Preventing Type 2 DiabetesPreventing Type 2 Diabetes

Selay LamSelay Lam

PGY1, Internal MedicinePGY1, Internal Medicine

October 29, 2008October 29, 2008

Learning ObjectivesLearning Objectives

This program will review the following This program will review the following aspects of type 2 diabetes:aspects of type 2 diabetes:

– risk factors and potential impactrisk factors and potential impact– primary prevention:primary prevention:

review lifestyle modification trialsreview lifestyle modification trials

review pharmacological trialsreview pharmacological trials

practical aspects practical aspects

Diabetes Mellitus Type 2Diabetes Mellitus Type 2

Due to some combination of:Due to some combination of:

1.1. GeneticsGenetics

2.2. Relative impairment in insulin secretionRelative impairment in insulin secretion

3.3. Insulin resistanceInsulin resistance

PrevalencePrevalence

Lifetime risk of developing diabetes (type 1 Lifetime risk of developing diabetes (type 1 or type 2) for individuals born in 2000or type 2) for individuals born in 2000– Male = 33% and Female = 39%Male = 33% and Female = 39%

Average reduction in life yearsAverage reduction in life years– Male = 12 yrs, and Female = 19 yrsMale = 12 yrs, and Female = 19 yrs

JAMA 2003 Oct 8;290(14):1884-90

Impaired Glucose Tolerance: (IGT)Impaired Glucose Tolerance: (IGT)– FBS FBS << 7 mmol/l 7 mmol/l– OGTT 7.8-11 mmol/lOGTT 7.8-11 mmol/l

Impaired Fasting Glucose: (IFG)Impaired Fasting Glucose: (IFG)– FBS 6.1-6.9 mmol/lFBS 6.1-6.9 mmol/l

Gestational Diabetes: Gestational Diabetes: – Dx in pregnancy (Type 1 or 2)Dx in pregnancy (Type 1 or 2)

Risk Factors for DM2Risk Factors for DM2

Risk Factors for DM2Risk Factors for DM2

Family HistoryFamily History– No family history of DM1 or 2 No family history of DM1 or 2 older onset older onset

with preserved endogenous insulin secretionwith preserved endogenous insulin secretion

EthnicityEthnicity– Asians, Hispanics, and Blacks (RR 2.26, 1.86, Asians, Hispanics, and Blacks (RR 2.26, 1.86,

and 1.34 respectively) and 1.34 respectively)

Diabetes Care. 2006 Jul;29(7):1585-90.

Risk Factors for DM2Risk Factors for DM2Obesity Obesity – increased risk of IGT or DM2bincreased risk of IGT or DM2b

N Engl J Med 1991; 325:147.

Risk Factors for DM2Risk Factors for DM2

Fat DistributionFat Distribution– degree of insulin resistance and the incidence degree of insulin resistance and the incidence

of type 2 diabetes are highest in those of type 2 diabetes are highest in those subjects with upper body or abdominal subjects with upper body or abdominal obesity (a waist-to-hip circumference ratio obesity (a waist-to-hip circumference ratio that is >0.95 in men and >0.85 in women)that is >0.95 in men and >0.85 in women)

Diabetes Care 1995 Jun;18(6):747-53. Diabetes Care 1994 Sep;17(9):961-9.

© Continuing Medical Implementation ® …...bridging the care gap

Risk Factors for DM2Risk Factors for DM2

Lifestyle FactorsLifestyle Factors– ExerciseExercise– Smoking Smoking

In a meta-analysis of 25 prospective cohort In a meta-analysis of 25 prospective cohort studies, smokers at increased risk of DM2 studies, smokers at increased risk of DM2 compared with nonsmokers with pooled RR 1.4compared with nonsmokers with pooled RR 1.4

JAMA. 2007 Dec 12;298(22):2654-64.

““Fitness Craze”Fitness Craze”

Risk Factors for DM2Risk Factors for DM2

DietaryDietary– western diet high in red meat, processed western diet high in red meat, processed

meat, high fat dairy products, sweets, and meat, high fat dairy products, sweets, and dessertsdesserts

Ann Intern Med 2002 Feb 5;136(3):201-9.

Type 2 Diabetes Prevention Type 2 Diabetes Prevention

What can be done?What can be done?

– Genetics: choose parents carefully!Genetics: choose parents carefully!

– Insulin secretion: unknownInsulin secretion: unknown

– Insulin resistance: lotsInsulin resistance: lots

Primary preventionPrimary prevention

Means the disease never happensMeans the disease never happens

Our context todayOur context today

……this means people do not progress to a this means people do not progress to a fasting glucose over 7.0 mM or a 2 hour pc fasting glucose over 7.0 mM or a 2 hour pc glucose over 11.a mM glucose over 11.a mM

Secondary preventionSecondary prevention

Means the disease is prevented from Means the disease is prevented from becoming worse becoming worse

Our context today….Our context today….

Means retinopathy or elevated creatinine do Means retinopathy or elevated creatinine do not occur (etc) not occur (etc)

Tertiary PreventionTertiary Prevention

Means that disease or complications are Means that disease or complications are prevented from getting worseprevented from getting worse

Our context today…Our context today…this means someone with retinopathy does this means someone with retinopathy does

not become blind; someone with an not become blind; someone with an increase in creatinine does not end up on increase in creatinine does not end up on dialysis (etc) dialysis (etc)

Prevention of Type II diabetesPrevention of Type II diabetes

We will concentrate on We will concentrate on Primary Primary PreventionPrevention this hour this hour

Primary Approaches to PreventionPrimary Approaches to Prevention

Programs targeting:Programs targeting: High-risk individuals (i.e. IGT or obesity)High-risk individuals (i.e. IGT or obesity) High-risk subgroups (i.e. ethnic group)High-risk subgroups (i.e. ethnic group) General population (i.e. exercise and General population (i.e. exercise and

healthy diet)healthy diet)

Evidence for PreventionEvidence for Prevention

An epidemiologic analysis projected that if An epidemiologic analysis projected that if all diabetes could be avoided (Caucasian all diabetes could be avoided (Caucasian males in US) through effective primary males in US) through effective primary preventionprevention– All cause mortality All cause mortality ↓ by 6.2%↓ by 6.2%– Cardiovascular mortality Cardiovascular mortality ↓ by 9.0%↓ by 9.0%

Health Care Manag Sci. 1999;2:223-227.

IFG

6060 9090 120120 150150 180180300-30MinutesFasting

Plasma glucose (mmol/l)

8.3

11.1

IGT

DiabetesFPG 7Normal

FPG <5.5

Diabetes

11.1

Normal<7.8

OGTT

Impaired Fasting Glucose, Impaired Impaired Fasting Glucose, Impaired Glucose Tolerance, and Type 2 DiabetesGlucose Tolerance, and Type 2 Diabetes

Lifestyle DM Prevention Trials:Lifestyle DM Prevention Trials: IGT progression to T2DM IGT progression to T2DM

Da Qing StudyDa Qing Study

Finnish Prevention TrialFinnish Prevention Trial

Diabetes Prevention Trial (DPP)Diabetes Prevention Trial (DPP)

Da Qing StudyDa Qing Study

577 lean + overweight IGT (1986-1992, 577 lean + overweight IGT (1986-1992, China) were randomly assigned to four China) were randomly assigned to four groups; at 6 years, incidence of DM2groups; at 6 years, incidence of DM2

1.1. Control 67.7%Control 67.7%

2.2. Diet Only 43.8%Diet Only 43.8%

3.3. Exercise Only41.1%Exercise Only41.1%

4.4. Diet and Exercise 46.0%Diet and Exercise 46.0%

31% Risk Reduction31% Risk Reduction

Dietary ModificationDietary Modification

Low calorieLow calorieLow fat (<30% energy consumed)Low fat (<30% energy consumed)Low saturated fat (<10% energy consumed)Low saturated fat (<10% energy consumed)High fibre diet (>15g/1000kcal)High fibre diet (>15g/1000kcal)Moderate- intensity physical activity of at Moderate- intensity physical activity of at least 30 minutes/dayleast 30 minutes/day

Resulting in loss of ~5% of initial body wtResulting in loss of ~5% of initial body wt

Finnish Diabetes Prevention Study Finnish Diabetes Prevention Study (DPS)(DPS)

522 middle aged overweight with IGT 522 middle aged overweight with IGT (1993-8, Finland) were randomly (1993-8, Finland) were randomly assigned to one of the following groups:assigned to one of the following groups:

1.1. Intensive lifestyle changesIntensive lifestyle changes 2.2. Placebo Placebo plus information on diet and plus information on diet and

exercise exercise

At 4 yrs, incidence of DM2At 4 yrs, incidence of DM2– 11% in intervention group vs. 23% in control11% in intervention group vs. 23% in control

Risk of DM2 Risk of DM2 ↓ by 58%↓ by 58%N Engl J Med, Vol. 344, No. 18, May 3, 2001

Sustainability of DPSSustainability of DPS

The Lancet; Nov 11-Nov 17, 2006; 368, 9548

Diabetes Prevention Program Diabetes Prevention Program (DPP)(DPP)

3234 obese subjects (1996-9, US) with IFG/ 3234 obese subjects (1996-9, US) with IFG/ IGT were randomly assigned to one of the IGT were randomly assigned to one of the following groups:following groups:

1.1. Intensive lifestyle changesIntensive lifestyle changes with the aim of with the aim of reducing weight by 7 percent through a low-fat diet reducing weight by 7 percent through a low-fat diet and exercise for 150 minutes per week. and exercise for 150 minutes per week.

2.2. Treatment with Treatment with metforminmetformin (850 mg twice daily) plus (850 mg twice daily) plus information on diet and exercise information on diet and exercise

3.3. PlaceboPlacebo plus information on diet and exercise plus information on diet and exercise

N Engl J Med, Vol. 346, No. 6. February 7, 2002

DPP ResultsDPP Results53% of DPP participants had metabolic 53% of DPP participants had metabolic syndrome (ATP III criteria) at baseline. syndrome (ATP III criteria) at baseline. At avg f/u of 3 yrs, % developed DM2At avg f/u of 3 yrs, % developed DM2– Intensive lifestyle group 14%Intensive lifestyle group 14%– Metformin 22%Metformin 22%– Placebo 29%Placebo 29%

At avg f/u of 3 yrs, % At avg f/u of 3 yrs, % developed metabolic developed metabolic syndromesyndrome– Intensive lifestyle 34%Intensive lifestyle 34%– Metformin 45%Metformin 45%– Placebo 51%Placebo 51%

Diabetes Prevention ProgramDiabetes Prevention ProgramProgression to Type 2 DiabetesProgression to Type 2 Diabetes

0

2

4

6

8

10

12

Placebo Metformin IntensiveLifestyle

Cas

es /

100

per

son

-yea

rs

Average follow-up of 2.8 years

31% *

58% *

*All pair-wise comparisons significantly different by group sequential log-rank test

The Diabetes Prevention Program Research Group. New Engl J Med 2002;346:393-403.

Younger Obesesubjects All Groups

Pharmacological PreventionPharmacological Prevention

Diabetes Prevention Program (DPP)Diabetes Prevention Program (DPP)United Kingdom Prospective Diabetes United Kingdom Prospective Diabetes Study (UKPDS)Study (UKPDS)Study to Prevent NIDDM (STOP-NIDDM)Study to Prevent NIDDM (STOP-NIDDM)Xenical in the Prevention of DM2 in Obese Xenical in the Prevention of DM2 in Obese Subjects (XENDOS) Subjects (XENDOS) Diabetes Reduction Assessment with Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication Ramipril and Rosiglitazone Medication (DREAM)(DREAM)

Diabetes Prevention Program Diabetes Prevention Program (DPP)(DPP)

Metformin (850mg BID) arm for an Metformin (850mg BID) arm for an average of 2.8yrs significantly decreased average of 2.8yrs significantly decreased progression to DM2 by 31% progression to DM2 by 31%

No significant effects in older age (>60y/o) No significant effects in older age (>60y/o) and less obese (BMI<35) subjectsand less obese (BMI<35) subjects

United Kingdom Prospective United Kingdom Prospective Diabetes Study (UKPDS)Diabetes Study (UKPDS)

Metformin Metformin

may reduce diabetes-related end points. may reduce diabetes-related end points. – sudden death, hypo- or hyperglycemia sudden death, hypo- or hyperglycemia

causing death, MI, angina, heart failure, causing death, MI, angina, heart failure, stroke, renal failure, amputation, retinopathy, stroke, renal failure, amputation, retinopathy, monocular blindness or cataract extraction, monocular blindness or cataract extraction, and all cause mortalityand all cause mortality

Study to Prevent NIDDM (STOP-Study to Prevent NIDDM (STOP-NIDDM)NIDDM)

1429 subjects with IGT 1429 subjects with IGT Acarbose 100mg TID with avg f/u 3.3yrsAcarbose 100mg TID with avg f/u 3.3yrsOverall 25% reduction with 1 OGGT, 36% Overall 25% reduction with 1 OGGT, 36% reduction with 2 OGGT (not affected by age or reduction with 2 OGGT (not affected by age or BMI)BMI)However, when drug was discontinued, effect However, when drug was discontinued, effect did not persistdid not persist

49% reduction in CV events, 50% reduction in 49% reduction in CV events, 50% reduction in progression of carotid intima-media thicknessprogression of carotid intima-media thickness

Xenical in the Prevention of DM2 in Xenical in the Prevention of DM2 in Obese Subjects (XENDOS)Obese Subjects (XENDOS)

Effect of orlistat in combination with an intensive Effect of orlistat in combination with an intensive lifestyle modification programlifestyle modification program

3305 obese individuals with or w/o IGT (4 yrs)3305 obese individuals with or w/o IGT (4 yrs)– Orlistat 120mg TIDOrlistat 120mg TID– Placebo TIDPlacebo TID

37% reduction37% reduction

BUT, high dropout rates (48%, 66%) and last BUT, high dropout rates (48%, 66%) and last observation carried forward was used for observation carried forward was used for analysisanalysis

Diabetes Care; Jan 2004; 27, 1.

Diabetes Reduction Assessment Diabetes Reduction Assessment with Ramipril and Rosiglitazone with Ramipril and Rosiglitazone

Medication (DREAM)Medication (DREAM)5269 IGT and/or IFG randomized to following groups:5269 IGT and/or IFG randomized to following groups:– Rosiglitazone 8 mg OD (3 yr) Rosiglitazone 8 mg OD (3 yr) – ControlControl

RosiglitazoneRosiglitazone ↓ ↓ incidence of DM2 by 60%, incidence of DM2 by 60%, but but whether effect persists after drug withdrawal is whether effect persists after drug withdrawal is unknown.unknown.No strong evidence that TZDs reduce CVD endpoints, No strong evidence that TZDs reduce CVD endpoints, and in particular there are no data on such risk and in particular there are no data on such risk reduction for people with metabolic syndrome. reduction for people with metabolic syndrome. Rosiglitazone may even be associated with an Rosiglitazone may even be associated with an increased incidence of myocardial infarction. increased incidence of myocardial infarction.

The Lancet; Sep 23-Sep 29, 2006; 368, 9541;N Engl J Med 2006;355:1551-62.

•Ramipril 15mg ODRamipril 15mg OD•Results suggest effect of Results suggest effect of ramiprilramipril on glucose metabolism, on glucose metabolism, but use for preventing DM2 is but use for preventing DM2 is not indicatednot indicated

Completed Diabetes Prevention TrialsCompleted Diabetes Prevention Trialsin Type 2 Diabetesin Type 2 Diabetes

Treatment Relative Treatment Relative RiskRisk

Finnish Diabetes Finnish Diabetes Intensive D&E vs ControlIntensive D&E vs Control 58% 58% Prevention StudyPrevention Study

DiabetesDiabetes Intensive D&E vs PlaceboIntensive D&E vs Placebo 58% 58% Prevention Prevention Metformin vs PlaceboMetformin vs Placebo 31% 31% Program Program Troglitazone vs Placebo*Troglitazone vs Placebo* 75% 75%

STOP-NIDDMSTOP-NIDDM Acarbose vs PlaceboAcarbose vs Placebo 25% 25%

TRIPODTRIPOD TZD vs Placebo in GDMTZD vs Placebo in GDM 56% 56%

DREAMDREAM TZD vs PlaceboTZD vs Placebo 60% 60%

Trial

* Troglitazone vs placebo discontinued after 10 months. Data collected after the 1st year of the study.

Elliott Lancet 2007; 369: 201–07

Can we prevent or delay diabetes?

Key MessagesKey Messages

Intensive and structured lifestyle Intensive and structured lifestyle modification (modification (↓↓5% of initial body weight) 5% of initial body weight) can reduce the risk of progression from can reduce the risk of progression from impaired glucose tolerance to type 2 by impaired glucose tolerance to type 2 by ~60%~60%Progression from prediabetes to DM2 can Progression from prediabetes to DM2 can also be reduced by pharmacologic therapy also be reduced by pharmacologic therapy with metformin (~30% reduction), with metformin (~30% reduction), acarbose (~30% reduction) and TXD acarbose (~30% reduction) and TXD (~60% reduction)(~60% reduction)

CDA RecommendationsCDA Recommendations

A structured program of lifestyle A structured program of lifestyle modification that includes moderate weight modification that includes moderate weight loss and regular physical activity should be loss and regular physical activity should be implemented to reduce progression to implemented to reduce progression to DM2DM2

In IGT, metformin or acarbose should be In IGT, metformin or acarbose should be consideredconsidered

In IGT and/or IFG and no know CVD, TZD In IGT and/or IFG and no know CVD, TZD could be considered to reduce risk of could be considered to reduce risk of developing DM2developing DM2