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Glycemic Management in Type 2 Diabetes Efficacy and Safety of Antihyperglycemic Therapies Introduced Since 2004 1.

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Presentation on theme: "Glycemic Management in Type 2 Diabetes Efficacy and Safety of Antihyperglycemic Therapies Introduced Since 2004 1."— Presentation transcript:

1 Glycemic Management in Type 2 Diabetes Efficacy and Safety of Antihyperglycemic Therapies Introduced Since

2 DPP-4 Inhibitors 2

3 FDA-Approved Agents Alogliptin Linagliptin Saxagliptin Sitagliptin Key Features Oral administration Increase endogenous GLP-1 and GIP levels Increase glucose-dependent insulin secretion Suppress glucagon production DPP-4 Inhibitors 3 DPP-4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

4 MonotherapyAdd-on to MetforminAdd-on to SU Alo 1 Lin 2 Sax 3 Sit 4 Alo 5 Lin 6 Sax 7 Sit 8 Alo 9 Lin 10, *Sax 11 Sit 12,† Baseline A1C (%) Glucose Control with DPP-4 Inhibitors Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) *SU + metformin. † With or without metformin. ‡ Absolute change from baseline (active-controlled trial). 1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315– Del Prato S, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Nauck MA, et al. Diabetes Obes Metab. 2007;9: 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: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Owens DR, et al. Diabet Med. 2011;28: Chacra AR, et al. Int J Clin Pract. 2009;63: Hermansen K, et al. Diabetes Obes Metab. 2007;9: Placebo-adjusted  A1C (%) ‡

5 MonotherapyAdd-on to MetforminAdd-on to SU Alo 1 Lin 2 Sax 3 Sit 4 Alo 5 Lin 6 Sax 7 Sit 8 Alo 9 Lin 10, *Sax 11 Sit 12,† Weight Change with DPP-4 Inhibitors Absolute Change from Baseline (Not Head-to-Head Trials) NR, value not reported. *SU + metformin. † With or without metformin. 1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315– Del Prato S, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Nauck MA, et al. Diabetes Obes Metab. 2007;9: 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: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Owens DR, et al. Diabet Med. 2011;28: Chacra AR, et al. Int J Clin Pract. 2009;63: Hermansen K, et al. Diabetes Obes Metab. 2007;9:  Weight (kg) NR

6 MonotherapyAdd-on to MetforminAdd-on to SU Alo 1 Lin 2 Sax 3 Sit 4 Alo 5 Lin 6 Sax 7 Sit 8 Alo 9 Lin 10, *Sax 11 Sit 12,† Hypoglycemia with DPP-4 Inhibitors Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) NR, value not reported. *SU + metformin. † With or without metformin. 1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315– Del Prato S, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Nauck MA, et al. Diabetes Obes Metab. 2007;9: 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: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Owens DR, et al. Diabet Med. 2011;28: Chacra AR, et al. Int J Clin Pract. 2009;63: Hermansen K, et al. Diabetes Obes Metab. 2007;9: Patients (%) NR

7 Safety Considerations with DPP-4 Inhibitors GI adverse events Minimal Pancreatitis 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 Pancreatic cancer 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 Renal impairment Kidney function monitoring and dose reduction required for alogliptin, saxagliptin, and sitagliptin when used in patients with moderate-to-severe renal impairment Linagliptin does not require dose adjustment or periodic monitoring of drug-related kidney function Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. 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,

8 Monotherapy 26 Weeks 1 Initial Combo w/ Pioglitazone 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Glyburide 26 Weeks 4 Add-on to Met + Pio 52 Weeks 5 Add-on to Insulin +/- Met 26 Weeks 6 N TreatmentPBOAloPioAloAlo + Pio MetAlo + Met GlyAlo + Gly Met+ Pio Alo+ Met+ Pio Ins+/- Met Alo+ Ins+/- Met Baseline A1C (%) P<0.001 vs comparator(s). 1.DeFronzo RA, et al. Diabetes Care. 2008;31:2315– Rosenstock J, et al. Diabetes Care. 2010;33:2406– Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Bosi E, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Diabetes Obes Metab. 2009;11: Glucose Control With Alogliptin  A1C (%) * * * * * *

9 P<0.01 vs comparator. 1.DeFronzo RA, et al. Diabetes Care. 2008;31:2315– Rosenstock J, et al. Diabetes Care. 2010;33:2406– Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Bosi E, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Diabetes Obes Metab. 2009;11: Weight Change With Alogliptin Monotherapy 26 Weeks 1 Initial Combo w/ Pioglitazone 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Glyburide 26 Weeks 4 Add-on to Met + Pio 52 Weeks 5 Add-on to Insulin +/- Met 26 Weeks 6 N TreatmentPBOAloPioAloAlo + Pio MetAlo + Met GlyAlo + Gly Met+ Pio Alo+ Met+ Pio Ins+/- Met Alo+ Ins+/- Met  Weight (kg) *

10 1.DeFronzo RA, et al. Diabetes Care. 2008;31:2315– Nesina (alogliptin) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; Nauck MA, et al. Int J Clin Pract. 2009;63: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Bosi E, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Diabetes Obes Metab. 2009;11: Hypoglycemia With Alogliptin Monotherapy 26 Weeks 1,2 Add-on to Metformin 26 Weeks 3 Add-on to Glyburide 26 Weeks 4 Add-on to Met + Pio 52 Weeks 5 Add-on to Insulin +/- Met 26 Weeks 6 N TreatmentPBOAloMetAlo + Met GlyAlo + Gly Met+ Pio Alo+ Met+ Pio Ins+/- Met Alo+ Ins+/- Met Patients Reporting Hypoglycemia (%)

11 Alogliptin: Warnings and Adverse Events Nesina (alogliptin) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; Adverse Events*Patients (%) Alogliptin 25 mg (n=5902) Placebo (n=2926) Active comparator (n=2257) Nasopharyngitis Headache Upper respiratory tract infection *Occurring in ≥4% of patients receiving alogliptin 25 mg and more commonly than in placebo-treated patients.

12 Monotherapy 24 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Initial Combo w/ Pioglitazone 24 Weeks 3 Add-on to Metformin 24 Weeks 4 Add-on to Metformin 2 Years 5 Add-on to Metformin + SU 24 Weeks 6 N TreatmentPBOLin Met HD Lin + Met LD Lin + Met HD PioLin + Pio MetLin + Met Glim + Met Lin + Met Met + SU Lin + Met + SU Baseline A1C (%) * P< vs comparator. † P< vs placebo and vs metformin 1000 mg twice daily. HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily). 1. Del Prato S, et al. Diabetes Obes Metab. 2011;13: Haak T, et al. Diabetes Obes Metab. 2012;14: Gomis R, et al. Diabetes Obes Metab. 2011;13: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: Gallwitz B, et al. Lancet. 2012;380: Owens DR, et al. Diabet Med. 2011;28: Glucose Control With Linagliptin  A1C (%) * * * * †

13 Initial Combo w/ Metformin 24 Weeks 1 Initial Combo w/ Pioglitazone 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Metformin 2 Years 4 N TreatmentLinMet HD Lin + Met LD Lin + Met HD PioLin + Pio MetLin + Met Glim + Met Lin + Met Weight Changes With Linagliptin  Weight (kg) * P< vs comparator. HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily). 1. Haak T, et al. Diabetes Obes Metab. 2012;14: Gomis R, et al. Diabetes Obes Metab. 2011;13: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: Gallwitz B, et al. Lancet. 2012;380: *

14 Monotherapy 24 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Initial Combo w/ Pioglitazone 24 Weeks 3 Add-on to Metformin 24 Weeks 4 Add-on to Metformin 2 Years 5 Add-on to Metformin + SU 24 Weeks 6 N TreatmentPBOLin Met HD Lin + Met LD Lin + Met HD PioLin + Pio MetLin + Met Glim + Met Lin + Met Met + SU Lin + Met + SU Hypoglycemia With Linagliptin Patients Reporting Hypoglycemia (%) HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily). 1. Del Prato S, et al. Diabetes Obes Metab. 2011;13: Haak T, et al. Diabetes Obes Metab. 2012;14: Gomis R, et al. Diabetes Obes Metab. 2011;13: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: Gallwitz B, et al. Lancet. 2012;380: Owens DR, et al. Diabet Med. 2011;28:

15 Linagliptin: Warnings and Adverse Events Tradjenta (linagliptin) prescribing information. Ridgefield, CT: Boehringer Ingelheim, Inc.; Adverse Events*Patients (%) Linagliptin 5 mg (n=3625) Placebo (n=2176) Nasopharyngitis Diarrhea Cough *Occurring in ≥2% of patients receiving linagliptin 5 mg and more commonly than in placebo-treated patients.

16 Monotherapy 24 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Metformin 18 Weeks 4 Add-on to Glyburide vs Uptitration 24 Weeks 5 Add-on to TZD 24 Weeks 6 N TreatmentPBOSaxMetSax + Met MetSax + Met Sit + Met Sax + Met GlySax + Gly TZDSax + TZD Baseline A1C (%) P< vs comparator. 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25: Jadzinsky M, et al. Diabetes Obes Metab. 2009;11: DeFronzo RA, et al. Diabetes Care. 2009;32: Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26: Chacra AR, et al. Int J Clin Pract. 2009;63: Hollander P, et al. J Clin Endocrinol Metab. 2009;94: Glucose Control With Saxagliptin *  A1C (%) * * * *

17 Monotherapy 24 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Metformin 18 Weeks 4 Add-on to Glyburide vs Uptitration 24 Weeks 5 Add-on to TZD 24 Weeks 6 N TreatmentPBOSaxMetSax + Met MetSax + Met Sit + Met Sax + Met GlySax + Gly TZDSax + TZD *P=0.01 vs glyburide uptitration. 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25: Jadzinsky M, et al. Diabetes Obes Metab. 2009;11: DeFronzo RA, et al. Diabetes Care. 2009;32: Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26: Chacra AR, et al. Int J Clin Pract. 2009;63: Hollander P, et al. J Clin Endocrinol Metab. 2009;94:  Weight (kg) Weight Changes With Saxagliptin *

18 Monotherapy 24 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Metformin 18 Weeks 4 Add-on to Glyburide vs Uptitration 24 Weeks 5 Add-on to TZD 24 Weeks 6 N TreatmentPBOSaxMetSax + Met MetSax + Met Sit + Met Sax + Met GlySax + Gly TZDSax + TZD 1. Rosenstock J, et al. Curr Med Res Opin. 2009;25: Jadzinsky M, et al. Diabetes Obes Metab. 2009;11: DeFronzo RA, et al. Diabetes Care. 2009;32: Scheen AJ, et al. Diabetes Metab Res Rev. 2010;26: Chacra AR, et al. Int J Clin Pract. 2009;63: Hollander P, et al. J Clin Endocrinol Metab. 2009;94: Hypoglycemia With Saxagliptin Patients Reporting Hypoglycemia (%)

19 Saxagliptin: Adverse Events Adverse Events*Patients (%) Saxagliptin 5 mgPlacebo Headache Upper respiratory tract infection Urinary tract infection *Occurring in ≥5% of patients receiving saxagliptin 5 mg and more commonly than in placebo-treated patients. Onglyza (saxagliptin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb

20 *P<0.001 vs active comparator monotherapy. † P<0.001 vs active comparator dual therapy. 1. Nauck MA, et al. Diabetes Obes Metab. 2007;9: Goldstein BJ, et al. Diabetes Care. 2007;30: Charbonnel B, et al. Diabetes Care. 2006;29: Vilsbøll T, et al. Diabetes Obes Metab. 2010;12: Derosa G, et al. Metab Clin Exp. 2010;59: Dobs AS, et al. J Diabetes. 2013;5: Glucose Control With Sitagliptin Monotherapy vs Glipizide 52 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Insulin 24 Weeks 4 Add-on to Pioglitazone vs Met + Pio 12 Months 5 Add-on to Rosiglitazone + Metformin 54 Weeks 6 N TreatmentGlipSitMetSitSit+ Met MetSit+ Met InsSit+ Ins Met + Pio Sit + Pio Rosi + Met Sit + Rosi + Met Baseline A1C (%)  A1C (%) * * * †

21 *P<0.001 vs glipizide; † P<0.05 vs sitagliptin. 1. Aschner P, et al. Diabetes Care. 2006;29: Nauck MA, et al. Diabetes Obes Metab. 2007;9: Rosenstock J, et al. Clin Ther. 2006;28: Hermansen K, et al. Diabetes Obes Metab. 2007;9: Vilsbøll T, et al. Diabetes Obes Metab. 2010;12: Derosa G, et al. Metab Clin Exp. 2010;59:  Weight (kg) Weight Changes With Sitagliptin Monotherapy 24 Weeks 1 Monotherapy 52 Weeks 2 Add-on to Pioglitazone 24 Weeks 3 Add-on to Glimepiride 24 Weeks 4 Add-on to Insulin 24 Weeks 5 Add-on to Pio vs Met + Pio 12 Months 6 N TreatmentPBOSitGlipSitPioSit + Pio GlimSit + Glim InsSit + Ins Met + Pio Sit + Pio † *

22 1. Nauck MA, et al. Diabetes Obes Metab. 2007;9: Goldstein BJ, et al. Diabetes Care. 2007;30: Charbonnel B, et al. Diabetes Care. 2006;29: Rosenstock J, et al. Clin Ther. 2006;28: Hermansen K, et al. Diabetes Obes Metab. 2007;9: Vilsbøll T, et al. Diabetes Obes Metab. 2010;12: Hypoglycemia With Sitagliptin Sitagliptin vs Glipizide 52 weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Add-on to Metformin 24 Weeks 3 Add-on to Pioglitazone 24 Weeks 4 Add-on to Glimepiride 24 Weeks 5 Add-on to Insulin 24 Weeks 6 N TreatmentGlipSitPBOMetSit + Met MetSit + Met PioSit + Pio GlimSit + Glim Sit + Glim + Met InsSit + Ins Patients Reporting Hypoglycemia (%)

23 Selected Adverse Events With Sitagliptin: Pooled Data Adverse EventIncidence per 100 patient-yearsDifference (95% CI) Sitagliptin 100 mgNonexposed Constipation (0.1, 1.4) Diarrhea (-3.6, -1.0) Headache (-0.7, 1.4) Nasopharyngitis (-0.3, 2.1) Pancreatitis (-0.20, 0.14) Rash (-0.1, 0.8) Upper respiratory tract infection (-1.6, 1.0) Williams-Herman D, et al. BMC Endocr Disord. 2010;10(7). Engel SS, et al. Int J Clin Pract. 2010;64:

24 GLP-1 Receptor Agonists 24

25 FDA-Approved Agents Albiglutide Exenatide Exenatide ER Liraglutide Key Features Injectable administration Mimic action of native GLP-1 Increase glucose-dependent insulin secretion Suppress glucagon production Slow gastric emptying GLP-1 Receptor Agonists 25 ER, extended release; GLP-1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

26 MonotherapyAdd-on to MetforminAdd-on to SU Alb 1 Exe 2 Exe ER 3 Lir 4 Alb 5 Exe 6 Exe ER 7 Lir 8 Alb 9, *Exe 10 Exe ER 11,† Lir 12 Baseline A1C (%) Glucose Control with GLP-1 Receptor Agonists Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) *Metformin with or without SU or TZD. † Metformin with or without SU. ‡ Absolute change from baseline (active-controlled trial). 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Ahrén B, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. 6. DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26: Placebo-adjusted  A1C (%) ‡ ‡ ‡ ‡ ‡ ‡

27 MonotherapyAdd-on to MetforminAdd-on to SU Alb 1 Exe 2 Exe ER 3 Lir 4 Alb 5 Exe 6 Exe ER 7 Lir 8 Alb 9, *Exe 10 Exe ER 11,† Lir 12 Weight Change with GLP-1 Receptor Agonists *Metformin with or without SU or TZD. † Metformin with or without SU. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Ahrén B, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. 6. DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26:  Weight (kg) Absolute Change from Baseline (Not Head-to-Head Trials)

28 MonotherapyAdd-on to MetforminAdd-on to SU Alb 1 Exe 2 Exe ER 3 Lir 4 Alb 5 Exe 6 Exe ER 7 Lir 8 Alb 9, *Exe 10 Exe ER 11,† Lir 12 Hypoglycemia with GLP-1 Receptor Agonists *Metformin with or without SU or TZD. † Metformin with or without SU. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Ahrén B, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. 6. DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26: Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Patients (%)

29 Safety Considerations with GLP1 Receptor Agonists GI adverse events Common Usually dose dependent and transient Usually reduced with dose titration Pancreatitis 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 GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis Pancreatic cancer 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 Medullary thyroid cancer Animal data showed an increased incidence of C-cell tumors with liraglutide and extenatide ER treatment, but confirmatory population studies are lacking Labeling for liraglutide and exenatide ER: 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 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 is contraindicated in patients with severe renal insufficiency or ESRD ER, extended release. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. 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,

30 Monotherapy vs Placebo 52 Weeks 1 Add-on to Metformin 104 Weeks 2 Add-on to Met +/- SU +/- TZD 32 Weeks 3 Add-on to Basal Insulin 26 Weeks 4 N TreatmentPBOAlb † MetGlim+ Met Sit+ Met Alb+ Met Lira+ Met+/- SU Alb+ Met+/- SU LisproAlb Baseline A1C (%) *P< vs placebo. **P<0.001 vs active compatators. † All albiglutide dosages shown are 50 mg once weekly. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Ahrén B, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. 3. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Rosenstock J, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. Glucose Control With Albiglutide  A1C (%) * ** *

31 Monotherapy vs Placebo 52 Weeks 1 Add-on to Metformin 104 Weeks 2 Add-on to Met +/- SU +/- TZD 32 Weeks 3 Add-on to Basal Insulin 26 Weeks 4 N TreatmentPBOAlb † MetGlim + Met Sit + Met Alb + Met Lira+ Met+/- SU Alb+ Met+/- SU LisproAlb *P< vs glimepiride or lispro. **P< vs albiglutide. † All albiglutide dosages shown are 50 mg once weekly. 1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Ahrén B, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. 3. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Rosenstock J, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. Weight Change With Albiglutide  Weight (kg) * ** *

32 Add-on to Metformin 104 Weeks 1 Add-on to Met +/- SU +/- TZD 32 Weeks 2 N TreatmentMetGlim + Met Sit + Met Alb + Met Lira+ Met+/- SU Alb+ Met+/- SU *P< vs glimepiride or lispro. **P< vs albiglutide. † All albiglutide dosages shown are 50 mg once weekly. 1. Ahrén B, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. 2. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Blood Pressure Change With Albiglutide  Systolic BP (mmHg) Decrease of <1 mmHg in both groups

33 Monotherapy vs Placebo 52 Weeks 1 Add-on to Metformin 104 Weeks 2 Add-on to Met +/- SU +/- TZD 32 Weeks 3 Add-on to Basal Insulin 26 Weeks 4 N TreatmentPBOAlb † MetGlim + Met Sit + Met Alb + Met Lira+ Met+/- SU Alb+ Met+/- SU LisproAlb *P< vs glimepiride or lispro. **P< vs albiglutide. † All albiglutide dosages shown are 50 mg once weekly. 1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Ahrén B, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. 3. Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Rosenstock J, et al. Diabetes Care Jun 4. pii: DC_ [Epub ahead of print]. Hypoglycemia With Albiglutide Patients with documented symptomatic hypoglycemia (%)

34 Albiglutide: Adverse Events Adverse Events* Patients (%) Albiglutide (n=923) Placebo (n=468) Upper respiratory tract infection Diarrhea Nausea Injection site reaction Cough Back pain Arthralgia Sinusitis Influenza *Adverse events of interest occurring in ≥5% of patients receiving albiglutide. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.

35 Glucose Control With Exenatide *P<0.001 vs comparator. † All exenatide dosages shown are 10 μg BID. 1. Moretto TJ, et al. Clin Ther. 2008;30: DeFronzo RA et al. Diabetes Care. 2005;28: Buse JB, et al. Diabetes Care. 2004;27: Zinman B, et al. Ann Intern Med. 2007;146: Kendall DM et al. Diabetes Care. 2005;28: Heine RJ, et al. Ann Intern Med. 2005;143: Monotherapy 24 Weeks 1 Add-on to Metformin 30 Weeks 2 Add-on to Sulfonylurea 30 Weeks 3 Add-on to TZD 16 Weeks 4 Add-on to Metformin + SU 30 Weeks 5 Add-on to Met + SU vs Glargine 26 Weeks 6 N Treatment†PBOExeMetExe + Met SUExe + SU TZDExe + TZD Met + SU Exe + Met + SU Glar + Met + SU Exe + Met + SU Baseline A1C (%)  A1C (%) * * * * *

36 Weight Reduction With Exenatide *P<0.05 vs comparator. **P< vs glargine. † All exenatide dosages shown are 10 μg BID. 1. Moretto TJ, et al. Clin Ther. 2008;30: DeFronzo RA et al. Diabetes Care. 2005;28: Buse JB, et al. Diabetes Care. 2004;27: Zinman B, et al. Ann Intern Med. 2007;146: Kendall DM et al. Diabetes Care. 2005;28: Heine RJ, et al. Ann Intern Med. 2005;143: Monotherapy 24 Weeks 1 Add-on to Metformin 30 Weeks 2 Add-on to Sulfonylurea 30 Weeks 3 Add-on to TZD 16 Weeks 4 Add-on to Metformin + SU 30 Weeks 5 Add-on to Met + SU vs Glargine 26 Weeks 6 N Treatment†PBOExeMetExe + Met SUExe + SU TZDExe + TZD Met + SU Exe + Met + SU Glar + Met + SU Exe + Met + SU  Weight (kg) * * * * * **

37 *P<0.05 vs placebo. Moretto TJ, et al. Clin Ther. 2008;30:  Systolic BP (mmHg) Blood Pressure Changes With Exenatide Monotherapy 24 Weeks N233 TreatmentPBOExe 10 μg BID *

38 Monotherapy 24 Weeks 1 Add-on to Metformin 30 Weeks 2 Add-on to Sulfonylurea 30 Weeks 3 Add-on to TZD 16 Weeks 4 N Treatment†PBOExeMetExe + Met SUExe + SU TZDExe + TZD † All exenatide dosages shown are 10 μg BID. 1. Moretto TJ, et al. Clin Ther. 2008;30: DeFronzo RA et al. Diabetes Care. 2005;28: Buse JB, et al. Diabetes Care. 2004;27: Zinman B, et al. Ann Intern Med. 2007;146: Patients Reporting Hypoglycemia (%) Hypoglycemia With Exenatide

39 Exenatide: Adverse Events Adverse Events* Patients (%) Monotherapy+ Met and/or SU+ TZD +/- Met Exe (n=155) PBO (n=77) Exe (n=963) PBO (n=483) Exe (n=121) PBO (n=112) Nausea Vomiting Diarrhea13663 Feeling Jittery94 Dizziness96 Headache96 Dyspepsia Asthenia42 GERD3130 Hyperhidrosis31 *Occurring in ≥2% of patients receiving exenatide Byetta (exenatide) injection prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP

40 *Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. † Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone. 1. Drucker DJ, et al. Lancet. 2008;372: Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: Diamant M, et al. Lancet. 2010;375: Buse JB, et al. Lancet. 2013;381: Glucose Control With Exenatide ER Add-on to OAs* 30 Weeks 1 Monotherapy vs OAs 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Met +/- SU 26 Weeks 4 Add-on to OAs † 26 Weeks 5 N TreatmentExe BID Exe ER SitPioMetExe ER Sit+ Met Pio+ Met Exe ER+ Met Glar + OAs Exe ER + OAs Lira + OAs Exe ER + OAs Baseline A1C (%)  A1C (%) P<0.001 P< P<0.01 P=0.017 P=0.02

41 *Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. † Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone. 1. Drucker DJ, et al. Lancet. 2008;372: Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: Diamant M, et al. Lancet. 2010;375: Buse JB, et al. Lancet. 2013;381: Add-on to OAs* 30 Weeks 1 Monotherapy vs OAs 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Met +/- SU 26 Weeks 4 Add-on to OAs † 26 Weeks 5 N Treatment (mg/day) Exe BID Exe ER SitPioMetExe ER Sit+ Met Pio+ Met Exe ER+ Met Glar + OAs Exe ER + OAs Lira + OAs Exe ER + OAs Weight Reduction With Exenatide ER P<  Weight (kg) P<0.001

42 *Metformin, sulfonylurea, thiazolidinedione, or combination of any 2 of these agents. † Metformin, sulfonylurea, metformin + sulfonylurea, or metformin + pioglitazone. 1. Drucker DJ, et al. Lancet. 2008;372: Russell-Jones D, et al. Diabetes Care. 2012;35: Bergenstal RM, et al. Lancet. 2010;376: Diamant M, et al. Lancet. 2010;375: Buse JB, et al. Lancet. 2013;381: Add-on to OAs* 30 Weeks 1 Monotherapy vs OAs 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Met +/- SU 26 Weeks 4 Add-on to OAs † 26 Weeks 5 N TreatmentExe BID Exe ER SitPioMetExe ER Sit+ Met Pio+ Met Exe ER+ Met Glar + OAs Exe ER + OAs Lira + OAs Exe ER + OAs Hypoglycemia With Exenatide ER Patients reporting hypoglycemia (%)

43 Exenatide Extended Release: Adverse Events Adverse Events* Patients (%) Monotherapy+ Met+ Met +/- SU Exe ER (n=248) Sit (n=163) Pio (n=163) Met (n=246) Exe ER (n=160) Sit (n=166) Pio (n=165) Exe ER (n=233) Glar (n=233) Nausea Diarrhea Injection site reaction Constipation Headache Dyspepsia Vomiting Fatigue *Adverse events of interest occurring in ≥5% of patients receiving exenatide extended release. Bydureon (exenatide extended release) injection prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP

44 *P< vs monotherapy. **P< vs dual therapy. ***P= vs glargine. † All liraglutide dosages shown are 1.8 mg QD. 1. Garber A, et al. Lancet. 2009;373: Nauck M, et al. Diabetes Care. 2009;32: Pratley RE, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26: Zinman B, et al. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetologia. 2009;52: Glucose Control With Liraglutide Monotherapy vs Glimepiride 52 Weeks 1 Add-on to Metformin 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Sulfonylurea 26 Weeks 4 Add-on to Met + TZD 26 Weeks 5 Add-on to Met + SU 26 Weeks 6 N TreatmentGlimLirMetGlim + Met Lir+ Met Sit+ Met Lir+ Met SURosi + SU Lir+ SU Rosi + Met Lir+ Rosi+ Met Met+ SU Glar+ Met+ SU Lir+ Met+ SU Baseline A1C (%)  A1C (%) * ** * *** *

45 Monotherapy vs Glimepiride 52 Weeks 1 Add-on to Metformin 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Sulfonylurea 26 Weeks 4 Add-on to Met + TZD 26 Weeks 5 Add-on to Met + SU 26 Weeks 6 N Treatment GlimLirMetGlim + Met Lir+ Met Sit+ Met Lir+ Met SURosi + SU Lir+ SU Rosi + Met Lir+ Rosi+ Met Met+ SU Glar+ Met+ SU Lir+ Met+ SU *P< vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU. † All liraglutide dosages shown are 1.8 mg QD. 1. Garber A, et al. Lancet. 2009;373: Nauck M, et al. Diabetes Care. 2009;32: Pratley RE, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26: Zinman B, et al. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetologia. 2009;52:  Weight (kg) Weight Reduction With Liraglutide * * * ** * * *** *

46 Blood Pressure Changes With Liraglutide Monotherapy vs Glimepiride 52 Weeks 1 Add-on to Metformin 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Sulfonylurea 26 Weeks 4,5 Add-on to Met + TZD 26 Weeks 6 Add-on to Met + SU 26 Weeks 7 N Treatment GlimLirMetGlim + Met Lir+ Met Sit+ Met Lir+ Met SURosi + SU Lir+ SU Rosi + Met Lir+ Rosi+ Met Met+ SU Glar+ Met+ SU Lir+ Met+ SU *P<0.05 vs comparator. † All liraglutide dosages shown are 1.8 mg QD. 1. Garber A, et al. Lancet. 2009;373: Nauck M, et al. Diabetes Care. 2009;32: Pratley RE, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26: Colagiuri S, et al. Diabetes. 2008;57(suppl 2): Abstr. 554-P. 6. Zinman B, et al. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetologia. 2009;52:  Systolic BP (mmHg) * * * *

47 *P<0.01 vs active comparator. † All liraglutide dosages shown are 1.8 mg QD. 1. Garber A, et al. Lancet. 2009;373: Nauck M, et al. Diabetes Care. 2009;32: Pratley RE, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26: Hypoglycemia With Liraglutide Monotherapy 52 Weeks 1 Add-on to Metformin 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Sulfonylurea 26 Weeks 4 N Treatment†GlimLirMetGlim+ Met Lir+ Met Sit+ Met Lir+ Met SURosi+ SU Lir+ SU * Patients Reporting Hypoglycemia (%) * *

48 Liraglutide: Adverse Events Adverse Events* Patients (%) Monotherapy+ Met+ Glim+ Met + TZD Lir (n=497) Glim (n=248) Lir (n=724) PBO (n=121) Lir (n=695) PBO (n=114) Lir (n=355) PBO (n=175) Nausea Diarrhea Vomiting Constipation Headache Dyspepsia *Adverse events of interest occurring in ≥5% of patients receiving liraglutide. Victoza (liraglutide) injection prescribing information. Princeton, NJ: Novo Nordisk Inc

49 SGLT2 Inhibitors 49

50 FDA-Approved Agents Canagliflozin Dapagliflozin Key Features Oral administration Inhibit reabsorption of glucose into the bloodstream from renal fluid SGLT2 Inhibitors 50 SGLT2, sodium-glucose cotransporter 2. DeFronzo RA, et al. Diabetes Obes Metab. 2012;14:5-14.

51 Glucose Control with SGLT2 Inhibitors Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) *Absolute change from baseline (active-controlled trial). 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: MonotherapyAdd-on to MetforminAdd-on to Insulin +/- OAs Can 1 Dap 2 Can 3 Dap 4 Can 5 Dap 6 Baseline A1C (%) Placebo-adjusted  A1C (%) * *

52 Weight Change with SGLT2 Inhibitors 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: MonotherapyAdd-on to MetforminAdd-on to Insulin +/- OAs Can 1 Dap 2 Can 3 Dap 4 Can 5 Dap 6  Weight (kg) Absolute Change from Baseline (Not Head-to-Head Trials)

53 Hypoglycemia with SGLT2 Inhibitors 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: MonotherapyAdd-on to MetforminAdd-on to Insulin +/- OAs Can 1 Dap 2 Can 3 Dap 4 Can 5 Dap 6 Patients (%) Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials)

54 Safety Considerations with SGLT2 Inhibitors Genitourinary infection Increased incidence; patients should be monitored and treated if necessary Increased LDL-C Small increases in LDL-C have been observed in clinical trials Bladder cancer Increased incidence of bladder cancers in patients receiving dapagliflozin Dapagliflozin labeling recommends not using in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer Renal impairment Monitor kidney function during therapy, especially in patients with GFR <60 mL/min/1.73 m 2 Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc

55 Monotherapy 26 Weeks 1 Add-on to Metformin 12 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Metformin + SU 52 Weeks 4 Add-on to OAs +/- Insulin in CKD † 26 Weeks 5 N Treatment (mg/day) PBOCanMetSit + Met Can + Met Glim + Met Can + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs Baseline A1C (%) *All dosages shown are canaglifozin 300 mg. † Estimated glumerular filtration rate mL/min/1.73 m 2. **P<0.001 vs placebo. ‡ Met criteria for noninferiority and superiority (upper limit of confidence interval <0.0%). 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Rosenstock J, et al. Diabetes Care. 2012;35: Cefalu WT, et al. Lancet. 2013;382: Schernthaner G, et al. Diabetes Care. 2013;36: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Glucose Control With Canagliflozin*  A1C (%) ** ‡

56 *All dosages shown are canaglifozin 300 mg. † Estimated glumerular filtration rate mL/min/1.73 m 2. **P<0.001 vs comparator. 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Rosenstock J, et al. Diabetes Care. 2012;35: Cefalu WT, et al. Lancet. 2013;382: Schernthaner G, et al. Diabetes Care. 2013;36: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Weight Change With Canagliflozin* Monotherapy 26 Weeks 1 Add-on to Metformin 12 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Metformin + SU 52 Weeks 4 Add-on to OAs +/- Insulin in CKD † 26 Weeks 5 N Treatment (mg/day) PBOCanMetSit + Met Can + Met Glim + Met Can + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs **  Weight (kg)

57 *All dosages shown are canaglifozin 300 mg. † Estimated glumerular filtration rate mL/min/1.73 m 2. **P<0.001 vs comparator. 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Rosenstock J, et al. Diabetes Care. 2012;35: Cefalu WT, et al. Lancet. 2013;382: Schernthaner G, et al. Diabetes Care. 2013;36: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Blood Pressure Change With Canagliflozin* Monotherapy 26 Weeks 1 Add-on to Metformin 12 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Metformin + SU 52 Weeks 4 Add-on to OAs +/- Insulin in CKD † 26 Weeks 5 N Treatment (mg/day) PBOCanMetSit + Met Can + Met Glim + Met Can + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs **  Systolic BP (mmHg)

58 *All dosages shown are canaglifozin 300 mg. † Estimated glumerular filtration rate mL/min/1.73 m Stenlof K, et al. Diabetes Obes Metab. 2013;15: Rosenstock J, et al. Diabetes Care. 2012;35: Cefalu WT, et al. Lancet. 2013;382: Schernthaner G, et al. Diabetes Care. 2013;36: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Hypoglycemia With Canagliflozin* Monotherapy 26 Weeks 1 Add-on to Metformin 12 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Metformin + SU 52 Weeks 4 Add-on to OAs +/- Insulin in CKD † 26 Weeks 5 N Treatment (mg/day) PBOCanMetSit + Met Can + Met Glim + Met Can + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs Patients reporting hypoglycemia (%)

59 Canagliflozin: Adverse Events Adverse Events* Patients (%) Canagliflozin 100 mg (n=833) Canagliflozin 300 mg (n=834) Placebo (n=646) Female genital mycotic infections Urinary tract infections Increased urination Male genital mycotic infections Vulvovaginal pruritis Thirst Constipation Nausea *Adverse events of interest occurring in ≥2% of patients receiving canagliflozin. Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc

60 Monotherapy 24 Weeks 1 Initial Combo with Metformin 24 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Pioglitazone 24 Weeks 4 Add-on to Sitagliptin +/- Metformin 24 Weeks 5 Add-on to insulin + OAs 24 Weeks 6 N Treatment (mg/day) PBODapMetDapDap + Met Glip + Met Dap + Met PioDap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs Baseline A1C (%) *All dosages shown are dapaglifozin 10 mg. **P<0.001 vs placebo. ***P< vs comparator. 1. Ferrannini E, et al. Diabetes Care. 2010;33: Henry RR, et al. Int J Clin Pract. 2012;66: Nauck MA, et al. Diabetes Care. 2011;34: Rosenstock J, et al. Diabetes Care. 2012;35: Jabbour SA, et al. Diabetes Care. 2014;37: Wilding JPH, et al. Ann Intern Med. 2012;156: Glucose Control With Dapagliflozin*  A1C (%) ** ***

61 Monotherapy 24 Weeks 1 Initial Combo with Metformin 24 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Pioglitazone 24 Weeks 4 Add-on to Sitagliptin +/- Metformin 24 Weeks 5 Add-on to insulin + OAs 24 Weeks 6 N Treatment (mg/day) PBODapMetDapDap + Met Glip + Met Dap + Met PioDap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs *All dosages shown are dapaglifozin 10 mg. **P<0.001 vs placebo. ***P< vs comparator. 1. Ferrannini E, et al. Diabetes Care. 2010;33: Henry RR, et al. Int J Clin Pract. 2012;66: Nauck MA, et al. Diabetes Care. 2011;34: Rosenstock J, et al. Diabetes Care. 2012;35: Jabbour SA, et al. Diabetes Care. 2014;37: Wilding JPH, et al. Ann Intern Med. 2012;156: Weight Change With Dapagliflozin*  Weight (kg) ** ***

62 Monotherapy 24 Weeks 1 Initial Combo with Metformin 24 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Pioglitazone 24 Weeks 4 Add-on to Sitagliptin +/- Metformin 24 Weeks 5 Add-on to insulin + OAs 24 Weeks 6 N Treatment (mg/day) PBODapMetDapDap + Met Glip + Met Dap + Met PioDap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs *All dosages shown are dapaglifozin 10 mg. 1. Ferrannini E, et al. Diabetes Care. 2010;33: Henry RR, et al. Int J Clin Pract. 2012;66: Nauck MA, et al. Diabetes Care. 2011;34: Rosenstock J, et al. Diabetes Care. 2012;35: Jabbour SA, et al. Diabetes Care. 2014;37: Wilding JPH, et al. Ann Intern Med. 2012;156: Blood Pressure Change With Dapagliflozin*  Systolic BP (mmHg)

63 Monotherapy 24 Weeks 1 Initial Combo with Metformin 24 Weeks 2 Add-on to Metformin 52 Weeks 3 Add-on to Pioglitazone 24 Weeks 4 Add-on to Sitagliptin+/- Metformin 24 Weeks 5 Add-on to insulin + OAs 24 Weeks 6 N Treatment (mg/day) PBODapMetDapDap + Met Glip + Met Dap + Met PioDap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs *All dosages shown are dapaglifozin 10 mg. 1. Ferrannini E, et al. Diabetes Care. 2010;33: Henry RR, et al. Int J Clin Pract. 2012;66: Nauck MA, et al. Diabetes Care. 2011;34: Rosenstock J, et al. Diabetes Care. 2012;35: Jabbour SA, et al. Diabetes Care. 2014;37: Wilding JPH, et al. Ann Intern Med. 2012;156: Hypoglycemia With Dapagliflozin* Patients reporting hypoglycemia (%)

64 Dapagliflozin: Adverse Events Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company Adverse Events* Patients (%) Dapagliflozin 5 mg (n=1145) Dapagliflozin 10 mg (n=1193) Placebo (n=1393) Female genital mycotic infections Nasopharyngitis Urinary tract infections Back pain Increased urination Male genital mycotic infections Nausea Influenza Dyslipidemia Constipation Discomfort with urination *Adverse events occurring in ≥2% of patients receiving dapagliflozin.

65 Monotherapy 24 Weeks 1 Add-on to Metformin 24 Weeks 2 Add-on to Metformin 104 Weeks 3 Add-on to Met + SU 24 Weeks 4 Add-on to Pio +/- Met 24 Weeks 5 Add-on to MDI insulin 52 Weeks 6 N Treatment (mg/day) PBOSitEmpMetEmp + Met Glim + Met Emp + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met InsEmp+ Ins Baseline A1C (%) *All dosages shown are empaglifozin 25 mg. **P<0.001 vs placebo. ***P<0.05 vs active comparator. 1. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Haring HU, et al. Diabetes Care. 2014;37: Ridderstrale M, et al. Lancet Diabetes Endocrinol. 2014; Jun 16. Epub ahead of print. 4. Haring HU, et al. Diabetes Care. 2013;36: Kovacs CS, et al. Diabetes Obes Metab. 2014;16: Rosenstock J, et al. Diabetes Care. 2014;37: Glucose Control With Empagliflozin*  A1C (%) ** ***

66 Monotherapy 24 Weeks 1 Add-on to Metformin 24 Weeks 2 Add-on to Metformin 104 Weeks 3 Add-on to Met + SU 24 Weeks 4 Add-on to Pio +/- Met 24 Weeks 5 Add-on to MDI insulin 52 Weeks 6 N Treatment (mg/day) PBOSitEmpMetEmp + Met Glim + Met Emp + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met InsEmp+ Ins *All dosages shown are empaglifozin 25 mg. **P<0.001 vs placebo. ***P< vs active comparator. 1. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Haring HU, et al. Diabetes Care. 2014;37: Ridderstrale M, et al. Lancet Diabetes Endocrinol. 2014; Jun 16. Epub ahead of print. 4. Haring HU, et al. Diabetes Care. 2013;36: Kovacs CS, et al. Diabetes Obes Metab. 2014;16: Rosenstock J, et al. Diabetes Care. 2014;37: Weight Change With Empagliflozin*  Weight (kg) ** ***

67 Monotherapy 24 Weeks 1 Add-on to Metformin 24 Weeks 2 Add-on to Metformin 104 Weeks 3 Add-on to Met + SU 24 Weeks 4 Add-on to Pio +/- Met 24 Weeks 5 Add-on to MDI insulin 52 Weeks 6 N Treatment (mg/day) PBOSitEmpMetEmp + Met Glim + Met Emp + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met InsEmp+ Ins *All dosages shown are empaglifozin 25 mg. **P<0.05 vs placebo. ***P<0.001 vs active comparator. 1. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Haring HU, et al. Diabetes Care. 2014;37: Ridderstrale M, et al. Lancet Diabetes Endocrinol. 2014; Jun 16. Epub ahead of print. 4. Haring HU, et al. Diabetes Care. 2013;36: Kovacs CS, et al. Diabetes Obes Metab. 2014;16: Rosenstock J, et al. Diabetes Care. 2014;37: Blood Pressure Change With Empagliflozin*  Systolic BP (mm Hg) ** *** ** ***

68 Monotherapy 24 Weeks 1 Add-on to Metformin 24 Weeks 2 Add-on to Metformin 104 Weeks 3 Add-on to Met + SU 24 Weeks 4 Add-on to Pio +/- Met 24 Weeks 5 Add-on to MDI insulin 52 Weeks 6 N Treatment (mg/day) PBOSitEmpMetEmp + Met Glim + Met Emp + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met InsEmp+ Ins *All dosages shown are empaglifozin 25 mg. 1. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Haring HU, et al. Diabetes Care. 2014;37: Ridderstrale M, et al. Lancet Diabetes Endocrinol. 2014; Jun 16. Epub ahead of print. 4. Haring HU, et al. Diabetes Care. 2013;36: Kovacs CS, et al. Diabetes Obes Metab. 2014;16: Rosenstock J, et al. Diabetes Care. 2014;37: Hypoglycemia With Empagliflozin* Patients reporting hypoglycemia (%) <1

69 Empagliflozin: Adverse Events Jardiance (empagliflozin) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc Adverse Events* Patients (%) Empagliflozin 10 mg (n=999) Empagliflozin 25 mg (n=977) Placebo (n=995) Urinary tract infections Female genital mycotic infections Upper respiratory tract infection Increased urination Dyslipidemia Arthralgia Male genital mycotic infections Nausea *Adverse events occurring in ≥2% of patients receiving empagliflozin at rates greater than placebo.

70 Inhaled Insulin 70

71 Inhaled Insulin Inhaled administration Rapid-acting insulin –Peak levels achieved in ~15 minutes 71 Rave K, et al. J Diabetes Sci Technol. 2008;2:

72 Glucose Control with Inhaled Insulin *Difference from placebo (95% CI): -0.40% (-0.57% to -0.23%). Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; Add-on to Metformin and/or Other OAs 24 Weeks PlaceboTechnosphere insulin N353 Baseline A1C (%)8.3  A1C (%) * *

73 Weight Change with Inhaled Insulin Add-on to Metformin and/or Other OAs 24 Weeks PlaceboTechnosphere insulin N353 *  Weight (kg) Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

74 Hypoglycemia with Inhaled Insulin Add-on to Metformin and/or Other OAs 24 Weeks N353 NonsevereSevere PBOTIPBOTI Patients With Hypoglycemia (%) TI, technosphere insulin. Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

75 Safety Considerations with Inhaled Insulin Lung disease Contraindicated in asthma, COPD, and other chronic lung diseases Perform spirometry to assess lung function before initiating technosphere insulin, after 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms Do not use in patients with active lung cancer and use with caution in patients with a history of lung cancer or those at risk for lung cancer Heart failure Observe for signs and symptoms of fluid retention or heart failure, especially when used with TZDs HypoglycemiaIncrease frequency of glucose monitoring Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

76 Inhaled Insulin: Adverse Events Adverse Events* Patients (%) Technosphere insulin (n=1991) Placebo (n=290) Active comparators (n=1363) Cough Throat pain or irritation Headache Diarrhea Productive cough Fatigue Nausea *Adverse events of interest occurring in ≥2% of patients receiving technosphere insulin. Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

77 Class Comparisons Noninsulin Agents 77

78 DPP-4 InhibitorsGLP-1 Receptor AgonistsSGLT2 Inhibitors Alo 1 Lin 2 Sax 3 Sit 4 Alb 5 Exe 6 Exe ER 7 Lir 8 Can 9 Dap 10 Emp 11 Baseline A1C (%) Glucose Reduction DPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin (Absolute Changes from Baseline; Not Head-to-Head Trials) 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 Jun 4. pii: DC_ [Epub ahead of print]. 6. 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:  A1C (%)

79 DPP-4 InhibitorsGLP-1 Receptor Agonists SGLT2 Inhibitors Alo 1 Lin 2 Sax 3 Sit 4 Alb 5 Exe 6 Exe ER 7 Lir 8 Can 9 Dap 10 Emp 11 Weight Reduction DPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin (Separate Studies; Not Head-to-Head Trials) 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 Jun 4. pii: DC_ [Epub ahead of print]. 6. 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:  Weight (kg) NR

80 Effects of Antihyperglycemic Therapies on Blood Pressure Class ∆ Systolic BP, mmHg (95% CI) ∆ Diastolic BP, mmHg (95% CI) Newer therapies GLP-1 receptor agonists (-5.49 to -1.66) (-2.02 to -0.73) DPP-4 inhibitors (-1.2 to 0.8) — SGLT2 inhibitors (-4.65 to -2.90) (-2.27 to -1.23) Older therapies Metformin (-3.01 to 0.82) (-2.15 to 0.21) TZDs (-6.13 to -3.27) (-5.82 to -1.77) 1. Vilsbøll T, et al. BMJ Jan 10;344:d7771. doi: /bmj.d Monami M, et al. Diabetes Obes Metab. 2013;15: Vasilakou D, et al. Ann Intern Med. 2013;159: Wulffelé M, et al. J Intern Med. 2004;256: Qayyum R, Adomaityte J. J Clin Hypertens (Greenwich). 2006;8: Meta-analyses


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