Dm Prevention Update Feb-09

DIABETES PREVENTION SM ALL ST EP S…

BI G

RE WARD S

Mohammad O. Daoud Consultant Endocrinologist 02/25/09

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Objectives §Introduction §Basics §Pre-DM & DM Risk §DM Prevention Trials §Conclusion

02/25/09

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Understanding Pathogenesis and Pathophysiology May Lead to

Cure

Prevention 02/25/09

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Goals of DM Prevention 1-Delaying the onset of diabetes 2-Preserving beta cell function 02/25/09

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Objectives §Introduction

§Basics §Pre-DM & DM Risk §DM Prevention Trials §Conclusion

02/25/09

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Normal Islet β-Cell Response

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

02/25/09

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Normal Physiology of Glucose Homeostasis Carbohydr ate

Gu t

Pancreas β Insulin /Amylin α Glucagon

↓Hepatic glucose production ↑Glucose uptake and storage of glycogen

Digesti ve enzym

Blood glucose

Insul in

L ive

Regulation of lipolysis Adipo se tissue

Musc le Insulin-stimulated glucose uptake 02/25/09

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Metabolic Defects Contributing to β- Cells Impaired Insulin Secretion

Pancre as

Abn. α - Cells Glucagon Secretion?

Hyperglyce mia

L ive Increased hepatic glucose

Decreased glucose uptake Adipose tissue and muscle

Insulin Resistance 02/25/09

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Normoglycemia to Type2-DM

DeFonzo RA. Ann review of Diabetes 1998: 1-93 02/25/09

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The Belfast Diet Study BiPhasic Loss of -cell Function Diagno Slow decline sis phase ~2%/year

-cell function (HOMA%B)

60 50

Rapid decline phase ~18%/year

40 30 20 10 0

–15

–10

–5

0

5

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Adjusted time from diagnosis (years) Diet failure in years Diet failure in years 2– 8–10 No diet failure in 10 years4 Diet failure in years 5–7 Bagust A & Beale S. QJM 2003; 96:28–288. Diet failure: additional non-dietary intervention required. 10 02/25/09

Natural History of Type 2 DM development of complications Obesity IGT/IFG (Uncontrolled) Prediabetes

Diabetes

Type 2 diabetes

Macrovascular complications Microvascular complications

– 0 – 1 2 10 duration 0(years) 20Diabetes 0

3 0 02/25/09

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Objectives §Introduction §Basics

§Pre-DM & DM Risk §DM Prevention Trials §Conclusion

02/25/09

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What is PreDiabetes? Pre-diabetes is a medical 

condition where blood glucose is higher than normal but not high enough to be called diabetes 

It increases the risk for type 2 diabetes and cardiovascular 

NIDDK, National Diabetes Statistics 2007. 02/25/09

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

What is Pre? before Most peopleDiabetes have pre-diabetes they develop Type 2 diabetes





Most people with Pre-Diabetes develop type 2 diabetes within 10 years



 

Progression to diabetes is

NOT inevitable NIDDK, National Diabetes Statistics 2007.

02/25/09

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Asymptomatic Adults Testing 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 risk factor

 

American Diabetes Association. Diabetes Care 2009; 31;(Suppl.1):S13-61 CDA cpg-Sept-2008 ;www.diabetes.ca

02/25/09

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Risk Factors for Diabetes 

  



Overweight (BMI ≥ GDM /Macrosomia 25) History of vascular Physical inactivity dis.  Signs of IR Hypertension/ Rx Abnormal lipid (Ex. PCOS or levels Family history of diabetes; 1st A. degree Repeat testing at least Nigricans) every 3 years (B) American Diabetes Association. Diabetes Care 2009; 31;(Suppl.1):S13-61 02/25/09

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Testing for Type 2 DM in Asymptomatic Children / Adolescents Overweight Plus any two of the following risk factors: ●

● Family history of type 2 diabetes in first or second-degree relative ● Race/ethnicity ● Insulin Resistance : A. Nigricans, HTN, Dyslipidemia,

Age of initiation: age

10 years or at onset of

puberty, if puberty occurs at a younger age Frequency: every 3 years Test: FPG preferred

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Diagnostic Testing ♦ Fasting No caloric intake for at least 8 hrs

♦ Normal FP Glucose: <100 mg/dl (5.6mmol/L)

♦ Casual ♦     Any time of    the day regardless      of the last meal      time    02/25/09

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Oral Glucose Tolerance Test § 1. Take fasting venous

blood for glucose (12 hour fast) § 2. Give drink of 75g of anhydrous glucose or 410mls Lucozade Original § 3. Wait 2 hours – no food or exercise permitted § 4. Take further 02/25/09

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Diagnostic Testing ♦IFG:

Impaired Fasting Glucose FPG  

♦                      

♦       02/25/09

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Diagnostic Criteria for Pre-Diabetes and Diabetes

American Diabetes Association. Diabetes Care 2008; 31;(Suppl.1):S12-54. 02/25/09

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Natural History of IFG and IGT

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%

In the Diabetes Prevention Project 11% of subjects with both IGT and IFG progressed to type 2 diabetes each year 02/25/09

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IFG and IGT Prrvention of Type 2 DM The efficacy of interventions for primary prevention of type 2 DM has primarily been demonstrated among individuals with IGT Not individuals with IFG (who do not also have IGT) 02/25/09

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% with CVD

Risk of Cardiovascular Disease Is Elevated Prior to Diagnosis of T2DM

*MI=myocardial infarction. Adapted from: Hu F, et al. Diabetes Care. 2002;25:1129-1134. 02/25/09

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Hemoglobin A1C HbA1C (Glycated Hemoglobin) currently is not recommended to Dx diabetes BUT May be helpful in predicting DM

02/25/09

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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 women followed for 10 years: Individuals with baseline A1C in the highest quintile (A1C >5.22), the adjusted 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; 02/25/09

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02/25/09

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Objectives §Introduction §Basics §Pre-DM & DM Risk

§DM Prevention Trials §Conclusion

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DIABETES PREVENTION THE EVIDENCE

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Prediabetes – Target For Intervention? § Blocking damage to beta-cell ? limited

§ Defects seen in this stage associated with life style factors

§ Visceral obesity as an obvious target

§ Drugs targeting insulin resistance 02/25/09

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TYPE 2 DM PREVENTION / DELAY Ø The cost-effectiveness of intervention strategies is unclear

Ø The huge burden of DM and the potential benefits of prevention suggest that prevention is worthwhile.

02/25/09

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Recent T2DM Prevention Studies • • • • • • • •

Da Qing

Diet/Exercise

DPS

Lifestyle

Chinese Study

Acarbose/Metformin

2001

DPP

Lifestyle/Metformin

2002

STOP-NIDDM

Acarbose

TRIPOD

Troglitazone

2002

XENDOS

Diet/ Orlistat

2003

DREAM

Rosiglitazone

2006

02/25/09

1997 2001

2002

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The Da Qing IGT Study

Diabetes Care 1997;20:537-44 02/25/09

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Da Qing Study/China Ø Men and women Ø RR of developing Type 2 DM with IGT in all interventions Ø Randomized to -Control group Diet (31%), -Diet only -Exercise only -Diet plus exercise

02/25/09

Exercise (46%) Diet + exercise (42%)

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Da Qing Study/China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet. 2008 May 24;371(9626):1783-9. 

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



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

 Risk

02/25/09

Reduction of 43 % 37

02/25/09

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Finnish Diabetes Prevention Study (DPS) § 522 Middle aged obese subjects with IGT § Mean age 55 years § Mean BMI 33.2 kg/m2

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med

02/25/09

2001 May

3;344(18):1343-50.

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Finnish Diabetes Prevention Study (DPS) § Diet and exercise Counselling (Control Group) Or Intensive individualized instruction on weight reduction, food intake, and guidance on increasing physical activity (Intervention Group). § Average follow-up of 3.2 years 02/25/09

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Life Style Changes

Finnish study (DPS) § Weight loss averaged 9.2 lb at 1 year , 7.7

lb after 2 years, and 4.6 lb after 5 years § “Moderate exercise," such as brisk walking, for 30 min/day “ § 58% RR in the incidence of diabetes in the intervention group compared with the control subjects (11% Vs. 23 %)

02/25/09

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Finnish study

Sustained reduction in the incidence of Type 2 DM by lifestyle intervention § After a median of 4 years of active intervention with median total follow-up of 7 years § A 58% RR in 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 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study.

Lancet. 2006 Nov 11;368(9548):1673-9.

02/25/09

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Diabetes Prevention Program (DPP) The DPP was a major clinical trial to determine whether diet and exercise or the oral diabetes drug metformin could prevent or delay the onset of type 2 DM. 



3234 subjects (average



DPP Research Group. N Engl J Med 2002, Vol.346, No. 6. 02/25/09

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Diabetes Prevention Program (DPP) Three intervention groups: 1-The intensive nutrition and exercise counselling (“lifestyle”) group 2 &3 - Either of two masked medication treatment groups: group

Metformin (850 mg BID) or the placebo group. 02/25/09

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DPP Participants 

Adults at high risk for type 2 diabetes



  

 

Presence of IGT /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 Pacific Islanders



DPP Research Group. N Engl J Med 2002, Vol.346, No. 6.

02/25/09

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DPP Methods Lifestyle intervention 5% to 7% weight reduction Healthy low-calorie, low-fat diet 30 minutes of physical activity, 5 days a week

Metformin (850 mg BID) Oral diabetes drug

Placebo DPP Research Group. N Engl J Med 2002, 02/25/09

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DPP Methods DPP Curriculum:



  

Diet Exercise Behavior change modification



Taught one-on-one by case managers 



DPP Research Group. N Engl J Med 2002, Vol.346, No. 6.

02/25/09

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Mean Change in Leisure Physical Activity Lifest

Metfor Place

The DPP Research Group, NEJM

Mean Weight Change Place Metfor Lifest

There was a 16 %Reduction in DM risk for every kilogram reduction in weight The DPP Research Group, NEJM

Life Style Group Results (DPP) § Average followup of 2.8 years

§ 50% : 7% weight  § Mean wt loss: 12 § A 58% RR in the lb or 6% of progression to initial body DM (lifestyle weight group) § 74% maintained at least 150 § 31% min/week of RR(Metformin *Metformin was as effective as TLC inmoderately individuals aged 24 to 44 years or in those with a BMI 35 kg/m2

02/25/09

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Life Style Group Results (DPP) Over an average follow-up of 2.8 years The incidence of diabetes (cases per 100 person-years): p-yr) NNT § Placebo § Metformin

(cases/ 100 11.0 7.8

*Metformin was as effective as TLC in individuals aged 24 to 44 years or in those with a BMI 35 kg/m2 02/25/09

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DM Prevention Thiazolidinediones

02/25/09

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TRIPOD Study § Troglitazone in Prevention of Diabetes (TRIPOD) § 266 Hispanic women with previous GDM § Either placebo or Troglitazone § Median follow-up of 30 Ms § Troglitazone was associated with a 56% RR in

progression to diabetes 02/25/09

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Rosiglitazone prevents Type 2 DM

62% RRR in the risk of progression to DM (HR 0.38, 95% CI, 0.33–0.44) 5269 subject s with IGT and/or impaire d fasting glucose

The DREAM trial

RR 60%

Lancet 2006;368:1096-1105 02/25/09

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DM Prevention Thiazolidinediones -TRIPOD trial (Troglitazone in Prevention of Diabetes) -Rosiglitazone in the DREAM trial -Pioglitazone in Prevention of Diabetes (PIPOD) study & and Actos Now for Prevention of Diabetes (ACT-NOW)

Currently Thiazolidinediones are Not Recommended for DM prevention 02/25/09

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02/25/09

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STOP-NIDDM Study Results

•1429 subjects, 49% male, age 40-70 years •IGT, BMI 25-40 kg/m2 •3 year follow-up, 24% not taking study medication Randomisation

T2DM

RR

p

Placebo

41.8%

…

…

Acarbose (300 mg/d)32.8% <0.001

25%

Absolute risk reduction

9.0%

Chiasson J-P et al, The Lancet02/25/09 2002;

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STOP-NIDDM Study

Risk Reduction 25% Acarbos e Placeb o

Chiasson et al, Lancet

02/25/09

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STOP-NIDDM Study Results Acarbose treatment was also associated with; -49% reduction in CV events (p=0.032) - 50 % reduction in the progression When the drug was discontinued, the effect of acarbose did not persist Chiasson J-P et al, The Lancet 2002;

02/25/09

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XENDOS Study XENical in the prevention of D.Mellitus in Obese

Subjects 3305 patients studied Orlistat ability to delay type 2 DM when added to TLC in a group with BMI 30 kg/m2 with or without IGT Outcome :After 4 years of Rx: 1- 45% RR in the IGT group 2- No effect observed in those 02/25/09

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Impact of ARBs and ACE-Is on the development of New Onset Type 2 § 11 trials with 66.608 patients § ACEI’s and ARBs did prevent new

onset type 2 diabetes by 22%

§ The DREAM trial (Ramipril) and

the Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events trial failed to show same results

Diabetes Care. 2005;28:2261-66 – Meta-analysis 02/25/09

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02/25/09

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Objectives §Introduction §Basics §Pre-DM & DM Risk §DM Prevention Trials

§Conclusion 02/25/09

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MNT Weight Management

ØWeight loss is recommended for all overweight or obese adults, who have, or at risk for developing, type 2 DM Individuals at risk for DM:

Encourage interventions that facilitate 02/25/09

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MNT Physical Activity Ø A regular physical activity program, is recommended for all patients with or at risk of diabetes who are capableof participating. Ø Start modest physical activity , gradually increase the duration / frequency to 30 – 45 min of

moderate aerobic activity 3–5 days per week, when possible. 02/25/09

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DM Type 2 Lifestyle Intervention

§ Intensive diet and/or exercise can delay the onset of diabetes: Real effort is needed

§ Interventions at a much earlier stage

might be more effective at preventing, rather than delaying T2DM

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T2DM Prevention (Pharmacology)

§ Therapies tested to date delay, but

mayn’t /don’t prevent progression to T2DM

§ Some of the benefit of these therapies may disappear within 1-2 months of discontinuation

02/25/09

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T2DM Prevention (Pharmacology) Some agents are able to prevent or delay diabetes The impact on CVD risk factors is less clear !? Long-term effects on CV events are ? Early pharmacologic Rx benefit Vs. withholding Rx until DM develops ?

02/25/09

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Diabetes Prevention The ADA -2009 Recommendations

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

Specific goals include: -Modest weight loss (5 -10 % of body Wt) -Moderate-intensity exercise (30 minutes daily;150 minutes/week) -Smoking cessation. 02/25/09

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Diabetes Prevention The ADA -2009 Recommendations

Monitoring to be performed every 1 year (E)

§ Drug therapy should not be routinely used

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Importance of Small, but 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 02/25/09

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Conclusio § The ADA /CDA recommends screening for IFG/IGT in individuals at high risk for diabetes

§ A large proportion of Pre-Diabetics {(IFG) and (IGT)} progress to Type 2 DM But NOT Inevitable

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Conclusio

§ Therapeutic Lifestyle Changes (TLC) /Drugs can Prevent /Delay progression to Type 2 Diabetes

§ The beneficial effects of such TLC intervention appears to continue after the original intervention

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Conclusion CDA Recommendations ØIntensive TLC with weight loss of at least 5% of initial BW can reduce the risk of progression from IGT to Type 2 DM by almost 60%. For IGT (Grade A, Level 1A) and For IFG [Grade D, Consensus]. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee CDA –Sept-2008 02/25/09

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Conclusion CDA Recommendations In individuals with IGT, pharmacologic therapy with Metformin [Grade A, Level 1A) Or Alpha- Glucosidase inhibitor [Grade A, Level 1A ) should be considered to reduce the risk of type 2 diabetes. In individuals with IGT and/or IFG and no known CV disease: Rx with a Thiazolidinedione could be considered to reduce the risk of type 2 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee CDA –Sept-2008 02/25/09

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Conclusion CDA Recommendations

Progression from Pre-Diabetes to Type 2 DM can also be reduced by pharmacologic therapy : ØMetformin (~30% reduction) ØAcarbose (~30% reduction) ØThiazolidinedione (~60% reduction). Canadian Diabetes Association Clinical Practice Guidelines Expert Committee CDA –Sept-2008 02/25/09

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DM Prevention Thiazolidinediones Currently Thiazolidinediones are Not Recommended for DM prevention Adverse effects (fluid retention, weight gain, heart failure, MI, Peripheral bone #)

Higher cost Rx Vs Prevention ? Sustained effect after D/C … 02/25/09

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ADA Treatment of IFG/IGT Population IFG

or IGT

Both IFG & IGT with -Age < 60 yrs -BMI ≥ 35 kg/m2 -F.Hx of DM in 1st degree relatives -High TAG -Low HDL -HTN -HbA1c > 6% 02/25/09

Treatment Lifestyle Modifications Lifestyle Modifications &/Or (E) Metformin In the DPP, metformin was most effective compared to lifestyle in those with BMI of at least 35 kg/m2 and age < 60 years. 84



Diabetes Prevention Type 2 diabetes prevention is: §PROVEN §POSSIBLE §POWERFUL

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DIABETES PREVENTION SM AL L STEP S…

BIG

REW ARD S

QUESTI ONS? Mohammad O. Daoud Consultant Endocrinologist 02/25/09

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