Glycemic Management in Type 2 Diabetes

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

DPP-4 Inhibitors

DPP-4 Inhibitors FDA-Approved Agents Key Features 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, 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.

Glucose Control with DPP-4 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 DPP-4 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 DPP-4 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 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:

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 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,

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). 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. 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 (%) 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: Warnings and 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: Warnings and 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

GLP-1 Receptor Agonists

GLP-1 Receptor Agonists
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 ER, extended release; GLP-1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

Glucose Control with GLP-1 Receptor Agonists
Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb1 Exe2 Exe ER3 Lir4 Alb5 Exe6 Exe ER7 Lir8 Alb9,* Exe10 Exe ER11,† Lir12 Baseline A1C (%) 8.1 7.8 8.5 8.3 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; 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 Change with GLP-1 Receptor Agonists
Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb1 Exe2 Exe ER3 Lir4 Alb5 Exe6 Exe ER7 Lir8 Alb9,* Exe10 Exe ER11,† Lir12  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; 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:

Hypoglycemia with GLP-1 Receptor Agonists
Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb1 Exe2 Exe ER3 Lir4 Alb5 Exe6 Exe ER7 Lir8 Alb9,* Exe10 Exe ER11,† Lir12 Patients (%) *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:

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 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,

Glucose Control With Albiglutide
Monotherapy vs Placebo 52 Weeks1 Add-on to Metformin 104 Weeks2 Add-on to Met +/- SU +/- TZD 32 Weeks3 Add-on to Basal Insulin 26 Weeks4 N 296 1049 841 586 Treatment PBO Alb† Met Glim+ Met Sit+ Met Alb+ Met Lira+ Met+/- SU Alb+ Met+/- SU Lispro Alb Baseline A1C (%) 8.0 8.1 8.2 8.4 8.5  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].

Weight Change With Albiglutide
Monotherapy vs Placebo 52 Weeks1 Add-on to Metformin 104 Weeks2 Add-on to Met +/- SU +/- TZD 32 Weeks3 Add-on to Basal Insulin 26 Weeks4 N 296 1049 841 586 Treatment PBO Alb† Met Glim + Met Sit + Met Alb + Met Lira+ Met+/- SU Alb+ Met+/- SU Lispro Alb  Weight (kg) * * ** *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].

Blood Pressure Change With Albiglutide
Add-on to Metformin 104 Weeks1 Add-on to Met +/- SU +/- TZD 32 Weeks2 N 1049 841 Treatment Met Glim + Met Sit + Met Alb + Met Lira+ Met+/- SU Alb+ Met+/- SU  Systolic BP (mmHg) Decrease of <1 mmHg in both groups *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:

Hypoglycemia With Albiglutide
Monotherapy vs Placebo 52 Weeks1 Add-on to Metformin 104 Weeks2 Add-on to Met +/- SU +/- TZD 32 Weeks3 Add-on to Basal Insulin 26 Weeks4 N 296 1049 841 586 Treatment PBO Alb† Met Glim + Met Sit + Met Alb + Met Lira+ Met+/- SU Alb+ Met+/- SU Lispro Alb Patients with documented symptomatic hypoglycemia (%) *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].

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 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

SGLT2 Inhibitors

SGLT2 Inhibitors FDA-Approved Agents Key Features Canagliflozin
Dapagliflozin Key Features 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 Can3 Dap4 Can5 Dap6 Baseline A1C (%) 8.1 7.8 8.2 8.6 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: 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:

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 Can3 Dap4 Can5 Dap6  Weight (kg) 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:

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 Can3 Dap4 Can5 Dap6 Patients (%) 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:

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 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

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 (%) ** ** ** ** ‡ *Estimated glumerular filtration rate mL/min/1.73 m2. **P<0.001 vs placebo. †All dosages shown are canaglifozin 300 mg. ‡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) ** ** ** ** ** *Estimated glumerular filtration rate mL/min/1.73 m2. **P<0.001 vs comparator. †All dosages shown are canaglifozin 300 mg. 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) ** ** *Estimated glumerular filtration rate mL/min/1.73 m2. **P<0.001 vs comparator. †All dosages shown are canaglifozin 300 mg. 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 (%) *Estimated glumerular filtration rate mL/min/1.73 m2. †All dosages shown are canaglifozin 300 mg. 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 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 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
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 Dap + Met Glip + Met Pio Dap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs  Weight (kg) *** ** *** *** *** *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:

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 Dap + Met Glip + Met Pio Dap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs  Systolic BP (mmHg) *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
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 Dap + Met Glip + Met Pio Dap + Pio Sit+/- Met Dap+ Sit+/- Met Ins+/- OAs Dap+ Ins+/- OAs Patients reporting hypoglycemia (%) *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:

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

Inhaled Insulin

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

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

Safety Considerations with Technosphere 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 Hypoglycemia Increase frequency of glucose monitoring Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Technosphere Insulin: Adverse Events
Patients (%) Technosphere 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 technosphere insulin. Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.

Class Comparisons Noninsulin Agents

Glucose Reduction DPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin (Absolute Changes from Baseline; Not Head-to-Head Trials) DPP-4 Inhibitors GLP-1 Receptor Agonists SGLT2 Inhibitors Alo1 Lin2 Sax3 Sit4 Alb5 Exe6 Exe ER7 Lir8 Can9 Dap10 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 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:

(Separate Studies; Not Head-to-Head Trials) GLP-1 Receptor Agonists
Weight Reduction DPP-4 Inhibitors, GLP-1 Receptor Agonists, and SGLT2 Inhibitors Added to Metformin (Separate Studies; Not Head-to-Head Trials) DPP-4 Inhibitors GLP-1 Receptor Agonists SGLT2 Inhibitors Alo1 Lin2 Sax3 Sit4 Alb5 Exe6 Exe ER7 Lir8 Can9 Dap10 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 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:

Effects of Antihyperglycemic Therapies on Blood Pressure
Meta-analyses Class ∆ Systolic BP, mmHg (95% CI) ∆ Diastolic BP, mmHg Newer therapies GLP-1 receptor agonists1 -3.57 (-5.49 to -1.66) -1.38 (-2.02 to -0.73) DPP-4 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. 75

Glycemic Management in Type 2 Diabetes

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