1. Therapy of Type 2 Diabetes Mellitus: UPDATE
Glycemic Goals in the Care of Patients with Type 2 Diabetes ADA and AACE Guidelines:
Room For Improvement
(Be HAPPY/ Avoid Burnout, While Caring for Patients with DM)
Stan Schwartz MD, FACP, FACE
Affiliate, Main Line Health System
Clinical Associate Professor of Medicine, Emeritus,
U of Pa.
Part 3 1

2. Treatment of Type 2 Diabetes: Pathophysiologic Approaches

3. Natural History of Type 2 Diabetes
Age
Envir.+ Other Disease
Genes
Macrovascular Complications
Obesity (visceral)
Poor Diet Inactivity
IR phenotype Atherosclerosis obesity hypertensionHDL,TG,
HYPERINSULINEMIA
Endothelial dysfunction PCO,ED
Disability
Insulin Resistance
MI CVA Amp
pp>7.8
IGT – OMINOUS OCTET Type II DM
8 mechanisms of hyperglycemia
DEATH
 Beta Cell Secretion
Eye Nerve Kidney
Blindness Amputation CRF
Disability
Risk of Dev. Complications
ETOH BP Smoking
Microvascular Complications 3 3

4. Prevention Age 0-15 15-40+ 15-50+ 25-70+ Genes DEATH
Envir.+ Other Disease
Genes
Macrovascular Complications
Obesity (visceral)
Poor Diet Inactivity
IR phenotype Atherosclerosis obesity hypertensionHDL,TG,
HYPERINSULINEMIA
Endothelial dysfunction PCO,ED
Disability
Insulin Resistance
MI CVA Amp
pp>7.8
IGT – OMINOUS OCTET Type II DM
8 mechanisms of hyperglycemia
DEATH
 Beta Cell Secretion
Eye Nerve Kidney
Blindness Amputation CRF
Disability
Risk of Dev. Complications
ETOH BP Smoking
Microvascular Complications 4 4

5. Treat Pre-Diabetes to Prevent DM: Delay/ Prevent/ Reverse Beta-Cell Dysfunction
72% 80 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
Diabetes Mellitus Reduction (%)
DREAM
41%
25%
42%
58%
31%
55%
62%
55%
See “Pre-Diabetes: The Challenge of Prevention” Slide kit from your Eli Lilly medical education department with respect to details of the above studies. Earlier therapeutic intervention may result in delay of onset of type 2 diabetes.
IFG = impaired fasting glucose
PIOPOD
ActNOW
FINNISH=Tuomilehto J, et al. N Engl J Med 2001; 344:
DA QING=Pan XR, et al. Diabetes Care. 1997; 20:
DPP=Diabetes Prevention Program. Nathan DM, et al. N Engl J Med 2002; 346:
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):
XENDOS=XEnical in the Prevention of Diabetes in Obese Subjects. Torgerson JS, et al. Diabetes Care 2004; 27 (1):
DREAM=Diabetes Reduction Assessment with Ramipril & Rosiglitazone Medication. Gerstein H, et al. Lancet 2006; 368:

6. Prevention Increased with Use of Incretin
9 m,
105 pts

7. IN DPP TRIAL- if Achieve Normal Glucose Tolerance--Markedly Delay Future Overt Diabetes
10 % / YEAR PROGRESS TO DM
IF NO TREATMENT
~50% reduction
in risk = 5%/ YEAR
IF DON’T REACH NGT
BUT Only ~18% risk
6 years after study
ie: only 3%/yr incidence IF GET TO NORMAL GLUCOSE TOLERANCE

8. Treating elevated PPG leads to
Clinical Consequences of Abnormal First- phase Secretion and Elevated Post-Prandial Sugars, ie: treat PPG
PPG increases
Variability
Microvasular disease and adverse pregnancy outcomes
ASVD risk factors
adverse CV outcomes
Treating elevated PPG leads to
Reduce Pregnancy Outcomes
Reduce micro/macrovascular risk// CV Outcomes
Prevent Diabetes

9. Alter the Natural History of Diabetes
Age
Envir.+ Other Disease
Genes
Macrovascular Complications
Obesity(visceral)
Poor Diet Inactivity
IR Phenotype Atherosclerosis Obesity HypertensionHDL,TG,
HYPERINSULINEMIA
Endothelial Dysfunction PCO,ED
Disability
Insulin Resistance
MI CVA Amp
pp>7.8
IGT Type 2 DM
DEATH
 -Cell Secretion
Blindness Amputation CRF
Eye Nerve Kidney
Risk of Complications
ETOH BP Smoking
Disability
Microvascular Complications 9

11. ADOPT: Treatment effect on primary outcome
Hazard ratio (95% CI)
Rosiglitazone vs metformin, 0.68 (0.55–0.85), P < 0.001
Rosiglitazone vs glyburide, 0.37 (0.30–0.45), P < 0.001 40
Glyburide 30
Cumulative incidence of mono-therapy failure* (%)
Metformin 20
Rosiglitazone 10 1 2 3 4 5
Years
*Time to FPG >180mg/dL
Kahn SE et al. N Engl J Med. 2006;355: 11

12. Natural History of Type 2 Diabetes Insulin Resistance
Age
Envir.+ Other Disease
Genes
Macrovascular Complications
Obesity (visceral)
Poor Diet Inactivity
IR phenotype Atherosclerosis obesity hypertensionHDL,TG,
HYPERINSULINEMIA
Endothelial dysfunction PCO,ED
Disability
Insulin Resistance
MI CVA Amp
pp>7.8
IGT – OMINOUS OCTET Type II DM
8 mechanisms of hyperglycemia
DEATH
 Beta Cell Secretion
Eye Nerve Kidney
Blindness Amputation CRF
Disability
Risk of Dev. Complications
ETOH BP Smoking
Microvascular Complications 12 12