Pioglitazone ADVANTAGES Improves insulin resistance fatmuscle decreases insulin

· Pioglitazone ADVANTAGESØ Improves insulin resistance (fat/muscle), decreases insulin conc. , improves endothelial dysfunction , dysfibrinolysis, BP, decreased microalbumin, improved beta -cell function, treats PCOS and steatohepatitis Lipids (GLIA study) l Advantage to pio - decrease TG, decreased # of buoyant LDL particles, decrease non-HDL chol. May use in renal insufficiency Ø No hypoglycemia used alone or with metformin , incretin mimetics Ø Potential to delay or prevent DM and progression; lower secondary failure rate than SU/met Ø 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 Ø Disadvantages No liver toxicity Bone loss in women = risk/benefit evaluation for each patient Edema-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. 2. 3. 4. 5. 6. 7. Lipid benefit Carotid lesions- stop progression Coronary- decrease atheroma volume 16% decrease MACE 28% decreased MI 37% decrease time to ACS 47% decreased secondary CVA in 3 years- SPARCL=16% in 6 years 1. Post MI- decreased mortality if sent home on pio 2. 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 calciumchannel 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 Usea 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 Ø Improves insulin resistance in liver Ø High initial response rate Ø Effective, 2% Hb. A 1 c (1% with extended-release metformin) Ø No initial weight gain or modest weight loss (UKPDS) Ø Advantageous lipid profile Ø No hypoglycemia when used alone or with TZD, incretins Ø Potential to delay or prevent DM and progression, but secondary failure is = SU Ø Decreases MIs (39% UKPDS obese subgroup, retrospective analysis) Ø Decreases AGEs, improved endothelial dysfunction Ø 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