Thread by @NadiaJamilMD

Excited for the second session of Day 2 of #AACECVMET where Ralph A. DeFronzo, BMS, MD, MS, BS (@UTHealthSA) talks about "SGLT2 Inhibitors and GLP-1 RAs: Cardio-Renal Metabolic Drugs for the Ages", moderated by Joseph A. Vassalotti, MD (@Joe_Vassalotti) #EndoTwitter #diabetes

@UTHealthSA @Joe_Vassalotti Ominous Octet for hyperglycemia: increased lipolysis, increased glucose reabsorption (kidney), decreased glucose uptake (muscle), neutrotransmitter dysfunction, increased HGP (liver), increased glucagon secretion, decreased insulin secretion, decreased incretin effect #AACECVMET

@UTHealthSA @Joe_Vassalotti SGLT2 inhibitors: reduce HbA1C, corrects a novel pathophysiologic defect, reversal of glucotoxicity, promotes weight loss, reduces blood pressure, no hypoglycemia, and complements action of other antidiabetic agents = improves glycemic control and CV risk factors #AACECVMET

@UTHealthSA @Joe_Vassalotti Dapagliflozin reverses glucotoxicity and improves beta cell function and insulin sensitivity in T2DM patients: lowering both fasting and post-prandial glucose. #AACECVMET

@UTHealthSA @Joe_Vassalotti Subclinical CVD affects 2/3rds of T2DM pts; at time of diagnosis, clinically manifest CVD is present in 15-20%. 70-80% of mortality attributable to CVD & manifests 15 years earlier. Heart failure is 2-2.5 fold more common, and CKD in T2DM increases CV mortality ~3-fold #AACECVMET

@UTHealthSA @Joe_Vassalotti Despite lowering of blood pressure, there is surprisingly no benefit regarding the nonfatal stroke component of MACE for SGLT2 inhibitors #AACECVMET

@UTHealthSA @Joe_Vassalotti Empagliflozin effect on patients with heart failure and preserved ED: lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group #AACECVMET

@UTHealthSA @Joe_Vassalotti GLP-1 Receptor Agonists: effectively reduce HbA1C, preserve beta cell function, inhibit glucagon secretion, promote weight loss, correct 6 of the pathophysiologic defects in T2DM, do no cause hypoglycemia, reduce CV events, and have excellent safety profile. #AACECVMET

@UTHealthSA @Joe_Vassalotti Molecular actions GLP-1 on beta cell: glucose-dependent inc insulin secretion; inc insulin gene transcription (Pdx-1), inc beta cell glucose sensitivity (increased GLUT2 & glucokinase; restores glucose responsitivity to resistant beta cells); dec beta cell apoptosis #AACECVMET

@UTHealthSA @Joe_Vassalotti Compared to semaglutide 1mg, tirzepatide demonstrates greater improvement in HbA1C and weight loss. Has not yet been compared to 2mg semaglutide directly in studies. #AACECVMET

@UTHealthSA @Joe_Vassalotti GLP-1 RAs and cardiovascular protection mechanisms of action: direct myocardial effect GLP-1 receptors in human heart, anti-atherogenic, anti-inflammatory, anti-oxidative stress, anti-thrombotic, weight loss, decreased postprandial lipemia, reduced blood pressure #AACECVMET

@UTHealthSA @Joe_Vassalotti Diabetic nephropathy is the leading cause of ESRD in US and worldwide; 50% of patients entering renal replacement programs have diabetes. Diabetic kidney disease is rising worldwide #AACECVMET

@UTHealthSA @Joe_Vassalotti The CREDENCE (canaglifozin) and DAPA-CKD (dapagliflozin) trials demonstrate improvement in renal specific composite outcome. However, bc of the multifactorial etiology of DM nephropathy, treatment requires multiple meds to slow/halt the progression of DM kidney disease #AACECVMET

@UTHealthSA @Joe_Vassalotti Ominous Octect for DM nephropathy: deranged tubuloglomerular feedback, hyperglycemia, hypoxia, hypertention, obesity/lipotoxicity, podocyte drop-out/albuminuria, and tubular/growth factor hypothesis. SGLT-2 inhibitors correct 6 of the 8 problems! #AACECVMET

@UTHealthSA @Joe_Vassalotti Finerenone resulted in lower risks of CKD progression (renal composite score (ESRD, renal death, decrease in GFR >40%)) and cardiovascular events (CV death, nonfatal MI, nonfatal stroke, and HHF) than placebo. #AACECVMET

@UTHealthSA @Joe_Vassalotti Pioglitazone (TZDs) reduces CV events as noted in the PROACTIVE study (decreased time to death, MI, or stroke). In IRIS study, pts without diabetes who had insulin resistance w/ recent hx of ischemic stroke/TIA, the risk of stroke/MI was lower on pioglitazone #AACECVMET

@UTHealthSA @Joe_Vassalotti Key Point: SGLT2 inhibitors and GLP-1 RAs should be considered as First Line therapy in all T2DM pts: lower HbA1C, reduce BP, promote weight loss, no hypoglycemia, reduce MACE, and slow/prevent progression of DM (and non-DM) kidney disease #AACECVMET

@UTHealthSA @Joe_Vassalotti EDICT Study looks at initial therapy: combination therapy with metformin/pioglitazone/exenatide in newly diagnosed T2DM patients produces greater and more reduction in A1c than sequential add-on therapy with metformin, sulfonylurea, and basal insulin #AACECVMET

@UTHealthSA @Joe_Vassalotti DeFronzo Algorithm: SGLT2i, GLP-1 RA, pioglitazone, metformin. It utilizes the cardio-renal-metabolic drugs in combination #AACECVMET