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

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1 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 1

2 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 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 Diabetes By The Numbers 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;

3 History of Diabetes Treatment Options insulin metformin TZD amalylin DPP-4i SU -glucosidase inhibitors meglitinide GLP-1 SGLT-2i DPP-4i = dipeptidyl peptidase 4 inhibitor GLP-1 = glucagon-like peptide-1 receptor agonist SGLT-2i = sodium-glucose cotransporter-2 inhibitor SU = sulfonylurea TZD = thiazolidinedione Cavailoa, TS. Endotext [Internet] Mar 31; Top Diabetes Products (Total Sales 2016) Class Insulin DPP-4i GLP-1 Insulin Insulin Insulin DPP-4i + Biguanide Brand/Generic Name Lantus/glargine Januvia/sitagliptin Victoza/liraglutide Novolog/aspart Humalog/lispro Levemir/detemir JanuMet/ sitagliptin+ metformin Insulin NovologMix/aspart + aspart protamine SGLT-2i + Biguanide InvokaMet/ canagliflozin + metformin Class Insulin DPP-4i DPP-4i GLP-1 SGLT-2i DPP-4i Insulin GLP-1 Alpha-Glucosidase inhibitor DPP-4i Brand/Generic Name Humulin/NPH Tradjenta/linagliptin Galvus/vildagliptin* Trulicity/dulaglutide Farixa/dapagliflozin Onglyza/saxagliptin Toujeo/glargine (conc) Bydureon/exenatide Precose/Acarbose Nesina/alogliptin *not FDA approved Source: Evaluate Pharma; Fierce Pharma ASCVD = atherosclerotic cardiovascular disease CHF = chronic heart failure CKD = chronic kidney disease Background CHF CKD ASCVD Weight Side effects Cost A1c Agent Patient preference 3

4 First line metformin + comprehensive lifestyle No ASCVD or CKD ASCVD - GLP-1 or - SGLT-2i with proven CV benefit If A1c above goal, add - GLP-1* or SGLT-2i* - DPP-4i 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* - DPP-4i if not on GLP-1 Hypoglycemia - SGLT-2i, GLP-1, DPP-4i or TZD If A1c above goal, - If on TZD: add SGLT-2i, GLP-1, or DPP-4i - If on SGLT-2i: add GLP-1, DPP-4i, or TZD - If on GLP-1: add SGLT-2i or TZD - If on DPP-4i: add SGLT-2i or TZD Weight Gain - GLP-1* or SGLT-2i If A1c above goal, add - Follow as outlined above If A1c above goal, add - DPP-4i 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 DPP-4i with lowest acquisition cost ^avoid TZD and saxagliptin in setting of HF If A1c above goal, add - Follow as outlined above *with proven benefit -summarized chart to focus on newer non-insulin therapies Adapted from American Diabetes Association. Diabetes Care Jan;42(Suppl 1):S94. Overview Mechanisms, efficacy, and side effects Cardiovascular outcomes Renal effects Weight effects Cost Combination therapy Classes SGLT-2 Inhibitors (Oral) Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Ertugliflozin (Steglatro) GLP-1 Agonists (SQ) Albiglutide (Tanzeum) Dulaglutide (Trulicity) Exenatide (Byetta) Exenatide ER (Bydureon) Liraglutide (Victoza) Lixisenatide (Adlyxin) Semaglutide (Ozempic) DPP-4 Inhibitors (Oral) Alogliptin (Nesina) Linagliptin (Tradjenta) Saxagliptin (Onglyza) Sitagliptin (Januvia) 4

5 SGLT-2 Inhibitors: Mechanism of Action Adapted from Edward C. Chao Clin Diabetes 2014;32:4-11 SGLT-2 Inhibitors: flozins Efficacy with metformin Warnings and precautions % 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) 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 GLP-1 Agonists: Mechanism of Action Meier JJ. Nat Rev Endocrinol. 2012;8:

6 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 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: Administration Albiglutide (Tanzeum) Dulaglutide (Trulicity) Exenatide (Byetta) Exenatide ER (Bydureon) Liraglutide (Victoza) Lixisenatide (Adlyxin) Semaglutide (Ozempic) Twice daily dosing Once daily dosing Weekly Dosing DPP-4 Inhibitors: Mechanism of Action DPP-4i enzyme inactivates GLP-1 DPP-4i inhibitors block DPP-4i the DPP-4i inhibitors enzyme block the DPP-4i enzyme Adapted from Strucker DJ. Diabetes Care. 2007;30:

7 DPP-4 Inhibitors: gliptins Efficacy with metformin Warnings and precautions % 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) Outcomes 7

8 Cardiovascular Outcomes 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 Jan; 41(1):14-31 Completed and Ongoing CVOTs EXAMINE TECOS CARMELINA CAROLINA Dapa- HF CREDENCE DECLARE VERTIS -TIMI 58 CV EMPEROR- Reduced REWIND Dapa- CKD EMPEROR- Preserved EMPA-REG PIONEER 6 OUTCOME LEADER CANVAS PROGRAM SGLT2i ELIXA SUSTAIN-6 EXSCEL GLP-1 DPP-4i FREEDOM-CVO HARMONY Adapted from Cefalu Jan;41(1):14-31 Outcomes et al. Dia Care 2018 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) Mean age (years) Mean BMI (kg/m 2 ) Previous CV disease (%) > Mean A1c (%) Mean duration of diabetes (years) >10 (>57%) Zinman et al. N Engl J Med Nov 26;373: Ṅeal et al. N Engl J Med 2017; 377: Wiviott, SD et al. N Engl J Med Nov 10. DECLARE-TIMI 58 (dapagliflozin) 8

9 Baseline Characteristics for GLP-1 Agonist ELIXA (lixisenatide) EXSCEL (exenatide) HARMONY Outcomes (albiglutide) LEADER (liraglutide) N 6,068 14,752 9,463 9,340 3,297 Median duration (years) Mean age (years) Mean BMI (kg/m 2 ) Previous CV disease (%) Mean A1c (%) Mean duration of diabetes (years) SUSTAIN-6 (semaglutide) Pfeffer MA et al. N Engl J Med Dec 3;373(23): Holman et al. N Engl J Med Sep 28;377(13): Marso et al. N Engl J Med 2016;375: Holman et al. N Engl J Med Sep 28;377(13): Marso et al. N Engl J Med 2016; 375: Hernandez et al. Lancet Oct 1. pii: S (18)32261-X 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) Mean age (years) Mean BMI (kg/m 2 ) Previous CV disease (%) Mean A1c (%) Mean duration of diabetes (years) Rosenstock J et al. JAMA Nov 9. Green JB et al. N Engl J Med Jul 16;373(3): White WB et al. Am Heart J Oct;162(4): Scirica et al. N Engl J Med Oct 3;369(14): ASCVD Benefit Trial Results (SGLT-2i) Results Primary Composite CV death Fatal/Non-Fatal MI EMPA-REG OUTCOME (empagliflozin vs. 10.5% vs.12.1% HR % CI % vs. 5.9% HR % CI % vs. 5.4% HR % CI CANVAS Program (canagliflozin vs. *participants per 1000 patient-years 26.9 vs 31.5 HR % CI vs HR % CI vs HR % CI Fatal/Non-Fatal Stroke 3.5% vs. 3.0% HR % CI All Cause Mortality 5.7% vs. 8.3% HR % CI vs. 9.6% HR % CI vs HR % CI

10 ASCVD Benefit Trial Results (GLP-1s) EXSCEL (exenatide ER vs. HARMONY Outcomes (albiglutide vs. LEADER (liraglutide vs. SUSTAIN-6 (semaglutide vs. Results Primary Composite 11.4% vs. 12.2% HR % CI % vs. 9% HR % CI % vs. 14.9% HR % CI % vs. 8.9% HR % CI CV death 4.6% vs. 5.2% HR % CI % vs. 3% HR % CI % vs. 6.0 HR % CI % vs. 2.8% HR % CI Fatal/Non-Fatal MI 6.6% vs. 6.7% HR % CI % vs. 5% HR % CI % vs. 7.3% HR % CI *non-fatal MI only 2.9% vs 3.9% HR % CI Fatal/Non-Fatal Stroke 2.5% vs. 2.9% HR % CI % vs. 2% HR % CI % vs. 4.3% HR % CI *non-fatal stroke only 1.6% vs. 2.7% HR % CI All Cause Mortality 6.9% vs. 7.9% HR % CI % vs. 4% HR % CI % vs. 9.6% HR % CI % vs. 3.6% HR % CI ASCVD Neutral Trial Results *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. Results Primary Composite 8.8% vs. 9.4% HR % CI % vs. 13.2% HR % CI % vs. 12.1% HR % CI % vs. 11.8% HR 0.96 Upper level of 95% CI % vs. 7.2% HR % CI % vs. 9.6% HR % CI CV death 2.9% vs. 2.9% HR % CI % vs. 5.2% HR % CI % vs. 7.6% HR % CI % vs. 4.9% HR % CI % vs. 2.9% HR % CI % vs. 5.0% HR % CI Fatal/Non- Fatal MI *ischemic stroke only 2.7% vs. 2.7% HR % CI % vs. 8.6% HR % CI % vs. 4.2% HR % CI *non-fatal only 6.9% vs. 6.5% HR % CI % vs. 3.4% HR % CI % vs. 4.3% HR % CI Fatal/Non- Fatal Stroke 4.6% vs. 5.1% % CI % vs. 2.0% HR % CI % vs. 2.5% HR % CI *non-fatal only 1.1% vs. 1.2% HR % CI *ischemic stroke only 1.95 vs. 1.7% HR % CI % vs. 2.5% HR % CI All Cause Mortality 6.2% vs. 6.6% HR % CI % vs. 7.4% HR % CI % vs. 10.7% HR % CI % vs. 6.5% HR % CI % vs. 4.2% HR % CI % vs. 7.3% HR % CI Systematic Review and Meta-analysis CV mortality, 56 trials Treatment Comparator HR (95% CI) DPP-4i 1.00 ( ) GLP-1 vs. Control 0.85 ( ) SGLT-2i 0.79 ( ) Control 1.00 ( ) GLP-1 vs. DPP-4i 0.85 ( ) SGLT-2i 0.79 ( ) Control 1.17 ( ) DPP-4i vs. GLP ( ) SGLT-2i 0.93 ( ) Control 1.27 ( ) DPP-4i vs. SGLT-2i 1.27 ( ) GLP ( ) Favors Treatment Favors Comparator Zheng SL et al. JAMA Apr 17;319(15): HR (95% CI) 10

11 Systematic Review and Meta-analysis All-cause mortality, 97 trials Treatment Comparator HR (95% CI) DPP-4i 1.02 ( ) GLP-1 vs. Control 0.88 ( ) SGLT-2i 0.80 ( ) Control 0.98 ( ) GLP-1 vs. DPP-4i 0.86 ( ) SGLT-2i 0.78 ( ) Control 1.14 ( ) DPP-4i vs. GLP ( ) SGLT-2i 0.91 ( ) Control 1.25 ( ) DPP-4i vs. SGLT-2i 1.28 ( ) GLP ( ) Favors Favors Treatment Comparator 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 11

12 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 Results (SGLT-2i) Results HF Hospitalization EMPA-REG OUTCOME (empagliflozin vs. 2.7% vs. 4.1% HR % CI CANVAS Program (canagliflozin vs. *participants per 1000 patient-years 5.5 vs. 8.7 HR % CI DECLARE-TIMI 58 (dapagliflozin vs. 2.5% vs. 3.3% HR % CI

13 HF Risk Results (DPP-4i) Results SAVOR-TIMI 53 (saxagliptin vs. HF Hospitalization 3.5% vs. 2.8% HR % CI HF Neutral Results (GLP-1) *results not significant Results ELIXA (lixisenatide vs. EXSCEL (exenatide ER vs. HARMONY Outcomes (albiglutide vs. LEADER (liraglutide vs. SUSTAIN-6 (semaglutide vs. HF Hospitalization 4.0% vs. 4.2% HR % CI % vs. 3.1% HR % CI Not reported 4.7% vs. 5.3% HR % CI % vs. 3.3% HR % CI HF Neutral Results (DPP-4i) *results not significant CARMELINA (linagliptin vs. TECOS (sitagliptin vs. EXAMINE (alogliptin vs. Results HF Hospitalization 6% vs. 6.5% HR % CI % vs. 3.1% HR % CI % vs. 3.3% HR % CI Systematic Review and Meta-analysis HF events, 58 trials Treatment Comparator HR (95% CI) DPP-4i 1.13 ( ) GLP-1 vs. Control 0.93 ( ) SGLT-2i 0.62 ( ) Control 0.88 ( ) GLP-1 vs. DPP-4i 0.82 ( ) SGLT-2i 0.55 ( ) Control 1.08 ( ) DPP-4i vs. GLP ( ) SGLT-2i 0.67 ( ) Control 1.60 ( ) DPP-4i vs. SGLT-2i 1.81 ( ) GLP ( ) Favors Treatment Favors Comparator HR (95% CI) 13

14 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) Perkovic V et al. Lancet Diabetes Endocrinol Sep;6(9): 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 ) HR 0.62 (95% CI ) HR 0.56 (95% CI ) HR 0.45 (95% CI ) HR 0.60 (95% CI ) HR 0.58 (95% CI ) HR 0.50 (95% CI ) Composite: worsening nephropathy HR 0.76 (95% CI ) 14

15 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 Janssen Research & Development, LLC. 16 Jul available at Accessed 10/29/18. GLP-1 Agonists Evidence From CVOTs Study Outcome Result LEADER (liraglutide) Composite: worsening nephropathy New onset macroalbuminuria HR 0.78 (95% CI ) HR 0.74 (95% CI ) SUSTAIN-6 (semaglutide) Composite: worsening nephropathy New onset macroalbuminuria HR 0.64 (95% CI ) HR 0.54 (95% CI ) Mann JFE et al. N Engl J Med Aug 31;377(9): DPP-4 Inhibitor Evidence From CVOTs Study Outcome Result SAVOR-TIMI 53 (saxagliptin) Composite: worsening nephropathy HR 1.08 (95% CI ) CARMELINA (linagliptin) Composite: worsening nephropathy HR 0.98 (95% CI ) 15

16 Renal Dose Adjustments SGLT-2 Inhibitors Agent Renal Dose Adjustment (egfr ml/minute/1.73 m 2 ) Canagliflozin 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 Dulaglutide Exenatide Exenatide ER Liraglutide Lixisenatide Semaglutide None None CrCl <30 or ESRD: do not use CrCl <30 or ESRD: do not use None egfr <15 or ESRD: do not use None 16

17 DPP-4 Inhibitors Agent Renal Dose Adjustment (CrCl ml/minute; egfr ml/minute/1.73 m 2 ) Alogliptin 25 mg daily Linagliptin Saxagliptin 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 17

18 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: kg at 2 years (95% CI 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 Nov-Dec;29(8): Vilsbøll T et al. BMJ Jan 10;344:d7771. Gurgle, HE et al. Vasc Health Risk Manag. 2016;12:

19 Change in Weight (kg) 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 * p = not significance; ** not significant between dulaglutide 1.5 and exenatide twice daily; $ -6 p<0.0001; ^p = dulaglutide 0.75 mg vs. exenatide twice daily; + p < ; p = not Dar, S et al. Practical Diabetes 32;8: b. reported for weight difference; ++ p = Pratley RE et al. Lancet Diabetes Endocrinol Apr;6(4): Cost Class Agent AWP ($) for 30 day supply (as of 11/26/2018) SGLT-2 inhibitors Canagliflozin 100 & 300 mg/day Dapagliflozin 5 &10 mg/day Empagliflozin 10 & 25 mg/day Ertugliflozin 5 & 15 mg/day GLP-1 agonists Albiglutide 30 & 50 mg/week Dulaglutide 0.75 & 1.5 mg/week Exenatide 5 & 10 mcg twice daily Exenatide ER 2 mg/week (all dosage forms) Liraglutide 1.8 mg/day Lixisenatide 20 mcg/day Semaglutide 0.5 & 1 mg/week DPP-4 inhibitors Alogliptin 6.25, 12.5 & 25 mg/day Linagliptin 5 mg/day Saxagliptin 2.5 & 5 mg/day Sitagliptin 25, 50 & 100 mg/day

20 Combination Therapies SGLT-2 Inhibitor + DPP-4 Inhibitor Study design Systematic review and meta-analysis of SGLT-2i + DPP-4i vs. SGLT-2i vs. DPP-4i N=4,828 from 14 RCTs Outcomes Combo therapy vs. SGLT- 2i vs. DPP-4i A1c from baseline: -0.31% (95% CI to -0.24%) vs % (95% CI -0.80% to -0.61%) Body weight: -0.36kg (95% CI to 1.19kg) vs kg (95% CI to kg) SBP: -0.04mmHg (95% CI to -1.49mmHg) vs. -5.9mmHg (95% CI to -2.95mmHg) Li D et al. Diabetes Obes Metab Aug;20(8): SGLT-2 Inhibitor + GLP-1 Agonist Study design Endpoints Outcomes Combo therapy vs. exenatide or dapagliflozin Randomized, double blind trial comparing exenatide ER + dapagliflozin vs. exenatide or dapagliflozin alone N=695 for 28 weeks 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 Frías JP et al. Lancet Diabetes Endocrinol Dec;4(12):

21 SGLT-2 Inhibitor + Insulin Study design Meta-analysis determining safety and efficacy of a SGLT- 2i + insulin vs. insulin + placebo N=4,235 from 7 RCTs Outcomes SGLT-2i + insulin vs. placebo Reduction in A1c: -0.56% (95% CI to -0.44%) Weight loss: kg (95% CI to -2.16kg) Insulin dose: units (95% CI to units) Severe Hypoglycemia: RR 1.24 (95% CI 0.91 to 1.70) Tang H et al. Diabetes Obes Metab Jan;19(1): GLP-1 Agonist + Insulin Study design Systematic review and meta-analysis comparing GLP-1 + basal insulin vs. other glucose-lowering treatments N=4,348 from 15 RCTs Outcomes GLP-1 + insulin vs. other A1c from baseline: -0.44% (95% CI to -0.29%) Compared to basal-bolus: -0.1% (95% CI to 0.02%) Weight loss: 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 ) Compared to basal-bolus: RR 0.67 (95% CI ) Eng et al. Lancet Dec 20;384(9961): 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) 21

22 Putting It All Together 2019 ADA STANDARDS OF MEDICAL CARE IN DIABETES American Diabetes Association. Diabetes Care 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 If A1c still above goal in 3-6 months Consider adding the other class with CVD benefit (SGLT-2i or GLP-1) DPP4-i if not on a GLP-1 empagliflozin > canagliflozin liraglutide > semaglutide > exenatide ER 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 above goal in 3-6 months Add the other class with proven CVD benefit DPP-4i (not saxagliptin) in the setting of HF if not on a GLP-1 empagliflozin > canagliflozin liraglutide > semaglutide > exenatide ER 22

23 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 DPP-4i, 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 SGLT-2i Intermediate Fournier s gangrene Amputation: canagliflozin Bone fx: canagliflozin Bladder cancer: dapagliflozin ASCVD and HF benefit: canagliflozin, empagliflozin HF benefit: dapagliflozin Benefit: canagliflozin, empagliflozin Loss High GLP-1 High Thyroid C-cell tumor: albiglutide, dulaglutide, exenatide ER, liraglutide Retinopathy: semaglutide?acute pancreatitis ASCVD benefit: liraglutide Macroalbuminuira benefit: liraglutide, semaglutide Loss High DPP-4i Intermediate Joint pain?acute pancreatitis Potential HF risk: saxagliptin, alogliptin (FDA warning) Neutral Neutral High 23

24 Questions? 24