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 9
Stan Schwartz MD,FACP
Affiliate, Main Line Health System
Emeritus, Clinical Associate Professor of Medicine,
U of Pa. 1

2. Mean Change in CIMT- Pioglitazone stopped progression
0.020
Glimepiride
Pioglitazone
0.015
0.012
0.010
LS Mean Change From Baseline Posterior Wall CIMT (mm)
0.005
0.000
-0.001
-0.005
-0.010
Baseline CIMT Least squares (LS) mean (standard error)
Glimepiride (n=186)
0.779 (0.0085) mm
Pioglitazone (n=175)
0.771 (0.0085) mm
Treatment group difference (final visit) (95% CI: , )
P=0.017

3. Primary Endpoint: Change in Percent Atheroma Volume (%)
0.9
P < 0.001
Glimepiride (n=181)
0.7
Pioglitazone (n=179)
0.73
0.5
Change in PAV (%)
0.3
P = 0.002
0.1
Slides from this deck are to be used only to respond to the specific unsolicited question posed.
These slides are intended as a library from which only the individual slides needed to respond to the question posed are used.
This slide shows the results for the primary efficacy parameter, the change in percent atheroma volume measured by intravascular ultrasound. The glimepiride group (shown in blue) had highly significant progression, 0.73%, p<.001, compared with baseline.
Pioglitazone-treated patients had a reduction of -0.16%, which was statistically unchanged from baseline. The between groups p value was
These data demonstrate that, after 18 months of treatment, patients assigned to glimepiride had unequivocal progression of coronary atherosclerosis, whereas pioglitazone-treated patients had no progression of coronary atherosclerosis.
To our knowledge, this is the first study in which a diabetes therapy has been shown to slow or prevent progression of coronary atherosclerosis.
-0.16
-0.1
P = 0.44
-0.3
Presented at: American College of Cardiology
March 29-April 1, 2008; Chicago, IL

4. Cardiac death, MI, coronary revasc, ACS (%)
PROactive in the Context of Other Landmark Clinical Trials in Diabetic Patients
HPS
CARE 30
Placebo 40
Placebo
CHD death, MI, revasc (%)
22% RRR
P <
25% RRR
P = 0.05 30
Vascular events (%) 20 20 10
Simvastatin
Pravastatin 10 1 2 3 4 5 6 1 2 3 4 5
Years
Years
Lancet. 2003;361.
Circulation. 1998;98.
MICRO-HOPE
PROactive
PROactive vs landmark clinical trials: Comparative benefit in patients with diabetes 25
Cardiac death, MI, coronary revasc, ACS (%) 20
Placebo
25% RRR
P =
Placebo
The cardioprotective benefits demonstrated with pioglitazone in PROactive by study end (3 years) were similar to the benefits observed in subgroups of patients with diabetes at the end of other landmark clinical trials.
Comparing the benefits of year 3 in each trial, observed benefits are greater in PROactive. Separation of the curves occurred prior to 1 year in PROactive, earlier than either CARE or HPS.
CV risk reduction at study end (active vs placebo groups):
HPS (Heart Protection Study): At a mean 4.8 year follow-up, simvastatin 40 mg daily reduced CV death, MI, stroke, or revascularization by 22% in 5963 participants with diabetes.
CARE (Cholesterol and Recurrent Events): At a median 5 year follow-up, pravastatin 40 mg/day reduced CHD death or MI 20% in 586 patients with a previous MI.
MICRO-HOPE (MIcroalbuminuria, Cardiovascular, and Renal Outcomes-Heart Outcomes Prevention Evaluation): After 4.5 years, ramipril 10 mg once daily reduced CV death, MI, and stroke by 25% in 3577 high-risk patients with diabetes.
PROactive: In the subgroup of patients with prior MI, at the 3 year follow-up, pioglitazone 15–45 mg/day reduced cardiac death, nonfatal MI, coronary revascularization, and ACS by 19%. A longer follow-up would be expected to further improve these benefits.
Slide citations:
HPS: Collins R et al. Lancet. 2003;361:
CARE: Goldberg RB et al. Circulation. 1998;98:
MICRO-HOPE: HOPE Study Investigators. Lancet. 2000;355:
PROactive: Erdmann E et al. 20
16% RRR
P = 0.034 15
MI, stroke, CV death
(%) 15 10 10
Ramipril
Pioglitazone 5 5 1 2 3 4 5 1 2 3
Years
Years 4
Lancet. 2000;355.
Lancet. 2005;366. 4

8. Stroke Reduction: Proactive vs SPARCL

9. Sent home after
CHF episode:
TZD patients
do no worse
than Metformin patients;
And Do BEST
if sent home on BOTH

10. AFTER AMI;
Patients sent home on TZD =Mortality vs. metformin
And if on both, do better!!

11. Synthesis- Edema / CHF Fluid retention-
Several mechanisms may underlie the development of peripheral oedema.
1. TZDs exhibit some properties of L-type calcium channel antagonism like calcium- channel blockers, 
2. increase expression of vascular endothelial growth
factor (VEGF),
 3. improvement in insulin sensitivity associated
a. actions on sodium reabsorption at the level of the kidney,
b. augmenting insulin-mediated vasodilatation.
4.renal effect PPARγ-Induced Stimulation of Amiloride-Sensitive Sodium Current in Renal Collecting Duct Principal Cells is Serum and Insulin Dependent (DOI: / )
Not Cardiac issue
Increase CHF likely due to salt retention in patients with Diastolic Dysfunction

12. Implications for Therapy
Treat Central Mechanisms IR
Treat Peripheral IR- fat, liver, muscle
Treat Inflammation
Treat Biome