P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N

(Pre) diabetes & sustained glycemic control: How and what is the time to act?

Dr Stanley S Schwartz, MDUniversity of PennsylvaniaPhiladelphia, USA

Cardio Diabetes Master ClassAsian chapterJanuary 28-30 2011, Shanghai

Slide lecture prepared and held by:

Presentation topic

Natural History of Type 2 Diabetes

IR phenotypeAtherosclerosisobesityhypertensionHDL,TG,HYPERINSULINEMIAEndothelial dysfunctionPCO,ED

Envir.+ Other Disease

Obesity (visceral)Poor Diet Inactivity

Insulin Resistance

Risk of Dev. Complications

ETOHBPSmoking

EyeNerveKidney

Beta Cell Secretion

Genes

BlindnessAmputationCRF

Disability

Disability

MICVAAmp

Age 0-15 15-40+ 15-50+25-70+

Macrovascular Complications

IGT/IFG Type II DM

Microvascular Complications

DEATHFBS>5.5,ppg>7.8

Type 2 Diabetes: Two Principal Defects; Overview

Reaven GM. Physiol Rev. 1995;75:473-486Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.

Insulin resistance- lipotoxicity

-cell dysfunction/Failure; dec. mass

± Environment ± Environment

IFG IGT

GenesGenes

Type 2 diabetesGlucose

Toxicity

Glucose

Toxicity

hepatic

peripheral Abn. Firstphase

1st & 2nd

DM will NOT occur if B-cells not genetically predisposed

Genes that Cause or are Associated with Diabetes

Insulin actionInsulin receptor PPARG

Obesity FTO MCR4

Insulin SecretionNeonatal KCNJ11/Kir6.2

ABCC8/Sur1 Insulin

MODY HNF-1α,1β, 4 αGlucokinasePDX1/IPF1Neurod1/Beta2KLF11CEL

Mitochondrial diabetesType 2

CDKAL1TCF7L2HHEX/IDESLC30A8/ZNT8 WFS1

NOTCH2-ADAM30

UnknownIGFBP2CDKN2A/BKIF11JAZF1CDC123-CAMK1DTSPAN8-LGR5THADAADAMTS9NOTCH-ADAM30

PHENOTYPE- eg: age of presentation, IFG/ IGT/Both/ severity depends on number of which kind of genes a person inherits – GENOTYPE

Modified from McCarthy, NEJM 363:24,2339.

Service J. Diabetologia. 1983;25:316.

Time (h) for glucose to return to premeal value

Meal Size (% total daily calories)

1.31.7

2.11.9

2.4

4.1

2.4

4.1

4.7

0

1

2

3

4

5

8:00 AM1:00 PM6:00 PM

Small meal(12.5%)

Medium meal(25%)

Large meal(50%)

Time of Meal

Size and Time of Meal Determine Postprandial Duration

Glucose FFA

FFA

Increasedglucosamine

Otherpathways

Otherpathways

Glucose

Impaired insulinsecretion from -cell

Insulin resistancein muscle and fat

Mechanism of Glucotoxicity and Lipotoxicity The Glucosamine Hypothesis

Hawkins M et al. J Clin Invest. 1997;99:2173-2182; Rossetti L. Endocrinology. 2000;141:1922-1925

FFA=free fatty acid

Insulin Secretion Increases With Decreasing Insulin Action and Vice Versa

Insu

lin S

ecre

tio

nIn

sulin

Sec

reti

on

AIR

(µ

U/m

L)

Insulin ResistanceInsulin Resistance

M-low (mg/kg EMBS per minuteM-low (mg/kg EMBS per minute))

IGTIGT

NGTNGT

NGTNGTNGTNGT NGTNGT

DIADIA

500

400

300

200

100

0

00 11 22 33 44 55

ProgressorsProgressors

Non-ProgressorsNon-Progressors

Changes in AIR relative to changes in M-low in 11 Pima Indian subjects in whom glucose tolerancedeteriorated from normal (NGT) to impaired (IGT) to diabetic (DIA) (progressors), and in 23 subjectswho retained NGT (nonprogressors). The lines represent the prediction line and the lower and upper

limits of the 95% confidence interval of the regression between AIR and M-low asderived from a reference population of 277 Pima Indians with NGT.

SAM: Insulin Secretion/Insulin Resistance Index During OGTT- Progressive loss of Beta-cell Function

Adapted from Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

Whether Lean or Obese

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars

• PPG increases – Variability– Microvasular disease and adverse pregnancy outcomes– ASVD risk factors – adverse CV outcomes

• Treating elevated PPG leads to– Reduce Microvasular disease and Pregnancy Outcomes– Reduce CV Markers and Outcomes– Prevent Diabetes

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars

• PPG increases – Variability– Microvasular disease and adverse pregnancy outcomes– ASVD risk factors – adverse CV outcomes

• Treating elevated PPG leads to– Reduce Pregnancy Outcomes– Reduce CV Markers and Outcomes– Prevent Diabetes

Prevalence of Retinopathy vs Durationof Type 2 Diabetes

Patients with retinopathy(%)

Harris MI et al. Diabetes Care. 1992;15:815-819

Years

0

20

40

60

80

-10 -6.5 -4.2 0 5 10 15 20

Wisconsin population

Australian population

Apparent onsetprior to diagnosis DM=Prediabetes

Time of diagnosis

0

20

40

60

80

100

120

140

160

180

1st Trimester 2nd Trimester 3rd trimesterr

>97

90–96

75–89

50–74

25–49

10–24

3–9

<3

Abnormal PPG associated with Macrosomia

Mea

n N

on

fast

ing

Glu

cose

Mea

n N

on

fast

ing

Glu

cose

Infant Infant Birth Birth Weight Weight PercentilPercentilee

Jovanovic-Peterson et al. Am J Obstet Gynecol 1991;164:103.Jovanovic-Peterson et al. Am J Obstet Gynecol 1991;164:103...

Macrosomia associated with increased C-section rate, infant morbidity

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars

• PPG increases – Variability– Microvasular disease and adverse pregnancy outcomes– ASVD risk factors – adverse CV outcomes

• Treating elevated PPG leads to– Reduce Pregnancy Outcomes– Reduce CV Markers and Outcomes– Prevent Diabetes

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars

• PPG increases – Variability– Microvasular disease and adverse pregnancy outcomes– ASVD risk factors – adverse CV outcomes

• Treating elevated PPG leads to– Reduce Pregnancy Outcomes– Reduce CV Markers and Outcomes– Prevent Diabetes

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars

• PPG increases – Variability– Microvasular disease and adverse pregnancy outcomes– ASVD risk factors – adverse CV outcomes

• Treating elevated PPG leads to– Reduced Microvasular disease and Pregnancy Outcomes– Reduce CV Markers and Outcomes– Prevent Diabetes

Reduction of Retinopathy in Patients with IGT in Da Qing Study

Gong et al Diabetologia 54 :300,2011

Effectiveness of Postprandial Monitoring and Treatment Reduces Adverse Outcomes

0

5

10

15

20

25

30

35

40

45

No Care

Preprandial

Postprandial

Large for Gestational AgeLarge for Gestational Age Cesarean Section Neonatal Cesarean Section Neonatal hypoglycemia hypoglycemia

** ††

‡‡*P=.05*P=.05

††P=.04P=.04

‡‡P=.01P=.01

DeVeciana et al. N Engl J Med 1995;26:774.DeVeciana et al. N Engl J Med 1995;26:774.

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars

• PPG increases – Variability– Microvasular disease and adverse pregnancy outcomes– ASVD risk factors – adverse CV outcomes

• Treating elevated PPG leads to– Reduce Pregnancy Outcomes– Reduce CV Markers and Outcomes– Prevent Diabetes

Early Treatment, Even in Overt Diabetes, Decreases Micro and Macro Vascular RISK

&DCCT

Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars

• PPG increases – Variability– Microvasular disease and adverse pregnancy outcomes– ASVD risk factors – adverse CV outcomes

• Treating elevated PPG leads to– Reduce Pregnancy Outcomes– Reduce CV Markers and Outcomes– Delay or Prevent Diabetes

preserve beta-cell function and alter the natural history of type 2 Diabetes?

Is it Possible to Delay the Onset of Type 2 DM?

FINNISH=Tuomilehto J, et al. N Engl J Med 2001; 344: 1343-50DA QING=Pan XR, et al. Diabetes Care. 1997; 20: 537-44DPP=Diabetes Prevention Program. Nathan DM, et al. N Engl J Med 2002; 346:393-403STOP-NIDDM=Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus. Chiasson JL, et al. Lancet 2002; 359:2072–77TRIPOD=Troglitazone in the Prevention of Diabetes. Buchanan T, et al. Diabetes 2002; 51(9): 2796-2803XENDOS=XEnical in the Prevention of Diabetes in Obese Subjects. Torgerson JS, et al. Diabetes Care 2004; 27 (1): 155-61DREAM=Diabetes Reduction Assessment with Ramipril & Rosiglitazone Medication. Gerstein H, et al. Lancet 2006; 368:1096-1105

0

10

20

30

40

50

60

70

Diabetes Prevention Clinical Trials

Finnish-Diet+ Exercise

Da Qing – Diet + Exercise

DPP-Lifestyle

DPP-Metformin

STOP-NIDDM

TRIPOD

XENDOS

Dia

bete

s M

ellit

us

Red

uct

ion

(%

)

DREAM

41%

25%

42%

58% 58%

31%

55%

62%

PIOPOD

55%

80

ActNOW

80%

ACT NOWStudy Results: Time to Occurrence of Diabetes (Kaplan-Meier analysis)

0

0.05

0.15

0.20

0.30

Cu

mu

lati

ve H

azar

d

10 20 400 30

Months

50

0.10

0.25

Placebo

Pioglitazone 1.5%per year

6.8%per year

HR = 0.19(95%, CI) = 0.09, 0.39P<0.00001

DeFronzo RA. ADA Scientific Sessions, Late-Breaking Clinical Studies, June 9, 2008.

NNT = 3.5 patients with IGT for 1 year to prevent the development of 1 case of T2DM

80% reduction in progression to DM

β cell-specific effects of (PPAR-γ ) agonists in type 2 diabetes mellitus

Incretins

• Increases Insulin Secretion and decreases glucagon secretion in a Glucose-dependent manner

• Thus low risk hypoglycemia vs Sus• Improves First-phase insulin release, inc. b-cell mass in rodents• GLP-1 receptor agonists (not DPP-4 inhibitors) also decrease

appetite, and slows gastric emptying which usually results in weight loss

P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N

And Reduce Variability

Augers for Avoiding Step-Care Therapy; use Early CombinationTherapy

Relative Contribution of FBG and PPG Varies With A1C Range

Adapted from Monnier L, et al. Diabetes Care. 2003;26:881-885.

Can’t get to glycemic goals, UNLESS control PPG (incretins, alpha-glucosidase inhibitors, TZDs, glinides,

fast-insulin analogues)

Inc PPG increases Micro- and macro- vascular disease

Therapeutic Strategies for Improving B-cell function, treating Prediabetes, PPG, DM

Central dec. Dopasym.tone,inc HGP, PPG Fast-acting bromocryptine

The New ADA Guidelines for Type 2 Diabetes:AKA- David Nathan’s Regimen- DNR

Revised Treatment AlgorithmRevised Treatment Algorithm

Intensive insulin

At diagnosis:Lifestyle + metforminSTEP 1

STEP 2

Tier 1* Tier 2†

STEP 3

Add basal insulin

Add sulfonylurea

Add GLP-1 agonist

Add pioglitazone ± SU

HbA1C >7.0%

NOT Glyburide, chlorpropamide NOT Rosiglitazone

Does Not Address Pathophysiology, Preservation B-cell function, PPG control

•Monotherapy•Metformin•Pioglitazone•GLP-1 agonist•DPP-4 Inhibitor•(or AGI)

Dual Combination• Metformin• Pioglitazone• GLP-1 agonist• DPP-4 Inhibitor(or AGI / secretagogue /

colesevelam)

AGI = alpha glucosidase inhibitor

Triple Combination• Metformin• Pioglitazone• GLP-1 agonist• DPP-4 Inhibitor(or AGI / secretagogue /

colesevelam)

Insulin*• +/- Other

agents*Insulin analogsNot NPH/regular If over 9.0% or above

and symptomaticIf triple combo fails

6.5% 7.5% 9.0 HbA1c Continuum – if not at goal, advance Rx 12%

Asymptomatic

Symptomatic

Principles of the AACE Guidelines / A1C Goal less than or equal to 6.5%

1. Minimize risk/severity of Hypoglycemia 5. Lifestyle Modification Essential and NO SMOKING

2. Minimize risk/severity of Weight gain6. Combination frequently required; Complimentary mechanisms of action

3. Fast therapeutic changes (2-3 months, earlier even better)

7. When using insulin, add an insulin-sensitizing agent if possible

4. Address fasting and postprandial glucose 8. Cost is important but, safety and efficacy trump cost

Therapeutic Choice Should Match The Drug With Patient CharacteristicsDiet and Exercise

Provided by Dr. Stanley S. Schwartz.