Halting the Rise, Newest Non- Insulin Options for Lowering A1c

Halting the Rise, Newest Non- Insulin Options for Lowering A1c Alecia Rottinghaus, PharmD PGY-1 Pharmacy Resident Iowa City Veterans Affairs Health Care System January 29 th, 2019 Disclosures Alecia Rottinghaus does not have any actual or potential conflict of interests to disclose and will not be discussing off-label use of medications Goal Upon conclusion of this presentation, attendees will be able to identify the three newer non-insulin agents (SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors) used to treat type 2 diabetes and determine their place in therapy Pharmacists Objectives 1. List three factors to consider when deciding what diabetes medication to recommend for a patient 2. Diagram the different mechanism of action between a GLP-1 agonist and a DPP-4 inhibitor 3. Identify two side effects or contraindications associated with each class of the newer non-insulin agents 4. For a patient with known cardiovascular disease and stage 4 chronic kidney disease, determine if a DPP-4 inhibitor, GLP-1 agonist, and/or a SGLT-2 inhibitor are reasonable treatment recommendations 5. Identify which two GLP-1 agonists are associated with the most weight loss Pharmacy Technician Objectives Diabetes By The Numbers 1. Match the name of diabetes medication to the correct class (SGLT-2 inhibitor, GLP-1 agonist, and DPP-4 inhibitor) 2. List two expected side effects associated with a GLP-1 agonist 3. Explain what new class of diabetes medication has NOT been shown to provide cardiovascular benefit 4. Identify which newer classes of diabetes medication are associated with weight loss In 2015, 30.3 million people were reported to have diabetes in the United States (US) 95% of these are type 2 diabetes 23.8% of these were undiagnosed 1.5 million Americans are diagnosed yearly 7 th leading cause of death in the US in 2015 ~ 1 out of 10 people Centers for Disease Control and Prevention. Atlanta, GA: U.S. Department of Health and Human Services; 2017. 1

Top Diabetes Products (Total Sales 2016) Class Brand/Generic Name Class Brand/Generic Name History of Diabetes Treatment Options Insulin GLP-1 Lantus/glargine Januvia/sitagliptin Victoza/liraglutide Insulin Humulin/NPH Tradjenta/linagliptin Galvus/vildagliptin* Insulin Novolog/aspart GLP-1 Trulicity/dulaglutide insulin 1923 1956 1994 1995 1996 1997 2005 2006 2013 SU metformin = dipeptidyl peptidase 4 inhibitor GLP-1 = glucagon-like peptide-1 receptor agonist SGLT-2i = sodium-glucose cotransporter-2 inhibitor -glucosidase inhibitors TZD SU = sulfonylurea TZD = thiazolidinedione meglitinide amalylin GLP-1 SGLT-2i Insulin Insulin + Biguanide Humalog/lispro Levemir/detemir JanuMet/ sitagliptin+ metformin Insulin NovologMix/aspart + aspart protamine SGLT-2i + Biguanide InvokaMet/ canagliflozin + metformin SGLT-2i Insulin GLP-1 Alpha-Glucosidase inhibitor Farixa/dapagliflozin Onglyza/saxagliptin Toujeo/glargine (conc) Bydureon/exenatide Precose/Acarbose Nesina/alogliptin Cavailoa, TS. Endotext [Internet]. 2017 Mar 31; 2000-. *not FDA approved Source: Evaluate Pharma; Fierce Pharma First line metformin + comprehensive lifestyle Background Side effects ASCVD CHF CKD ASCVD = atherosclerotic cardiovascular disease CHF = chronic heart failure CKD = chronic kidney disease Weight Cost ASCVD - GLP-1 or - SGLT-2i with proven CV benefit If A1c above goal, add - GLP-1* or SGLT-2i* - if not on GLP-1 HF or CKD - SGLT-2i with evidence - GLP-1* if SGLT-2i* not tolerated or indicated If A1c above goal, add - GLP-1* or SGLT-2i* - if not on GLP-1 Hypoglycemia - SGLT-2i, GLP-1, or TZD If A1c above goal, - If on TZD: add SGLT-2i, GLP-1, or - If on SGLT-2i: add GLP-1,, or TZD - If on GLP-1: add SGLT-2i or TZD - If on : add SGLT-2i or TZD No ASCVD or CKD Weight Gain - GLP-1* or SGLT-2i If A1c above goal, add - Follow as outlined above If A1c above goal, add - if not on GLP-1 Cost Issue - SU or TZD If A1c above goal, add - Follow as outlined above If A1c above goal, add - Basal insulin, SGLT-2i or with lowest acquisition cost A1c Agent Patient preference ^avoid TZD and If A1c above goal, add saxagliptin in setting of HF - Follow as outlined above *with proven benefit -summarized chart to focus on newer non-insulin therapies Adapted from American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S94. Overview Mechanisms, efficacy, and side effects Classes SGLT-2 Inhibitors (Oral) GLP-1 Agonists (SQ) DPP-4 Inhibitors (Oral) Cardiovascular outcomes Renal effects Weight effects Cost Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Ertugliflozin (Steglatro) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Exenatide (Byetta) Exenatide ER (Bydureon) Liraglutide (Victoza) Lixisenatide (Adlyxin) Semaglutide (Ozempic) Alogliptin (Nesina) Linagliptin (Tradjenta) Saxagliptin (Onglyza) Sitagliptin (Januvia) Combination therapy 2

SGLT-2 Inhibitors: Mechanism of Action SGLT-2 Inhibitors: flozins Efficacy with metformin Warnings and precautions 0.4-0.7% A1c reduction Fournier s gangrene Lower limb amputation (canagliflozin) Bone fractures (canagliflozin) Bladder cancer (dapagliflozin) Side effects Genitourinary infections Volume depletion Hypotension Diabetic ketoacidosis (rare) Adapted from Edward C. Chao Clin Diabetes 2014;32:4-11 American Diabetes Association. Diabetes Care 2018 Jan; 41(Supplement 1): S73-S85. Professional Resource, Managmenet of New-Onset Type 2 Diabetes. Pharmacist s letter/prescriber s Letter. October 2016. GLP-1 Agonists: Mechanism of Action GLP-1 Agonists: tides Efficacy with metformin Warnings and precautions ~1% A1c reduction Thyroid C-cell tumors (albiglutide, dulaglutide, exenatide ER, liraglutide, semaglutide) Diabetic retinopathy (semaglutide) Possible acute pancreatitis Side effects Injection site reactions Nausea, vomiting, diarrhea Meier JJ. Nat Rev Endocrinol. 2012;8:728-742 American Diabetes Association. Diabetes Care 2018 Jan; 41(Supplement 1): S73-S85. Professional Resource, Managmenet of New-Onset Type 2 Diabetes. Pharmacist s letter/prescriber s Letter. October 2016 Twice daily dosing Once daily dosing Weekly Dosing GLP-1 Agonists: Administration Albiglutide (Tanzeum) Dulaglutide (Trulicity) Exenatide (Byetta) Exenatide ER (Bydureon) Liraglutide (Victoza) Lixisenatide (Adlyxin) Semaglutide (Ozempic) DPP-4 Inhibitors: Mechanism of Action enzyme inactivates GLP-1 inhibitors block the inhibitors enzyme block the enzyme Adapted from Strucker DJ. Diabetes Care. 2007;30:1335-1341 3

DPP-4 Inhibitors: gliptins Efficacy with metformin Warnings and precautions 0.5-0.7% A1c reduction Side effects Nasopharyngitis Joint pain Potential risk for heart failure: saxagliption, alogliptin Possible acute pancreatitis American Diabetes Association. Diabetes Care 2018 Jan; 41(Supplement 1): S73-S85. Professional Resource, Managmenet of New-Onset Type 2 Diabetes. Pharmacist s letter/prescriber s Letter. October 2016 Patient Case CG is a 67 year-old male with type 2 diabetes currently on metformin 1000mg twice daily. Past medical history includes MI (2 years ago), hypertension (well-controlled), and hyperlipidemia (well-controlled). His most recent A1c is 7.9% with a goal of <7.5%. He would like to try oral therapy before going to an injection. egfr 52 ml/min/1.73m 2, CrCl 63 ml/min, BMI 32 kg/m 2 Which class would you recommend for CG? a) SGLT-2 inhibitor b) GLP-1 agonist c) DPP-4 inhibitor Cardiovascular (CV) Cardiovascular Trials (CVOTs) Phase 2 and 3 trials Inclusion criteria: Patients at higher risk for CV events Sufficient size and duration for meaningful evaluation of CV risk Major adverse cardiac events (MACE) outcomes must include: CV death Non-fatal MI Non-fatal stroke Cefalu WT et al. Diabetes Care. 2018 Jan; 41(1):14-31 Completed and Ongoing CVOTs TECOS CARMELINA CAROLINA 2013 2015 2016 2017 2018 2019 2020 EMPA-REG PIONEER 6 OUTCOME LEADER CANVAS PROGRAM SGLT2i ELIXA SUSTAIN-6 EXSCEL GLP-1 FREEDOM-CVO HARMONY Adapted from Cefalu Jan;41(1):14-31 et al. Dia Care 2018 EMPEROR- Preserved Dapa- CKD Dapa- HF CREDENCE DECLARE VERTIS -TIMI 58 CV EMPEROR- Reduced REWIND EXAMINE SAVOR- TIMI 53 Baseline Characteristics for SGLT-2 Inhibitor Trials EMPA-REG OUTCOME (empagliflozin) CANVAS Program (canagliflozin) N 7,020 10,142 17,160 Median duration (years) 3.1 3.6 4.2 Mean age (years) 63.1 63 64 Mean BMI (kg/m 2 ) 30.6 31.9 32 Previous CV disease (%) >99 66 41 Mean A1c (%) 8.1 8.2 8.3 Mean duration of diabetes (years) >10 (>57%) 13.5 10 Zinman et al. N Engl J Med. 2015 Nov 26;373:2117-2128 Ṅeal et al. N Engl J Med 2017; 377:644-657 Wiviott, SD et al. N Engl J Med. 2018 Nov 10. DECLARE-TIMI 58 (dapagliflozin) 4

Baseline Characteristics for GLP-1 Agonist ELIXA (lixisenatide) EXSCEL (exenatide) HARMONY (albiglutide) LEADER (liraglutide) N 6,068 14,752 9,463 9,340 3,297 Median duration (years) 2.1 3.2 1.6 3.8 2 Mean age (years) 60 62 64.1 65 64.6 Mean BMI (kg/m 2 ) 30 31.8 32.3 32.5 32.8 Previous CV disease (%) 100 73.1 70 81 60 Mean A1c (%) 7.7 8 8.7 8.7 8.7 Mean duration of diabetes (years) 9.3 12 14.1 12.8 13.9 SUSTAIN-6 (semaglutide) Baseline Characteristics for DPP-4 Inhibitor CARMELINA (linagliptin) EXAMINE (alogliptin) SAVOR-TIMI 53 (saxagliptin) TECOS (sitagliptin) N 6,979 5,380 16,492 14,671 Median duration (years) 2.2 1.5 2.1 3 Mean age (years) 66.1 61 65 65 Mean BMI (kg/m 2 ) 31.4 28.7 31 30.2 Previous CV disease (%) 57 100 78 74 Mean A1c (%) 7.9 8 8 7.2 Mean duration of diabetes (years) 15 7.1 10.3 11.6 Pfeffer MA et al. N Engl J Med. 2015 Dec 3;373(23):2247-57. Holman et al. N Engl J Med. 2017 Sep 28;377(13):1228-1239 Marso et al. N Engl J Med 2016;375:311-22. Holman et al. N Engl J Med. 2017 Sep 28;377(13):1228-1239. Marso et al. N Engl J Med 2016; 375:1834-1844 Hernandez et al. Lancet. 2018 Oct 1. pii: S0140-6736(18)32261-X Rosenstock J et al. JAMA. 2018 Nov 9. Green JB et al. N Engl J Med. 2015 Jul 16;373(3):232-42. White WB et al. Am Heart J. 2011 Oct;162(4):620-626. Scirica et al. N Engl J Med. 2013 Oct 3;369(14):1317-26. ASCVD Benefit Trial (SGLT-2i) EMPA-REG OUTCOME (empagliflozin vs. CANVAS Program (canagliflozin vs. *participants per 1000 patient-years ASCVD Benefit Trial (GLP-1s) EXSCEL (exenatide ER vs. HARMONY (albiglutide vs. LEADER (liraglutide vs. SUSTAIN-6 (semaglutide vs. Primary Composite CV death Fatal/Non-Fatal MI 10.5% vs.12.1% HR 0.86 95% CI 0.74-0.99 3.7% vs. 5.9% HR 0.62 95% CI 0.49-0.77 4.8% vs. 5.4% HR 0.87 95% CI 0.70-1.09 Fatal/Non-Fatal Stroke 3.5% vs. 3.0% HR 1.18 95% CI 0.89-1.56 All Cause Mortality 5.7% vs. 8.3% HR 0.68 95% CI 0.57-0.82 26.9 vs 31.5 HR 0.86 95% CI 0.75-0.97 11.6 vs. 12.8 HR 0.87 95% CI 0.72-1.06 11.2 vs. 12.6 HR 0.89 95% CI 0.73-1.09 7.9 vs. 9.6% HR 0.87 95% CI 0.69-1.09 17.3 vs. 19.5 HR 0.87 95% CI 0.74-1.01 11.4% vs. 12.2% Primary Composite HR 0.91 95% CI 0.83-1.00 CV death 4.6% vs. 5.2% HR 0.88 95% CI 0.76-1.02 Fatal/Non-Fatal MI 6.6% vs. 6.7% HR 0.97 95% CI 0.85-1.10 Fatal/Non-Fatal Stroke 2.5% vs. 2.9% HR 0.85 95% CI 0.70-1.03 All Cause Mortality 6.9% vs. 7.9% HR 0.86 95% CI 0.77 0.97 7% vs. 9% HR 0.78 95% CI 0.68-0.90 3% vs. 3% HR 0.93 95% CI 0.73-1.19 4% vs. 5% HR 0.75 95% CI 0.61-0.90 2% vs. 2% HR 0.86 95% CI 0.66-1.44 4% vs. 4% HR 0.95 95% CI 0.79-1.16 13% vs. 14.9% HR 0.87 95% CI 0.78-0.97 4.7% vs. 6.0 HR 0.78 95% CI 0.66-0.93 6.3% vs. 7.3% HR 0.86 95% CI 0.73-1.00 3.7% vs. 4.3% HR 0.86 95% CI 0.71-1.06 8.2% vs. 9.6% HR 0.85 95% CI 0.74-0.97 6.6% vs. 8.9% HR 0.74 95% CI 0.58-0.95 2.7% vs. 2.8% HR 0.98 95% CI 0.65-1.48 *non-fatal MI only 2.9% vs 3.9% HR 0.74 95% CI 0.51-1.08 *non-fatal stroke only 1.6% vs. 2.7% HR 0.61 95% CI 0.38 0.99 3.8% vs. 3.6% HR 1.05 95% CI 0.74-1.50 ASCVD Neutral Trial *results not significant DECLARE-TIMI 58 (dapagliflozin vs. ELIXA (lixisenatide vs. CARMELINA (linagliptin vs. EXAMINE (alogliptin vs. SAVOR-TIMI 53 (saxagliptin vs. TECOS (sitagliptin vs. Primary Composite 8.8% vs. 9.4% HR 0.93 95% CI 0.84-1.03 13.4% vs. 13.2% HR 1.02 95% CI 0.89-1.17 12.4% vs. 12.1% HR 1.02 95% CI 0.89-1.17 11.3% vs. 11.8% HR 0.96 Upper level of 95% CI 1.16 7.3% vs. 7.2% HR 1.00 95% CI 0.89-1.12 9.6% vs. 9.6% HR 0.99 95% CI 0.88-1.09 Systematic Review and Meta-analysis CV death 2.9% vs. 2.9% HR 0.98 95% CI 0.82-1.17 Fatal/Non- *ischemic stroke only Fatal MI 2.7% vs. 2.7% HR 1.01 95% CI 0.84-1.21 Fatal/Non- 4.6% vs. 5.1% Fatal 0.89 Stroke 95% CI 0.77-1.01 All Cause 6.2% vs. 6.6% Mortality HR 0.93 95% CI 0.82-1.04 5.1% vs. 5.2% HR 0.98 95% CI 0.78-1.22 8.9% vs. 8.6% HR 1.03 95% CI 0.87-1.22 2.2% vs. 2.0% HR 1.12 95% CI 0.79-1.58 7.0% vs. 7.4% HR 0.94 95% CI 0.78-1.13 7.3% vs. 7.6% HR 0.96 95% CI 0.81-1.14 4.7% vs. 4.2% HR 1.12 95% CI 0.9-1.4 2.3% vs. 2.5% HR 0.88 95% CI 0.63-1.23 10.5% vs. 10.7% HR 0.98 95% CI 0.84-1.13 4.1% vs. 4.9% HR 0.85 95% CI 0.66-1.10 *non-fatal only 6.9% vs. 6.5% HR 1.08 95% CI 0.88-1.33 *non-fatal only 1.1% vs. 1.2% HR 0.91 95% CI 0.55-1.50 5.7% vs. 6.5% HR 0.88 95% CI 0.71-1.09 3.2% vs. 2.9% HR 1.03 95% CI 0.87-1.22 3.2% vs. 3.4% HR 0.95 95% CI 0.80-1.12 *ischemic stroke only 1.95 vs. 1.7% HR 1.11 95% CI 0.88-1.39 4.9% vs. 4.2% HR 1.11 95% CI 0.96-1.27 5.2% vs. 5.0% HR 1.03 95% CI 0.89-1.19 4.1% vs. 4.3% HR 0.95 95% CI 0.81-1.11 2.4% vs. 2.5% HR 0.97 95% CI 0.79-1.19 7.5% vs. 7.3% HR 1.01 95% CI 0.90-1.14 CV mortality, 56 trials Treatment Comparator HR (95% CI) 1.00 (0.91-1.11) GLP-1 vs. Control 0.85 (0.77-0.94) SGLT-2i 0.79 (0.69-0.91) Control 1.00 (0.90-1.10) GLP-1 vs. 0.85 (0.74-0.98) SGLT-2i 0.79 (0.66-0.94) Control 1.17 (1.06-1.30) vs. GLP-1 1.18 (1.02-1.36) SGLT-2i 0.93 (0.78-1.10) Control 1.27 (1.10-1.46) vs. SGLT-2i 1.27 (1.07-1.51) GLP-1 1.08 (0.91-1.29) Favors Treatment Favors Comparator Zheng SL et al. JAMA. 2018 Apr 17;319(15):1580-1591. 0.5 1.0 2.0 HR (95% CI) 5

Systematic Review and Meta-analysis All-cause mortality, 97 trials Treatment Comparator HR (95% CI) 1.02 (0.94-1.11) Favors Favors Comparator GLP-1 vs. Control 0.88 (0.81-0.94) Treatment SGLT-2i 0.80 (0.71-0.89) Control 0.98 (0.90-1.06) GLP-1 vs. 0.86 (0.77-0.96) SGLT-2i 0.78 (0.68-0.90) Control 1.14 (1.06-1.23) vs. GLP-1 1.17 (1.04-1.30) SGLT-2i 0.91 (0.79-1.04) Control 1.25 (1.12-1.40) vs. SGLT-2i 1.28 (1.11-1.47) GLP-1 1.10 (0.96-1.26) 0.5 1.0 2.0 HR (95% CI) ASCVD CVOTs Summary Superior to placebo for the primary composite outcome Empagliflozin and canagliflozin Liraglutide, semaglutide, and albiglutide Superior to placebo for reduction of CV death and all-cause mortality Empagliflozin Liraglutide Semaglutide is superior to placebo for reduction of non-fatal stroke Albiglutide is superior to placebo for reduction of fatal or nonfatal MI All other trials showed non-inferiority Patient Case CG is a 67 year-old male with type 2 diabetes currently on metformin 1000mg twice daily. Past medical history includes MI (2 years ago), hypertension (wellcontrolled), and hyperlipidemia (well-controlled). His most recent A1c 7.9%, with goal of <7.5%. Desires oral therapy before trying an injection. egfr 52 ml/min/1.73m 2, CrCl 63 ml/min, BMI 32 kg/m 2 What would you recommend for CG? a) Saxagliptin 5mg daily b) Empagliflozin 10mg daily c) Liraglutide 0.6mg daily for one week, then increase to 1.2mg daily d) Dapagliflozin 5mg daily Case continued a) Saxagliptin 5mg daily b) Empagliflozin 10mg daily Shown to be beneficial to reduce CV events for patients with history of ASCVD (MI 2 years ago) c) Liraglutide 0.6mg daily for one week, then increase to 1.2mg daily d) Dapagliflozin 5mg daily Heart Failure (HF) HF Benefit (SGLT-2i) HF Hospitalization EMPA-REG OUTCOME (empagliflozin vs. 2.7% vs. 4.1% HR 0.65 95% CI 0.50-0.85 CANVAS Program (canagliflozin vs. *participants per 1000 patient-years 5.5 vs. 8.7 HR 0.67 95% CI 0.52-0.87 DECLARE-TIMI 58 (dapagliflozin vs. 2.5% vs. 3.3% HR 0.73 95% CI 0.61-0.88 6

HF Neutral (GLP-1) *results not significant ELIXA (lixisenatide vs. EXSCEL (exenatide ER vs. HARMONY (albiglutide vs. LEADER (liraglutide vs. SUSTAIN-6 (semaglutide vs. HF Risk () SAVOR-TIMI 53 (saxagliptin vs. HF Hospitalization 4.0% vs. 4.2% HR 0.96 95% CI 0.75-1.23 3.0% vs. 3.1% HR 0.94 95% CI 0.78-1.13 Not reported 4.7% vs. 5.3% HR 0.87 95% CI 0.73-1.05 3.6% vs. 3.3% HR 1.11 95% CI 0.77-1.61 HF Hospitalization 3.5% vs. 2.8% HR 1.27 95% CI 1.07-1.51 HF Neutral () *results not significant CARMELINA (linagliptin vs. TECOS (sitagliptin vs. EXAMINE (alogliptin vs. HF Hospitalization 6% vs. 6.5% HR 0.98 95% CI 0.82-1.18 3.1% vs. 3.1% HR 1.00 95% CI 0.83-1.20 3.9% vs. 3.3% HR 1.19 95% CI 0.90-1.58 Systematic Review and Meta-analysis HF events, 58 trials Favors Favors Treatment Comparator HR (95% CI) Treatment Comparator 1.13 (1.00-1.28) GLP-1 vs. Control 0.93 (0.84-1.02) SGLT-2i 0.62 (0.54-0.72) Control 0.88 (0.78-1.00) GLP-1 vs. 0.82 (0.70-0.95) SGLT-2i 0.55 (0.46-0.67) Control 1.08 (0.98-1.18) vs. GLP-1 1.22 (1.05-1.42) SGLT-2i 0.67 (0.57-0.80) Control 1.60 (1.39-1.84) vs. SGLT-2i 1.81 (1.50-2.18) GLP-1 1.48 (1.25-1.76) 0.3 1.0 3.0 HR (95% CI) HF Summary Reduced HF hospitalization Empagliflozin Canagliflozin Dapagliflozin Avoid in the setting of HF Saxagliptin FDA warning: saxaglipitin and alogliptin All other CVOTs showed non-inferiority to placebo in the setting of HF when reported Renal Effects SGLT-2 Inhibitors Evidence From CVOTs Study Outcome Result EMPA-REG OUTCOME (empagliflozin) CANVAS Program (canagliflozin) DECLARE-TIMI 58 (dapagliflozin) Composite: worsening nephropathy New onset macroalbuminuria Doubling of serum creatinine Initiation of renal-replacement therapy Composite: worsening nephropathy New onset macroalbuminuria Doubling of serum creatinine HR 0.61 (95% CI 0.53-0.70) HR 0.62 (95% CI 0.54-0.72) HR 0.56 (95% CI 0.39-0.79) HR 0.45 (95% CI 0.21-0.97) HR 0.60 (95% CI 0.47-0.77) HR 0.58 (95% CI 0.50-0.68) HR 0.50 (95% CI 0.30-0.84) Composite: worsening nephropathy HR 0.76 (95% CI 0.67-0.87) Perkovic V et al. Lancet Diabetes Endocrinol. 2018 Sep;6(9):691-704. 7

CREDENCE Canagliflozin vs. placebo in patients with diabetic nephropathy Stopped at a planned interim analysis for achieving the primary efficacy endpoint, a composite of end-stage renal disease (ESRD), doubling of serum creatinine, and renal or CV death GLP-1 Agonists Evidence From CVOTs Study Outcome Result LEADER (liraglutide) SUSTAIN-6 (semaglutide) Composite: worsening nephropathy New onset macroalbuminuria Composite: worsening nephropathy New onset macroalbuminuria HR 0.78 (95% CI 0.67-0.92) HR 0.74 (95% CI 0.60-0.91) HR 0.64 (95% CI 0.46-0.88) HR 0.54 (95% CI 0.37-0.77) Janssen Research & Development, LLC. 16 Jul 2018. available at http://www.janssen.com/phase-3-being-stopped-earlypositive-efficacy. Accessed 10/29/18. Mann JFE et al. N Engl J Med. 2017 Aug 31;377(9):839-848. DPP-4 Inhibitor Evidence From CVOTs Study Outcome Result SAVOR-TIMI 53 (saxagliptin) CARMELINA (linagliptin) Composite: worsening nephropathy Composite: worsening nephropathy HR 1.08 (95% CI 0.88-1.32) HR 0.98 (95% CI 0.82-1.18) Renal Dose Adjustments SGLT-2 Inhibitors Agent Renal Dose Adjustment (egfr ml/minute/1.73 m 2 ) Canagliflozin 100-300 mg daily Dapagliflozin Empagliflozin Ertugliflozin egfr 45-59: max dose 100 mg daily egfr 30-45: do not initiate or continue egfr <30, ESRD, dialysis: contraindicated egfr 30-60: do not initiate or continue egfr <30: contraindicated egfr 30-45: do not initiate or continue egfr <30: contraindicated egfr 30-45: do not initiate or continue egfr <30: contraindicated GLP-1 Agonists Agent Renal Dose Adjustment (CrCl ml/minute; egfr ml/minute/1.73 m 2 ) Albiglutide None Dulaglutide None Exenatide CrCl <30 or ESRD: do not use Exenatide ER CrCl <30 or ESRD: do not use Liraglutide None Lixisenatide egfr <15 or ESRD: do not use Semaglutide None 8

DPP-4 Inhibitors Agent Renal Dose Adjustment (CrCl ml/minute; egfr ml/minute/1.73 m 2 ) Alogliptin 25 mg daily Linagliptin Saxagliptin 2.5-5 mg daily Sitagliptin 100 mg daily CrCl 30-59: 12.5 mg daily CrCl <30: 6.25 mg daily None egfr <45: 2.5 mg daily egfr 30-44: 50 mg daily egfr <30: 25 mg daily Renal Effects Summary Reduced CKD progression Empagliflozin Canagliflozin Dapagliflozin Reduced macroalbuminiuria Liraglutide Semaglutide Product labels need to be verified to determine renal dose adjustments Patient Case CG returns 4 years later after recently being diagnosed with CHF. Kidney function has declined and metformin has been stopped. Last time you chose to initiate empagliflozin, but know this is no longer an option due to renal function. A1c 8.4%, goal <8%. egfr 29 ml/min/1.73m 2, CrCl 35 ml/min, BMI 34 kg/m 2 PMH: T2DM, MI (6 years ago), CHF, HTN, HLD What would you recommend for CG? a) Saxagliptin 5mg daily b) Canagliflozin 100mg daily c) Liraglutide 0.6mg daily for one week, then increase to 1.2mg daily d) Dapagliflozin 5mg daily Patient Case What would you recommend for CG? a) Saxagliptin 5mg daily b) Canagliflozin 100mg daily c) Liraglutide 0.6mg daily for one week, then increase to 1.2mg daily In patients with CHF or CKD, initiate GLP-1 agonist with CV benefit if unable to initiate SGLT-2i due to renal function or other contraindication d) Dapagliflozin 5mg daily Weight Effects Weight Effects SGLT-2 inhibitors: average weight loss of 1.5-3kg Meta-analysis: -2.99 kg at 2 years (95% CI -3.64 to -2.34) GLP-1 agonists: average weight loss of 2-5kg Meta-analysis: -2.9kg at 1.7 years (95% CI -3.6 to -2.2) DPP-4 inhibitors: weight neutral Liu, XY et al. J Diabetes Complications. 2015 Nov-Dec;29(8):1295-303 Vilsbøll T et al. BMJ. 2012 Jan 10;344:d7771. Gurgle, HE et al. Vasc Health Risk Manag. 2016;12:239-49. 9

Change in Weight (kg) 0.5 0-0.5-1 -1.5-2 -2.5-3 -3.5-4 SUSTAIN 7 AWARD-6 AWARD-1 HARMONY 7 GetGoal-X DURATION-6 DURATION-5 LEAD-6 DURATION-1 ^, ** $ * $ * + ++ * -4.5 Exenatide 2x/day Exenatide weekly Liraglutide Lixisenatide -5 Albiglutide Dulaglutide 1.5 Dulaglutide 0.75 Semaglutide 1.0 Semaglutide 0.5-5.5 * p = not significance; ** not significant between dulaglutide 1.5 and exenatide twice daily; $ -6 p<0.0001; ^p = 0.001 dulaglutide 0.75 mg vs. exenatide twice daily; + p < 0.0005; p = not Dar, S et al. Practical Diabetes 32;8: 297-300b. reported for weight difference; ++ p = 0.011 Pratley RE et al. Lancet Diabetes Endocrinol. 2018 Apr;6(4):275-286. Cost Class Agent AWP ($) for 30 day supply (as of 11/26/2018) SGLT-2 inhibitors Canagliflozin 100 & 300 mg/day 557.50 Dapagliflozin 5 &10 mg/day 557.45 Empagliflozin 10 & 25 mg/day 557.94 Ertugliflozin 5 & 15 mg/day 321.84 GLP-1 agonists Albiglutide 30 & 50 mg/week 626.41 Combination Therapies Dulaglutide 0.75 & 1.5 mg/week 876.24 Exenatide 5 & 10 mcg twice daily 850.06 Exenatide ER 2 mg/week (all dosage forms) 792.19 Liraglutide 1.8 mg/day 1044.47 Lixisenatide 20 mcg/day 707.42 Semaglutide 0.5 & 1 mg/week 875.28 DPP-4 inhibitors Alogliptin 6.25, 12.5 & 25 mg/day 234.00 Linagliptin 5 mg/day 493.78 Saxagliptin 2.5 & 5 mg/day 489.89 Sitagliptin 25, 50 & 100 mg/day 515.52 SGLT-2 Inhibitor + DPP-4 Inhibitor SGLT-2 Inhibitor + GLP-1 Agonist Study design Systematic review and meta-analysis of SGLT-2i + vs. SGLT-2i vs. N=4,828 from 14 RCTs Study design Randomized, double blind trial comparing exenatide ER + dapagliflozin vs. exenatide or dapagliflozin alone N=695 for 28 weeks Combo therapy vs. SGLT- 2i vs. A1c from baseline: -0.31% (95% CI -0.38 to -0.24%) vs. -0.71% (95% CI -0.80% to -0.61%) Body weight: -0.36kg (95% CI -1.91 to 1.19kg) vs. -2.05 kg (95% CI -2.40 to -1.69 kg) SBP: -0.04mmHg (95% CI -1.57 to -1.49mmHg) vs. -5.9mmHg (95% CI -8.85 to -2.95mmHg) Endpoints Combo therapy vs. exenatide or dapagliflozin Primary: change in A1c from baseline Secondary: change from baseline in fasting plasma glucose, weight, systolic blood pressure; weight loss 5%; A1c <7% Primary: -0.4% (95% CI -0.6 to -0.1) -0.6% (95% CI -0.8 to -0.3) Secondary: combo was significantly superior Li D et al. Diabetes Obes Metab. 2018 Aug;20(8):1972-1976. https://doi.org/10.1111/dom.13294 Frías JP et al. Lancet Diabetes Endocrinol. 2016 Dec;4(12):1004-1016. 10

SGLT-2 Inhibitor + Insulin GLP-1 Agonist + Insulin Study design Meta-analysis determining safety and efficacy of a SGLT- 2i + insulin vs. insulin + placebo N=4,235 from 7 RCTs Study design Systematic review and meta-analysis comparing GLP-1 + basal insulin vs. other glucose-lowering treatments N=4,348 from 15 RCTs SGLT-2i + insulin vs. placebo Reduction in A1c: -0.56% (95% CI -0.67 to -0.44%) Weight loss: -2.63 kg (95% CI -3.10 to -2.16kg) Insulin dose: -8.79 units (95% CI -13.36 to -4.22 units) Severe Hypoglycemia: RR 1.24 (95% CI 0.91 to 1.70) GLP-1 + insulin vs. other A1c from baseline: -0.44% (95% CI -0.60 to -0.29%) Compared to basal-bolus: -0.1% (95% CI -0.17 to 0.02%) Weight loss: -3.22 kg (95% CI -4.9 to -1.54kg) Compared to basal-bolus: -5.66kg (95% CI -9.8 to -1.51kg) Hypoglycemia: RR 0.99 (95% CI 0.76-1.29) Compared to basal-bolus: RR 0.67 (95% CI 0.56-0.8) Tang H et al. Diabetes Obes Metab. 2017 Jan;19(1):142-147. Eng et al. Lancet. 2014 Dec 20;384(9961):2228-34. Combination Products SGLT-2 inhibitors: canagliflozin + metformin (Invokamet), empagliflozin + linagliptin (Glyxambi), empagliflozin + metformin (Synjardy), ertugliflozin + metformin (Segluromet), ertugliflozin + sitagliptin (Steglujan) GLP-1 agonists: lixisenatide + insulin glargine (Soliqua100/33), liraglutide + insulin degludec (Xulotphy100/3.6) DPP-4 inhibitors: alogliptin + metformin (Kazano), alogliptin + pioglitazone (Oseni), linagliptin + metformin (Jentadueto), linagliptin + empagliflozin (Glyxambi), saxagliptin + metformin (Kombiglyze XR), sitagliptin + metformin (Janumet, Janumet XR) Putting It All Together 2019 ADA STANDARDS OF MEDICAL CARE IN DIABETES American Diabetes Association. Diabetes Care. 2019 Jan;42(Suppl 1):S7-S193. First line continues to be metformin and comprehensive lifestyle ASCVD: either a SGLT-2i or GLP-1 with proven CVD benefit, if egfr adequate First line continues to be metformin and comprehensive lifestyle HF or CKD: SGLT-2i with evidence of reducing HF and/or CKD progression if egfr adequate OR GLP-1 with proven CVD benefit (after SGLT-2i) If A1c still above goal in 3-6 months If A1c above goal in 3-6 months Consider adding the other class with CVD benefit (SGLT-2i or GLP-1) Add the other class with proven CVD benefit DPP4-i if not on a GLP-1 empagliflozin > canagliflozin liraglutide > semaglutide > exenatide ER (not saxagliptin) in the setting of HF if not on a GLP-1 empagliflozin > canagliflozin liraglutide > semaglutide > exenatide ER 11

First line continues to be metformin and comprehensive lifestyle Minimize weight gain or promote weight loss: GLP-1 with good efficacy for weight loss OR SGLT-2i if egfr adequate If A1c above goal in 3-6 months Add agent listed above If A1c above goal in 3-6 months, if not on GLP-1 semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide Dual and Triple Therapy Continue metformin unless contraindicated or no longer tolerated Consider dual therapy in newly diagnosed type 2 diabetes when A1c 1.5% above goal If injectable needed to lower glucose, GLP-1 agonists are preferred over insulin in most cases Consider insulin initiation if evidence of ongoing catabolism, symptomatic hyperglycemia, or very high A1c (>10%) or blood glucose levels ( 300 mg/dl) Overall Summary Class Efficacy Warnings CV outcomes Renal effects Weight change Cost Questions SGLT-2i Intermediate Fournier s gangrene Amputation: canagliflozin Bone fx: canagliflozin Bladder cancer: dapagliflozin GLP-1 High Thyroid C-cell tumor: albiglutide, dulaglutide, exenatide ER, liraglutide Retinopathy: semaglutide?acute pancreatitis ASCVD and HF benefit: canagliflozin, empagliflozin HF benefit: dapagliflozin ASCVD benefit: liraglutide Benefit: canagliflozin, empagliflozin Macroalbuminuira benefit: liraglutide, semaglutide Loss Loss High High? Intermediate Joint pain?acute pancreatitis Potential HF risk: saxagliptin, alogliptin (FDA warning) Neutral Neutral High 12