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
P H Y S I C IAN S ’ A CAD E M Y F O R CAR D I O VAS C U LAR E D U CAT I O N
Natural History of Type 2 Diabetes
Age
0-15
Genes
Insulin
Resistance
15-40+
15-50+
25-70+
Envir.+
Other
Disease
Macrovascular Complications
Obesity (visceral)
Poor Diet
Inactivity
IR phenotype
Atherosclerosis
obesity
hypertensionHDL,TG,
HYPERINSULINEMIA
Endothelial dysfunction
PCO,ED
FBS>5.5,ppg>7.
8
IGT/IFG
 Beta Cell
Secretion
ETOH
Risk of Dev.
Complications BP
Smoking
Eye
Nerve
Kidney
Disability
MI
CVA
Amp
DEATH
Type II DM
Blindness
Amputation
CRF
Disability
Microvascular Complications
Type 2 Diabetes: Two Principal Defects; Overview
Genes
Genes
Insulin resistancelipotoxicity
b-cell dysfunction/
Failure; dec. mass
peripheral
±Environment
hepatic
Abn. First
phase
±Environment
1st & 2nd
IFG
IGT
Glucose
Toxicity
Glucose
Type 2 diabetes
Toxicity
DM will NOT occur if B-cells not genetically predisposed
Reaven GM. Physiol Rev. 1995;75:473-486
Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;
Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.
Genes that Cause or are Associated with Diabetes
Insulin Secretion
Insulin action
Neonatal
Insulin receptor
PPARG
KCNJ11/Kir6.2
ABCC8/Sur1
Insulin
MODY
HNF-1α,1β, 4 α
Glucokinase
PDX1/IPF1
Neurod1/Beta2
KLF11
CEL
Mitochondrial diabetes
Type 2
CDKAL1
TCF7L2
HHEX/IDE
SLC30A8/ZNT8
WFS1
NOTCH2-ADAM30
PHENOTYPEObesity
eg: age of
FTO
presentation,
MCR4
IFG/ IGT/Both/
Unknown
severity
IGFBP2
CDKN2A/B
KIF11
JAZF1
CDC123-CAMK1D
TSPAN8-LGR5
THADA
ADAMTS9
NOTCH-ADAM30
depends on number of
which kind of
genes
a person inherits –
GENOTYPE
Modified from McCarthy, NEJM 363:24,2339.
Size and Time of Meal Determine
Postprandial Duration
Time of Meal
8:00 AM
1:00 PM
6:00 PM
5
4
Time (h) for
glucose to return 3
to premeal value
4.7
4.1
2.4
1.9
2
4.1
2.4
2.1
1.7
1.3
1
0
Small meal
(12.5%)
Medium meal
(25%)
Large meal
(50%)
Meal Size (% total daily calories)
Service J. Diabetologia. 1983;25:316.
Mechanism of Glucotoxicity and Lipotoxicity
The Glucosamine Hypothesis
Glucose
FFA
Glucose
Other
pathways
FFA
Increased
glucosamine
Impaired insulin
secretion from b-cell
Other
pathways
Insulin resistance
in muscle and fat
FFA=free fatty acid
Hawkins M et al. J Clin Invest. 1997;99:2173-2182; Rossetti L. Endocrinology.
2000;141:1922-1925
Insulin Secretion Increases With Decreasing Insulin
Action and Vice Versa
Non-Progressors
400
AIR (µU/mL)
Insulin Secretion
500
300
NGT
NGT
200
IGT
100
Progressors
DIA
0
0
NGT NGT
1
2
3
4
5
Insulin Resistance
M-low (mg/kg EMBS per minute)
Changes in AIR relative to changes in M-low in 11 Pima Indian subjects in whom glucose tolerance
deteriorated from normal (NGT) to impaired (IGT) to diabetic (DIA) (progressors), and in 23 subjects
who 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 as
derived from a reference population of 277 Pima Indians with NGT.
SAM: Insulin Secretion/Insulin Resistance Index During
OGTT- Progressive loss of Beta-cell Function
Whether Lean or Obese
IGT
Adapted from Gastaldelli A, et al. Diabetologia. 2004;47:31-39.
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 Duration
of Type 2 Diabetes
Patients with
retinopathy
(%)
Time of diagnosis
Apparent onset
prior to
diagnosis DM=
Prediabetes
Years
Harris MI et al. Diabetes Care. 1992;15:815-819
Abnormal PPG associated with
Macrosomia
Infant
Birth
Weight
Percentil
e
180
160
>97
140
90–96
120
75–89
100
50–74
80
25–49
60
10–24
3–9
40
<3
20
0
1st Trimester
2nd Trimester
3rd trimesterr
Macrosomia associated with increased C-section rate, infant morbidity
Jovanovic-Peterson et al. Am J Obstet Gynecol 1991;164:103..
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
45
40
35
30
No Care
25
Preprandial
20
15
10
Postprandial
*
†
‡
5
†P=.04
0
Large for Gestational Age
hypoglycemia
*P=.05
‡P=.01
Cesarean Section
Neonatal
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?
80%
Diabetes Mellitus Reduction (%)
80
70
60
62%
58%
58%
55%
55%
50
42%
41%
40
DPP-Lifestyle
DPP-Metformin
31%
30
Finnish-Diet+ Exercis
Da Qing – Diet +
Exercise
25%
STOP-NIDDM
20
TRIPOD
10
XENDOS
DREAM
0
Diabetes Prevention Clinical Trials
PIOPOD
ActNOW
FINNISH=Tuomilehto J, et al. N Engl J Med 2001; 344: 1343-50
DA QING=Pan XR, et al. Diabetes Care. 1997; 20: 537-44
DPP=Diabetes Prevention Program. Nathan DM, et al. N Engl J Med 2002; 346:393-403
STOP-NIDDM=Study TO Prevent Non-Insulin-Dependent Diabetes Mellitus. Chiasson JL, et al. Lancet 2002; 359:2072–77
TRIPOD=Troglitazone in the Prevention of Diabetes. Buchanan T, et al. Diabetes 2002; 51(9): 2796-2803
XENDOS=XEnical in the Prevention of Diabetes in Obese Subjects. Torgerson JS, et al. Diabetes Care 2004; 27 (1): 155-61
DREAM=Diabetes Reduction Assessment with Ramipril & Rosiglitazone Medication. Gerstein H, et al. Lancet 2006; 368:1096-1105
ACT NOW
Study Results: Time to Occurrence of Diabetes (Kaplan-Meier analysis)
Cumulative Hazard
0.30
Placebo
HR = 0.19
(95%, CI) = 0.09, 0.39
P<0.00001
0.25
0.20
6.8%
per year
80% reduction
in progression to DM
0.15
0.10
Pioglitazone
0.05
1.5%
per year
0
0
10
NNT = 3.5 patients with IGT for 1 year to prevent
the development of 1 case of T2DM
20
30
40
Months
DeFronzo RA. ADA Scientific Sessions, Late-Breaking Clinical Studies, June 9, 2008.
50
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 IAN S ’ A CAD E M Y F O R CAR D I O VAS C U LAR E D U CAT 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
Inc PPG
increases
Microand
macrovascular
disease
Can’t get to glycemic goals, UNLESS control PPG
(incretins, alpha-glucosidase inhibitors, TZDs, glinides,
fast-insulin analogues)
Adapted from Monnier L, et al. Diabetes Care. 2003;26:881-885.
Therapeutic Strategies for Improving B-cell function,
treating Prediabetes, PPG, DM
Central dec. Dopa
sym.tone,inc HGP,
 PPG
Fast-acting
bromocryptine
The New ADA Guidelines for Type 2 Diabetes:
AKA- David Nathan’s Regimen- DNR
Revised Treatment Algorithm
At diagnosis:
Lifestyle + metformin
STEP 1
Tier 2†
Tier 1*
HbA1C >7.0%
STEP 2
Add basal
insulin
STEP 3
Add
sulfonylurea
Add GLP-1
agonist
Add pioglitazone
± SU
Intensive insulin
NOT Glyburide, chlorpropamide
NOT Rosiglitazone
Does Not Address Pathophysiology,
Preservation B-cell function, PPG control
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 gain
6. 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
Asymptomatic
6.5%
7.5%
9.0
HbA1c Continuum – if not at goal, advance Rx 12%
Symptomatic
•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)
Triple Combination
• Metformin
• Pioglitazone
• GLP-1 agonist
• DPP-4 Inhibitor
(or AGI / secretagogue /
colesevelam)
Insulin*
• +/- Other
agents
*Insulin analogs
Not NPH/regular
 If over 9.0% or above
and symptomatic
If triple combo fails
Diet and Exercise
Therapeutic Choice Should Match The Drug With Patient Characteristics
AGI = alpha glucosidase inhibitor
Provided by Dr. Stanley S. Schwartz.