CV Risk of SU and Insulin So benefit of both SU/Insulin in research studies –UKPDS, DCCT/EDIC But adverse risk in ‘real world’ use Pharmacoepidemiology and Drug Safety. 2008;(17):753-759.

Link between hypoglycemia and acute cardiovascular events in type 2 diabetes Retrospective, observational study (n=860,845) assessing association between hypoglycemia and acute CV events Patients who experienced hypoglycemia had 79% higher odds of an acute CV event than patients without hypoglycemia The final study cohort comprised 860,845 patients with type 2 diabetes. Johnston et al. Diabetes Care 2011; 34:1164–70

No SULFONYLUREAS or Glinides No SULFONYLUREAS or Glinides lose ischemic preconditioning; beta-cell apoptosis, could not pass FDA CV safety if new one applied not cheap, if consider test strip cost, accidents ER visits, hospitalizations Delay Insulin HYPOGLYCEMIA- cv risk Increase Weight Increase Insulin Resistance

Exquisitely controlled levels of insulin released into the portal vein NOTE: There is NO perfect Exogenous Insulin: All result in HyperInsulinemia and Potential Hypoglycemia Exquisitely controlled levels of insulin released into the portal vein Fine-tuned, physiologically appropriate insulinemia Endogenous Insulin ‘Obligatory’ excess peripheral insulin to get modicum of reduced hepatic glucose production Exogenous Insulin Insulin Resistance β-cell Dysfunction ------- Potential β-cell Exhaustion Hypoglycemia Obesity Hyperinsulin-emia Atherosclerosis All because all insulin results in hyperinsulinemia with risk of negative consequences Weight gain Hypertension Dyslipidemia Cancer Chronic Inflammation Type II Diabetes

THUS: SELECT AGENTS THAT CAN PRESERVE Reduced Need for Insulin:Debunking a Myth: Taking DeFronzo’s EASD 2015 Lecture 1 step further  MYTH: “Most Patients with ‘T2DM’ will eventually progress to insulin because of inexorable β-Cell loss” - But data obtained on SU=apoptosis Hyperinsulinism with weight gain> increased IR> adipocytokines and increased TG which decrease beta-cell function - Think of bariatric patients –no insulin after 25 years DM/ 20 years insulin - Most patients dying with DM have > 20% β-Cell mass- Butler - Need to remove >80% pancreas in sub-total pancreatectomies to leave patient with DM post-op Triple therapy Durable Effect in Improving Beta-Cell Function- DeFronzo(Diabetes, Obesity, Metab 2015) THUS: SELECT AGENTS THAT CAN PRESERVE β-Cell function/mass

ADA 2015 Goals WRONG ANSWER- as long as don’t use Hypoglycemic Agents

β-Cell Centric Classification of DM: SEGUE INTO THERAPY The β-cell centric classification A. individualizes care B. Identifies and treats patient-specific etiologies and mediating pathways of hyperglycemia EGREGIOUS ELEVEN One CORE Defect- the β-Cell (at least) 6 treatable Causes of β-Cell Damage / HYPERGLYCEMIA 4 treatable mediators of HYPERGLYCEMIA resulting from β-Cell Damage

Hyperglycemia 3A. β-Cell-Centric Construct: Egregious Eleven The β-Cell is the FINAL COMMON DENOMINATOR of β-Cell Damage 8. Colon/Biome Increased appetite Decreased morning dopamine surge Increased sympathetic tone 7. Brain 1. Pancreatic β-cells ↓ β-Cell function ↓ β-Cell mass Abnormal-microbiota; possible decreased GLP-1 secretion Insulin 9. Immune Dysregulation/ Inflammation FINAL COMMON DENOMINATOR INSULIN RESISTANCE 2. ↓Incretin effect 3. α-cell defect 6. Liver Increased glucose production ↓Amylin ↑ Glucagon 5. Muscle 10. Stomach/ Small intestine Hyperglycemia Decreased peripheral muscle uptake Increased rate of glucose absorption Upregulation of SGLT-2 4. Adipose Increased lipolysis 11. Kidney Increased glucose re-absorption

Hyperglycemia 3B. β-Cell-Centric Construct: Egregious Eleven Targeted Treatments for Mediating Pathways of Hyperglycemia 8. Colon/Biome 1. Pancreatic β-cells ↓ β-Cell function ↓ β-Cell mass 7. Brain Probiotics Incretins Metformin Incretins Dopamine agonist-QR Appetite Suppressants Insulin Incretins, Ranolazine 9. Immune Dysregulation/ Inflammation FINAL COMMON DENOMINATOR INSULIN RESISTANCE Incretins, Anti-Inflammatories Immune modulators 2. ↓Incretin effect 3. α-cell defect 6. Liver Metformin TZDs Incretins ↓Amylin ↑ Glucagon Incretins Pramlintide 5. Muscle 10. Stomach/ Small intestine TZDs Metformin Hyperglycemia GLP-1 Agonists Pramlintide AGI 4. Adipose 11. Kidney TZDs Metformin SGLT2 inhibitors Use Least Number of Agents that treat Most Number of Mechanisms of hyperglycemia

- HYPERGLYCEMIA - - SGLT2 3.Muscle- Hepatic glucose production: Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes, Match Patient Characteristics to Drug Characteristics- Consider glycemic efficacy, weight reduction and CV benefits NOT COMPETITION- EARLY COMBINATION 1.Pancreatic insulin Secretion: Incretin, ranolazine 5.Gut CHO Absorption: Incretin, Pramlintide, Glucosidase inh. - 7.Brain- TZD,INCRETIN, bromocryptine 2.Pancreatic glucagon Secretion- Incretin 8.Kidney- SGLT2 HYPERGLYCEMIA Peripheral glucose uptake De - - 3.Muscle- TZD, Incretin Hepatic glucose production: Metformin, incretin 4.Liver 6.Fat- TZD, metformin 10

Patient-Centric Diagnosis & Process of Care/Therapy Traditional Labs/Testing FBS, RBS, HgA1c Specific Therapy addressing Genotype At Risk Individuals Genes Etiologic Diagnostic Markers: β-Cell, Insulin resistance, Inflammation, Environment, Genes Pre-Diabetes Targeted Therapies- All Mechanisms Start Early B = β-cell: (Incretins) Br= Brain: (Bromocriptine-QR) I = Inflammation: (Incretin, drugs in development) R = Resistance: Metformin, pioglitazone E = Environment: Diet/exercise; regulators of the gut microbiota Might consider Multiple Agents [ per DeFronzo pre-dm protocol*] Diabetes Targeted Therapies B = β-cell: Incretin, glucagon-suppressing agents, SGLT-2 inhibitors Br= Brain: Bromocriptine-QR, appetite suppressants I = Inflammation: Incretin (Drugs in development) R = Resistance: Metformin, pioglitazone (Drugs in development) E = Environment: Diet/exercise; regulators of the gut microbiota ( ) = Not proven

But Guidelines Gluco-Centric Shouldn’t we take into account avoiding hypo Shouldn’t we take into account avoiding weight gain Shouldn’t we take into account CV risk