Pioglitazone ADVANTAGES-

Improves insulin resistance (fat/muscle), decreases insulin conc., improves endothelial dysfunction , dysfibrinolysis, BP, decreased microalbumin, improved beta-cell function, treats PCOS and steatohepatitisLipids (GLIA study)

Advantage to pio - decrease TG, decreased # of buoyant LDL particles, decrease non-HDL chol.

May use in renal insufficiency No hypoglycemia used alone or with metformin , incretin mimetics Potential to delay or prevent DM and progression; lower secondary failure rate than

SU/met Pio decreased prospective composite endpoint (MI,CVA, death) 16% in PROactive

trial (Can’t assume class effect) , dec. risk second MI/ACS, decreased risk second stroke 47%

NO BLADDER CA 10 year KP study- 2014, Decrease Breast CA

DisadvantagesNo liver toxicityBone loss in women = risk/benefit evaluation for each patientEdema-renal sodium and total body water retention

- can be prevented/minimized (patient selection, NAS diet)- treated with spironolactone, amilioride, triamterene

Weight gain not an obligatory side effect- studies- portion control/ education freq.CHF not a cardiac issue except more susceptible with diastolic dysfunction

–function of renal sodium and total body water retention -Can be prevented/reduced- low salt diet/ patient selection; ranolazine

CV BENEFITS PIOGLITAZONE

1. Lipid benefit2. Carotid lesions- stop progression3. Coronary- decrease atheroma volume4. 16% decrease MACE5. 28% decreased MI6. 37% decrease time to ACS7. 47% decreased secondary CVA

in 3 years- SPARCL=16% in 6 years1. Post MI- decreased mortality if sent home on pio2. Post CHF admission- decreased mortality if sent

home on pio

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:10.1159/000358636)• Not Cardiac issue• Increase CHF likely due to salt retention in patients with Diastolic Dysfunction

Weight Gain With TZD Use- a Common (‘core’) Effect

• TZDs can increase weight (not edema)• 2-8 lbs• But 50% with no increased weight or even weight

loss- on eucaloric or hypocaloric diet (EVIDENT trial)• Obviated with combination with GLP-1 (exenatide)-

no weight gain; actually combination causes nearly as much weight LOSS (~4 lb) as with exenatide alone (~5 lbs/ 30 weeks)

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

Disadvantages: 1. GI

2. Lactic Acidosis- addressable

Implications for Therapy

Treat Central Mechanisms IR

Treat Peripheral IR- fat, liver, muscle

Treat Inflammation

Treat Biome