obese.
A person with a BMI of 30 carries 5 times higher risk of developing diabetes than a person with a normal BMI.
0
2
4
6
8
10
12
14
<20
20-2
2.4
22.5
-24.
9
25-2
6.9
27-2
9.9
30-3
4.9>3
5
IGT
(%
)
0
100
200
300
<20
20-2
2.4
22.5
-24.
9
25-2
6.9
27-2
9.9
30-3
4.9
>35
To
tal
no
. w
ith
IG
T
Body mass index (kg/m2)
Obesity and prevalence of IGT
Lindahl et al. Diabetes Care 1999;22:1988-1992
IGT and risk of diabetes
0 1 2 3 4 5 6 7 8 9 10
Triglycerides >2.5 mmol/l (221 mg/dl)
Impaired glucose tolerance
Highest quartile 2-hour insulinHighest quartile fasting insulin
HDL <1 mmol/l (39 mg/dl)
Waist-hip ratio >1.0BMI >30 gm-2
HypertensionFamily history of diabetes
Mykkanen et al (1993)
Relative risk of developingdiabetes ( 95% CI)
Consequences of IGT
All cause mortality is 1.96 times higher than in people with normal glucose tolerance
Mortality per 1000 person-years is 20.8 for IGT as compared to 40.9 with DM.
40-50% of adults with IGT will develop type 2 diabetes within ten years.
IGT clusters with other and is itself a CV risk factor.
Whom and when to screen for IGT
Individuals >45 yrs of age especially who have BMI of >25 kg/m2.
Individuals <45 with BMI >30 or who have one or more of the following risk factors:+ive family history,LowHDL, high TG, HTN, h/o GDM, Infant birth wt >9lbs, belonging to noncaucasian group.
‘Risk Factors’ for Type 2 Diabetes
CENTRAL CENTRAL OBESITYOBESITY
GENETIC FACTORSGENETIC FACTORS- Ethnicity- Ethnicity- Family history - Family history (40%)(40%)
INCREASING INCREASING AGEAGE
GESTATIONAL GESTATIONAL DIABETES DIABETES
AND PARITYAND PARITY
PHYSICAL PHYSICAL INACTIVITYINACTIVITY
Primary Prevention in Diabetes
Williams G, Pickup JC. Handbook of Diabetes. 2nd Edition, Blackwell Science. 1999.
Strategies In Prevention Of Diabetes
Intensive lifestyle counseling
Pharmacotherapy:Established antidiabetic agents:
Metformin, Acarbose, GlitazonesACE inhibitors and ARBs
Ramipril, Losartan, Valsartan, Candesarttan
PROSPECTIVE TRIALS OF DIABETES PREVEENTION
1. Da Qing Impaired Glucose Tolerance and Diabetes Study
2. The Finnish Study(DPS)
3. The Diabetes Prevention Program(DPP)
4. Troglitazone in Prevention of Diabetes(TRIPOD)
5. Study to prevent NIDDM (STOP-NIDDM)
6. Xenical in the Prevention of Diabetes in Obese Subjects(XENDOS)
Da Qing impaired glucose tolerance and Diabetes study
Number of patients: 577 with IGTMean BMI: <25 vs >25 kg/m2
Major intervention: control vs diet only vs exercise only vs both
Average follow up: 6 yrs.Conclusion:Incidence of diabetes:
control group 67.7%, Diet only 43.8%, Exercise only 41.1% and 46% in both intervention (p<0.05)26.3% in <25 and 51.1% in >25 BMI subjects
The Finnish study(DPS)
Number of patients: 522 with IGTMean age: 55Mean BMI: 31 kg/m2
Major intervention: Intensive lifestyle counseling.
Average follow up: 3.2 yrs.Relative risk reduction: 58% with
ILSC (incidence of DM in control group 23% vs 11% in Intensive Group)
NNT: 22 for one yr and 5 for 5yrs
The Diabetes Prevention Program(DPP)
Number of patients: 3,234 with IGTMean age: 51Mean BMI: 34 kg/m2
Major intervention: Intensive LSC vs Metformin+ standard LSC vs Placebo+standard LSC
Average follow up: 2.8 yrs.Relative risk reduction: 58% with ILSC
31% with Metformin
NNT: 7 for ILSC and 14 for Metformin for 3yrs
Troglitazone in Prevention of Diabetes(TRIPOD study)
Number of patients: 235 with GDMMajor intervention: Troglitazone vs PlaceboAverage follow up: 2.6 yrs.
Relative risk reduction: 56% with Troglitazone
Study was dropped following withdrawal of the drug from the market in 1998
Study to Prevent- NIDDM(STOP-NIDDM trial)
Number of patients: 1429 with IGTMean age: 55Mean BMI: 31 kg/m2
Major intervention: Acarbose vs Placebo
Average follow up: 3.3 yrs.Relative risk reduction: 32% for DM and
34% for HTNNNT: 11 cases for 3.3yrs
Xenical in Prevention of Diabetes in Obese Subjects(XENDOS)
Number of patients: 3305 with obesity79% with normal and 21% with IGT
Mean BMI:30 kg/m2
Major intervention: Orlistat 120mg TDSObjective: To see the effect of Orlistat on
the progression of diabetesAverage follow up: 4 yrs.
Relative risk reduction: 37% in all (p=0.0032) ,45% in IGT subjects (p=0.0024)
TRIALS SHOWING A REDUCTION IN THE DEVELOPMENT OF DIABETES
1. The Heart Outcomes Prevention Evaluation(HOPE).
2. Losartan Intervention for Endpoint(LIFE) Reduction in Hypertension Study
3. West of Scotland Coronary Prevention Study(WOSCOPS).
4. The Heart and Estrogen/Progestin Replacement Study(HERS).
5. Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity(CHARM}
The Heart Outcomes Prevention Evaluation (HOPE)
Number of patients: 9297 with high risk of vascular disease
Mean age: 55 or olderMajor intervention: Ramipril 10mgPrimary endpoint: composite outcome of
Stroke, MI or cardiovascular death.Average follow up: 4.5 yrs.Post hoc analysis of 5270 nondiabetic
subjects revealed a 34% lower rate of newer diabetes in treated group(p<0.001).
Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study
Number of patients: 9193 with HTN & LVH.Mean age: 55-80Objectives: to assess the ability of
Losartan to reduce cardiovascular morbidity and mortality.
Intervention: Losartan vs Atenolol
In 7998 nondiabetic subjects Losartan reduced the new onset of diabetes by 25% as compared to Atenolol (p=0.001)
West of Scotland Coronary Prevention Study(WOSCOPS)
Number of patients: 5974 with h/o MIMean age: 45-65Objective: to assess cardiovascular
eventsIntervention: Pravastatin vs Placebo
30% reduction in the development of diabetes with Pravastatin compared to placebo
The Heart and Estrogen/Progestron
Replacement Study (HERS)
Number of patients: 2763 postmeno-
pausal womenIntervention: Combination of conjugated
estrogen and progesteron vs placebo.Primary endpoint: Occurrence of CHD
Average follow up: 4.1 yrs.Conclusion: no reduction in CHD. Out of
2029 nondiabetic women a 35%(p=0.006) risk reduction for the development of DM was noted with an NNT of 30 for 4 yrs.
Cadesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity
(CHARM)
Number of patients: 7601 with CHF Intervention: Candesartan Primary endpoint: CHF hospitalization
or CV death Average follow up: 3.2 yrs Conclusion: Significant reduction in
CHF hospitalization(p<0.0001). 22% reduction in new-onset DM.
TRIALS IN PROGRESS
1. The Early Diabetes Prevention Trial (EDIT).
2. Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication(DREAM).
3. Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR).
The Early Diabetes Intervention Trial (EDIT)
Number of patients: 631 with IGTIntervention: Acarbose vs Metformin vs
combination of A+M vs Placebo Primary endpoint: Occurrence of DMAverage follow up: 6 yrs.
Interim results: at 3 yrs 522 subjects have remained in the trial showing an 8% risk reduction with Acarbose(p=0.12) and 37% for Metformin(p=0.17)
Expected follow up for 6 yrs.
Diabetes Reduction Assessment with Ramipril
and Rosiglitazone Medication(DREAM)
Number of patients: 4000 with IGTIntervention: Combination of Ramipril and
Rosiglitazone vs placeboPrimary endpoint: new onset DM or
all-cause mortalityAverage follow up: 3 yrs.
Ongoing trial, results expected in April 2007.
Nateglinide and Valsartan in Impared
Glucose Tolerance Outcomes Research (NAVIGATOR)
Number of patients: 7500 with IGT Intervention: Valsartan vs Nateglinide Primary endpoint: new onset DM or CV events
and all-cause mortalityAges of the participants: 50 yrs or older with CVD
55 yrs or older with risk factors for CVD
Average follow up: 5-6 yrs.
Ongoing trial (results in 2006-7)
Diabetes Prevention Strategies And Outcomes
INTERVENTION
Intensive lifestyleMetforminAcarbose
PravastatinRamiprilEstrogen/progesteroneILSC + OrlistatTroglitazoneLosartanCandesartanRosiglitazoneNatiglinide &Valsartan
STUDY
DPP, FDPDPP,EDITSTOP-NIDDM, EDITWOSCOPSHOPE,DREAMHERSXENDOSTRIPODLIFECHARMDREAMNAVIGATOR
RR
58% a
31% a
25% a
ongoing30% a
34% a
35% a
37%56% 25%22%
ongoingongoing
a versus standard lifestyle advice b versus intensive lifestyle advice
Metformin: the foundation oral therapy that offers prevention
of type 2 diabetes and its complications
Clinical outcome benefits with Metformin
Prevention of complications
Patients allocated to metforminn=342
Metformin
dosing
protocol
850 mg
1700 mg
2550 mg
Follow up 6-20 yearsMedian 10 years
UKPDS 34. Lancet 1998;352:854-65
Patients randomised to Metformin in theUK Prospective Diabetes Study
Diabetes-related deaths
All-cause mortality
Any diabetes-related
endpoint
Myocardial infarction
Stroke
*Compared with conventional therapy (overweight group)
Change in risk*
42%
36%
32%
39%
41%
P value
0.017
0.011
0.0023
0.01
0.13
Change in risk*
20%
8%
7%
21%
14%
P value
0.19
0.49
0.46
0.11
0.60
MetforminIntensive (n=342)
Sulphonylurea / InsulinIntensive (n=951)
UKPDS 34. Lancet 1998;352:854-65
Benefits beyond blood glucose controlwith metformin in the UKPDS
Clinical outcomes for metforminin the UKPDS
Myocardialinfarction StrokeDiabetes deaths
42% 39% 41%
Median dose = 2550 mg/day
UKPDS 34. Lancet 1998;352:854-65
Risk reductions from intervention studies in type 2 diabetes
Clinical Outcomes
Diabetes-related deaths (%)
All-cause mortality (%)
All MI (%)
Fatal MI (%)
All stroke (%)
Fatal stroke (%)
Follow-up (years)
UKPDSSU/Ins
n=3867
10
6
16
6
(+)11
(+)17
10.7
UKPDSCaptoprilAtenololn=1148
32
18
21
28
44
58
8.4
HOPERamipril
n=3577
37
24
22
-
33
-
4.5
HOTFelodipine
Aspirinn=1501
67
43
51
-
30
-
3.8
4SSimva-statinn=202
36
43
55
-
62
-
5.4
UKPDSMetformin
n=753
42
36
39
50
41
25
10.7
Optimising the dose of Metformin
Prevention of complications
0
1000
2000
3000
Austria Ita
ly
Belgiu
mUSA
Germ
any
Switzer
land
Portugal UK
Spain
France
Metformin is frequently under-dosedM
etfo
rmin
do
sag
e (m
g/d
ay) Metformin dose in the UKPDS
Metformin dose in clinical practice
Scarpello. Br J Diabetes Vasc Dis 2001;1:28-36
Optimising metformin dosage: evidence-based conclusions
Glycaemic benefits
Clinical benefits
Tolerance and safety
Metformin daily dosage (mg)
500
1000
1500
2000
2500
3000
850
1700
2550
Metformin: foundation therapy for prevention of type 2 diabetes and its complications
Reduced morbidity and mortality in the UKPDS
Unique reduction of cardiovascular complications beyond that expected from blood glucose control
IDF and ADA guidelines favour the use of metformin as foundation therapy for type 2 diabetes where possible
The antihyperglycaemic efficacy of metformin is dose-related with an optimal daily dose of 2000 mg/day
Metformin is well tolerated across its dosage range
Gastrointestinal side-effects are usually transient
Minimised by slow dosage titration
Only about 5% of patients cannot tolerate metformin
Proven to prevent or delay type 2 diabetes (DPP)
Conclusions
We face a global pandemic of type 2 diabetes.
IGT and type 2 diabetes are stages in the progression of dysglycaemia.
Interventions at the IGT stage (pharmacological or lifestyle) may delay or prevent type 2 diabetes.
Failure to identify IGT meant that there was a “missed opportunity to prevent diabetes.”
Conclusion
"Every year a person can live free of diabetes means an added year of life free of the pain, disability, and
medical costs incurred by this disease"
Benefits of diabetes prevention for patients