Generic Name: Saxagliptin Hydrochloride
Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
VA Class: HS502
Chemical Name: (1S,3S,5S) - 2 - [(2S) - Amino(3 - hydroxytricyclo(3.3.1.13,7)dec - 1 - yl)acetyl]2 - azabicyclo(3.1.0)hexane - 3 - carbonitrile
Molecular Formula: C18H25N3O2•H2O
CAS Number: 945667-22-1

Warning(s)

Special Alerts:

[Posted 02/11/2014] ISSUE: FDA has requested clinical trial data from the manufacturer of saxagliptin to investigate a possible association between use of the type 2 diabetes drug and heart failure. FDAs request resulted from a study published in the New England Journal of Medicine (NEJM), which reported an increased rate of hospitalization for heart failure, when the heart does not pump blood well enough, with use of saxagliptin (marketed as Onglyza and Kombiglyze XR) compared to an inactive treatment. The study did not find increased rates of death or other major cardiovascular risks, including heart attack or stroke, in patients who received saxagliptin. The manufacturer is expected to submit the trial data to FDA by early March 2014, after which FDA will conduct a thorough analysis and report findings publicly.

At this time, FDA considers information from the NEJM study to be preliminary. Analysis of the saxagliptin clinical trial data is part of a broader evaluation of all type 2 diabetes drug therapies and cardiovascular risk.

BACKGROUND: Saxagliptin is used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. It works by increasing the amount of insulin produced by the body after meals, when blood sugar is high.

RECOMMENDATION: Patients should not stop taking saxagliptin and should speak with their health care professionals about any questions or concerns. Health care professionals should continue to follow the prescribing recommendations in the drug labels.

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.

For more information visit the FDA website at: and .

Introduction

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.1 3

Uses for Onglyza

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise for management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone.1 2 3 10 25 31

Used in combination with metformin (separately or as fixed combination of saxagliptin and extended-release metformin), a sulfonylurea, a thiazolidinedione (e.g., a peroxisome proliferator-activated receptor-γ [PPAR-γ] agonist) or insulin for management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and metformin, sulfonylurea, thiazolidinedione monotherapy, and/or insulin.1 4 5 6 7 25 27 29 30 Patients initially receiving an oral antidiabetic agent will eventually require multiple oral antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control because of declining β2-cell function with disease progression.15 16 17 18 19 20

Slideshow: Prediabetes - Am I at Risk?

American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) suggests a DPP-4 inhibitor as one of several alternatives for initial monotherapy in patients with metformin contraindications (e.g., renal disease, hepatic disease, GI intolerance, risk of lactic acidosis).25 DPP-4 inhibitors also recommended as part of combination therapy, particularly with both postprandial and fasting plasma glucose elevations.25

Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis; insulin is required in these conditions.1 2

Onglyza Dosage and Administration

General

  • Individualize dosage of saxagliptin in fixed combination with extended-release metformin hydrochloride based on patient’s current antidiabetic regimen, clinical response, and tolerability.27 Undertake any change in therapy with care and appropriate monitoring because changes in glycemic control can occur.27

Administration

Oral Administration

Saxagliptin Monotherapy

Administer once daily without regard to meals.1 2 21

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.2 If the missed dose is not remembered until time of next dose, skip missed dose and resume regular schedule.2 Do not double dose to replace missed dose.2

Saxagliptin/Metformin Hydrochloride Fixed Combination

Administer once daily with the evening meal, increasing dosage gradually to minimize adverse GI effects of extended-release metformin hydrochloride component.27

Swallow whole; do not cut, chew, or crush.27 28

If a dose is missed, take the next dose as prescribed unless a healthcare provider instructs otherwise; do not take an extra dose the next day.27 28

Dosage

Available as saxagliptin hydrochloride (anhydrous); dosage expressed in terms of saxagliptin.1

Adults

Diabetes Mellitus
Monotherapy
Oral

2.5 or 5 mg once daily.1 Higher dosages (e.g., 10 mg once daily) did not provide additional benefit in clinical trials and are not recommended by manufacturer.1 5 27 32

If used with a potent CYP3A4/5 inhibitor, limit dosage to 2.5 mg daily.1 (See Interactions.)

Saxagliptin/Metformin Hydrochloride Fixed-combination Therapy
Oral

Patients inadequately controlled on saxagliptin 5 mg daily as monotherapy: Initially, 5 mg of saxagliptin and 500 mg of extended-release metformin hydrochloride once daily; increase metformin dosage gradually to minimize adverse GI effects of metformin.27

Patients inadequately controlled on monotherapy with extended-release metformin hydrochloride: Dosage should provide metformin hydrochloride at the patient’s current dosage, or the nearest therapeutically appropriate dosage.27 Following a switch from immediate-release to extended-release metformin, closely monitor glycemic control and adjust dosage accordingly.27

Patients inadequately controlled on saxagliptin 2.5 mg daily as monotherapy: Initially, 2.5 mg of saxagliptin and 1 g of extended-release metformin hydrochloride daily. 27 Use the individual components in patients who require 2.5 mg of saxagliptin and are either metformin naive or require a metformin hydrochloride dose >1 g.27

If used with a potent CYP3A4/5 inhibitor, limit dosage to 2.5 mg of saxagliptin and 1 g of extended-release metformin hydrochloride.27 (See Interactions.)

Prescribing Limits

Adults

Diabetes Mellitus
Oral

Saxagliptin dosages >5 mg daily did not provide additional benefit in clinical trials and are not recommended by manufacturer.1 5 27 32

Fixed combination with extended-release metformin hydrochloride: Maximum 5 mg of saxagliptin and 2 g of metformin hydrochloride daily.27

Special Populations

Hepatic Impairment

No dosage adjustment recommended.1

Renal Impairment

Saxagliptin Monotherapy
Oral

Mild renal impairment: No saxagliptin dosage adjustment recommended.1

Moderate or severe renal impairment (Clcr ≤50 mL/minute): 2.5 mg once daily.1

End-stage renal disease requiring hemodialysis: 2.5 mg once daily, following hemodialysis.1

Peritoneal dialysis: Not studied.1

Saxagliptin/Metformin Hydrochloride Fixed-Combination Therapy
Oral

Fixed combination of saxagliptin and extended-release metformin hydrochloride contraindicated in patients with renal impairment.27

Geriatric Patients

Because of the greater frequency of decreased renal function in geriatric patients, select dosage with caution.1

Cautions for Onglyza

Contraindications

  • Known serious hypersensitivity (e.g., anaphylaxis, angioedema, exfoliative skin reaction) to saxagliptin or any ingredient in the formulation.1 27

Warnings/Precautions

Pancreatitis and Precancerous Changes

Acute pancreatitis reported during postmarketing experience.1 27

FDA is evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous cellular changes in patients with type 2 diabetes mellitus receiving incretin mimetics.36 37 The agency has not yet reached any new conclusions about safety risks with incretin mimetics.36 FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete or when there is additional information to report.36

FDA states that at this time clinicians should continue to follow the recommendations in the prescribing information for incretin mimetics.36

Monitor patients for manifestations of pancreatitis.1 27 If pancreatitis is suspected, promptly discontinue saxagliptin and institute appropriate management.1 27 Not studied in patients with a history of pancreatitis; unknown whether such patients are at increased risk for pancreatitis.1 27

Concomitant Therapy with Hypoglycemic Agents

Increased risk of hypoglycemia in patients receiving saxagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin;1 reduction in sulfonylurea or insulin dosage may be necessary.1 27

Reduction in Lymphocyte Counts

Dose-related mean decreases in absolute lymphocyte count reported with saxagliptin dosages of 5 and 10 mg daily;1 clinical importance not known.1 When clinically indicated (i.e., settings of unusual or prolonged infection), measure lymphocyte count.1

Sensitivity Reactions

Risk of serious allergic and hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative skin conditions); rash and urticaria also reported.1 27 Onset usually within first 3 months after treatment initiation, but may occur after first dose.1 27 (See Cautions: Contraindications.)

If serious hypersensitivity reactions suspected, promptly discontinue drug, assess for other potential causes, institute appropriate treatment, and initiate alternative antidiabetic therapy.1 27

Use caution in patients with a history of angioedema to other DPP-4 inhibitors; unknown whether such patients will be predisposed to angioedema with saxagliptin.1 27

Macrovascular Outcomes

Evidence of macrovascular risk reduction with saxagliptin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.1

Use of Fixed Combinations

When saxagliptin is used in fixed combination with metformin, consider the cautions, precautions, and contraindications associated with metformin.27

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Eliminated in part by kidneys; assess renal function periodically since geriatric patients are more likely to have decreased renal function.1

Renal Impairment

Renal impairment increases exposure to saxagliptin and its active metabolite.1 (See Special Populations under Pharmacokinetics.) Dosage adjustment recommended for patients with moderate or severe renal impairment or end-stage renal disease requiring hemodialysis.1 (See Renal Impairment under Dosage and Administration.)

Fixed combination of saxagliptin and extended-release metformin hydrochloride contraindicated in patients with renal impairment.27

Assess renal function prior to initiation of therapy and periodically thereafter.1 27

Common Adverse Effects

Saxagliptin monotherapy: Upper respiratory infection, urinary tract infection, headache.1

Saxagliptin and extended-release metformin hydrochloride fixed-combination therapy: Headache, nasopharyngitis.1 27 28

Interactions for Onglyza

Metabolized principally via CYP3A4 and CYP3A5.1

Saxagliptin and its active metabolite do not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro and do not induce CYP isoenzymes 1A2, 2B6, 2C9, or 3A4 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4/5 inhibitors: Substantial increases in saxagliptin plasma concentrations and AUC are expected.1 Limit saxagliptin dosage to 2.5 mg daily when used concomitantly with a potent CYP3A4/5 inhibitor.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4: Pharmacokinetic interactions unlikely.1

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum-, magnesium-, and simethicone-containing)

Decreased peak concentration of saxagliptin; AUC unchanged12

No dosage adjustment required1

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Ketoconazole: Decreased peak concentration and AUC of ketoconazole; increased peak concentration and AUC of saxagliptin1 12 24

Itraconazole: Substantial increase in plasma concentrations and AUC of saxagliptin expected1

Limit saxagliptin dosage to 2.5 mg daily1

Digoxin

Pharmacokinetic interaction unlikely1

No dosage adjustment required1

Diltiazem

Increased peak concentration of diltiazem; increased peak concentration and AUC of saxagliptin and 5-hydroxy saxagliptin12

No dosage adjustment required1

Famotidine

Increased peak concentration of saxagliptin12

No dosage adjustment required1

HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Substantial increase in plasma concentrations and AUC of saxagliptin expected1

Limit saxagliptin dosage to 2.5 mg daily1

Hormonal contraceptives

Ethinyl estradiol/norgestimate: No appreciable effect on ethinyl estradiol or norgestimate pharmacokinetics

No dosage adjustment required1

Macrolide antibiotics (e.g., clarithromycin, telithromycin)

Substantial increase in plasma concentrations and AUC of saxagliptin expected1

Limit saxagliptin dosage to 2.5 mg daily1

Metformin

Decreased peak concentration of saxagliptin; no effect on saxagliptin AUC or metformin pharmacokinetics12

No dosage adjustment required1

Nefazodone

Substantial increase in plasma concentrations and AUC of saxagliptin expected1

Limit saxagliptin dosage to 2.5 mg daily1

Omeprazole

Saxagliptin pharmacokinetics not substantially altered1 12

No dosage adjustment required1

Pioglitazone

Increased peak concentration of pioglitazone; AUC not appreciably altered12

No dosage adjustment required1

Rifampin

Decreased peak concentration and AUC of saxagliptin12

No dosage adjustment required1

Simvastatin

Increased peak concentration and AUC of saxagliptin12

No dosage adjustment required1 22

Sulfonylureas (e.g., glyburide)

Glyburide: Increased peak concentrations of glyburide and saxagliptin

May need to decrease sulfonylurea dosage to reduce risk of hypoglycemia1

Onglyza Pharmacokinetics

Absorption

Bioavailability

Estimated oral bioavailability is 67%.11

Onset

Rapidly absorbed following oral administration;11 peak plasma concentrations generally attained in 2 hours following administration of recommended doses.1

Food

Food does not appear to affect absorption. 1 21

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Negligible.1 11

Elimination

Metabolism

Metabolized principally via CYP3A4 and CYP3A5 to active metabolite 5-hydroxy saxagliptin.1 11

Elimination Route

Saxagliptin and its metabolites excreted in urine and feces.1

Half-life

2.5 hours.1 11

Special Populations

Hepatic impairment increases peak concentrations and AUC of saxagliptin by ≤8 and ≤77%, respectively, and increases peak concentrations and AUC of active metabolite by ≤59 and ≤33%, respectively.1 Not considered clinically important.1

Mild renal impairment increase AUC of saxagliptin and its active metabolite by 20 and 70%, respectively; not considered clinically important.1 However, moderate or severe renal impairment increases AUC of saxagliptin and its active metabolite by 2.1- and 4.5-fold, respectively.1

Removed by hemodialysis.1

Pharmacokinetics in pediatric patients not elucidated.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1 27

Actions

  • Inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 8 9 25 26

  • More selective for inhibition of DPP-4 than for DPP-8 or DDP-9.14

  • Increases circulating concentrations of GIP and GLP-1 in a glucose-dependent manner.1 8

  • GIP and GLP-1 stimulate insulin synthesis and release from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated).1 8 9 25

  • GLP-1 also decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, leading to reduced hepatic glucose production.1 9 25

  • Lowers fasting plasma glucose concentrations and reduces glucose excursions following glucose load or meal in patients with type 2 diabetes mellitus.1 25

  • Saxagliptin usually not associated with hypoglycemia or substantial changes in body weight.2 3 4 10 25

Advice to Patients

  • Importance of patients reading patient medication guide before initiating therapy and each time drug is dispensed.1 2

  • Importance of informing patients of the potential risks and benefits of saxagliptin and of alternative therapies.1 2 Importance of not using saxagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1 2

  • Importance of informing patients about possibility of acute pancreatitis, which may be severe or fatal, with saxagliptin therapy.1 2 27 Importance of patients informing clinicians about a history of pancreatitis, gallstones, alcoholism, or high triglyceride levels.1 2 27 Importance of informing patients about signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back that may or may not be accompanied by vomiting; importance of patient discontinuing saxagliptin and promptly notifying clinician if such signs or symptoms are present.1 2 27

  • Importance of informing clinician if hypoglycemia occurs, particularly if concomitant therapy with a sulfonylurea antidiabetic agent (i.e., insulin secretagogue) or insulin is used; a lower dosage of the sulfonylurea or insulin may be required in such cases.1 2 27 28

  • Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.1 2

  • Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.1 2

    Importance of informing patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA1c, with a goal of decreasing these levels toward the normal range.1 2

  • Importance of informing patients of the potential need to adjust their dosage based on changes in renal function over time.1 2

  • Importance of informing clinician if any unusual symptom develops or if any existing symptom persists or worsens.1 2

  • Risk of serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions.1 2 If signs or symptoms of such reactions occur (e.g., rash, skin flaking or peeling, hives, swelling of the skin, swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing), importance of discontinuing saxagliptin-containing therapy and informing clinician promptly.1 2 27 28

  • Importance of advising patient not to split or cut saxagliptin tablets.1 Importance of swallowing saxagliptin/metformin tablets whole and not cutting, crushing, or chewing them.27 28 Importance of advising patients receiving saxagliptin/metformin that occasionally the inactive components of the tablet may remain intact and be passed in the stool as a soft, hydrated mass resembling the original tablet.27 28

  • Importance of taking saxagliptin exactly as directed by clinician.2 Importance of informing patients that if they miss a dose, they should take the dose as soon as it is remembered unless it is almost time for the next dose.2 In that case, the missed dose should be skipped and the next dose taken at the regular time; patients should not take 2 doses at the same time unless instructed to do so by their clinician.1 2

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., allergies, kidney disease).2

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Saxagliptin Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg (of saxagliptin)

Onglyza

Bristol-Myers Squibb

5 mg (of saxagliptin)

Onglyza

Bristol-Myers Squibb

Saxagliptin Hydrochloride Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g

Kombiglyze XR

Bristol-Myers Squibb

5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 500 mg

Kombiglyze XR

Bristol-Myers Squibb

5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g

Kombiglyze XR

Bristol-Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Kombiglyze XR 2.5-1000MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$119.99 or 90/$344.98

Kombiglyze XR 5-1000MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$236.98 or 90/$679.00

Kombiglyze XR 5-500MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$240.00 or 90/$699.98

Onglyza 2.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$240.00 or 90/$658.98

Onglyza 5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$235.98 or 90/$635.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 25, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Bristol-Myers Squibb. Onglyza (saxagliptin) tablets prescribing information. Princeton, NJ; 2013 Apr.

2. Bristol-Myers Squibb. Onglyza (saxagliptin) tablets medication guide. Princeton, NJ; 2013 May.

3. Rosenstock J, Aguilar-Salinas C, Klein E et al. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009; 25:2401-11. [PubMed 19650754]

4. Jadzinsky M, Pfützner A, Paz-Pacheco E et al. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009; 11:611-22. [PubMed 19515181]

5. DeFronzo RA, Hissa MN, Garber AJ et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009; 32:1649-55. [PubMed 19478198]

6. Chacra AR, Tan GH, Apanovitch A et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomized controlled trial. Int J Clin Pract. 2009; 63:1395-406. [PubMed 19614786]

7. Hollander P, Li J, Allen E et al. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009; 94:4810-9. [PubMed 19864452]

8. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006; 368:1696-705. [PubMed 17098089]

9. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006; 3:153-65. [PubMed 16517403]

10. Bristol-Myers Squibb Company. Clinical Study Report CV181-038 Synopsis Clinical Study Results Website. Accessed 2009 Aug 6.

11. Fura A, Khanna A, Vyas V et al. Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections. Drug Metab Dispos. 2009; 37:1164-71. [PubMed 19251818]

12. Bristol-Myers Squibb. Onglyza (saxagliptin) tablets prescribing information. Princeton, NJ; 2009 July.

13. Frederich R, Alexander JH, Fiedorek FT et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010; 122:16-27. [PubMed 20463410]

14. Wang A, Dorso C, Kopcho L et al. Implications of the prolonged dissociation rate of saxagliptin, a highly potent and selective dpp4 inhibitor, on plasma dpp measurments. Diabetes. 2008 Jun; Suppl. 1: A576-577.

15. Hirsch IB, Bergenstal RM, Parkin CG et al. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 2005; 23(2):78-86.

16. Buse J. Combining insulin and oral agents. Am J Med. 2000; 108(Suppl 6A):23S-32S. [IDIS 446200] [PubMed 10764847]

17. Florence JA, Yeager BF. Treatment of type 2 diabetes mellitus. Am Fam Physician. 1999; 59:2835-44. [IDIS 428714] [PubMed 10348076]

18. Bastyr EJ, Johnson ME, Trautman ME et al. Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther. 1999; 21:1703-4. [IDIS 438022] [PubMed 10566566]

19. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999; 131:281-303. [IDIS 430576] [PubMed 10454950]

20. Rathmann W, Kostev K, Haastert B. Glycemic durability of monotherapy for diabetes. N Engl J Med. 2007; 356:1378-9; author reply 1380. [PubMed 17392313]

21. Patel CG, Zhang J, Li L et al. Effect of a high-fat meal on the pharmacokinetics of saxagliptin in healthy subjects. J Clin Pharmacol. 2010; 50:1211-6. [PubMed 20150522]

22. Girgis S, You X, Li L et al. Effect of simvastatin on the pharmacokinetics of saxagliptin in healthy subjects. J Clin Pharmacol. 2007;47:1188.

23. Girgis S, Patel C, Li L et al. Effect of diltiazem on the pharmacokinetics of saxagliptin in healthy subjects.J Clin Pharmacol. 2007;47:1199.

24. Boulton DW, Brenner E, Royzman K et al. Effect of ketoconazole on the pharmacokinetics of saxagliptin in healthy subjects.J Clin Pharmacol. 2007;47:1203.

25. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009 Sep-Oct; 15:540-59.

26. Augeri DJ, Robl JA, Betebenner DA et al. Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005; 48:5025-37. [PubMed 16033281]

27. Bristol-Myers Squibb. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets prescribing information. Princeton, NJ; 2010 November.

28. Bristol-Myers Squibb. Kombiglyze XR (saxagliptin and metformin HCl extended-release) tablets patient information. Princeton, NJ; 2010 November.

29. Stenlöf K, Raz I, Neutel J et al. Saxagliptin and metformin XR combination therapy provides glycemic control over 24 hours in patients with T2DM inadequately controlled with metformin. Curr Med Res Opin. 2010; 26:2355-63. [PubMed 20804445]

30. Göke B, Gallwitz B, Eriksson J et al. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomized controlled trial. Int J Clin Pract. 2010; 64:1619-31. [PubMed 20846286]

31. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab. 2008; 10:376-86. [PubMed 18355324]

32. Bristol Myers Squibb. AMCP formulary submission dossier for Onglyza (saxagliptin). Princeton, NJ; 2009 Aug 6.

33. Bristol-Myers Squibb Canada. Product monograph for Onglyza (saxagliptin) tablets 5 mg. Montreal, Canada; 2011 Aug 30.

36. Food and Drug Administration. Early communication: reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas. Silver Spring, MD; 2013 Mar 14. From FDA website.

37. Singh S, Chang HY, Richards TM et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013; 173:534-9. [PubMed 23440284]

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