dm prevention update feb-09

8/14/2019 DM Prevention Update Feb-09

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DIABETES PREVENTION

SMALL STEPSBIG REWARD S Mohammad O. Daoud

Consultant Endocrinologist


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Objectives

Introduction

BasicsPre-DM & DM RiskDM Prevention Trials

Conclusion


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Understanding

Pathogenesis andPathophysiology

May Lead to

Cure

Prevention


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Goals of DM Prevention

1-Delaying the onset of

diabetes

2-Preserving beta cell

function


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Objectives

Introduction

BasicsPre-DM & DM RiskDM Prevention Trials

Conclusion


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Normal Islet -CellRes onse

Pickup and Willliams; Textbook of Diabetes.3rd Edition.Blackwell 2003


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Normal Physiology of GlucoseHomeostasis

HepaticglucoseproductionGlucoseuptake andstorage of

glycogen Insulin-stimulated glucose

Regulation oflipolysis

Adipose

Carbohydr

Blood

Digestive

Gu

Pancreas Insulin

/Amylin

MuscL

Insul


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Metabolic Defects Contributing

Insulin Resistance

Hyperglyce

Decreasedglucose

Pancre- Cells

ImpairedInsulin

Increasedhepatic

L

Adipose tissue and

Abn. - CellsGlucagon

Secretion?


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Normoglycemia to Type--

DeFonzo RA. Ann reviewof Diabetes 1998: 1-93


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The Belfast Diet Study Bi-

Phasic Loss of-cell Function60

50

40

30

20

10

015 10 5 0 5 10

-ce

llfunction(HOMA%B)

Adjusted time from diagnosis (years)

Bagust A & Beale S. QJM 2003;96:28288.Diet failure: additional non-dietary intervention required.

Diet failure in years

Diet failure in years

Diet failure in years 2

No diet failure in 10 years

Slow declinephase

Rapid declinephase

Diagno


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Natural History of Type 2 DMv l m nt f m li ti n

Diabetes duration (years)

0 1 2 3

Obesity IGT/IFG DiabetesType 2 diabetes

Microvascular complications

Macrovascular complications

Prediabetes


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Objectives

IntroductionBasics

Pre-DM & DM RiskDM Prevention Trials

Conclusion


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What is Pre-

Pre-diabetes is a medicalcondition where blood glucoseis higher than normal but nothigh enough to be calleddiabetes

It increases the risk for type 2diabetes and cardiovascularNIDDK, National Diabetes Statistics 2007.


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What is Pre- Most people have pre-diabetes beforethey develop Type 2 diabetes

Most people with Pre-Diabetesdevelop type 2 diabetes within10 years

Progression to diabetes is NOT inevitable

NIDDK, National Diabetes Statistics2007.


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Asymptomatic AdultsTestin for Diabetes and Pre-DM

Should be considered in:

Age 40-45 or older without

risk factors

Adults of any age who are

overweight with another riskfactor

American Diabetes Association. Diabetes Care 2009;

31;(Suppl.1):S13-61


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Risk Factors for Diabetes

Overweight (BMI 25)

Physical inactivity

Hypertension/ Rx Abnormal lipid

levels Family history of

diabetes; 1st

GDM /MacrosomiaHistory of vasculardis.

Signs of IR

(Ex. PCOS or

A.Repeat testing at leastever 3 ears (B)


31;(Suppl.1):S13-61


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Testing for Type 2 DM inAsymptomatic Children / Adolescents

Overweight Plus any two of the followingrisk factors:

Family history of type 2 diabetes in first or second-degree

relative Race/ethnicity

Age of initiation: age 10 years or at onset ofuberty, if puberty occurs at a younger age

Frequency: every 3 yearsTest: FPG preferred


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Diagnostic Testing

FastingNo caloric

intake for at least

8 hrs

CasualAny time of

the day regardlessof the last mealtime

Normal FPGlucose:


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Oral Glucose Tolerance Test

1. Take fasting venousblood for glucose (12 hourfast)

2. Give drink of 75g ofanhydrous glucose or410mls Lucozade Original

3. Wait 2 hours no food orexercise permitted


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Diagnostic Testing

IFG: Impaired Fasting GlucoseFPG


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Diagnostic Criteria forPre-Diabetes and Diabetes



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Natural History of IFG

In the Diabetes Prevention Project 11% ofsubjects with both IGT and IFG progressedto type 2 diabetes each year

Progression to Type 2 DM over 5-6 years

Neither IGT or IFG 4-5%

IFG only 20-35% IGT only 20-35% Both IFG and IGT 35-65%


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IFG and IGTPrrvention of T e 2 DM

The efficacy of interventions forprimary prevention of type 2 DM

hasprimarily been demonstratedamong individuals with IGT

Not individuals with IFG


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Hemoglobin A1C

HbA1C (Glycated Hemoglobin)currently is not recommended to

Dx diabetesBUT

May be helpful in predicting DM


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Hemoglobin A1C

Patients with IFG and A1C 5.9 % had a 50%risk of progression to DM within six years (1)

In a prospective cohort study of 26,563 womenfollowed for 10 years: Individuals with baselineA1C in the highest quintile (A1C >5.22), theadjusted relative risk of diabetes was 8.2 (2)

1-Epidemiological Study on the Insulin Resistance Syndrome(DESIR).Droumaguet C et al , Diabetes Care. 2006 Jul;29(7):1619-25.

2- Hb A1c predicts DM but not CVD in nondiabetic women;


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Objectives

IntroductionBasics


Conclusion


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DIABETESPREVENTION


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Prediabetes Target ForIntervention?

Blocking damage to beta-cell ?limited

Defects seen in this stageassociated with life style factors

Visceral obesity as an obvious

target


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TYPE 2 DMPREVENTION / DELAY

The cost-effectiveness of intervention

strategies is unclear

The huge burden of DM and the potentialbenefits of prevention suggest that

prevention is worthwhile.

R T2DM


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Recent T2DMPrevention Studies

Da Qing Diet/Exercise 1997

DPS Lifestyle 2001

Chinese Study Acarbose/Metformin 2001

DPP Lifestyle/Metformin 2002

STOP-NIDDM Acarbose 2002

TRIPOD Troglitazone 2002

XENDOS Diet/ Orlistat 2003

DREAM Rosiglitazone 2006


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The Da Qing IGT Study

Diabetes Care


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Da Qing Study/China

Men and womenwith IGT

Randomized to

-Control group-Diet only

-Exercise only-Diet plus

exercise

RR of developing Type 2 DMin all interventions

Diet (31%),Exercise (46%)

Diet +

exercise (42%)


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Da Qing Study/China

Group-based lifestyle interventions over 6 years canprevent or delay DM for up to 14 years

Those in the active intervention group had a lowercumulative incidence of DM than the control group(80% vs. 93% respectively)

Risk Reduction of 43 %

Da Qing Diabetes Prevention Study: a 20-yearfollow-up study.


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Finnish Diabetes PreventionStudy (DPS)

522 Middle aged obese subjectswith IGT

Mean age 55 years Mean BMI 33.2 kg/m2

Prevention of type 2 diabetes mellitus by changes inlifestyle among subjects with impaired glucosetolerance.


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Finnish Diabetes PreventionStudy (DPS)

Diet and exercise

Counselling (Control Group)

Or Intensive individualized instructionon weight reduction, food intake,and guidance on increasingphysical activity (InterventionGroup).

Average follow-up of 3.2 years


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Life Style Changes

Finnish study (DPS) Weight lossaveraged 9.2 lb at 1 year , 7.7

lb after 2 years, and 4.6 lb after 5 years

Moderate exercise," such as briskwalking, for 30 min/day

58% RRin the incidence of diabetes inthe intervention group compared with

the control subjects (11% Vs. 23 %)


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Finnish study Sustainedreduction in the incidence of Type 2

After a median of 4 years of activeintervention with median total follow-up of 7years

A 58% RRin the incidence of DM Incidence rates during the follow-up 4.6

% Vs. 7.2% (p=0.0401), indicating 36%

RRR

Sustained reduction in the incidence of type 2 diabetesby lifestyle intervention: follow-up of the Finnish

Diabetes Prevention Study.


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The DPP was a major clinicaltrial to determine whether

diet and exercise or the oraldiabetes drug metformincould prevent or delay the

onset of type 2 DM.

Diabetes Prevention

Program (DPP)

DPP Research Group. N Engl J Med 2002,

Di b t P ti


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Diabetes PreventionProgram

Three intervention groups:

1-The intensive nutrition and exercise

counselling (lifestyle) group

2 &3 - Either of two maskedmedication

treatment groups:

Metformin (850 mg BID)group

or the placebo group.


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DPP Participants

Adults at high risk for type 2 diabetes

Presence ofIGT /IFG Mean age 51 years

Mean body mass index (BMI) 34 68% women 45% minority groups

African Americans

Hispanics/Latinos American Indians Asian Americans and PacificIslanders



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DPP Methods


Lifestyle intervention5% to 7% weight reductionHealthy low-calorie, low-fat diet

30 minutes ofphysical activity, 5days a week

Metformin (850 mg BID)

Oral diabetes drug


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DPP Methods

DPP Curriculum: Diet Exercise Behavior change modification

Taught one-on-one by case

managers


Mean Change in Leis re Ph sical


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Mean Change in Leisure PhysicalActivity

Place

Metfor

Lifest

The DPP Research Group, NEJM

M W i h Ch


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Place

Metfor

Lifest

Mean Weight Change

The DPP Research Group, NEJM

There was a 16 %Reductionin DM risk for every kilogram


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Life Style Group Results

Average follow-up of 2.8 years

A 58% RR in theprogression toDM (lifestylegroup)

31%RR(Metformin

50% : 7%

weight Mean wt loss: 12

lb or 6% ofinitial bodyweight

74% maintainedat least 150min/weekof

*Metformin was as effective as TLC in individuals aged 24 to 44

years or in those with a BMI 35 kg/m2


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Life Style Group Results

Over an average follow-upof 2.8 years

The incidence of diabetes(cases per 100person-years):

(cases/ 100

p-yr) NNT Placebo 11.0 Metformin 7.8

*Metformin was as effective as TLC in individuals aged 24 to 44

years or in those with a BMI 35 kg/m2


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DM Prevention

Thiazolidinediones


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TRIPOD Study

Troglitazone in Prevention ofDiabetes (TRIPOD)

266 Hispanic women withprevious GDM

Either placebo or Troglitazone

Median follow-up of 30 Ms

Troglitazone was associated

with a 56% RR in

Rosiglitazone prevents Type 2


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Rosiglitazone prevents Type 2

The DREAM trial Lancet 2006;368:1096-1105

62% RRR in the risk of progression to DM (HR 0.38, 95% CI,

RR 60%

5269subjects withIGT

and/orimpairedfasting

DM P ti


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DM PreventionThiazolidinediones

-TRIPOD trial (Troglitazone in Preventionof Diabetes)-Rosiglitazone in the DREAM trial

-Pioglitazone in Prevention of Diabetes(PIPOD) study & andActos Now for Prevention of Diabetes

Currently Thiazolidinediones areNot Recommended for DMprevention


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STOP-NIDDM Study Results


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STOP-NIDDMStudy Results

1429 subjects, 49% male, age 40-70 yearsIGT, BMI 25-40 kg/m2

3 year follow-up, 24% not taking study medication

Chiasson J-P et al, The Lancet 2002;

Randomisation T2DM RR p

Placebo 41.8%

Acarbose (300 mg/d)32.8% 25%


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STOP-NIDDM Study

Risk Reduction

Acarbos

Placeb

Chiasson et al, Lancet

STOP-NIDDM Study Results


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STOP-NIDDMStudy Results

Chiasson J-P et al, The Lancet 2002;

Acarbose treatment was also

associated with;

-49% reduction in CV events

(p=0.032)

When the drug was discontinued, theeffect of acarbose did not persist


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ENDOS St d


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ENDOS StudyXENical in the prevention of

D.Mellitus in Obese

3305 patients studied

Orlistat ability to delay type 2 DMwhen added to TLC in a group withBMI 30 kg/m2 with or without IGT

Outcome :After 4 years of Rx:

1- 45% RR in the IGT group

-


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Impact of ARBs and ACE-Is on the


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Impact of ARBs and ACE Is on thedevelo ment of New Onset T e 2

Diabetes Care. 2005;28:2261-66 Meta-analysis

11 trials with 66.608 patientsACEIs and ARBs did prevent new

onset type 2 diabetes by 22%

The DREAMtrial (Ramipril) andthe Telmisartan to Prevent

Recurrent Stroke andCardiovascular Events trial failedto show same results


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Objectives

IntroductionBasics


Conclusion


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MNT Weight

Weight loss isrecommended for alloverweight or obese adults,who have, or at risk fordeveloping, type 2 DM

Individuals at risk for DM:

Encourageinterventions that facilitate


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MNTPhysical Activity

A regular physical activity program,is recommended for all patients

with or at risk of diabetes who arecapableof participating.

Start modest physical activity ,

gradually increase the duration /frequency to 30 45 min ofmoderate aerobic activity 35da s er week, when ossible.


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T2DM Pre ention


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T2DM Prevention(Pharmacolo )

Therapies tested to date delay, butmaynt /dont prevent progression toT2DM

Some of the benefit of these therapiesmay disappear within 1-2 months ofdiscontinuation

T2DM Prevention


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T2DM Prevention(Pharmacolo )

Some agents are able to prevent or delaydiabetes

The impact on CVD risk factors is lessclear !?

Long-term effects on CV events are ?

Early pharmacologic Rx benefit Vs.withholding Rx until DM develops ?

Di b t P ti


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Diabetes PreventionThe ADA -2009

Lifestyle modification as the primary interventionin subjects with IGT (A) or IFG (E)

Specific goals include:

-Modest weight loss (5 -10 % of body Wt)

-Moderate-intensity exercise (30 minutesdaily;150 minutes/week)

-Smoking cessation.

Diabetes Prevention


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Diabetes PreventionThe ADA -2009

Monitoring to be performed every1 year (E)

Drug therapy should not be

routinely used

Importance of Small, but


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p ,Permanent Changes

1 biscuit / day (1/2 cookie) = 50 kcal =18250 kcal / year

= + 2,5 kg /year

1 km walking / day = 50 kcal = 18250 kcal /

year

= - 2,5 kg / year


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Conclusio


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Conclusio The ADA /CDA recommends

screening for IFG/IGT in individualsat high risk for diabetes

A large proportion of Pre-Diabetics{(IFG) and (IGT)} progress to

Type 2 DM But NOT Inevitable

Conclusio


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Conclusio

Therapeutic Lifestyle Changes(TLC) /Drugs can Prevent /Delayprogression to Type 2 Diabetes

The beneficial effects of such TLCintervention appears to continue

after the original intervention

Conclusion


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ConclusionCDA Recommendations

Intensive TLC with weight loss of atleast 5% of initial BW can reduce therisk of progression from IGT to Type 2

DM by almost 60%.

For IGT (Grade A, Level 1A) andFor IFG [Grade D,

Consensus].

Canadian Diabetes Association Clinical PracticeGuidelines Expert Committee CDA Sept-2008

Conclusion


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Conclusion

CDA RecommendationsIn individuals with IGT, pharmacologic therapywithMetformin[Grade A, Level 1A) OrAlpha- Glucosidase inhibitor[Grade A, Level1A )

should be considered to reduce the risk of type2 diabetes.

In individuals with IGT and/or IFG and no knownCV disease:

Rx with a Thiazolidinedione

Canadian Diabetes Association Clinical Practice

Guidelines Expert Committee CDA Sept-2008

Conclusion


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Conclusion

CDA Recommendations

Progression from Pre-Diabetesto Type 2 DM can also bereduced by pharmacologic

therapy :

Metformin (~30% reduction)

Acarbose (~30% reduction)Thiazolidinedione (~60%

Canadian Diabetes Association Clinical Practice

Guidelines Expert Committee CDA Sept-2008

DM P ti


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DM Prevention

ThiazolidinedionesCurrently Thiazolidinediones areNot Recommended for DMprevention

Adverse effects (fluid retention, weight

gain, heart failure, MI, Peripheral bone #)Higher costRx Vs Prevention


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Di b


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Diabetes

Type 2 diabetes prevention is:PROVEN

POSSIBLE

POWERFUL


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DIABETES PREVENTION


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DIABETES PREVENTIONDIABETES PREVENTION

SMALLMALL STEP STEP SBIGIG REW ARD SREW ARD S

QUESTIONS?UESTIONS? Mohammad O. DaoudConsultant Endocrinologist

dm prevention update feb-09

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