Pioglitazone  ADVANTAGES-  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) 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 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.Lipid benefit 2.Carotid lesions- stop progression 3.Coronary- decrease atheroma volume 4.16% decrease MACE 5.28% decreased MI 6.37% decrease time to ACS 7.47% 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 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

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%  HbA 1c (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