PREVENTION OF TYPE 2 DIABETES

DR JAVAID IQBAL FCPS ASSISTANT PROFESSOR MEDICINE FMH CM AND

DCONSULTANT DIABETOLOGISTDIABETIC INSTITUTE PAKISTAN

Discussion with Family Physicians At UHS on

Diabetes

case1A 49 YEAR OLD FEMALE HAS BEEN REFERRED

TO YOU BY DENTIST FOR ADVICE WITH FOLLOWING LAB REPORTS

FASTING BSR 119HBA1C 6.3% HER MOTHER IS DIABETIC PHYSICAL

EXAMINATION REMARKABLE FOR WEIGHT 160 LB HEIGHT 5-3

BP 135/89 AND NECK EXAM. SHOWED BELOW

Neck exam

Questions ?Is she diabetic or normal?

What will be her long ter management ?What additional pathology she has?

AN APPROACH TO SUCH SCENARIOS

Can you guess normal values of fasting Random and HA1c?

NORMAL VALUES OF BLOOD SUGAR

Fasting plasma glucose (FPG) <100 mg/dL (5.6 mmol/L).

Two-hour glucose during OGTT <140 mg/dL (7.8 mmol/L).

Normal HbA1c Less than 5.7%

WHAT ARE VALUES OF BSR BSF AND HBA1c IN DIABETICS?

ADA Criteria for the Diagnosis of Diabetes

A1C ≥6.5%OR

Fasting plasma glucose (FPG)≥126 mg/dl (7.0 mmol/l)

OR

Two-hour plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT

OR

A random plasma glucose ≥200 mg/dl (11.1 mmol/l) in the presence of

symptoms

What is state of this patient?

She is ----------------

Fasting

Diabetes >126 mg/dL

Normal 70-99 mg/dL

Impaired fasting glucose

100-125 mg/dL

Diabetes >200 mg/dL

Normal <140 mg/dL

Impaired glucosetolerance

140-199 mg/dL

OGTT

ADA Standards of Care. Diabetes Care, Suppl.1, 2010; ADA , EASD, IDF International

Expert Committee Report on HbA1c for Diagnosis of Diabetes.

Pre-diabetes(54 million)

Diabetes >6.5%

Normal <5.7.0%

High risk for diabetes 5.7-6.4%

HbA1c

New

Who will be labelled as PREDIABETIC?

Prediabetes: IFG, IGT, Increased A1C

Fasting plasma glucose between 100 and 125 mg/dL (5.6 to 6.9 mmol/L).

Impaired glucose tolerance (IGT) Two-hour plasma glucose value during a 75 g oral glucose tolerance test between 140 and 199 mg/dL (7.8 to 11.0 mmol/L).

A1C Persons with 5.7 to 6.4 percent

Will you manage this patient Actively?

Can we make her normoglycemic?

Can we delay onset of TYPE 2 Diabetes?

WHY IS IT IMPORTANT TO MANAGE PREDIABETICS ?

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.

What clinical risks ensue if prediabetes is not treated

In the large DECODE Study, risks for all-cause mortality increased linearly as the 2-hour blood glucose level increased from 95 to 200 mg/dL.

In the Diabetes Prevention Program, approximately 8% of patients with impaired glucose tolerance had diabetic retinopathy as did nearly 13% of those whose condition progressed to diabetes.

The STOP NIDDM trial showed an increase in hypertension (> 140/90 mm Hg) in the placebo-treated patients with impaired glucose tolerance during a 3-year period, with an increase in clinical cardiovascular disease (CVD) events by approximately 5% during 4 years.

The Honolulu Heart Study showed that postchallenge hyperglycemia was associated with an increase in sudden death during a 23-year follow-up.

Road Map to Prevent Type 2 Diabetes

EarlyIdentification

Therapeutic Lifestyle

Management Pharmacologic

PersistentMonitoring ofGlucose and

Risk ReductionMeasures

Intervention

Age 30 or above for populations at high risk:

FPG or 2-h OGTT is therecommended screening procedure

•Medical nutritiontherapy (MNT)

•Physical fitnessProgram

•Weight loss

• 5%-7% reduction in bodyweight (if overweight)

• 30 minutes exercise, 5 times per week at the equivalence of brisk walking

Non-FDA approved*• TZD**• Metformin• Orlistat• AGI

* Shown to be effective in delaying theonset of type 2 diabetes in clinical studies

** A recent report (NEJM; 6/14/07) suggestsa possible link of rosiglitazone tocardiovascular events that requires furtherevaluation

• Hypertension• Dyslipidemia• Physical fitness• Weight control

• Family history of diabetes• Cardiovascular disease• Overweight• Sedentary lifestyle• Latino/Hispanic, African

American, Asian American,Native American, or Pacific Islander

• Previously identified IGTor IFG

• Hypertension• Elevated triglycerides,

low HDL, or both• History of gestational

diabetes• Delivery of a baby weighing

>9 lbs• Severe psychiatric illness

WHO SHOULD BE SCREENED AFTER AGE OF 30Family history of diabetesCardiovascular diseaseOverweightSedentary lifestyleLatino/Hispanic, AfricanAmerican, Asian American,Native American, or Pacific Islander

Previously identified IGTor IFG

HypertensionElevated triglycerides,low HDL, or both

History of gestationaldiabetes

Delivery of a baby weighing>9 lbs

Severe psychiatric ill

2-Track Approach to Reduce Risk Associated With Prediabetes

• Therapeutic lifestyle management

• Pharmacotherapy in high-risk patients

(1) Lower glucose to

prevent microvascular complications

and progression to diabetes

• Therapeutic lifestyle management

• Blood pressure goals: <130/80 mm Hg

• LDL goal: <100 mg/dL

(2) Address cardiovascular

disease risk factors

.

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:

I. ObesityII. Body fat distribution III. Physical inactivityIV. High blood glucose

Feasibility of Preventing T2DM

Interventions to Reduce Risks Associated With PrediabetesTherapeutic lifestyle management is the

cornerstone of all prevention effortsNo 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.

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.

Self-Reported Risk Reduction Activities in Patients With Prediabetes (National Health and Nutrition Examination Survey Data)

0%20%40%60%80% 68% 60% 55%

42%

Percent of Patients

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

Interventions Proven to Delay or Prevent T2DM Development

Intervention

Rate of Conversion to

Normal Glucose Tolerance

Lifestyle (3 trials) 52%-58%Metformin (2 trials) 26%-31%Acarbose (1 trial) 25%Pioglitazone (1 trial) 48%

.

Prevention of T2DM: Lifestyle Modification Trials

Study N BMIkg/m2

Time(years)

RRR% ARR % NNT

Diabetes

Prevention

Study

523 31.0 3 58 12 22

, Diabete

s Prevent

ion Progra

m

2161 34.0 3 58 15 21

The Chinese Prevention Study

Series10

2

4

6

8

10

12

14

11.6

4.1

Inci

den

ce o

f D

iab

etes

(%

/yr)

RRR=65%

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.

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.

Effect of Acarbose on Reversion of IGT to NGT

200

210

220

230

240

250

P<0.0001

Placebo Acarbose

Nu

mb

er

of

Pa

tien

ts

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)

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.

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

Medical Weight-Loss StrategiesOrlistat may prevent progression from

prediabetes to diabetesLorcaserin, 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)

QYSMIA 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.

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%

Lorcaserin 3.3% at 52 weeks 6888/510 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.

BLOOD PRESSURE MANAGEMENT

DPP Year 1: Mean Change in Blood Pressure

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

-3.4

-0.91 -0.9

Lifestyle Metformin Placebo

-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

-3.6

-1.3

-0.89

Lifestyle Metformin Placebo

Ch

ang

e in

BP

(mm

Hg

)

Baseline BP 124 124 124 79 78 78

Systolic Diastolic

BP, blood pressure; DPP, Diabetes Prevention Program.Ratner R, et al. Diabetes Care. 2005;28:888.

Placebo Metformin Lifestyle0

5

10

15

20

25

30

35

40

Baseline

12 months

24 months

36 months

Pr e

vale

nce

of H

yper

ten

sio

n(%

of p

atie

nts

)

*

Effects of Metformin, Lifestyle Modifications, and Placebo on Hypertension Over 36 Months in DPP

P<0.001

P=0.08 P<0.001

DPP, Diabetes Prevention Program; HTN, hypertension.Ratner R, et al. Diabetes Care. 2005;28:888-894.

Hypertension defined as BP 140/90 mmHg

Cu

mu

lat i

ve I n

cid

ence

(%

)

0 4321 5

Years After Randomization

8

6

4

2

0

12

10

18

16

14

Acarbose

Placebo

RRR = 34% P=0.0059

BP, blood pressure; IGT, impaired glucose tolerance; STOP NIDDM, Study to Prevent Non-Insulin Dependent Diabetes Mellitus Trial

Chiasson JL, et al. JAMA. 2003;290:486-494.

STOP NIDDM: Incidence of New Cases of Hypertension in IGT Patients

DPP Study: Mean Change in Total and LDL Cholesterol

DPP, Diabetes Prevention Program; LDL-C, low-density lipoprotein.DPP Research Group. Diabetes Care. 2005;28:2472–2479.

Ratner R, et al. Diabetes Care. 2005;28:888-894.

-2.5

-2

-1.5

-1

-0.5

0

-2.3

-0.9

-1.2

Lifestyle Metformin Placebo

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-0.700000000

000001

-0.3

-1.3

Lifestyle Metformin Placebo

Ch

ang

e in

Lip

ids

(%)

Baseline (mg/dL) 202 127

Total Cholesterol LDL-C

DPP Study: Mean Change in Triglycerides and HDL Cholesterol

DPP, Diabetes Prevention Program.DPP Research Group. Diabetes Care. 2005;28:2472–2479.

Ratner R, et al. Diabetes Care. 2005;28:888-894.

-30

-25

-20

-15

-10

-5

0

-25.4

-7.4

-11.9

Lifestyle Metformin Placebo

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1

0.3

-0.1

Lifestyle Metformin Placebo

Ch

ang

e in

Lip

ids

(mg

/dL

)

Baseline (mg/dL) 172 40

Triglycerides HDL-C

SUMMARY

Diabetes Prevention ProgramScreened 158,177

OGTT, then randomize

Metformin1073

Lifestyle1079

3819 randomized

Placebo1082

Thiazolidinedione585

3% Wt loss5% Wt loss ~10 month followup

31% Risk Reduction

58 %Risk Reduction

Diabetes Rate11 % per year

23 %Risk Reduction

Diabetes Prevention Program Research Diabetes Prevention Program Research GpGp, , NEJM NEJM 346(6): 393346(6): 393--403, 2002.403, 2002.

SUMMARY SLIDESStudy Highlights Individuals with prediabetes have glucose levels lower

than those with diabetes but higher than normal (fasting glucose level, 100 - 125 mg/dL; 2-hour levels, 140 - 199 mg/dL).

Prediabetes may be associated with, or may increase the risk for, cardiovascular disease and microvascular complications, and it may lead to the development of overt type 2 diabetes.

All patients with prediabetes should have intensive lifestyle management, which is safe and effective in improving glycemia and in decreasing cardiovascular risk.

Treatment goals for blood pressure and lipid control should match those for diabetes.

INTERVENTIONIndividuals with prediabetes should lose 5% to 10% of body weight and maintain it long term.

Regular, moderate-intensity physical activity is recommended for 30 to 60 minutes daily at least 5 days weekly.

Diet should be low in total fat, saturated fat, and trans-fatty acids and should include adequate dietary fiber.

SUMMARY For blood pressure control, lower sodium intake and

avoidance of excess alcohol are recommended. No drugs are currently FDA approved for prediabetes,

so decisions to start pharmacotherapy must be based on a risk-benefit analysis.

For persons with prediabetes at particularly high risk, pharmacologic glycemic treatment may be considered in addition to lifestyle changes.

Metformin and acarbose are safe and effective in helping prevent diabetes.

Although thiazolidinediones decrease the risk for progression from prediabetes to diabetes, safety concerns include congestive heart failure or fractures

Hypertension in prediabeticsAngiotensin-converting enzyme

inhibitors or angiotensin receptor blockers are recommended as first-line agents and calcium channel blockers as second-line treatment of hypertension.

Thiazides and/or β-blockers should be used with caution because of adverse effects on glycemia.

All persons with prediabetes who are not at increased risk for gastrointestinal tract, intracranial, or other bleeding should take aspirin. 

TARGETS LDL AND BP . Statins are recommended if needed to

achieve treatment goals for low-density lipoprotein cholesterol levels (100 mg/dL), nonhigh-density lipoprotein cholesterol levels (130 mg/dL), and apolipoprotein B (90 mg/dL).

Patients with prediabetes should have the same target blood pressure as do persons with diabetes (systolic < 130 mg Hg; diastolic 80 mm Hg)

Monitoring Highest-risk patients should be

monitored more often.The costs of prediabetes management

may be offset by cost savings from reduced patient-years of the disease, complications, and hospitalizations.

Monitoring for patients with prediabetes should include an annual glucose tolerance test and twice-yearly testing for microalbuminuria and fasting plasma glucose, hemoglobin A1C, and lipid levels.

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