Metformin although effective has become obsolete

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4 Metformin although effective has become obsolete Does not address core needs as well as other agents (ominous octet) Does not address metabolic parameters (blood pressure, Hgb A1C) as well as other agents Micro and Macrovascular benefits not as robust as other agents Mortality data not as promising as other agents

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11 Case Presentation 62 y/o female T2DM, hypertension, hyperlipidemia. Hx MI, T2DM 15 years Rxed metformin 1000 mg daily, linagliptin 5 mg daily, glargine insulin 46 units daily Other meds rosuvastatin 20 mg daily, lisinopril 10 mg daily Px 130/80 Ext DPN no ret. BMI 32 Labs A1C 8.4% egfr 64 cc/min Glycemic profile mean 160, lowest 122, highest 242 acb and acd smbg. Lipids TC 142 LDL-C 68, HDL-C 46, TG 124, Other labs negative

12 All-cause mortality hazard ratio A1C and Mortality in Clinical Practice Retrospective Cohort Study (N=27,965) A1C (%) Currie CJ, et al. Lancet. 2010;375:

13 Con t What therapeutic choices? 1. uptitrate metformin 2. add SU 3. substitute GLP-1 for linagliptin 4. add SGLT-2 inhibitor 5. Increase glargine insulin 6. split dose glargine insulin 7. begin mealtime insulin 8. start patch pump (VGO) 9. start insulin pump 10. revisit lifestyle modification assess adherence

14 GLP-1 Receptor Agonists 14

15 GLP1 Receptor Agonists FDA-Approved Agents Albiglutide* Dulaglutide Exenatide Exenatide ER Liraglutide Lixisenatide Semiglutide Key Features Subcutaneous administration Mimic action of native GLP1 Increase glucose-dependent insulin secretion Suppress glucagon production Slow gastric emptying ER, extended release; GLP1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 2016;22:

16 Therapeutic Potential of Enhancing GLP-1 Activity: GLP-1 Receptor Agonists and DPP-4 Inhibitors Two classes of agents have been developed based on the therapeutic potential of enhancing GLP-1 activity 1 GLP-1 receptor agonists: agents that mimic the actions of GLP-1 Protease DPP-4 inhibitors: agents that prolong the activity of endogenous GLP-1 GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4 1. Garber. Rev Diabet Stud 2011;8:307-22

17 Glucoregulatory Role of GLP-1 and GIP Effects in Humans On ingestion of food: GLP-1 secreted by L-cells, GIP secreted by K-cells β-cell workload Promotes satiety and reduces appetite β-cell response β-cells: enhance glucose-dependent insulin secretion GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide 1. Flint et al. J Clin Invest 1998;101: Larsson et al. Acta Physiol Scand 1997;160: Nauck et al. Diabetologia 1996;39: Drucker. Diabetes 1998;47: cells: Postprandial glucagon secretion Liver: Insulin/glucagon: reduces hepatic glucose output Stomach: slows gastric emptying

18 GLP-1 Has a Broad Range of Biological Activity Cardiovascular System 1 Cardiovascular risk factors Weight Blood pressure Lipid profile Intestine Brain Appetite 1 Satiety 2 Stomach Gastric emptying 1 Liver Glucose production 2 GLP-1 Direct actions Indirect actions Muscle and Adipose Tissue Glucose uptake 2 Pancreas Insulin secretion 1 Glucagon secretion 3 1. Smilowitz et al. Circulation. 2014;129(22): Gupta. Indian J Endocrinol Metab. 2013;17(3): Kalra S, et al. Indian J Endocrinol Metab. 2016;20(2):

19 A1C (%) Glucose Reduction DPP4 Inhibitors, GLP1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin (Absolute Changes from Baseline; Not Head-to-Head Trials) DPP4 Inhibitors GLP1 Receptor Agonists SGLT2 Inhibitors Alo 1 Lin 2 Sax 3 Sit 4 Alb 5 Dul 6 Exe 7 Exe ER 8 Lir 9 Can 10 Dap 11 Emp 12 Baseline A1C (%) Nauck MA, et al. Int J Clin Pract. 2009;63: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: DeFronzo RA, et al. Diabetes Care. 2009;32: Charbonnel B, et al. Diabetes Care. 2006;29: Ahrén B, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37:

20 Mean (SE) AUC for Visual Analog Score (mm) vs. Time (hour) 6-Week Continuous GLP-1 Infusion Increases Satiety and Reduces Food Intake Sensations of appetite in patients treated with GLP Satiety Fullness Prospective food intake Hunger *p=.03 for Satiety p=.008 p=.007 p= Time (week) GLP-1=glucagon-like peptide-1; AUC=area under curve Mean±SE; N=10; Only data of patients treated with GLP-1 shown Overall p values labeled for each sensation; *Only significant for week 0 vs week 1 after Bonferroni test Zander et al. Lancet 2002;359:

21 Weight (kg) Weight Reduction DPP4 Inhibitors, GLP1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin (Separate Studies; Not Head-to-Head Trials) DPP4 Inhibitors GLP1 Receptor Agonists SGLT2 Inhibitors Alo 1 Lin 2 Sax 3 Sit 4 Alb 5 Dul 6 Exe 7 Exe ER 8 Lir 9 Can 10 Dap 11 Emp NR NR, not reported. 1. Nauck MA, et al. Int J Clin Pract. 2009;63: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: DeFronzo RA, et al. Diabetes Care. 2009;32: Charbonnel B, et al. Diabetes Care. 2006;29: Ahrén B, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37:

22 Safety Considerations with GLP1 Receptor Agonists GI adverse events Pancreatitis Pancreatic cancer Medullary thyroid cancer Renal impairment ER, extended release. Common Usually dose dependent and transient Usually reduced with dose titration Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected Labeling for GLP1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Further assessments required from long duration-controlled studies or epidemiological databases Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking Labeling for albiglutide, dulaglutide, exenatide ER, and liraglutide: Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid tumors Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia syndrome type 2 Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide should not be used in patients with severe renal insufficiency or ESRD. Liraglutide was found to be safe in patients with moderate renal impairment and may confer a beneficial effect. Garber AJ, et al. Endocr Pract. 2016;22: ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28, Davies MJ, et al. Diabetes Care. 2016;39: Marso SP, et al. N Engl J Med. 2016;375:

23 Approved GLP-1 RAs Structure and Half-life Exenatide BID Liraglutide Exenatide QW Lixisenatide Albiglutide Semaglutide Dulaglutide DPP-4 Resistant to DPP-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS DPP-4 Partial resistant to DPP-4 HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG Albumin C-16 free fatty acid derivative via a glutamoyl spacer DPP-4 Resistant to DPP-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS Poly (D,L lactic-co-glycolic acid) microspheres DPP-4 Resistant to DPP-4 HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK DPP-4 Resistant to DPP-4 HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR DPP-4 DPP-4 Resistant to DPP-4 Resistant to DPP-4 HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG Recombinant fusion protein linked to human albumin Albumin HGEGTFTSDVSSYLEGQAAKEFIAWLVRGRG C-18 free fatty acid derivative Albumin via a glutamoyl-2xoeg spacer Modified IgG4 Fc domain Modified IgG4 Fc domain t 1/2 = hours and renal filtration t 1/2 = hours and multiple organ filtration Steady state over 6-7 weeks and renal filtration t 1/2 = ~3 hours and renal filtration t 1/2 = ~ 5 days and multiple organ filtration t 1/2 = 165 hours t 1/2 = ~5 days

24 Currently Available GLP-1 RAs Administration DAILY WEEKLY Reconstitution required Pre-injection waiting time after reconstitution Ready-to-use solution Exenatide BID 1 Lixisenatide 2 Liraglutide 3 Albiglutide 4 Dulaglutide 5 EQW Pen 6 EQW Bcise 7 Semaglutide 8 No No No Yes No Yes No ǂ No None None None 15 min/30 min (30 mg/50 mg Pen) Yes Yes Yes Reconstitution within device None None None None Yes Reconstitution within device Mix within device Yes Dose volume 0.02 ml (5 mg) 0.04 ml (10 mg) 0.20 ml (10 mg) 0.20 ml (20 mg) 0.20 ml (1.2 mg) 0.30 ml (1.8 mg) 0.50 ml (30 mg) 0.50 ml (50 mg) 0.50 ml (0.75 mg) 0.50 ml (1.5 mg) 0.65 ml (2 mg) 0.85 ml (2 mg) 0.75 ml (1 mg) ml (0.5 mg) (0.25 mg) Titration required Yes* Yes Yes Yes* No No No Yes Single-use/multi-use Multi-use Multi-use Multi-use Single-use Single-use Single-use Single-use Multi-use Hidden needle No No No No Yes No Yes No Needle attachment required Needle size (mm)/gauge Yes Yes Yes Yes No Yes No Yes 4 mm g Supplied separate 4 mm g Supplied separate 4 mm 32 g Supplied separate 5 mm / 29 g Unknown supply 5 mm / 29 g Pre-staked Unknown / 23 g Unknown supply Unknown 4-8 mm / 32 g 4mm needles enclosed Auto needle retraction No No No No Yes No No No Dose confirmation Visual Visual Visual Audible Visual/audible Audible Visual Audible/(Tactile) *Titrate if necessary; When administered in the prefilled pen, exenatide QW does not require reconstitution; however when administered in the single-dose kit, reconstitution is needed; ǂ shake the autoinjector hard in up and down motion until the medicine is mixed evenly. If you do not see any white medicine along the sides, bottom or top then shake for at least 15 seconds; BD=Becton Dickinson; QW=once weekly. 1. Byetta [Prescribing Information]. San Diego, CA: Amylin Pharmaceuticals, LLC; Adlyxin [Prescribing Information]. Bridgewater, NJ: Sanofi-Aventis; Victoza [Prescribing Information]. Plainsboro, NJ: Novo Nordisk A/S; Tanzeum [Prescribing Information]. Research Triangle Park, NC: GlaxoSmithKline LLC; Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; Bydureon [Summary of Product Characteristics]. AstraZeneca AB SE Södertälje Sweden; Bydureon Bcise [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; Ozempic [Prescribing Information]. Plainsboro, NJ: Novo Nordisk A/S; 2017

25 Overview of Approved GLP 1 Receptor Agonists GLP-1 receptor agonists subcutaneously administered peptides Human GLP-1 backbone Exendin-4 backbone Weekly Once daily Weekly Once daily or Twice daily Albiglutide Liraglutide Exenatide Exenatide Twice daily Dulaglutide Lixisenatide Once daily Semaglutide Click here for more details on the backbone of GLP-1 analog GLP-1=glucagon-like peptide-1 Madsbad et al. Diabetes Obes Metab 2011;13(5):

26 GLP-1 RAs: Key Efficacy and Safety GLP-1 RAs HbA 1c Effective in lowering HbA 1c 1,2,3 Weight Potential for weight loss 1,2,3 Hypoglycaemia Low potential for incidents 1,2 GI adverse events Nausea, diarrhoea, and vomiting that are mild to moderate in severity and transient in nature 2,4 1. Karagiannis T, et al. Diabetes Obes Metab. 2015;17(11): Liu FP, et al. J Diabetes. 2015;7(3): Singh S, et al. Diabetes Obes Metab. 2017;19(2): Prasad-Reddy L, et al. Drugs Context. 2015;9(4). DOI: /dic

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31 AVAILABLE BASAL INSULINS NPH Glargine Toujeo (Glargine U300) Levemir Degludec (Tresiba U100 and U200) 31

32 Copyright 2018 Eli Lilly and Company Structural Forms of the Insulin Polypeptide Insulin Monomers This is the active form of Insulin that circulates in blood and binds to the insulin receptor Insulin Hexamers Composed of 6 monomers These are the storage form of insulin both in the β-cell and in insulin vials Meah F and Juneja R. Med Clin North Am 2015;99:157-86

33 Relative Insulin Effect Insulin Detemir: Mechanism of Sustained Release and PK/PD 1 Soluble, long-acting basal human insulin analog Mechanism of Sustained Release Delayed absorption due to selfassociation of the drug molecules upon injection; delayed distribution to peripheral target tissues because of binding to albumin Half-life: 5-7 hours Relatively constant, reduced peak concentration-time profile Median duration of action was 7.6 to >24 hours Comparison of Time-Action Profile of Single Doses of Insulin Detemir and Insulin Glargine 2 Insulin Detemir Insulin Glargine 1. Levemir [Prescribing Information] Data from Pettus J et al. Diabetes Metab Res Rev 2015 Sep;32(6): Copyright 2018 Eli Lilly and Company Time (Hours)

34 Clinical Outcomes with Insulin Degludec DEVOTE Study Design N=7637 patients with T2D at high risk of CV events Age 50 years with with CVD or renal disease Age 60 years with 1 CV risk factor Randomization Degludec: n=3818 Glargine: n=3819 Noninferiority study: prespecified margin <1.3 for upper bound of 95% CI of the HR for the primary endpoint; superiority tested if noninferiority criterion met Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke Key secondary endpoints Adjudicated severe hypoglycemia Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina All-cause death CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; DEVOTE, Trial Comparing Cardiovascular Safety of Insulin Degludec With Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events; HR, hazard ratio; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2017;377:

35 Clinical Outcomes with Insulin Degludec and Glargine DEVOTE CV Outcomes (N=7637) Median follow-up: 1.99 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.91 ( ) <0.001 (NI) Expanded composite endpoint 0.92 ( ) 0.22 All-cause death 0.91 ( ) 0.35 Noncardiovascular death 0.84 ( ) 0.28 CV death 0.96 ( ) 0.71 CV death excluding undetermined cause of death 0.91 ( ) 0.52 Nonfatal MI 0.85 ( ) 0.15 Nonfatal stroke 0.90 ( ) 0.50 Unstable angina hospitalization 0.95 ( ) 0.74 *CV death, nonfatal MI, or nonfatal stroke; Confirmed noninferiority; superiority, P=0.21. CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina. CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; NI, noninferiority. Marso SP, et al. N Engl J Med. 2017;377: Favors degludec Favors glargine 35

36 Clinical Outcomes with Insulin Degludec and Glargine DEVOTE Safety Outcomes (N=7637) Median follow-up: 1.99 years Hazard ratio (95% CI) P value Severe hypoglycemia* 0.60 ( ) <0.001 Unconsciousness or coma 0.81 ( ) 0.28 Seizure 1.02 ( ) 0.97 Nocturnal severe hypoglycemia 0.47 ( ) < severe hypoglycemia event 0.73 ( ) < Favors degludec Favors glargine *Episode requiring assistance from another person to actively administer carbohydrate or glucagon or take other corrective actions. CI, confidence interval. Marso SP, et al. N Engl J Med. 2017;377:

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39 Insulin Therapy in T2DM The progressive nature of T2DM should be regularly and objectively explained to T2DM patients. Avoid using insulin as a threat, describing it as a failure or punishment. Give patients a self-titration algorithm. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85

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41 Pharmacologic Therapy For T2DM: Recommendations (2) Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed T2DM who are symptomatic and/or have A1C >10% and/or blood glucose levels 300 mg/dl. E Consider initiating dual therapy in patients with newly diagnosed T2DM who have A1C >9%. E Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85

42 Combination Injectable Therapy in T2DM Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85

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