9/12/2014. Main Pathophysiological Defect in T1DM. Main Pathophysiological Defects in T2DM. Personalizing Diabetes Care: The Alphabet Soup of Options

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1 9/12/2014 Baptist Health South Florida 13th Annual Primary Focus Symposium June 28, 2014 Silvio Inzucchi MD Section of Endocrinology Yale University School of Medicine Half-Century of HTN & T2DM Medications in U.S. Number of Medication Classes zz zz adrenergic neuronal blockers α-1 blockers β-blockers central α-2 agonists diuretics Biguanides 2 Sulfonylureas vasodilators 1 Angiotensin II receptor blockers ACE Inhibitors Ca 2 channel blockers SGLT-2 inhibitors Dopamine agonists Renin inhibitors Glinides s α-gis Biguanides Bile acid sequestrants inhibitors Amylin mimetics R Agonists Personalizing Diabetes Care: The Alphabet Soup of Options Main Pathophysiological Defect in T1DM HYPERGLYCEMIA Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Main Pathophysiological Defects in T2DM incretin effect gut carbohydrate delivery & absorption glucagon HYPERGLYCEMIA? The Incretin System: Key Regulator of Post-Prandial Glucose abolism gastric emptying GIP glucagon hepatic uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 hepatic uptake 1

2 9/12/2014 Oral Class Biguanides Mechanism Advantages Extensive experience Microvascular risk Hypoglycemia Weight gain Low durability? Ischemic preconditioning Low s Activates PPAR-γ Durability TGs, HDL-C? CVD events (pio) Weight gain Edema / HF Bone fractures LDL-C? MI (rosi)? Bladder ca (pio) Mod Inhibitors Inhibits Increases, GIP Well tolerated Modest A1c? Pancreatitis Urticaria? HF Sitagliptin Saxagliptin Linagliptin Alogliptin Low Closes KATP channels Pioglitazone sensitivity Rosiglitazone Properties of anti-hyperglycemic agents Mechanism Advantages Activates receptors, glucagon Exenatide gastric emptying Liraglutide satiety Albiglutide Activates Glargine receptors Detemir Glucose disposal Degludec Hepatic NPH Disadvantages Cost Weight loss? Beta cell mass CVD risk factors GI? Pancreatitis Medullary ca Injectable incretin effect Universally effective Unlimited efficacy Microvascular risk Regular Lispro Aspart Glulisine Hypoglycemia Weight gain? Mitogenicity Injectable Training requirements Stigma V A R I A B L E gut carbohydrate delivery & absorption glucagon? HYPERGLYCEMIA Properties of anti-hyperglycemic agents Mechanism Inhibits renal SGLT-2 SGLT-2 Inhibitors Increases glucosuria Canagliflozin Dapagliflozin Empagliflozin Advantages Disadvantages Cost Use across spectrum of disease stages Weight loss BP Genital mycotic infections UTIs Hemodynamic side effects? Dehydration? Renal effects Not in CKD hepatic uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 The Complex Pathogenesis of T2DM incretin effect - Pre-Mixed 70/30 75/25 50/50 Class The Complex Pathogenesis of T2DM - Injectable receptor agonists $ GI side effects Lactic acidosis B-12 deficiency Not in CKD s Glyburide Glipizide Glimepiride Disadvantages Activates AMP-kinase Extensive experience formin Hepatic Weight loss-neutral? CVD events gut carbohydrate delivery & absorption glucagon? HYPERGLYCEMIA hepatic Properties of anti-hyperglycemic agents uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine

3 9/12/2014 Class Meglitinides Repaglinide Nateglinide AGIs Acarbose Miglitol Bile Acid Sequestrants Colesevelam Dopamine Agonists Bromocriptine Amylinomimetics Pramlintide Mechanism Closes KATP channels Retards CHO absorption Binds bile acids Activates FXR hepatic Alters hypothalamic metabolic regulation sensitivity glucagon gastric emptying satiety Advantages Targets PPG Non-systemic Targets PPG? CVD events LDL-C? CVD events CVD events Well tolerated Properties of niche anti-hyperglycemic agents Disadvantages $ Hypoglycemia Weight gain TID GI side effects Modest A1c TID GI side effects Modest A1c Side effect profile Modest A1c GI side effets Modest A1c Injectable TID Mod Mod Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS DCCT / EDIC* ACCORD ADVANCE VADT Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow-up * in T1DM Survival as a Function of HbA1c in T2DM after Treatment Intensification: Insights from UK s GPRD s N=27,965 N=20,005 Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Currie CJ et al. Lancet 2010;375:481 Age>50 During Diabetologia2012;55:

4 9/12/2014 ANTI-HYPERGLYCEMIC THERAPY Glycemic targets - HbA1c < 7.0% (mean PG mg/dl) - Pre-prandial PG <130 mg/dl - Post-prandial PG <180 mg/dl - Individualization is key: Tighter targets ( %) - younger, healthier Looser targets ( %) - older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia PG = plasma Less Intensive Most Intensive 6.0% Figure 1 Figure 1 Figure 1 Least Intensive 8.0% 7.0% Psychosocioeconomic Considerations ly Motivated, Adherent, Knowledgeable, Excellent Self-Care Capacities, & Comprehensive Support Systems Less motivated, Non-adherent, Limited insight, Poor Self-Care Capacities, & Weak Support Systems Hypoglycemia Risk Moderate Low Patient Age Disease Duration Other Comorbidities None Few/Mild Multiple/Severe Established Vascular Complications None Ismail-Beigi F et al. Annals Intern Med 2011 Figure 1 Early Micro Cardiovascular Advanced Micro 4

5 9/12/2014 AM3 ADA-EASD Position Statement on T2DM Therapies, 2012 SGLT2i??? SGLT2i??? DPP4 DPP4 GLP1 GLP1 (multiple daily doses) Inzucchi SE, et al. Diabetes Care. 2012;35: Basal Start: U/kg/day Adjust: by 2-4 U twice/week Target: FBG < OTHER CONSIDERATIONS Age: Older adults Bolus 0.05 U/kg/meal Adjust: by 1-2 U/meal Target: 2h PPG < Premixed Start: U/kg/day Adjust: by 2-4 U twice/week Target: -PM dose -AM dose Fig. 3. Sequential Strategies in T2DM - FBG PM BG Reduced life expectancy er CVD burden Reduced GFR At risk for adverse events from polypharmacy More likely to be compromised from hypos Less ambitious targets HbA1c < % if tighter targets not easily achieved Focus on drug safety 4. OTHER CONSIDERATIONS 4. OTHER CONSIDERATIONS Weight Sex/ethnic/racial/genetic differences - Majority of T2DM patients overweight / obese - Intensive lifestyle program - formin - receptor agonists -? Bariatric surgery - Consider LADA in lean patients - Little is known! MODY & other monogenic forms of diabetes Latinos: more resistance East Asians: more beta cell dysfunction Gender may drive concerns about adverse effects (e.g., bone loss from s) 5

6 Slide 25 AM3 I recommend that we do 2 versions - this would be the show version and the next would be print version Angela McIntosh, 3/6/2014

7 9/12/ OTHER CONSIDERATIONS Comorbidities - Coronary Disease Insul - Heart Failure - Renal disease DPP4 GLP1 - Liver dysfunction - Hypoglycemia-prone (multiple daily doses) T2DM Anti-hyperglycemic Therapy: General Recommendations When Goal is to Avoid Weight Gain DPP4 When Goal is to Avoid Hypoglycemia GLP1 The 4 P s: Considerations in Choosing Specific Drugs for Patients with T2DM (multiple daily doses) When Goal is to Minimize Costs 6

8 9/12/2014 The 4 P s: Considerations in Choosing Specific Drugs for Patients with T2DM deficiency vs. resistance Ethnicity Stage of disease FPG vs. PPG Latent Autoimmune Diabetes of Adults (LADA) Rare monogenic diabetes (e.g., MODY) The 4 P s: Considerations in Choosing Specific Drugs for Patients with T2DM Distance from target? AGIs DPP4s SGLT2s BASs DAs Glinides s s s The 4 P s: Considerations in Choosing Specific Drugs for Patients with T2DM Hypoglycemia (, Ins) Weight (Pio, Ins, ) GI sx s(, GLP1) Edema (Pio) GU infections (SGLT2) Comorbidities CAD (? ) HF (Pio,? DPP4) CKD (, SGLT2,, Exen) Liver disease (several) Others Weight loss (, SGLT2) CVD benefit (,? Pio) Steatosis (Pio) LDL (Colesev) TGs (Pio) HTN (SGLT2) Investigational Agents for T2DM Other long-acting receptor agonists Other inhibitors Other Sodium-GLucose cotransporter (SGLT)-1/2 inhibitors Ranolazine Dual (α/γ α/γ) ) & Pan (α/γ/δ α/γ/δ)-ppar agonists 11β Hydroxysteroid Dehydrogenase (HSD)-1 inhibitors Fructose 1,6-bisphosphatase inhibitors Glucokinase activators G Protein-coupled Receptor (GPR)-40 & -119 agonists Protein Tyrosine Phosphatase (PTB)-1b inhibitors Carnitine Palmitoyltransferase (CPT)-1 inhibitors Acetyl CoA Carboxylase (ACC)-1 & -2 inhibitors Glucagon receptor antagonists Salicylates 7

9 9/12/2014 Baptist Health South Florida 13th Annual Primary Focus Symposium June 28, 2014 MMARY 1. T2DM has a complex pathogenesis with multiple defects. 2. The pharmacological options for lowering are expanding rapidly. 3. Foundation therapy remains lifestyle change with metformin 4. Beyond metformin, several options are available. 5. The clinician must weigh risks and benefits of each and design a treatment regimen individualized to the patient, both as regards to intensiveness and specific strategy. Silvio Inzucchi MD Section of Endocrinology Yale University School of Medicine 8