1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015
An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients:
Looking at Diabetes Medications with a Cardiologists Eye
Part 7
Stan Schwartz MD,FACP
Affiliate, Main Line Health System
Emeritus, Clinical Associate Professor of Medicine,
U of Pa. 1

2. The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß-Cell Dysfunction
Atherothrombosis
Liver
Artery
CRP, PAI-1
FFA, TNFa, IL-6
Angiotensinogen, PAI-1
FFA, TNFa
Obesity IR
Diabetes
ASVD
Adiponectin
Adiponectin
FFA
Visceral
fat cells
Resistin, TNFa
Leptin
Sns
FFA, TNFa, Leptin
Muscle
Brain
Pancreas 2 2

3. Overweight and Obesity Increase the Risk of CV Disease Mortality
0.6
3.0
2.6
2.2
1.8
1.4
1.0
Men
Women
Relative Risk of Cardiovascular Disease Mortality
These data are from the Cancer Prevention Study II, a prospective study of mortality in more than 1 million men and women in the United States. The risk of cardiovascular death was lowest at a BMI between 23.5 and 24.9 kg/m2 and was used as the reference BMI category. The mortality curves represent a continuum that begins to increase at a BMI of 26.5 kg/m2 in men and 25 kg/m2 in women. The risk of death from all causes was lowest at a BMI between 23.5 and 24.9 kg/m2 in men and 22.0 and 23.4 kg/m2 in women. A BMI between 23.5 and 24.9 kg/m2 was used as the reference BMI category for calculating relative risk. The mortality curves represent a continuum that begins to increase significantly at a BMI of 26.4 kg/m2 in men and 25 kg/m2 in women.
Normal weight
Overweight
Obese
> >40
BMI, kg/m2
Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment.
Calle EE, et al. N Engl J Med. 1999;341:
Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW. Body-mass index and mortality in a prospective cohort of US adults. N Engl J Med. 1999;341:

4. Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes
Intensified Lifestyle Intervention, 8.6% Weight Loss
Diabetes Support and Education, 0.7% Weight Loss 4 *
-0.2 3
Δ A1C (%)
-0.4
Δ HDL Cholesterol (mg/dL) 2
-0.6 1 *
-0.8
Systolic
Diastolic
-10
-2.5
Δ Triglycerides (mg/dL)
Δ Blood Pressure (mm Hg) *
-20
-5.0
-30 *
-7.5 *
-40
Randomized, controlled trial; n = 5145; Patients with type 2 diabetes, age >18 y; Mean ± SE Intensified lifestyle intervention (n = 2496) vs diabetes support and education (n = 2463) therapy; *P<0.001 between groups
Look AHEAD Research Group. Diabetes Care. 2007;30: 4

5. and Insulin Resistance
Pleotrophic Effects of PIOGLITAZONE: Modifying The Adipocytokine Syndrome: A Model Relating Obesity, Insulin Resistance and ß-Cell Dysfunction and ASCVD
Reduce Atherosclerotic
Risk Factors
Liver:
↓Insulin resistance
↓Atherothrombosis
↓CRP, PAI-1
↓ FFA, TNFa, IL-6
Angiotensinogen, PAI-1 et al
↓FFA, TNFa
↑Adiponectin
↑Adiponectin
Improves peripheral
Insulin Resistance in
PIOGLITAZONE
↓ FFA
resistin, TNFa
Muscle
↓Size /# Visceral Fat Cells
and Insulin Resistance
↓FFA, TNFa,
Brain:
Improve Satiety
Decrease Hyperinsulinemia
PANCREAS:Improve beta cell function

6. Effect of Pioglitazone on Abdominal Fat Distribution
Visceral Fat, Decreased
Baseline
After PIO
SC Fat, Increased
Miyazaki Y, Matsuda M, DeFronzo RA. Diabetes Care. 2002;25:

8. Presrvation of B-Cell functionLeads to DURABILITY OF GLYCEMIC CONTROL WITH Pioglitazone1
Hanefeld (n=250)
Chicago (n=232)
Charbonnel (n=317)
PERISCOPE (n=178)
Rosenstock (n=115)
RECORD (n=301)
Tan (n=249)
PIO
Change in HbA1c (%)
PIO
ROSI
PIO -1
PIO
PIO -2 1 2 3 4 5 6
TIME (years) 8

10. Metformin Advantages Improves insulin resistance in liver
High initial response rate
Effective, 2% HbA1c (1% with extended-release metformin)
No initial weight gain or modest weight loss (UKPDS)
Advantageous lipid profile
No hypoglycemia when used alone or with TZD, incretins
Potential to delay or prevent DM and progression, but secondary failure is = SU
Decreases MIs (39% UKPDS obese subgroup,retrospective analysis)
Decreases AGEs, improved endothelial dysfunction
Cheap 10 10

11. Don’t order metformin as admit to hospital
Disadvantages
GI side effects on initiation
Hold after radiologic studies using intravascular iodinated contrast media until Cr stable
Risk of lactic acidosis: Don’t use if…
Cr >1.4 female, >1.5 male
Cr Clearance <70 (age >70), blood levels increase
Cr Clearance <40, lactic acidosis cases seen
Impaired hepatic function
(CHF not a contr-indication any more)
Don’t order metformin as admit to hospital 11 11

12. TZD TZD MECHANISM OF ACTION Effect of Meds on Fat Topography
Direct PPAR effect on vascular cells to
decrease endothelial dysfunction and inflammation
IR, TG, FFA
Insulin, BP,
Inflam.
En Dys.
IR, TG, FFA
Insulin, BP Inflam.
En Dys.
TZD
Intra-muscular fat
Subcutaneous fat
Intra-abdominal fat
The clinical significance of fat re-distribution from ectopic sites such as the abdominal viscera, liver, muscle and even from the circulation to the subcutaneous fat depot during thiazolidinedione therapy is highlighted by the occurrence of simultaneous changes in insulin resistance.
Intra-hepatic fat 12 12