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Cardio Diabetes Master Class Asian chapter January 28-30 2011, Shanghai. Presentation topic. (Pre) diabetes & sustained glycemic control: How and what is the time to act?. Slide lecture prepared and held by:. Dr Stanley S Schwartz, MD University of Pennsylvania Philadelphia, USA. - PowerPoint PPT Presentation
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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.