Glycemic Management in Type 2 Diabetes

Glycemic Management in Type 2 Diabetes
Efficacy and Safety of Modern Antihyperglycemic Therapies

Glycemic Management in Type 2 Diabetes: Efficacy and Safety of Modern Antihyperglycemic Therapies
DPP4 Inhibitors

DPP4 Inhibitors FDA-Approved Agents Key Features Alogliptin
Linagliptin Saxagliptin Sitagliptin Oral administration Increase endogenous GLP1 and GIP levels Increase glucose-dependent insulin secretion Suppress glucagon production DPP4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 2016;22:

Glucose Control with DPP4 Inhibitors
Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,† Baseline A1C (%) 7.9 8.0 7.5 8.1 8.2 8.6 8.4 7.8 8.5 8.3 Placebo-adjusted  A1C (%) ‡ *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:

Weight Change with DPP4 Inhibitors
Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,†  Weight (kg) NR NR 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:

Hypoglycemia with DPP4 Inhibitors
Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alo1 Lin2 Sax3 Sit4 Alo5 Lin6 Sax7 Sit8 Alo9 Lin10,* Sax11 Sit12,† Patients (%) 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:

Safety Considerations with DPP4 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 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 CHF Potentially increased risk of congestive heart failure hospitalization with alogliptin and saxagliptin Garber AJ, et al. Endocr Pract. 2016;22: White W, et al. N Engl J Med. 2013;369: Scirica BM, et al. Circulation. 2014;130: 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,

Glucose Control With Alogliptin
Monotherapy 26 Weeks1 Initial Combo w/ Pioglitazone 26 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Glyburide 26 Weeks4 Add-on to Met + Pio 52 Weeks5 Add-on to Insulin +/- Met 26 Weeks6 N 329 655 527 500 803 390 Treatment PBO Alo Pio Alo + Pio Met Alo + Met Gly Alo + Gly Met+ Pio Alo+ Met+ Pio Ins+/- Met Alo+ Ins+/- Met Baseline A1C (%) 7.9 8.8 8.0 8.1 8.3 9.3  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:

Weight Change With Alogliptin
Monotherapy 26 Weeks1 Initial Combo w/ Pioglitazone 26 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Glyburide 26 Weeks4 Add-on to Met + Pio 52 Weeks5 Add-on to Insulin +/- Met 26 Weeks6 N 329 655 527 500 803 390 Treatment PBO Alo Pio Alo + Pio Met Alo + Met Gly Alo + Gly Met+ Pio Alo+ Met+ Pio Ins+/- Met Alo+ Ins+/- Met  Weight (kg) * 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:

Hypoglycemia With Alogliptin
Monotherapy 26 Weeks1,2 Add-on to Metformin 26 Weeks3 Add-on to Glyburide 26 Weeks4 Add-on to Met + Pio 52 Weeks5 Add-on to Insulin +/- Met 26 Weeks6 N 329 527 500 803 390 Treatment PBO Alo Met Alo + Met Gly Alo + Gly Met+ Pio Alo+ Met+ Pio Ins+/- Met Alo+ Ins+/- Met Patients Reporting Hypoglycemia (%) 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:

Alogliptin: Adverse Events
Patients (%) Alogliptin 25 mg (n=5902) Placebo (n=2926) Active comparator (n=2257) Nasopharyngitis 4.4 3.0 5.0 Headache 4.2 2.5 5.4 Upper respiratory tract infection 2.1 *Occurring in ≥4% of patients receiving alogliptin 25 mg and more commonly than in placebo-treated patients. Nesina (alogliptin) prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2013. 11

Glucose Control With Linagliptin
Monotherapy 24 Weeks1 Initial Combo w/ Metformin 24 Weeks2 Initial Combo w/ Pioglitazone 24 Weeks3 Add-on to Metformin 24 Weeks4 Add-on to Metformin 2 Years5 Add-on to Metformin + SU 24 Weeks6 N 503 791 389 700 1552 1055 Treatment PBO Lin Met HD Lin + Met LD Lin + Met HD Pio Lin + Pio Met Lin + Met Glim + Met Met + SU Lin + Met + SU Baseline A1C (%) 8.0 8.7 8.5 8.6 8.1 7.7 8.2  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:

Weight Changes With Linagliptin
Initial Combo w/ Metformin 24 Weeks1 Initial Combo w/ Pioglitazone 24 Weeks2 Add-on to Metformin 24 Weeks3 2 Years4 N 791 389 700 1552 Treatment Lin Met HD Lin + Met LD Lin + Met HD Pio Lin + Pio Met Lin + Met Glim + Met  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:

Hypoglycemia With Linagliptin
Monotherapy 24 Weeks1 Initial Combo w/ Metformin 24 Weeks2 Initial Combo w/ Pioglitazone 24 Weeks3 Add-on to Metformin 24 Weeks4 Add-on to Metformin 2 Years5 Add-on to Metformin + SU 24 Weeks6 N 503 791 389 700 1552 1055 Treatment PBO Lin Met HD Lin + Met LD Lin + Met HD Pio Lin + Pio Met Lin + Met Glim + Met Met + SU Lin + Met + SU 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:

Linagliptin: Adverse Events
Patients (%) Linagliptin 5 mg (n=3625) Placebo (n=2176) Nasopharyngitis 7.0 6.1 Diarrhea 3.3 3.0 Cough 2.1 1.4 *Occurring in ≥2% of patients receiving linagliptin 5 mg and more commonly than in placebo-treated patients. Tradjenta (linagliptin) prescribing information. Ridgefield, CT: Boehringer Ingelheim, Inc.; 2014. 15

Glucose Control With Saxagliptin
Monotherapy 24 Weeks1 Initial Combo w/ Metformin 24 Weeks2 Add-on to Metformin 24 Weeks3 18 Weeks4 Add-on to Glyburide vs Uptitration 24 Weeks5 Add-on to TZD 24 Weeks6 N 401 1306 743 801 768 565 Treatment PBO Sax Met Sax + Met Sit + Met Gly Sax + Gly TZD Sax + TZD Baseline A1C (%) 7.9 8.0 9.4 8.1 7.7 8.4 8.5 8.2  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:

Weight Changes With Saxagliptin
Monotherapy 24 Weeks1 Initial Combo w/ Metformin 24 Weeks2 Add-on to Metformin 24 Weeks3 18 Weeks4 Add-on to Glyburide vs Uptitration 24 Weeks5 Add-on to TZD 24 Weeks6 N 401 1306 743 801 768 565 Treatment PBO Sax Met Sax + Met Sit + Met Gly Sax + Gly TZD Sax + TZD * Weight (kg) *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:

Hypoglycemia With Saxagliptin
Monotherapy 24 Weeks1 Initial Combo w/ Metformin 24 Weeks2 Add-on to Metformin 24 Weeks3 18 Weeks4 Add-on to Glyburide vs Uptitration 24 Weeks5 Add-on to TZD 24 Weeks6 N 401 1306 743 801 768 565 Treatment PBO Sax Met Sax + Met Sit + Met Gly Sax + Gly TZD Sax + TZD Patients Reporting Hypoglycemia (%) 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:

Saxagliptin: Adverse Events
Patients (%) Saxagliptin 5 mg Placebo Headache 6.5 5.9 Upper respiratory tract infection 7.7 7.6 Urinary tract infection 6.8 6.1 *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

Glucose Control With Sitagliptin
Monotherapy vs Glipizide 52 Weeks1 Initial Combo w/ Metformin 24 Weeks2 Add-on to Metformin 24 Weeks3 Add-on to Insulin 24 Weeks4 Add-on to Pioglitazone vs Met + Pio 12 Months5 Add-on to Rosiglitazone + Metformin 54 Weeks6 N 1172 1091 701 641 151 278 Treatment Glip Sit Met Sit+ Met Ins Sit+ Ins Met + Pio Sit + Pio Rosi + Met Sit + Rosi + Met Baseline A1C (%) 7.5 8.7 8.9 8.8 8.0 8.6 8.4 8.5  A1C (%) * * † * *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;5:68-79.

Weight Changes With Sitagliptin
Monotherapy 24 Weeks1 52 Weeks2 Add-on to Pioglitazone 24 Weeks3 Add-on to Glimepiride 24 Weeks4 Add-on to Insulin 24 Weeks5 Add-on to Pio vs Met + Pio 12 Months6 N 741 793 353 441 641 151 Treatment PBO Sit Glip Pio Sit + Pio Glim Sit + Glim Ins Sit + Ins Met + Pio  Weight (kg) * † *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:

Hypoglycemia With Sitagliptin
Sitagliptin vs Glipizide 52 weeks1 Initial Combo w/ Metformin 24 Weeks2 Add-on to Metformin 24 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Glimepiride 24 Weeks5 Add-on to Insulin 24 Weeks6 N 793 1091 701 353 441 641 Treatment Glip Sit PBO Met Sit + Met Pio Sit + Pio Glim Sit + Glim Sit + Glim + Met Ins Sit + Ins Patients Reporting Hypoglycemia (%) 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:

Selected Adverse Events With Sitagliptin: Pooled Data
Incidence per 100 patient-years Difference (95% CI) Sitagliptin 100 mg Nonexposed Constipation 2.6 1.9 0.8 (0.1, 1.4) Diarrhea 6.9 9.6 -2.3 (-3.6, -1.0) Headache 5.8 5.6 0.4 (-0.7, 1.4) Nasopharyngitis 7.7 7.0 0.9 (-0.3, 2.1) Pancreatitis 0.08 0.10 -0.02 (-0.20, 0.14) Rash 1.3 0.9 0.4 (-0.1, 0.8) Upper respiratory tract infection 8.6 9.0 -0.3 (-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: 23

GLP1 Receptor Agonists

GLP1 Receptor Agonists FDA-Approved Agents Key Features Albiglutide
Dulaglutide Exenatide Exenatide ER Liraglutide Lixisenatide Injectable 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:

Glucose Control with GLP1 Receptor Agonists
Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb1 Dul2 Exe3 Exe ER4 Lir5 Lix6 Alb7 Dul8 Exe9 Exe ER10 Lir11 Lix12 Alb13,* Exe14 Exe ER15,† Lir16 Baseline A1C (%) 8.1 7.6 7.8 8.5 8.3 8.0 8.2 8.6 8.4 Placebo-adjusted  A1C (%) ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ *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; Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Fonseca VA, et al. Diabetes Care. 2012;35: 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: Rosenstock J, et al. Diabetes Care. 2013;36: 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 Change with GLP1 Receptor Agonists
Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb1 Dul2 Exe3 Exe ER4 Lir5 Lix6 Alb7 Dul8 Exe9 Exe ER10 Lir11 Lix12 Alb13,* Exe14 Exe ER15,† Lir16  Weight (kg) *Metformin with or without SU or TZD. †Metformin with or without SU. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Fonseca VA, et al. Diabetes Care. 2012;35: 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: Rosenstock J, et al. Diabetes Care. 2013;36: 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:

Hypoglycemia with GLP1 Receptor Agonists
Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb1 Dul2 Exe3 Exe ER4 Lir5 Lix6 Alb7 Dul8 Exe9 Exe ER10 Lir11 Lix12 Alb13,* Exe14 Exe ER15,† Lir16 Patients (%) *Metformin with or without SU or TZD. †Metformin with or without SU. 1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Fonseca VA, et al. Diabetes Care. 2012;35: 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: Rosenstock J, et al. Diabetes Care. 2013;36: 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:

A1C Reductions With GLP1 RAs
Head-to-Head Trials Exenatide BID vs lixisenatide1 Exenatide BID vs liraglutide2 Exenatide BID vs exenatide OW3 Liraglutide vs albiglutide4 Liraglutide vs dulaglutide5 Liraglutide vs exenatide OW6 634 464 295 841 599 912 Exe Lix Exe BID Lir Exe OW Alb Dul Baseline A1C (%) 8.0 8.1 8.2 8.3 8.4 8.5  A1C (%) NI NotNI P<0.0001 NI P=0.02 P=0.002 BID, twice daily; OW, once weekly (extended release); NI, noninferior; Not NI, not noninferior. 1. Rosenstock J, et al. Diabetes Care. 2013;36: Buse JB, et al. Lancet. 2009;374: Drucker DJ, et al. Lancet. 2008; 372: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Dungan KM, et al. Lancet. 2014;384: Buse JB, et al. Lancet. 2013;381:

Weight Reductions With GLP1 RAs
Head-to-Head Trials Exenatide BID vs lixisenatide1 Exenatide BID vs liraglutide2 Exenatide BID vs exenatide OW3 Liraglutide vs albiglutide4 Liraglutide vs dulaglutide5 Liraglutide vs exenatide OW6 634 464 295 841 599 912 Exe Lix Exe BID Lir Exe OW Alb Dul  Weight (kg) P<0.0001 P=0.011 BID, twice daily; OW, once weekly (extended release) 1. Rosenstock J, et al. Diabetes Care. 2013;36: Buse JB, et al. Lancet. 2009;374: Drucker DJ, et al. Lancet. 2008; 372: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Dungan KM, et al. Lancet. 2014;384: Buse JB, et al. Lancet. 2013;381:

Systolic BP Reductions With GLP1 Receptor Agonists
Head-to-Head Trials Exenatide BID vs lixisenatide1 Exenatide BID vs liraglutide2 Exenatide BID vs exenatide OW3 Liraglutide vs albiglutide4 Liraglutide vs dulaglutide5 Liraglutide vs exenatide OW6 634 464 295 841 599 912 Exe Lix Exe BID Lir Exe OW Alb Dul <1  Systolic BP (mmHg) BID, twice daily; BP, blood pressure; OW, once weekly (extended release). 1. Rosenstock J, et al. Diabetes Care. 2013;36: Buse JB, et al. Lancet. 2009;374: Drucker DJ, et al. Lancet. 2008; 372: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Dungan KM, et al. Lancet. 2014;384: Buse JB, et al. Lancet. 2013;381:

Nausea Rates With GLP1 Receptor Agonists
Percentage of Patients Reporting Nausea in Head-to-Head Trials Exenatide BID vs lixisenatide1 Exenatide BID vs liraglutide2 Exenatide BID vs exenatide OW3 Liraglutide vs albiglutide4 Liraglutide vs dulaglutide5 Liraglutide vs exenatide OW6 Exe Lix Exe BID Lir Exe OW Alb Dul Patients (%) P<0.05 P<0.05 P<0.0001 BID, twice daily; OW, once weekly (extended release). 1. Rosenstock J, et al. Diabetes Care. 2013;36: Buse JB, et al. Lancet. 2009;374: Drucker DJ, et al. Lancet. 2008; 372: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Dungan KM, et al. Lancet. 2014;384: Buse JB, et al. Lancet. 2013;381:

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 GLP1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis Pancreatic cancer 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 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 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. ER, extended release. 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:

Glucose Control With Albiglutide
Monotherapy vs Placebo 52 Weeks1 Add-on to Metformin 104 Weeks2 Add on to Pio +/- Met 52 Weeks3 Add-on to Met +/- SU +/- TZD 32 Weeks4 Add-on to Met +/- SU 52 Weeks5 Add-on to Basal Insulin 26 Weeks6 N 296 1049 310 841 779 586 Treatment† PBO Alb 50 mg Met Glim+ Met Sit+ Met Alb 50 mg+ Met Pio+/- Met Alb 30 mg+ Pio+/- Met Lir Glar Alb 30 mg Lispro Baseline A1C (%) 8.0 8.1 8.2 8.4 8.3 8.5  A1C (%) ** * * * *P< vs placebo. **P<0.001 vs active comparators. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Ahrén B, et al. Diabetes Care. 2014;37: Reusch J, et al. Diabetes Obes Metab. 2014;16: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Weissman PN, et al. Diabetologia. 2014;57: Rosenstock J, et al. Diabetes Care. 2014;37:

Weight Change With Albiglutide
Monotherapy vs Placebo 52 Weeks1 Add-on to Metformin 104 Weeks2 Add on to Pio +/- Met 52 Weeks3 Add-on to Met +/- SU +/- TZD 32 Weeks4 Add-on to Met +/- SU 52 Weeks5 Add-on to Basal Insulin 26 Weeks6 N 296 1049 310 841 779 586 Treatment‡ PBO Alb 50 mg Met Glim+ Met Sit+ Met Alb 50 mg+ Met Pio+/- Met Alb 30 mg+ Pio+/- Met Lir Glar Alb 30 mg Lispro  Weight (kg) † * * * ** *P< vs glimepiride or insulin. **P< vs albiglutide. †Between-group difference shown; absolute changes not reported. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Ahrén B, et al. Diabetes Care. 2014;37: Reusch J, et al. Diabetes Obes Metab. 2014;16: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Weissman PN, et al. Diabetologia. 2014;57: Rosenstock J, et al. Diabetes Care. 2014;37:

Blood Pressure Change With Albiglutide
Add-on to Metformin 104 Weeks1 Add-on to Met +/- SU +/- TZD 32 Weeks2 Add-on to Met +/- SU 52 Weeks3 N 1049 841 779 Treatment Met Glim + Met Sit + Met Alb 50 mg+ Met Lira+ Met+/- SU Alb 50 mg+ Met+/- SU Glar Alb 30 mg  Systolic BP (mmHg) Decrease of <1 mmHg in both groups 1. Ahrén B, et al. Diabetes Care. 2014;37: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Weissman PN, et al. Diabetologia. 2014;57:

Hypoglycemia With Albiglutide
Monotherapy vs Placebo 52 Weeks1 Add-on to Metformin 104 Weeks2 Add on to Pio +/- Met 52 Weeks3 Add-on to Met +/- SU +/- TZD 32 Weeks4 Add-on to Met +/- SU 52 Weeks5 Add-on to Basal Insulin 26 Weeks6 N 296 1049 310 841 779 586 Treatment‡ PBO Alb 50 mg Met Glim+ Met Sit+ Met Alb 50 mg+ Met Pio+/- Met Alb 30 mg+ Pio+/- Met Lir Glar Alb 30 mg Lispro Patients with documented symptomatic hypoglycemia (%) 1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Ahrén B, et al. Diabetes Care. 2014;37: Reusch J, et al. Diabetes Obes Metab. 2014;16: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Weissman PN, et al. Diabetologia. 2014;57: Rosenstock J, et al. Diabetes Care. 2014;37:

Albiglutide: Adverse Events
Patients (%) Albiglutide (n=923) Placebo (n=468) Upper respiratory tract infection 14.2 13.0 Diarrhea 13.1 10.5 Nausea 11.1 9.6 Injection site reaction 2.1 Cough 6.9 6.2 Back pain 6.7 5.8 Arthralgia 6.6 6.4 Sinusitis Influenza 5.2 3.2 *Adverse events of interest occurring in ≥5% of patients receiving albiglutide. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2014.

Glucose Control With Dulaglutide
Monotherapy 52 Weeks1 52 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Pio + Met 52 Weeks4 Add-on to Met + SU 52 Weeks5 Add-on to Lispro 26 Weeks6 N 807 1098 599 976 884 Treatment† Met Dul Sit Lir Exe Glar Baseline A1C (%) 7.6 8.1 8.5  A1C (%) ** *** *** *** * *P<0.02 vs glargine. **P<0.01 vs metformin. ***P<0.001 vs comparator. †All dulaglutide dosages shown are 1.5 mg once weekly. 1. Umpierrez G, et al. Diabetes Care. 2014;37: Nauck M, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: Wysham C, et al. Diabetes Care. 2014;37: Giorgino F, et al. Diabetes Care. 2015;38: Blonde L, et al. Lancet. 2015:385:

Weight Reduction With Dulaglutide
Monotherapy 26 Weeks1 26 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Pio + Met 26 Weeks4 Add-on to Met + SU 52 Weeks5 Add-on to Lispro 26 Weeks6 N 807 1098 599 976 884 Treatment† Met Dul Sit Lir Exe Glar  Weight (kg) * * ** *P<0.05 vs glargine. **P<0.001 vs sitagliptin. †All dulaglutide dosages shown are 1.5 mg once weekly. 1. Umpierrez G, et al. Diabetes Care. 2014;37: Nauck M, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: Wysham C, et al. Diabetes Care. 2014;37: Giorgino F, et al. Diabetes Care. 2015;38: Blonde L, et al. Lancet. 2015:385:

Blood Pressure Change With Dulaglutide
Monotherapy 52 Weeks1 52 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Pio + Met 52 Weeks4 N 807 1098 599 976 Treatment† Met Dul Sit Lir Exe  Systolic BP (mmHg) †All dulaglutide dosages shown are 1.5 mg once weekly. 1. Umpierrez G, et al. Diabetes Care. 2014;37: Nauck M, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: Wysham C, et al. Diabetes Care. 2014;37:

Hypoglycemia With Dulaglutide
Monotherapy 52 Weeks1 52 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Pio + Met 26 Weeks4 N 807 1098 599 976 Treatment† Met Dul Sit Lir Exe Add-on to Met + SU 52 Weeks5 Add-on to Lispro 26 Weeks6 807 884 Glar Dul Patients reporting hypoglycemia (%) Hypoglycemia events/patient per year * * * *P<0.01 vs comparator. †All dulaglutide dosages shown are 1.5 mg once weekly. 1. Umpierrez G, et al. Diabetes Care. 2014;37: Nauck M, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: Wysham C, et al. Diabetes Care. 2014;37: Giorgino F, et al. Diabetes Care. 2015;38: Blonde L, et al. Lancet. 2015:385:

Dulaglutide: Adverse Events
Patients (%) Dulaglutide 1.5 mg (n=834) Dulaglutide 0.75 mg (n=836) Placebo (n=568) Nausea 21.1 12.4 5.3 Diarrhea 12.6 8.9 6.7 Vomiting 12.7 6.0 2.3 Abdominal pain 9.4 6.5 4.9 Decreased appetite 8.6 1.6 Dyspepsia 5.8 4.1 Fatigue 5.6 4.2 2.6 *Adverse events occurring in ≥5% of patients receiving dulaglutide. Trulicity (dulaglutide) injection prescribing information. Indianapolis, IN: Eli Lilly and Company; 2014.

Glucose Control With Exenatide
Monotherapy 24 Weeks1 Add-on to Metformin 30 Weeks2 Add-on to Sulfonylurea 30 Weeks3 Add-on to TZD 16 Weeks4 Add-on to Metformin + SU 30 Weeks5 Add-on to Met + SU vs Glargine 26 Weeks6 N 233 336 377 733 551 Treatment† PBO Exe Met Exe + Met SU Exe + SU TZD Exe + TZD Met + SU Exe + Met + SU Glar + Met + SU Baseline A1C (%) 7.8 8.2 8.7 8.6 7.9 8.5 8.3  A1C (%) * * * * * *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:

Weight Reduction With Exenatide
Monotherapy 24 Weeks1 Add-on to Metformin 30 Weeks2 Add-on to Sulfonylurea 30 Weeks3 Add-on to TZD 16 Weeks4 Add-on to Metformin + SU 30 Weeks5 Add-on to Met + SU vs Glargine 26 Weeks6 N 233 336 377 733 551 Treatment† PBO Exe Met Exe + Met SU Exe + SU TZD Exe + TZD Met + SU Exe + Met + SU Glar + Met + SU  Weight (kg) * * * ** * * *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:

Blood Pressure Changes With Exenatide
Monotherapy 24 Weeks N 233 Treatment PBO Exe 10 μg BID  Systolic BP (mmHg) * *P<0.05 vs placebo. Moretto TJ, et al. Clin Ther. 2008;30:

Hypoglycemia With Exenatide
Monotherapy 24 Weeks1 Add-on to Metformin 30 Weeks2 Add-on to Sulfonylurea 30 Weeks3 Add-on to TZD 16 Weeks4 N 233 336 377 Treatment† PBO Exe Met Exe + Met SU Exe + SU TZD Exe + TZD Patients Reporting Hypoglycemia (%) †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:

Exenatide: Adverse Events
Patients (%) Monotherapy + Met and/or SU + TZD +/- Met Exe (n=155) PBO (n=77) (n=963) (n=483) (n=121) (n=112) Nausea 8 44 18 40 15 Vomiting 4 13 1 Diarrhea 6 3 Feeling Jittery 9 Dizziness Headache Dyspepsia 7 Asthenia 2 GERD Hyperhidrosis *Occurring in ≥2% of patients receiving exenatide Byetta (exenatide) injection prescribing information. Wilmington, DE: AstraZeneca Pharmaceuticals LP

Glucose Control With Exenatide ER
Add-on to OAs* 30 Weeks1 Monotherapy vs OAs 26 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Met +/- SU 26 Weeks4 Add-on to OAs† 26 Weeks5 N 258 820 514 456 911 Treatment Exe BID Exe ER Sit Pio Met Sit+ Met Pio+ Met Exe ER+ Met Glar + OAs Exe ER + OAs Lira + OAs Baseline A1C (%) 8.3 8.5 8.6 8.4  A1C (%) P=0.02 P=0.017 P<0.01 P<0.001 P<0.0001 *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:

Weight Reduction With Exenatide ER
Add-on to OAs* 30 Weeks1 Monotherapy vs OAs 26 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Met +/- SU 26 Weeks4 Add-on to OAs† 26 Weeks5 N 258 820 514 456 911 Treatment (mg/day) Exe BID Exe ER Sit Pio Met Sit+ Met Pio+ Met Exe ER+ Met Glar + OAs Exe ER + OAs Lira + OAs  Weight (kg) P<0.0001 P<0.001 P<0.001 *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:

Hypoglycemia With Exenatide ER
Add-on to OAs* 30 Weeks1 Monotherapy vs OAs 26 Weeks2 Add-on to Metformin 26 Weeks3 Add-on to Met +/- SU 26 Weeks4 Add-on to OAs† 26 Weeks5 N 258 820 514 456 911 Treatment Exe BID Exe ER Sit Pio Met Sit+ Met Pio+ Met Exe ER+ Met Glar + OAs Exe ER + OAs Lira + OAs Patients reporting hypoglycemia (%) *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:

Exenatide Extended Release: Adverse Events
Patients (%) Monotherapy + Met + Met +/- SU Exe ER (n=248) Sit (n=163) Pio Met (n=246) (n=160) (n=166) Pio (n=165) (n=233) Glar Nausea 11.3 3.7 4.3 6.9 24.4 9.6 4.8 12.9 1.3 Diarrhea 10.9 5.5 12.6 20.0 7.3 9.4 4.0 Injection site reaction 10.5 6.7 10.2 5.0 1.2 6.0 Constipation 8.5 2.5 1.8 3.3 6.3 3.6 Headache 8.1 9.2 8.0 12.2 9.0 9.9 7.6 Dyspepsia 4.9 2.4 Vomiting 3.0 Fatigue 5.6 0.6 *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

Glucose Control With Liraglutide
Monotherapy vs Glimepiride 52 Weeks1 Add-on to Metformin 26 Weeks2 26 Weeks3 Add-on to Sulfonylurea 26 Weeks4 Add-on to Met + TZD 26 Weeks5 Add-on to Met + SU 26 Weeks6 N 746 1091 665 1041 821 581 Treatment† Glim Lir Met Glim + Met Lir+ Met Sit+ Met SU Rosi + SU Lir+ SU Rosi + Met Lir+ Rosi+ Met Met+ SU Glar+ Met+ SU Lir+ Met+ SU Baseline A1C (%) 8.4 8.3 8.5 8.6 8.2  A1C (%) * * * ** ** *** ** ** *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:

Weight Reduction With Liraglutide
Monotherapy vs Glimepiride 52 Weeks1 Add-on to Metformin 26 Weeks2 26 Weeks3 Add-on to Sulfonylurea 26 Weeks4 Add-on to Met + TZD 26 Weeks5 Add-on to Met + SU 26 Weeks6 N 746 1091 665 1041 821 581 Treatment† Glim Lir Met Glim + Met Lir+ Met Sit+ Met SU Rosi + SU Lir+ SU Rosi + Met Lir+ Rosi+ Met Met+ SU Glar+ Met+ SU Lir+ Met+ SU ***  Weight (kg) * * * * * ** * *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:

Blood Pressure Changes With Liraglutide
Monotherapy vs Glimepiride 52 Weeks1 Add-on to Metformin 26 Weeks2 26 Weeks3 Add-on to Sulfonylurea 26 Weeks4,5 Add-on to Met + TZD 26 Weeks6 Add-on to Met + SU 26 Weeks7 N 746 1091 665 1041 821 581 Treatment† Glim Lir Met Glim + Met Lir+ Met Sit+ Met SU Rosi + SU Lir+ SU Rosi + Met Lir+ Rosi+ Met Met+ SU Glar+ Met+ SU Lir+ Met+ SU  Systolic BP (mmHg) * * * * *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:

Hypoglycemia With Liraglutide
Monotherapy 52 Weeks1 Add-on to Metformin 26 Weeks2 26 Weeks3 Add-on to Sulfonylurea 26 Weeks4 N 746 1091 665 1041 Treatment† Glim Lir Met Glim+ Met Lir+ Met Sit+ Met SU Rosi+ SU Lir+ SU Patients Reporting Hypoglycemia (%) * * * *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:

Liraglutide: Adverse Events
Patients (%) Monotherapy + Met + Glim + Met + TZD Lir (n=497) Glim (n=248) (n=724) PBO (n=121) (n=695) (n=114) (n=355) (n=175) Nausea 28.4 8.5 15.2 4.1 7.5 1.8 34.6 8.6 Diarrhea 17.1 8.9 10.9 7.2 14.1 6.3 Vomiting 3.6 6.5 0.8 12.4 2.9 Constipation 9.9 4.8 5.3 0.9 5.1 1.1 Headache 9.1 9.3 9.0 6.6 8.2 4.6 Dyspepsia 5.2 *Adverse events of interest occurring in ≥5% of patients receiving liraglutide. Victoza (liraglutide) injection prescribing information. Princeton, NJ: Novo Nordisk Inc

Glucose Control With Lixisenatide
Monotherapy 12 Weeks1 Add-on to Metformin 24 Weeks2 24 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Stable Glargine±Met 24 Weeks5 Add-on to Titrated Glargine+OAs (Insulin-Naïve Patients) 24 Weeks6 N 361 484 639 495 446 Treatment† PBO Lix Met Lix+ Met Exe BID + Met Pio Lix+ Pio Glar Lix+ Glar Baseline A1C (%) 8.1 8.0 8.4 7.6  A1C (%) P<0.0001 P=0.0002 P<0.0001 * P<0.0001 P<0.0001 *Noninferiority criteria met. †All lixisenatide dosages shown are 20 g QD, administered in a 2-step dose increase regimen. 1. Fonseca VA, et al. Diabetes Care. 2012;35: Bolli GB, et al. Diabet Med. 2014;31: Rosenstock J, et al. Diabetes Care. 2013;36: Pinget M, et al. Diabetes Obes Metab. 2013;15: Riddle MC, et al. Diabetes Care. 2013;36: Riddle MC, et al. Diabetes Care. 2013;36:

Weight Reduction With Lixisenatide
Monotherapy 12 Weeks1 Add-on to Metformin 24 Weeks2 24 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Stable Glargine±Met 24 Weeks5 Add-on to Titrated Glargine+OAs (Insulin-Naïve Patients) 24 Weeks6 N 361 484 639 495 446 Treatment† PBO Lix Met Lix+ Met Exe BID + Met Pio Lix+ Pio Glar Lix+ Glar P=0.0012  Weight (kg) P<0.0001 P<0.01 †All lixisenatide dosages shown are 20 g QD, administered in a 2-step dose increase regimen. 1. Fonseca VA, et al. Diabetes Care. 2012;35: Bolli GB, et al. Diabet Med. 2014;31: Rosenstock J, et al. Diabetes Care. 2013;36: Pinget M, et al. Diabetes Obes Metab. 2013;15: Riddle MC, et al. Diabetes Care. 2013;36: Riddle MC, et al. Diabetes Care. 2013;36:

Hypoglycemia With Lixisenatide
Monotherapy 12 Weeks1 Add-on to Metformin 24 Weeks2 24 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Stable Glargine±Met 24 Weeks5 Add-on to Titrated Glargine+OAs (Insulin-Naïve Patients) 24 Weeks6 N 361 484 639 495 446 Treatment† PBO Lix Met Lix+ Met Exe BID + Met Pio Lix+ Pio Glar Lix+ Glar Patients Reporting Hypoglycemia (%) P<0.05 †All lixisenatide dosages shown are 20 g QD, administered in a 2-step dose increase regimen. 1. Fonseca VA, et al. Diabetes Care. 2012;35: Bolli GB, et al. Diabet Med. 2014;31: Rosenstock J, et al. Diabetes Care. 2013;36: Pinget M, et al. Diabetes Obes Metab. 2013;15: Riddle MC, et al. Diabetes Care. 2013;36: Riddle MC, et al. Diabetes Care. 2013;36:

Lixisenatide: Adverse Events
Patients (%) Placebo (n=1639) Lixisenatide (n=2869) Nausea 6 25 Vomiting 2 10 Headache 9 Diarrhea 8 Dizziness 4 7 *Occurring in ≥5% of patients receiving lixisenatide. Adlyxin (lixisenatide) injection prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC

SGLT2 Inhibitors

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

Glucose Control with SGLT2 Inhibitors
Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9 Baseline A1C (%) 8.1 7.8 7.9 8.2 8.6 8.3 Placebo-adjusted  A1C (%) * * *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: Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: Rosenstock J, et al. Diabetes Care. 2014;37:

Weight Change with SGLT2 Inhibitors
Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9  Weight (kg) 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: Rosenstock J, et al. Diabetes Care. 2014;37:

Hypoglycemia with SGLT2 Inhibitors
Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can1 Dap2 Emp3 Can4 Dap5 Emp6 Can7 Dap8 Emp9 Patients (%) <1 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: Rosenstock J, et al. Diabetes Care. 2014;37:

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 m2 Bone fractures Increased incidence of bone fractures in canagliflozin and dapagliflozin clinical trials Canagliflozin labeling includes specific warning about bone fractures DKA Potentially increased risk of diabetic ketoacidosis in patients with insulin deficiency and/or those undergoing acute metabolic stress Garber AJ, et al. Endocr Pract. 2016;22: Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc Jardiance (empagliflozin) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc Handelsman Y, et al. Endocr Pract. 2016;22:

Glucose Control With Canagliflozin
Monotherapy 26 Weeks1 Add-on to Metformin 12 Weeks2 52 Weeks3 Add-on to Metformin + SU 52 Weeks4 Add-on to OAs +/- Insulin in CKD† 26 Weeks5 N 584 451 1452 755 269 Treatment* (mg/day) PBO Can Met Sit + Met Can + Met Glim + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs Baseline A1C (%) 8.0 7.8 7.6 7.7 8.1  A1C (%) ** ** ** ** ‡ *All canagliflozin dosages shown are canaglifozin 300 mg. †Estimated glomerular filtration rate mL/min/1.73 m2. **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:

Weight Change With Canagliflozin
Monotherapy 26 Weeks1 Add-on to Metformin 12 Weeks2 52 Weeks3 Add-on to Metformin + SU 52 Weeks4 Add-on to OAs +/- Insulin in CKD† 26 Weeks5 N 584 451 1452 755 269 Treatment* (mg/day) PBO Can Met Sit + Met Can + Met Glim + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs  Weight (kg) ** ** ** ** ** *All canagliflozin dosages shown are canaglifozin 300 mg. †Estimated glomerular filtration rate mL/min/1.73 m2. **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 Weeks1 Add-on to Metformin 12 Weeks2 52 Weeks3 Add-on to Metformin + SU 52 Weeks4 Add-on to OAs +/- Insulin in CKD† 26 Weeks5 N 584 451 1452 755 269 Treatment* (mg/day) PBO Can Met Sit + Met Can + Met Glim + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs  Systolic BP (mmHg) ** ** *All canagliflozin dosages shown are canaglifozin 300 mg. †Estimated glomerular filtration rate mL/min/1.73 m2. **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:

Hypoglycemia With Canagliflozin
Monotherapy 26 Weeks1 Add-on to Metformin 12 Weeks2 52 Weeks3 Add-on to Metformin + SU 52 Weeks4 Add-on to OAs +/- Insulin in CKD† 26 Weeks5 N 584 451 1452 755 269 Treatment* (mg/day) PBO Can Met Sit + Met Can + Met Glim + Met Sit+ Met+ SU Can+ Met+ SU Ins + OAs Can + Ins + OAs Patients reporting hypoglycemia (%) *All canagliflozin dosages shown are canaglifozin 300 mg. †Estimated glomerular filtration rate mL/min/1.73 m2. 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:

Canagliflozin: Adverse Events
Patients (%) Canagliflozin 100 mg (n=833) Canagliflozin 300 mg (n=834) Placebo (n=646) Female genital mycotic infections 10.4 11.4 3.2 Urinary tract infections 5.9 4.3 4.0 Increased urination 5.3 4.6 0.8 Male genital mycotic infections 4.2 3.7 0.6 Vulvovaginal pruritis 1.6 3.0 Thirst 2.8 2.3 0.2 Constipation 1.8 0.9 Nausea 2.2 1.5 *Adverse events of interest occurring in ≥2% of patients receiving canagliflozin. Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc

Glucose Control With Dapagliflozin
Monotherapy 24 Weeks1 Initial Combo with Metformin 24 Weeks2 Add-on to Metformin 52 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Sitagliptin +/- Metformin 24 Weeks5 Add-on to insulin + OAs 24 Weeks6 N 485 603 814 480 451 808 Treatment* (mg/day) PBO Dap Met Dap + Met Glip + Met Pio Dap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs Baseline A1C (%) 7.8 8.0 9.1 8.1 7.9 8.3 8.4 8.7 8.5 8.6  A1C (%) *** *** *** ** *** *All dapagliflozin dosages shown are dapagliflozin 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
Monotherapy 24 Weeks1 Initial Combo with Metformin 24 Weeks2 Add-on to Metformin 52 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Sitagliptin +/- Metformin 24 Weeks5 Add-on to insulin + OAs 24 Weeks6 N 485 603 814 480 451 808 Treatment* (mg/day) PBO Dap Met Dap + Met Glip + Met Pio Dap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs  Weight (kg) *** ** *** *** *** *All dapagliflozin dosages shown are dapagliflozin 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:

Blood Pressure Change With Dapagliflozin
Monotherapy 24 Weeks1 Initial Combo with Metformin 24 Weeks2 Add-on to Metformin 52 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Sitagliptin +/- Metformin 24 Weeks5 Add-on to insulin + OAs 24 Weeks6 N 485 603 814 480 451 808 Treatment* (mg/day) PBO Dap Met Dap + Met Glip + Met Pio Dap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs  Systolic BP (mmHg) *All dapagliflozin dosages shown are dapagliflozin 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
Monotherapy 24 Weeks1 Initial Combo with Metformin 24 Weeks2 Add-on to Metformin 52 Weeks3 Add-on to Pioglitazone 24 Weeks4 Add-on to Sitagliptin+/- Metformin 24 Weeks5 Add-on to insulin + OAs 24 Weeks6 N 485 603 814 480 451 808 Treatment* (mg/day) PBO Dap Met Dap + Met Glip + Met Pio Dap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs Patients reporting hypoglycemia (%) *All dapagliflozin dosages shown are dapagliflozin 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:

Dapagliflozin: Adverse Events
Patients (%) Dapagliflozin 5 mg (n=1145) Dapagliflozin 10 mg (n=1193) Placebo (n=1393) Female genital mycotic infections 8.4 6.9 1.5 Nasopharyngitis 6.6 6.3 6.2 Urinary tract infections 5.7 4.3 3.7 Back pain 3.1 4.2 3.2 Increased urination 2.9 3.8 1.7 Male genital mycotic infections 2.8 2.7 0.3 Nausea 2.5 2.4 Influenza 2.3 Dyslipidemia 2.1 Constipation 2.2 1.9 Discomfort with urination 1.6 0.7 *Adverse events occurring in ≥2% of patients receiving dapagliflozin. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company

Glucose Control With Empagliflozin
Monotherapy 24 Weeks1 Add-on to Metformin 24 Weeks2 104 Weeks3 Add-on to Met + SU 24 Weeks4 Add-on to Pio +/- Met 24 Weeks5 Add-on to MDI insulin 52 Weeks6 N 899 638 1549 669 499 563 Treatment* (mg/day) PBO Sit Emp Met Emp + Met Glim + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met Ins Emp+ Ins Baseline A1C (%) 7.9 8.2 8.1 8.3  A1C (%) *** ** ** ** ** ** *All empagliflozin dosages shown are empagliflozin 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;2: 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
Monotherapy 24 Weeks1 Add-on to Metformin 24 Weeks2 104 Weeks3 Add-on to Met + SU 24 Weeks4 Add-on to Pio +/- Met 24 Weeks5 Add-on to MDI insulin 52 Weeks6 N 899 638 1549 669 499 563 Treatment* (mg/day) PBO Sit Emp Met Emp + Met Glim + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met Ins Emp+ Ins  Weight (kg) ** ** ** ** ** *** *** *All empagliflozin dosages shown are empagliflozin 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;2: 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
Monotherapy 24 Weeks1 Add-on to Metformin 24 Weeks2 104 Weeks3 Add-on to Met + SU 24 Weeks4 Add-on to Pio +/- Met 24 Weeks5 Add-on to MDI insulin 52 Weeks6 N 899 638 1549 669 499 563 Treatment* (mg/day) PBO Sit Emp Met Emp + Met Glim + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met Ins Emp+ Ins  Systolic BP (mm Hg) *** ** ** ** ** *** *All empagliflozin dosages shown are empagliflozin 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;2: 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
Monotherapy 24 Weeks1 Add-on to Metformin 24 Weeks2 104 Weeks3 Add-on to Met + SU 24 Weeks4 Add-on to Pio +/- Met 24 Weeks5 Add-on to MDI insulin 52 Weeks6 N 899 638 1549 669 499 563 Treatment* (mg/day) PBO Sit Emp Met Emp + Met Glim + Met Met+ SU Emp+ Met+ SU Pio+/- Met Emp+ Pio+/- Met Ins Emp+ Ins Patients reporting hypoglycemia (%) <1 <1 <1 *All empagliflozin dosages shown are empagliflozin 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;2: 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:

Empagliflozin: Adverse Events
Patients (%) Empagliflozin 10 mg (n=999) Empagliflozin 25 mg (n=977) Placebo (n=995) Urinary tract infections 9.3 7.6 Female genital mycotic infections 5.4 6.4 1.5 Upper respiratory tract infection 3.1 4.0 3.8 Increased urination 3.4 3.2 1.0 Dyslipidemia 3.9 2.9 Arthralgia 2.4 2.3 2.2 Male genital mycotic infections 1.6 0.4 Nausea 1.1 1.4 *Adverse events occurring in ≥2% of patients receiving empagliflozin at rates greater than placebo. Jardiance (empagliflozin) prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc

Noninsulin agents: Class Comparisons
Glycemic Management in Type 2 Diabetes: Efficacy and Safety of Modern Antihyperglycemic Therapies Noninsulin agents: Class Comparisons

(Absolute Changes from Baseline; Not Head-to-Head Trials)
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 Alo1 Lin2 Sax3 Sit4 Alb5 Dul6 Exe7 Exe ER8 Lir9 Can10 Dap11 Emp12 Baseline A1C (%) 7.9 8.1 8.0 8.2 8.6 8.4 7.8  A1C (%) 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:

(Separate Studies; Not Head-to-Head Trials)
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 Alo1 Lin2 Sax3 Sit4 Alb5 Dul6 Exe7 Exe ER8 Lir9 Can10 Dap11 Emp12 NR  Weight (kg) 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:

Effects of Antihyperglycemic Therapies on Blood Pressure
Meta-analyses Class ∆ Systolic BP, mmHg (95% CI) ∆ Diastolic BP, mmHg Newer therapies GLP1 receptor agonists1 -3.57 (-5.49 to -1.66) -1.38 (-2.02 to -0.73) DPP4 inhibitors2 -0.1 (-1.2 to 0.8) — SGLT2 inhibitors3 -3.77 (-4.65 to -2.90) -1.75 (-2.27 to -1.23) Older therapies Metformin4 -1.09 (-3.01 to 0.82) -0.97 (-2.15 to 0.21) TZDs5 -4.70 (-6.13 to -3.27) -3.79 (-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: 4. Wulffelé M, et al. J Intern Med. 2004;256:1-14. 5. Qayyum R, Adomaityte J. J Clin Hypertens (Greenwich). 2006;8:19-28. 86

Inhaled Insulin

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

Glucose Control with Inhaled Insulin
Add-on to Metformin and/or Other OAs 24 Weeks Placebo Inhaled insulin N 353 Baseline A1C (%) 8.3  A1C (%) * * *Difference from placebo (95% CI): -0.40% (-0.57% to -0.23%). Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Weight Change with Inhaled Insulin
Add-on to Metformin and/or Other OAs 24 Weeks Placebo Inhaled insulin N 353  Weight (kg) * Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Hypoglycemia with Inhaled Insulin
Add-on to Metformin and/or Other OAs 24 Weeks N 353 Nonsevere Severe PBO II Patients With Hypoglycemia (%) II, inhaled insulin. Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Safety Considerations with Inhaled Insulin
Lung disease Contraindicated in asthma, COPD, and other chronic lung diseases Perform spirometry to assess lung function before initiating inhaled 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 Hypoglycemia Increase frequency of glucose monitoring Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Inhaled Insulin: Adverse Events
Patients (%) Inhaled insulin (n=1991) Placebo (n=290) Active comparators (n=1363) Cough 25.6 19.7 5.4 Throat pain or irritation 4.4 3.8 0.9 Headache 3.1 2.8 1.8 Diarrhea 2.7 1.4 2.2 Productive cough 1.0 Fatigue 2.0 0.7 0.6 Nausea 0.3 *Adverse events of interest occurring in ≥2% of patients receiving inhaled insulin. Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Glargine U-300

Glucose Control With Glargine U-300
Add-on to OA, Insulin-Naive 6 Months1 Add-on to OA, Basal Insulin Users 6 Months2 Basal-Bolus Insulin Regimen 6 Months3 N 878 811 807 Treatment Gla 100 Gla 300 Baseline A1C (%) 8.6 8.5 8.2 8.3  A1C (%) 1. Bolli GB, et al. Diabetes Obes Metab. 2015;17: Yki-Järvinen H, et al. Diabetes Care. 2014;37: Riddle MC, et al. Diabetes Care. 2014;37:

Weight Change With Glargine U-300
Add-on to OA, Insulin-Naive 6 Months1 Add-on to OA, Basal Insulin Users 6 Months2 Basal-Bolus Insulin Regimen 6 Months3 N 878 811 807 Treatment Gla 100 Gla 300  Weight (kg) P=0.015 1. Bolli GB, et al. Diabetes Obes Metab. 2015;17: Yki-Järvinen H, et al. Diabetes Care. 2014;37: Riddle MC, et al. Diabetes Care. 2014;37:

Hypoglycemia With Glargine U-300
Add-on to OA, Insulin-Naive 6 Months1 Add-on to OA, Basal Insulin Users 6 Months2 Basal-Bolus Insulin Regimen 6 Months3 N 878 811 807 Treatment Gla 100 Gla 300 Overall* Nocturnal* Severe* *Percentage of patients reporting event. 1. Bolli GB, et al. Diabetes Obes Metab. 2015;17: Yki-Järvinen H, et al. Diabetes Care. 2014;37: Riddle MC, et al. Diabetes Care. 2014;37:

Risk of Hypoglycemia With Glargine U-300
Pooled Analysis of Phase III Trials (N=2496) Favors Glargine 300 Favors Glargine 100 Hypoglycemia any time of day Relative risk (95% CI) Confirmed (≤70 mg/dL) or severe 0.91 ( ) Documented symptomatic (≤70 mg/dL) 0.88 ( ) Nocturnal hypoglycemia 0.75 ( ) 0.75 ( ) Ritzel R, et al. Diabetes Obes Metab Apr 30. doi: /dom [Epub ahead of print].

Insulin Dose With Glargine U-300
Add-on to OA, Insulin-Naive 6 Months1 Add-on to OA, Basal Insulin Users 6 Months2 Basal-Bolus Insulin Regimen 6 Months3 N 878 811 807 Treatment Gla 100 Gla 300 Baseline dose (U/kg/day) 0.66 0.64 0.67  Insulin dose (U/kg/day) 1. Bolli GB, et al. Diabetes Obes Metab. 2015;17: Yki-Järvinen H, et al. Diabetes Care. 2014;37: Riddle MC, et al. Diabetes Care. 2014;37:

Safety Considerations with Glargine U-300
Hypoglycemia Increase frequency of glucose monitoring Hypokalemia Monitor potassium levels in at-risk patients and treat as necessary Heart failure Observe for signs and symptoms of fluid retention or heart failure, especially when used with thiazolidinediones Toujeo (glargine U-300) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC.

Glargine U-300: Adverse Events
Patients (%) Type 1 diabetes (n=304) Type 2 diabetes (n=1242) Nasopharyngitis 12.8 7.1 Upper respiratory infection 9.5 5.7 *Adverse events of interest occurring in ≥5% of patients receiving glargine 300 Units/mL. Toujeo (glargine U-300) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC.

Degludec

Insulin Degludec Basal insulin analog No pronounced peak
Duration of action >24 hours Moghissi E et al. Endocr Pract. 2013;19:

Glucose Control With Degludec
Add-on to OA, Insulin-Naive 52 Weeks1 Add-on to OA, Basal Insulin Users or Insulin-Naive 26 Weeks2 Basal-Bolus Insulin Regimen 52 Weeks3 N 1030 687 744 Treatment Deg Glar Deg OD Deg OD Flex Baseline A1C (%) 8.2 8.4 8.5 8.3  A1C (%) Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h intervals between doses; Glar = glargine; OD = once daily. 1. Zinman B, et al. Diabetes Care. 2012;35: Meneghini L, et al. Diabetes Care. 2013;36: Garber AJ, et al. Lancet Endocrinol. 2012;379:

Weight Change With Degludec
Add-on to OA, Insulin-Naive 52 Weeks1 Add-on to OA, Basal Insulin Users or Insulin-Naive 26 Weeks2 Basal-Bolus Insulin Regimen 52 Weeks3 N 1030 687 744 Treatment Deg Glar Deg OD Deg OD Flex  Weight (kg) Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h intervals between doses; Glar = glargine; OD = once daily. 1. Zinman B, et al. Diabetes Care. 2012;35: Meneghini L, et al. Diabetes Care. 2013;36: Garber AJ, et al. Lancet Endocrinol. 2012;379:

Hypoglycemia With Degludec
Add-on to OA, Insulin-Naive 52 Weeks1 Add-on to OA, Basal Insulin Users or Insulin-Naive 26 Weeks2 Basal-Bolus Insulin Regimen 52 Weeks3 N 1030 687 744 Treatment Deg Glar Deg OD Deg OD Flex Overall* Nocturnal* Severe* 2 events † † † † *Events per patient-year. †P<0.05 vs glargine. Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h intervals between doses; Glar = glargine; OD = once daily. 1. Zinman B, et al. Diabetes Care. 2012;35: Meneghini L, et al. Diabetes Care. 2013;36: Garber AJ, et al. Lancet Endocrinol. 2012;379:

Insulin Dose With Degludec
Add-on to OA, Insulin-Naive 52 Weeks1 Add-on to OA, Basal Insulin Users or Insulin-Naive 26 Weeks2 Basal-Bolus Insulin Regimen 52 Weeks3 N 1030 687 744 Treatment Deg Glar Deg OD Deg OD Flex Baseline dose U/kg/day 0.12 0.11 0.25 0.23 0.45 0.44  Insulin dose (U/kg/day) Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h intervals between doses; Glar = glargine; OD = once daily. 1. Zinman B, et al. Diabetes Care. 2012;35: Meneghini L, et al. Diabetes Care. 2013;36: Garber AJ, et al. Lancet Endocrinol. 2012;379:

Safety Considerations with Degludec
Hypoglycemia Increase frequency of glucose monitoring Hypokalemia Monitor potassium levels in at-risk patients and treat as necessary Heart failure Observe for signs and symptoms of fluid retention or heart failure; consider dosage reduction or discontinuation if heart failure occurs Tresiba (insulin degludec) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016.

Degludec: Adverse Events
Patients (%) Type 1 diabetes (n=1102) Type 2 diabetes (n=2713) Nasopharyngitis 23.9 12.9 Upper respiratory infection 11.9 8.4 Headache 11.8 8.8 Sinusitis 5.1 — Gastroenteritis Diarrhea 6.3 *Occurring in ≥5% of patients receiving degludec. Tresiba (insulin degludec) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016.

Fixed ratio combinations of glp1 RAs and basal insulin
Glycemic Management in Type 2 Diabetes: Efficacy and Safety of Modern Antihyperglycemic Therapies Fixed ratio combinations of glp1 RAs and basal insulin

Safety Considerations with Fixed Ratio Combinations of GLP1 RAs and Basal Insulin
Hypoglycemia Increase frequency of glucose monitoring Hypokalemia Monitor potassium levels in at-risk patients and treat as necessary Heart failure Observe for signs and symptoms of fluid retention or heart failure; consider dosage reduction or discontinuation if heart failure occurs GI adverse events Common Usually dose dependent and transient Usually reduced with dose titration Pancreatitis and pancreatic cancer 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 Medullary thyroid cancer Animal data showed an increased incidence of C-cell tumors with liraglutide treatment, but confirmatory population studies are lacking iDegLira patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid tumors iDegLira is 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. iGlarLixi should not be used in patients with ESRD. Liraglutide was found to be safe in patients with moderate renal impairment and may confer a beneficial effect. ESRD, end-stage renal disease. 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: Soliqua 100/33 (insulin glargine and lixisenatide injection) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC; Xultophy® 100/3.6 (insulin degludec and liraglutide injection) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016.

Glucose Control With iGlarLixi
Add-on to OA, Insulin-Naive 30 Weeks1 Add-on to Basal Insulin ± OAs 30 Weeks2 N 1070 736 Treatment Lixi Glar* iGlarLixi Baseline A1C (%) 8.1 8.5  A1C (%) P<0.0001 P<0.0001 P<0.0001 Per protocol maximum dose: 60 units/day. Glar, glargine; Lixi; lixisenatide; OAs, oral agents. 1. Rosenstock J, et al. Diabetes Care. 2016;39: Aroda VR, et al. Diabetes Care. 2016;39:

Weight Change With iGlarLixi
Add-on to OA, Insulin-Naive 30 Weeks1 Add-on to Basal Insulin ± OAs 30 Weeks2 N 1070 736 Treatment Lixi Glar iGlarLixi  Weight (kg) P<0.0001 P<0.0001 Glar, glargine; Lixi; lixisenatide; OAs, oral agents. 1. Rosenstock J, et al. Diabetes Care. 2016;39: Aroda VR, et al. Diabetes Care. 2016;39:

Hypoglycemia With iGlarLixi
Add-on to OA, Insulin-Naive 30 Weeks1 Add-on to Basal Insulin ± OAs 30 Weeks2 N 1070 736 Treatment Lixi Glar iGlarLixi Patients reporting symptomatic hypoglycemia* (%) *BG ≤70 mg/dL. BG, blood glucose; Glar, glargine; Lixi; lixisenatide; OAs, oral agents. 1. Rosenstock J, et al. Diabetes Care. 2016;39: Aroda VR, et al. Diabetes Care. 2016;39:

Insulin Dose With iGlarLixi
Add-on to OA, Insulin-Naive 30 Weeks1 Add-on to Basal Insulin ± OAs 30 Weeks2 N 1070 736 Treatment Lixi Glar iGlarLixi Dose* (units) NA *Dose range: units glargine; 5-20 g lixisenatide. Glar, glargine; Lixi; lixisenatide; NA, not applicable; OAs, oral agents. 1. Rosenstock J, et al. Diabetes Care. 2016;39: Aroda VR, et al. Diabetes Care. 2016;39:

iGlarLixi: Adverse Events
Patients (%) (N=834) Nausea 10.0 Nasopharyngitis 7.0 Diarrhea Upper respiratory tract infection 5.5 Headache 5.4 *Occurring in ≥5% of patients receiving iGlarLixi. Soliqua 100/33 (insulin glargine and lixisenatide injection) prescribing information. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2016.

Glucose Control With iDegLira
Add-on to OA, Insulin-Naive 26 Weeks1 Add-on to Basal Insulin ± OAs 26 Weeks2 N 1663 413 Treatment Lira Deg iDegLira Deg* Baseline A1C (%) 8.3 8.8 8.7  A1C (%) NI P<0.0001 P<0.0001 S P<0.0001 *Per protocol maximum dose: 50 units/day (no maximum dose of degludec alone was specified in the insulin naïve trial). Deg, degludec; Lira; liraglutide; NI, noninferior; S, superior. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2014;37:

Weight Change With iDegLira
Add-on to OA, Insulin-Naive 26 Weeks1 Add-on to Basal Insulin ± OAs 26 Weeks2 N 1663 413 Treatment Lira Deg* iDegLira  Weight (kg) P<0.0001 P<0.0001 P<0.0001 Deg, degludec; Lira; liraglutide. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2014;37:

Hypoglycemia With iDegLira
Add-on to OA, Insulin-Naive 26 Weeks1 Add-on to Basal Insulin ± OAs 26 Weeks2 N 1663 413 Treatment Lira Deg* iDegLira P<0.0001 P<0.0001 Patients reporting confirmed hypoglycemia* (%) *BG <56 mg/dL regardless of symptoms. BG, blood glucose; Deg, degludec; Lira; liraglutide. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2014;37:

Insulin Dose With iDegLira
Add-on to OA, Insulin-Naive 26 Weeks1 Add-on to Basal Insulin ± OAs 26 Weeks2 N 1663 413 Treatment Lira Deg iDegLira Deg* Dose* (units) P<0.0001 NA *Dose range: units glargine; mg lixisenatide (no maximum dose of degludec alone was specified in the insulin naïve trial). Deg, degludec; Lira; liraglutide; NA, not applicable. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2014;37:

iDegLira: Adverse Events
Patients (%) (N=834) Nasopharyngitis 9.6 Headache 9.1 Nausea 7.8 Diarrhea 7.5 Increased lipase 6.7 Upper respiratory infection 5.7 *Occurring in ≥5% of patients receiving iDegLira. Xultophy® 100/3.6 (insulin degludec and liraglutide injection) prescribing information. Plainsboro, NJ: Novo Nordisk Inc.; 2016.

Glycemic Management in Type 2 Diabetes

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