1

Prediabetes

Management

2

AACE Prediabetes Consensus Statement: Summary

• Untreated individuals with prediabetes are at increased risk for diabetes as well as for micro- and macrovascular complications

• Treatment goals are to prevent deterioration in glucose levels and modify other risk factors such as obesity, hypertension, and dyslipidemia – The same blood pressure and lipid goals are suggested for

prediabetes and diabetes

• Intensive lifestyle management is the cornerstone of all prevention efforts; pharmacotherapy targeted at glucose may be considered in high-risk patients

Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):1-53. Garber AJ, et al. Endocr Pract. 2008;14:933-946.

3

Prediabetes

• Epidemiologic evidence suggests that the complications of T2DM begin early in the progression from NGT to frank diabetes

• Prediabetes and diabetes are conditions in which early detection is appropriate, because– Duration of hyperglycemia is a predictor of adverse

outcomes– There are effective interventions to prevent disease

progression and to reduce complications

NGT, normal glucose tolerance ; T2DM , type 2 diabetes mellitus.Garber AJ, et al. Endocr Pract. 2008;14:933-946.

4

Policy Paradigm Shifts Needed to Stem Global Tide of T2DM

• Integrating primary and secondary prevention along a clinical continuum

• Early detection of prediabetes and undiagnosed diabetes

• Implementing cost-effective prevention and control by integrating community and clinical expertise/resources within affordable service delivery systems

• Sharing and adopting evidence-based policies at the global level

T2DM , type 2 diabetes mellitus.Narayan KM, et al. Health Aff (Millwood). 2012;31:84-92.

5

6

• There is a long period of glucose intolerance that

precedes the development of diabetes• Screening tests can identify persons at high risk • There are safe, potentially effective interventions

that can address modifiable risk factors: – Obesity– Body fat distribution – Physical inactivity– High blood glucose

T2DM, type 2 diabetes mellitus.Garber AJ, et al. Endocr Pract. 2008;14:933-946.

Feasibility of Preventing T2DM

7

Interventions to Reduce Risks Associated With Prediabetes

• Therapeutic lifestyle management is the cornerstone of all prevention efforts

• No pharmacologic agents are currently approved for the management of prediabetes– Pharmacotherapy targeted at glucose may be

considered in high-risk patients after individual risk-benefit analysis

Garber AJ, et al. Endocr Pract. 2008;14:933-946.

8

Lifestyle Intervention in Prediabetes

Persons with prediabetes should reduce weight by 5% to 10%, with long-term maintenance at this

level

A diet that includes caloric restriction, increased fiber intake, and (in some cases) carbohydrate

intake limitations is advised.

• A program of regular moderate-intensity physical activity for 30-60 minutes daily, at least 5 days a week, is recommended

Garber AJ, et al. Endocr Pract. 2008;14:933-946.

9

Primary Care-Based Counseling for T2DM Prevention: ADAPT

ADAPT, Avoiding Diabetes Thru Action Plan Targeting; T2DM , type 2 diabetes mellitus.

Mann DM, Lin JJ. Implement Sci. 2012;23:6.

10

Self-Reported Risk Reduction Activities in Patients With Prediabetes

0%20%40%60%80%

100%68% 60% 55%

42%

CDC. MMWR Morb Mortal Wkly Rep. 2008;57:1203-1205.

National Health and Nutrition Examination Survey

Pat

ien

ts

11

PREVENTION OF DIABETES: LIFESTYLE STUDIES

Prediabetes Management

12

Study Country N

Baseline BMI

(kg/m2)

Intervention period(years)

RRR(%) NNT

Diabetes Prevention Program

USA 3234 34.0 2.8 58 21

Diabetes Prevention

StudyFinland 523 31 4 39 22

Da Qing China 577 25.8 6 51 30

BMI, body mass index; NNT, number needed to treat; RRR, relative risk reduction; T2DM, type 2 diabetes mellitus.

DPP Research Group. N Engl J Med. 2002;346:393-403. Eriksson J, et al. Diabetologia. 1999;42:793-801.Li G, et al. Lancet. 2008;371:1783-1789. Lindstrom J, et al. Lancet. 2006;368:1673-1679.

Prevention of T2DM: Selected Lifestyle Modification Trials

13

Series10

2

4

6

8

10

12

4.8

7.8

11

T2DM Incidence in theDiabetes Prevention Program

Intensive lifestyle intervention*

(n=1079)

T2D

M i

nci

de

nce

per

10

0 p

erso

n-y

ear

s

Placebo(n=1082)

Metformin850mg BID(n=1073)

58%

31%

*Goal: 7% reduction in baseline body weight through low-calorie, low-fat diet and ≥150 min/week moderate intensity exercise.

IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.

DPP Research Group. N Engl J Med. 2002;346:393-403.

14

25-44 45-59 ≥600

2

4

6

8

10

12

14

11.610.8 10.8

6.77.6

9.6

6.2

4.7

3.1

PlaceboMetforminLifestyle

Effect of Age on Incidence of T2DM in the DPPT

2DM

in

cid

en

ce

per

10

0 p

erso

n-y

ear

s

48%59%

Age (years)

71%

*Goal: 7% reduction in baseline body weight through low-calorie, low-fat dietand ≥150 min/week moderate intensity exercise.

DPP, Diabetes Prevention Program;.

DPP Research Group. N Engl J Med. 2002;346:393-403.

15

22 to <30 30 to <35 ≥350

2

4

6

8

10

12

14

16

9 8.9

14.3

8.87.6 7.0

3.3 3.7

7.3PlaceboMetforminLifestyle

Effect of Weight on T2DM Incidence in the DPP

T2D

M i

nci

de

nce

per

10

0 p

erso

n-y

ear

s

65%

BMI (kg/m2)

51%

61%

*Goal: 7% reduction in baseline body weight through low-calorie, low-fat dietand ≥150 min/week moderate intensity exercise.

DPP, Diabetes Prevention Program.

DPP Research Group. N Engl J Med. 2002;346:393-403.

16

10-Year Weight Loss inthe DPP Outcomes Study

DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.DPP Research Group. Lancet. 2009;374:1677-1686.

10 32 54 76 8 109

Years

17DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.

DPP Research Group. Lancet. 2009;374:1677-1686.

10 32 54 76 8 109

PlaceboMetforminLifestyle

Years

10-Year Incidence of T2DM in the DPP Outcomes Study

18DPP, Diabetes Prevention Program; DPPOS, Diabetes Prevention

Program Outcomes Study; T2DM, type 2 diabetes mellitus.

DPP Research Group. Lancet. 2009;374:1677-1686.

10-Year Incidence of T2DM in the DPP Outcomes Study

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T2DM Prevention in Women With a History of GDM:

Effect of Metformin and Lifestyle Interventions

• Findings from the DPP:– Progression to diabetes is more common in

women with a history of GDM vs those without, despite equivalent degrees of IGT at baseline

• Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM

DPP, Diabetes Prevention Program; GDM, gestational diabetes mellitus;IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.

Ratner RE, et al. J Clin Endocrinol Metab. 2008;93:4774-4779.

20

T2DM Prevention in Women With a History of GDM:

Effect of Metformin and Lifestyle Interventions

• Findings from the DPP:– Progression to diabetes is more common in

women with a history of GDM vs those without, despite equivalent degrees of IGT at baseline

• Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM

DPP, Diabetes Prevention Program; GDM, gestational diabetes mellitus;IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.

Ratner RE, et al. J Clin Endocrinol Metab. 2008;93:4774-4779.

21

The Finnish Diabetes PreventionStudy: Lifestyle Modifications

DBP, diastolic blood pressure; SBP, systolic blood pressure.

Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.

Ch

ang

e f

rom

bas

elin

e

Weight (kg) Waist (cm) SBP (mm Hg) DBP (mm Hg)

-6

-5

-4

-3

-2

-1

0

Control (n=250) Diet intervention (n=256)

P<0.001 P<0.001P=0.007 P=0.02

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The Finnish Diabetes Prevention Study: Lifestyle Modifications

FPG 2-h PG Fasting insulin 2-h insulin-40

-30

-20

-10

0

10

Control (n=250) Diet intervention (n=256)

Ch

ang

e f

rom

bas

elin

e

P<0.001

P=0.003

P=0.001

(mg/dL) (mg/dL) (mg/mL) (g/mL)

DBP, diastolic blood pressure; SBP, systolic blood pressure.

Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.

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The Finnish Diabetes Prevention Study: Cumulative Incidence of Diabetes Over 4 Years

0

20

40

60

80 78

32

Control (n=250) Diet intervention (n=256)

Inci

den

ce

of

dia

bet

es(c

ases

/100

0 p

ers

on

-yea

rs)

DBP, diastolic blood pressure; SBP, systolic blood pressure.

Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.

58%

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Da Qing: Cumulative Incidence of Diabetes at 6-Year Evaluation

Pat

ien

ts w

ith

T2D

M a

t Y

ear

6 (%

)

IGT, impaired glucose tolerance.

Pan XR, et al. Diabetes Care. 1997;20:537-544.

Control Diet Exercise Diet + Exercise0

10

20

30

40

50

60

70

80

90

100

65.9

47.1 44.2 44.6

60

38.2

26.3

34.8

72.3

48 51.2 52.5

Total Lean Overweight

Patients with IGT (N=577)

25CI, confidence interval; DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.

Li G, et al. Lancet. 2008;371:1783-1789.

Cumulative T2DM Incidence During Follow-up in the Chinese Da Qing

Diabetes Prevention Study

26

Group Lifestyle Balance Program Intervention

• DPP lifestyle intervention was adapted to a 12-session group-based program

• Implemented in a community setting in 2 phases using a nonrandomized prospective design

• Significant decreases in weight, waist circumference, and BMI were noted in both phases vs baseline

• Average combined weight loss for both groups over the 3-month intervention was 7.4 pounds (3.5% relative loss, P<0.001)

University of Pittsburgh Primary Care Practice and Diabetes Prevention Support Center  

Phase 1 Post(n=51)

Phase 2 Post(n=42)

CompletersBoth phases

(n=67)

Phase 2 6 mo

Phase 2 12 mo

0

10

20

30

40

50

60

70

Weight Loss Achieved

Weight Loss > 3.5% Weight Loss > 5% Weight Loss >7%

Pe

rce

nt

DPP, Diabetes Prevention Program; mo, month.Kramer MK, et al. Am J Prev Med. 2009;37:505-511.

27

-25

-20

-15

-10

-5

0

5

10

15

6

-21.6

11.8

-13.5

Standard (4-6 months) DPP (4-6 months)Standard (12-14 months) DPP (12-14 months)

T

ota

l C

ho

lest

ero

l (%

)

• Pilot, cluster-randomized trial

• Group-based DPP lifestyle intervention vs brief counseling alone (control) among high-risk adults who attended a diabetes risk-screening event at one of two semi-urban YMCA facilities

DEPLOY, Diabetes Education & Prevention with a Lifestyle Intervention Offered at the YMCA; DPP, Diabetes Prevention Program; YMCA, Young Men’s Christian Association.

Ackermann RT, et al. Am J Prev Med. 2008;35:357-363.

Translating the DPP Into Community Intervention

The DEPLOY Pilot Study

P<0.001

P=0.002

28

Mean weight and physical activity min/week among participants by lifestyle intervention session

CVD, cardiovascular disease; DPP, Diabetes Prevention Program.Amundson HA, et al. Diabetes Educ. 2009;35:209-223.

Montana CVD and DPP

29

Translation of the DPP’s Lifestyle Intervention

• Four additional studies utilizing the DPP lifestyle interventions in community settings provided the following findings:– Promising evidence of the prevention of diabetes by

significantly decreasing glucose levels and adiposity– Statistically significant improvements in many behavioral

outcomes and anthropometrics, particularly at 6 months – Decreased fasting glucose and weight in at-risk African

Americans– Approaches that improve recruitment of participants from

underserved communities into research, especially research related to chronic disease risk factors

DPP, Diabetes Prevention Program.Boltri JM, et al. J Natl Med Assoc. 2011;103:194-202.Katula JA, et al. Diabetes Care. 2011;34:1451-1457. Ruggiero L, et al. Diabetes Educ. 2011;37:564-572.

Santoyo-Olsson J, et al. Gerontologist. 2011;51(Suppl 1):S82-93.

30

PREVENTION OF DIABETES: PHARMACOTHERAPY STUDIES

Prediabetes Management

31

Pharmacologic Interventions Proven to Delay or Prevent T2DM Development

T2DM, type 2 diabetes mellitus.Sherwin RS, et al. Diabetes Care. 2004;27,(Suppl 1): S47-S54.

Eriksson K-F, Lindgärde F. Diabetologia. 1991;34:891-898.Ramachandran A, et al. Diabetologia 2006;49:289-297.

Knowler WC, et al. N Engl J Med. 2002;346:393-403.Defronzo RA, et al. N Engl J Med. 2011;364:1104-15.

InterventionRate of Conversion to

Normal Glucose Tolerance

Metformin (2 trials) 26%-31%

Acarbose (1 trial) 25%

Pioglitazone (1 trial) 48%

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The Chinese Prevention Study

Series10

2

4

6

8

10

12

14

11.6

4.1

Inci

den

ce

of

Dia

bet

es (

%/y

r)

Control Metformin

The Effect of Metformin on the Progressionof IGT to Diabetes Mellitus (N=321)

IGT, impaired glucose tolerance; RRR, relative risk reduction.

Yang W, et al. Chin J Endocrinol Metab. 2001;17:131-136.

65%

33

Series10

10

20

30

40

50

6055.0

Effect of Lifestyle Modification and Metformin on Cumulative Diabetes Incidence

The Indian DPP (N=531)

n=136 n=133

Inci

den

ce (

%)

RRR (%)

Control LSM MET LSM & MET

28.5P=0.018

26.4P=0.029

28.2P=0.022

n=133 n=129

DPP, Diabetes Prevention Program; LSM, lifestyle modification; MET, metformin; RRR, relative risk reduction.

Ramachandran A, et al. Diabetologia 2006;49:289-297.

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Effect of Acarbose on Reversion of IGT to NGT

P<0.0001

Placebo Acarbose

Nu

mb

er

of

Pa

tien

ts

200

210

220

230

240

250

n=241(35.3%)

n=212(30.9%)

IGT, impaired glucose tolerance; NGT, normal glucose tolerance.Chiasson JL, et al. Lancet. 2002;359:2072-2077.

The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM)

35

DREAM: Rosiglitazone and New-Onset Diabetes or Death

DREAM Trial Investigators. Lancet. 2006;368:1096-1105.

No. at riskPlaceboRosiglitazone

26342635

24702538

21502414

11481310

177217

0.6

0.5

0 1 2 3 4

Follow-up (years)

0.4

0.3

0.2

0.1

0.0

Placebo

Cu

mu

lati

ve

haz

ard

ra

te

Rosiglitazone

60%

36

Pioglitazone for T2DM Prevention in IGT: ACT NOW

ACT NOW, Actos NOW for the Prevention of Diabetes; IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus.

Defronzo RA, et al. N Engl J Med. 2011;364:1104-1115.

Kaplan–Meier plot of hazard ratios for time to development of T2DM

37

Garber AJ, et al. Endocr Pract. 2008;14:933-946.

Special Concerns for Thiazolidinedione Use in Patients

With Prediabetes

• Because of concerns about long-term safety, use of thiazolidinediones should be reserved for higher risk populations and those failing other, lower-risk strategies

38

Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance

in Obese Patients With and Without Prediabetes

• Patients – N=152, weight 108.6 +/- 23.0 kg, BMI 39.6 +/- 7.0 kg/m2

(IGT or IFG 25%)

• Design– 24-week randomized controlled trial: exenatide or placebo

plus lifestyle intervention

• Results: – Exenatide-treated patients lost 5.1 kg from baseline vs 1.6 kg with

placebo (P<0.001) – Both groups reduced their daily caloric intake – IGT or IFG normalized at end point in 77% and 56% of exenatide

and placebo subjects, respectively

BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.Rosenstock J, et al. Diabetes Care. 2010;33:1173-1175.

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Medical Weight-Loss Strategies

• Orlistat may prevent progression from prediabetes to diabetes• Lorcaserin, a selective serotonin 2C agonist, is indicated for use

in obese patients with at least 1 weight-related comorbid condition (eg, hypertension, dyslipidemia, CVD, glucose intolerance, sleep apnea)

• Low-dose, immediate-release phentermine and controlled-release topiramate is recommended for obese or overweight patients with weight-related comorbidities such as hypertension, T2DM, dyslipidemia, or central adiposity

CVD, cardiovascular disease; obese, BMI ≥30 kg/m2; overweight, BMI ≥27 kg/m2; T2DM, type 2 diabetes mellitus.

Garber AJ, et al. Endocr Pract. 2008;14:933-946.

40

Pharmacologic Weight-Loss Strategies

Drug name

Placebo-subtracted

mean % body weight loss

from baseline

Patients (N) in clinical

program/ patients (n) with

diabetes

% of patients losing ≥5% of body weight

Clinical trial withdrawal

rates

Orlistat

2.4% (following 4 years of

treatment with orlistat 120 mg

TID)

7504/321

35.5%-54.8% (following 1 year of treatment with orlistat 120 mg

TID)

8.8%

Lorcaserin3.3% at 52

weeks6888/510 47.1% 36%-50%

Phentermine/ topiramate)  

3.5%-6.4% 3678/808 45%-70% 31%-40%

LOCF, last observation carried forward.Orlistat [package insert]. South San Francisco CA; Genentech USA; 2010.

Belviq [package insert]. Woodcliff Lake, NJ; Eisai Inc.; 2012.Qsymia [package insert]. Mountain View, CA; VIVUS , Inc; 2012.

41

Phentermine/Topiramate and Prevention of Type 2 Diabetes

Garvey TW, et al. Diabetes Care. 2014;37:912-921.

Prediabetes Metabolic syndrome0

1

2

3

4

5

6

7

3.5

6.4

1.81.5

0.4

1.3

Placebo Phen/TPM 7.5/46 Phen/TPM 15/92

An

nu

aliz

ed i

nc

iden

ce

of

T2D

M

88.6%

48.6% 79.7%76.6%