Silvio E. Inzucchi MD Section of Endocrinology Yale School of Medicine

Gegia Chapter of the American Association of Clinical Endocrinologists, 2017 Annual Meeting January 28, 2017 Silvio E. Inzucchi MD Section of Endocrinology Yale School of Medicine

DIABETES MANAGEMENT GUIDELINES 1. Pathophysiologicallybased therapeutic options in T2DM 2. ADA-EASD Statements 3. AACE & Other Guidelines 4. Considerations in Choosing Drugs 5. A Look to the Future

Multiple Complex Pathophysiological Abnmalities in T2DM incretin effect gut carbohydrate delivery & absption - - pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA? hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple Pathophysiologically-Based Therapies f T2DM GLP-1R agonists incretin effect DPP-4 inhibits gut A G I s carbohydrate delivery & absption Glinides Amylin mimetics - Insulin S U s pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA DA agonists? Metfmin T Z D s Bile acid sequestrants hepatic glucose production SGLT-2 inhibits renal glucose excretion - peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

2 2 2 1 GLP-1R agonists DPP-4 inhibits incretin enhancers Insulin S U s insulin providers Metfmin insulin sensitizers T Z D s SGLT-2 inhibits glucose excreter

Classes Generic Names A1c Sideeffects Insulin Degludec,Glargine, Detemir, NPH, Regular, Lispro, Aspart, Glulisine No limit Hypo,weight gain, injections SU s Glyburide, Glipizide, Glimepiride 1-1.5% Hypo, weight gain Metfmin Metfmin 1-1.5% GI,lactic acidosis, B-12 deficiency TZD s Rosiglitazone,Pioglitazone 1-1.5% Weightgain, edema, HF, bone fx s,?bladder ca DPP-4 i s Sitagliptin, Saxagliptin, Alogliptin, Linagliptin 0.5-1% Urticaria,?pancreatitis GLP-1 RA s Exenatide, Liraglutide, Albiglutide, Dulaglutide, Lixisenatide SGLT2-i s Canagliflozin,Dapagliflozin, Empagliflozin 1-1.5% GI,?pancreatic disease, injections 0.5-1% Polyuria, GUinfections, DKA,?bone fxs

Classes Generic Names A1c Costs Insulin Degludec,Glargine, Detemir, NPH, Regular, Lispro, Aspart, Glulisine No limit variable SU s Glyburide, Glipizide, Glimepiride 1-1.5% $ Metfmin Metfmin 1-1.5% $ TZD s Rosiglitazone, Pioglitazone 1-1.5% $ - $$$ DPP-4 i s Sitagliptin, Saxagliptin, Alogliptin, Linagliptin 0.5-1% $$$$ GLP-1 RA s Exenatide, Liraglutide, Albiglutide, Dulaglutide, Lixisenatide 1-1.5% $$$$ SGLT2-i s Canagliflozin,Dapagliflozin, Empagliflozin 0.5-1% $$$$

Half-Century of HTN & T2DM Medications in U.S. Number of Medication Classes 12 11 10 9 8 7 6 5 4 3 zz zz adrenergic neuronal blockers peripheral α-1 blockers β-blockers central α-2 agonists diuretics Biguanides Ca 2 channel blockers Angiotensin II recept blockers ACE Inhibits SGLT-2 inhibits Dopamine agonists Renin inhibits TZDs α-gis Biguanides Glinides Bile acid sequestrants DPP-4 inhibits Amylin mimetics GLP-1R Agonists insulin 2 1 vasodilats Sulfonylureas Adapted from: Inzucchi SE. Comparing and Choosing Oral Agents, in Clinical Diabetes, Fonseca VA, WB Saunders, 2006. 1950 1960 1970 1980 1990 2000 2010 2015

Type 2 DM Management Guidelines

Guideline vs. guideline Clinical Practice Guidelines statements that include recommendations intended to optimize patient care... infmed by a systematic review of evidence and an assessment of the benefits and harms of care options. multidisciplinary expert panel systematic review rate quality of evidence and strength of recommendations transparent process to minimize biases and COI s consider patient subgroups and patient preferences discuss alternative care options revised when new infmation available guideline noun guide line \ˈgīd-ˌlīn\ Definition: a rule instruction that shows tells how something should be done

DIABETES MANAGEMENT GUIDELINES 1. Pathophysiologicallybased therapeutic options in T2DM 2. ADA-EASD Statements 3. AACE & Other Guidelines 4. Considerations in Choosing Drugs 5. A Look to the Future

American Diabetes Assoc(ADA) -European Assocf the Study of Diabetes (EASD): 2006 Consensus Statement Diagnosis Lifestyle interventions metfmin No A1C 7% Yes* Add basal insulin - most effective Add sulfonylurea - least expensive Add glitazone - no hypoglycemia No A1C 7% No A1C 7% No A1C 7% Yes* Yes* Yes* Intensify insulin Add glitazone Add basal insulin Add sulfonylurea No A1C 7% Yes* No A1C 7% Yes* Add basal intensify insulin * Check A1C every 3 months until < 7% and then at least every 6 months. Although 3 al agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and expense. Intensive insulin metfmin ± glitazone Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.

ADA -EASD Consensus Statement (2008) STEP 1 STEP 2 STEP 3 Tier 1: Well-validated therapies At Diagnosis: Lifestyle Metfmin Lifestyle Metfmin Basal Insulin Lifestyle Metfmin Sulfonylurea a Lifestyle Metfmin Intensive Insulin Tier 2: Less well-validated therapies Lifestyle Metfmin Pioglitazone Lifestyle Metfmin Pioglitazone Sulfonylurea a Lifestyle Metfmin GLP-1 agonist b Lifestyle Metfmin Basal Insulin Reinfce lifestyle changes at every visit and check A1C every 3 months until < 7.0%, then at least every 6 months thereafter. Change interventions whenever A1C 7.0%. a Sulfonylureas other than glibenclamide (glyburide) chlpropamide. b Insufficient clinical use to be confident regarding safety. Nathan DM, et al. Diabetes Care. 2008;31:1

2012 ADA-EASD Position Statement : Management of Hyperglycemia in T2DM: A Patient-Centered Approach GLUCOSE-LOWERING THERAPY Glycemic targets - HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l]) - Pre-prandial PG <130 mg/dl (7.2 mmol/l) - Post-prandial PG <180 mg/dl (10.0 mmol/l) - Individualization is key: PG = plasma glucose Tighter targets (6.0-6.5%) - younger, healthier Looser targets (7.5-8.0%) -older, combidities, hypoglycemia prone, etc. Pharmacological options - Individualize drug choice - Minimize adverse effects, especially hypoglycemia - Patient-centered care Diabetes Care 2012;35:1364 1379 Diabetologia 2012;55:1577 1596

Figure 1 Diabetes Care 2012;35:1364 1379 Diabetologia 2012;55:1577 1596

Clinical Assessment of Individualized Glycemic Goals in T2DM: Fmulation of an Algithm Based on a Survey Among Leading Wldwide Diabetologists. 9.0% 8.5% Recommended HbA1c 8.0% 7.5% 7.0% 6.5% 6.0% 5.5% 5.0% Vignette 1 Vignette 2 Vignette 3 Vignette 4 Vignette 5 Vignette 6 Cahn A et al. Diabetes Care 2015;38:2293 2300 N=57 global diabetes experts

Diabetes Care 2012;35:1364 1379 Diabetologia 2012;55:1577 1596 2012 ADA-EASD Position Statement

Figure 1. Modulating intensiveness of A1c lowering in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects me stringent low Approach to the management of hyperglycemia HbA1c 7% less stringent Disease duration newly diagnosed long-standing Life expectancy long sht Usually not modifiable Imptant combidities absent few / mild severe Established vascular complications absent few / mild severe Patient attitude and expected treatment effts ly motivated, adherent, excellent self-care capacities less motivated, non-adherent, po self-care capacities Potentially modifiable Resources and suppt system Readily available limited Diabetes Care 2015;38:140-49; Diabetologia 2015 58:429-42

Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk gain hypoglycemia low Metfmin Sulfonylurea TZD Metfmin low risk gain edema, HF, fxs low Metfmin Thiazolidinedione Thiazolidinedione SU Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) est risk gain hypoglycemia variable Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i 2015 ADA-EASD Position Statement on Management of Hyperglycemia in T2DM Combination injectable therapy GLP-1-RA Insulin GLP-1-RA Insulin Basal Insulin Insulin Insulin GLP-1-RA If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGLT2-i: Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Monotherapy Efficacy * Hypo risk Weight Side effects Metfmin Costs intolerance contraindication HbA1c 9% Dual therapy Triple therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea moderate risk gain hypoglycemia low Metfmin Sulfonylurea TZD Metfmin low risk gain edema, HF, fxs low Metfmin Thiazolidinedione Thiazolidinedione SU Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk loss GI If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference choice dependent on a variety of patient- & disease-specific facts): DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) est risk gain hypoglycemia variable Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i Uncontrolled hyperglycemia (catabolic features, BG 300-350mg/dl, HbA1c 10-12%) Combination injectable therapy SGLT2-i GLP-1-RA Insulin SGLT2-i GLP-1-RA Insulin Basal Insulin SGLT2-i Insulin DPP-4-i Insulin Insulin SGLT2-i GLP-1-RA If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGLT2-i: Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

AMERICAN DIABETES ASSOCIATION Standards of Medical Care in Diabetes -2017 Diabetes Care 2017;40:S66 Anti-hyperglycemic therapy in T2DM: General recommendations

Figure 3. Approach to starting & adjusting insulin in T2DM # Injections 1 Basal Insulin (usually with metfmin /- other non-insulin agent) Start: 10U/day 0.1-0.2 U/kg/day Adjust: 10-15% 2-4 U once-twice weekly to reach FBG target. F hypo: Determine & address cause; dose by 4 units 10-20%. Complexity low 2 Add 1 rapid insulin* injections befe largest meal If not controlled after FBG target is reached ( if dose > 0.5 U/kg/day), treat PPG excursions with meal-time insulin. (Consider initial GLP-1-RA trial.) Change to premixed insulin* twice daily mod. Start: 4U, 0.1 U/kg, 10% basal dose. If A1c<8%, consider basal by same amount. Adjust: dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. F hypo: Determine and address cause; cresponding dose by 2-4 U 10-20%. Start: Divide current basal dose into 2/3 AM, 1/3 PM 1/2 AM, 1/2 PM. Adjust: dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. F hypo: Determine and address cause; cresponding dose by 2-4 U 10-20%. 3 If not controlled, consider basalbolus. Add 2 rapid insulin* injections befe meals ('basal-bolus ) If not controlled, consider basalbolus. Start: 4U, 0.1 U/kg, 10% basal dose/meal. If A1c<8%, consider basal by same amount. Adjust: dose by 1-2 U 10-15% once-twice weekly to achieve SMBG target. F hypo: Determine and address cause; cresponding dose by 2-4 U 10-20%. Diabetes Care 2015;38:140; Diabetologia 2015;10.1077/s00125-014-3460- Flexibility me flexible less flexible

AMERICAN DIABETES ASSOCIATION Standards of Medical Care in Diabetes -2017 Combination injectable therapy f type 2 diabetes Diabetes Care 2017;40:S67

DIABETES MANAGEMENT GUIDELINES 1. Pathophysiologicallybased therapeutic options in T2DM 2. ADA-EASD Statements 3. AACE & Other Guidelines 4. Considerations in Choosing Drugs 5. A Look to the Future

DM GUIDELINES: ADA-EASD vs. AACE ADA-EASD AACE Focus Glycemia Comprehensive (CV risk, weight, predm) A1c target <7.0% <6.5% Monotherapy metfmin various Combination therapy Therapeutic choices @ A1c 9.0% @ A1c 7.5% Me narrow Me broad

http://www.healthquality.va.gov/guidelines/cd/diabetes/dm20 10_FUL-v4e.pdf

Algithm f blood glucose lowering therapy in adults with type 2 diabetes

Oral Pharmacologic Treatment of T2DM: A Clinical Practice Guideline from the American College of Physicians 1 2 3 add als when lifestyle (has) failed monotherapy with metfmin add a second agent Qaseem A et al. Ann Intern Med 2012;156(3):218-231

Oral Pharmacologic Treatment of T2DM: A Clinical Practice Guideline Update from the American College of Physicians 1 2 3 add als when lifestyle (has) failed monotherapy with metfmin add a second agent Qaseem A et al. Ann Intern Med 2017 [Epub ahead of print 3 January 2017] doi: 10.7326/M16-1860

DIABETES MANAGEMENT GUIDELINES 1. Pathophysiologicallybased therapeutic options in T2DM 2. ADA-EASD Statements 3. AACE & Other Guidelines 4. Considerations in Choosing Drugs 5. A Look to the Future

6 P sof Personalizingof Diabetes Care 1. Pathophysiology Insulin resistance vs. deficiency? Stage of disease? 2. Potency Distance from A1c target? 3. Precautions 4.Pluses 5.Practicalities 6.Price Side effects, contraindications? (GI, renal, CV) Added benefits beyond glucose control? (weight, BP, CV events) Pills vs. injections? Frequency? Need f BG moniting? Branded vs. generic? Fmulary coverage?

Cost f 30 days of therapy Metfmin 1000mg QD Glipizide 10mg BID Pioglitazone 45mg QD NPH 50U QD (vials) Sitagliptin 100mg QD Glargine 50U QD (pen) Canagliflozin 300mg QD Liraglutide 1.8mg QD $4. $0 $100 $200 $300 $400 $500 $600 $700 183 X (!) $733. www.goodrx.com/, accessed June 18, 2016, (lowest price f New Haven, CT 06510)

DIABETES MANAGEMENT GUIDELINES 1. Pathophysiologicallybased therapeutic options in T2DM 2. ADA-EASD Statements 3. AACE & Other Guidelines 4. Considerations in Choosing Drugs 5. A Look to the Future

Pre-marketing Analyses Upper CL of 95% CI <1.8 F a HR=1.0 122 events Post-marketing Analyses Upper CL of 95% CI <1.3 F a HR=1.0 611 events sponss should demonstrate that the therapy will not result in an unacceptable increase in CV risk. Courtesy, Darren McGuire, UTSW Medical Ctr, 2015 1.0 1.3 Hazard Ratio Meta-analysis strategy using Phase 2/3 data Blinded central adjudication of CVD events Inclusion of -risk subjects: advanced CVD, elderly, CKD Minimum exposure of 2 years in large CVOT Approximately 15,000 pt-yrs 1.8

Large CV Outcomes Trials in Diabetes (Non-Insulin) Study SAVOR EXAMINE TECOS CAROLINA CARMELINA DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin Comparat placebo placebo placebo sulfonylurea placebo N 16,500 5,400 14,000 6,000 8,300 Results 2013 2013 2015 2017 2017 Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND GLP1-RA liraglutide lixisenatide semaglutide exenatide LR dulaglutide Comparat placebo placebo placebo placebo placebo N 16,500 14,000 6,000 5,400 8,300 Results 2016 2015 2016 2018 2019 Study EMPA-REG CANVAS DECLARE NCT01986881 SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin Comparat placebo placebo placebo placebo N 7300 4300 22,200 3900 Results 2015 2017 2019 2020

New Clinical Trial Data Influencing Treatment Decisions in T2DM 1. EMPA-REG Outcome The SGLT2 inhibit, empagliflozin, d 3-point MACE by 14%, driven by a 38% in CV death in 7020 T2DM patients with overt CVD. Also, 35% in HF hospitalization. 2. IRIS The TZD, pioglitazone, dfatal/non-fatal stroke & MI by 24% (and 52% progression to DM) in 3895 insulin resistant patients with stroke TIA. (Suppts MACE results from 2005 s PROactivestudy.) 3. LEADER The GLP-1 RA, liraglutide, d MACE by 13% in 9340 T2DM patients at CVD risk. (22% CV death and 15% all-cause death.) 4. SUSTAIN 6 The weekly GLP-1 RA, semaglutide, d MACE by 26% in 3297 T2DM patients at CVD risk. ( 61% stroke) Zinman B et al. N Engl J Med 2015;373:2117; Kernan WN et al. N Engl J Med 2016; 374:1321; Marso SP et al. N Engl J Med 2016;375:311; Marso SP et al. N Engl J Med 2016;375:1834

Glycemia Reduction Approaches in Diabetes:A Comparative Effectiveness Study Screening T2DM on metfmin alone HbA1c >6.8% at screening < 10 years duration at randomization Metfmin run-in Titrate metfmin to 1000 (min) 2000 (goal) mg/day HbA1c 6.8-8.5% at final run-in visit Randomization n=5000 eligible subjects Sulfonylurea (glimepiride) n=1250 DPP-IV inhibit (sitagliptin) n=1250 GLP-1 analog (liraglutide) n=1250 Insulin (glargine) n=1250 https://ptal.bsc.gwu.edu/web/grade

1. Increasing T2DM prevalance& complexity of therapeutic options have led to the need f treatment guidelines. 2. These tend not to be based on -quality evidence but instead on expert opinion and/ cost concerns. 3. Most begin quite similarly ( Lifestyle then metfmin ), but differ to varying degrees on what to do next. 4. Emerging data from recent CVOT trials should lead to some modifications in guidelines -particularly in those patients with overt CVD. 5. There will also always be a need f the wise and skilled physician to choose the optimal therapeutic regimen f (and with) each patient. t