Diabetes Mellitus 101 for Cardiologists (and Alike): 2015

Stan Schwartz MD,FACPAffiliate, Main Line Health System

Emeritus, Clinical Associate Professor of Medicine, U of Pa.

6105472000

An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients:in Cardiometabolic Patients:

Looking at Diabetes Medications with a Cardiologists EyeLooking at Diabetes Medications with a Cardiologists Eye

Part 7

The Adipocytokine Syndrome: A New Model for Insulin Resistance and ß-

Cell Dysfunction

Muscle

Pancreas

Liver

Brain

Visceralfat cells

FFA, TNF Leptin

Leptin

Sns

FFA, TNF IL-6

Angiotensinogen, PAI-1

Adiponectin

CRP, PAI-1Atherothrombosis

FFA, TNFAdiponectin

Artery

FFAResistin, TNF

ObesityObesityIRIRDiabetesDiabetesASVDASVD

Overweight

Overweight and Obesity Increase the Risk of CV Disease Mortality

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;341:1097-1105.

Normal weight Obese

Rel

ativ

e R

isk

of

Car

dio

vasc

ula

r D

isea

se

Mor

tali

ty

0.6

3.0

2.6

2.2

1.8

1.4

1.0

>18 25 30 >40

BMI, kg/m2

WomenMen

Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes

-0.8

-0.6

-0.4

-0.2

0

Δ A

1C (

%)

* Δ H

DL

Ch

oles

tero

l (m

g/d

L)

*

Intensified Lifestyle Intervention, 8.6% Weight LossDiabetes Support and Education, 0.7% Weight Loss

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 groupsLook AHEAD Research Group. Diabetes Care. 2007;30:1374-1383

-40

-30

-20

-10

0

Δ T

rigl

ycer

ides

(mg/

dL

)*

-7.5

-5.0

-2.5

0

Δ B

lood

Pre

ssu

re(m

m H

g)

*

*

0

1

2

3

4

Systolic Diastolic

Pleotrophic Effects of PIOGLITAZONE: Modifying The Adipocytokine Syndrome:

A Model Relating Obesity, Insulin Resistance and ß-Cell Dysfunction and ASCVD

Muscle

PANCREAS:Improve beta cell function

Liver:↓↓Insulin resistance

Brain:Improve Satiety

↓↓FFA, TNF

↓ ↓ FFA, TNF IL-6

Angiotensinogen, PAI-1 et al

↑↑Adiponectin

↓↓CRP, PAI-1↓↓Atherothrombosis

↓↓FFA, TNF↑↑Adiponectin

Reduce Atherosclerotic Risk Factors

↓ ↓ FFAresistin, TNF↓↓Size /# Visceral Fat Cells

and Insulin Resistance

PIOGLITAZONEPIOGLITAZONEImproves peripheral Insulin Resistance in

Decrease Hyperinsulinemia

Baseline After PIO

Effect of Pioglitazone on Abdominal Fat Effect of Pioglitazone on Abdominal Fat DistributionDistribution

SC Fat, Increased

Visceral Fat, Decreased

Miyazaki Y, Matsuda M, DeFronzo RA. Diabetes Care. 2002;25:517-23.

-2

-1

0

1

Ch

ang

e in

Hb

A1c

(%

)

TIME (years)0 1 2 3 4 5 6

PIOPIO

PIO

Presrvation of B-Cell functionLeads to DURABILITY OF GLYCEMIC CONTROL WITH

Pioglitazone Hanefeld (n=250)

Charbonnel (n=317)

Chicago (n=232)

PIO

PERISCOPE (n=178)

PIO

RECORD (n=301)

Rosenstock (n=115)

ROSI

Tan (n=249)

PIO

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

Metformin 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

Intra-muscular fat

Intra-hepatic fat

Intra-abdominalfat

Subcutaneousfat

TZD MECHANISM OF ACTION

Effect of Meds on Fat Topography

Direct PPAR effect on vascular cells to decrease endothelial dysfunction and inflammation

IR, TG, FFAInsulin, BP Inflam.En Dys.

TZD

IR, TG, FFAInsulin, BP, Inflam.En Dys.