Generic Name: Sitagliptin Phosphate
Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
VA Class: HS502
Chemical Name: 7 - [(3R) - 3 - amino - 1 - oxo - 4 - (2,4,5 - trifluorophenyl)butyl] - 5,6,7,8 - tetrahydro - 3 - (trifluoromethyl) - 1,2,4 - triazolo[4,3 - a]pyrazine phosphate monohydrate
Molecular Formula: C16H15F6N5O•H3O4P•H2O
CAS Number: 654671-77-9

Introduction

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.1 9 11

Uses for Januvia

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1 3 4 9

Used in combination with metformin (given separately or as the fixed combination) as initial therapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus1 11 21 when treatment with both sitagliptin and metformin is appropriate.11

Slideshow: Can Prescription Drugs Lead to Weight Gain?

Used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione [peroxisome proliferator-activated receptor-γ agonist]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with one or more oral antidiabetic agents and/or insulin.1 2 5 9 11

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).29 DPP-4 inhibitors also recommended as part of combination therapy, particularly with both postprandial and fasting plasma glucose elevations.29

Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis; insulin is required in these conditions.1 10 11

Januvia Dosage and Administration

General

  • Individualize dosage of sitagliptin/metformin hydrochloride in fixed combination based on patient's current antidiabetic regimen, clinical response, and tolerability.11

    Use of combination therapy initially or as maintenance therapy may not be appropriate in all patients; use according to clinician discretion.1 11

    Undertake any change in therapy with care and appropriate monitoring because changes in glycemic control can occur.1 11

Administration

Oral Administration

Sitagliptin Monotherapy

Administer orally once daily with or without food.1 10

If a dose is missed, take missed dose as soon as it is remembered followed by resumption of regular schedule.1 If the missed dose is remembered at time of next dose, skip missed dose and resume the regular schedule.1 Do not double dose to replace missed dose.1

Sitagliptin/Metformin Hydrochloride Fixed Combination

Administer twice daily with meals, increasing dosage gradually to minimize adverse GI effects of metformin hydrochloride component.11 13

If a dose is missed, take missed dose with a meal23 as soon as it is remembered followed by resumption of regular schedule.13 If missed dose is remembered at time of next dose, skip missed dose and resume regular schedule.13 Do not double dose to replace missed dose.13

Dosage

Available as sitagliptin phosphate (as the monohydrate); dosage expressed in terms of sitagliptin.1

Adults

Diabetes Mellitus
Monotherapy
Oral

100 mg once daily.1 10

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy
Oral

Patients not currently receiving metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride twice daily as the fixed combination.11 Increase dosage gradually to reduce adverse GI effects of metformin.11

Patients currently receiving metformin hydrochloride: Initially, 50 mg of sitagliptin and 500 mg of metformin hydrochloride or 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination, depending on the patient's existing dosage of metformin hydrochloride.11 23

Patients currently receiving metformin hydrochloride 850 mg twice daily: 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily as the fixed combination.11

Efficacy and safety of switching therapy from oral antidiabetic agents other than sitagliptin or metformin hydrochloride specifically to the fixed combination of sitagliptin and metformin hydrochloride not established.11

Combination Therapy with Sitagliptin and Other Oral Antidiabetic Agents or Insulin Given as Separate Components
Oral

Combination therapy with metformin hydrochloride: Sitagliptin 100 mg once daily has been used.5 10 21 24

Combination therapy with an insulin secretagogue (e.g., sulfonylurea) with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.1 22 Reduced dosage of concomitant insulin secretagogue may be needed to decrease risk of hypoglycemia.1

Combination therapy with a thiazolidinedione (e.g., pioglitazone, rosiglitazone) with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.1 2 10

Combination therapy with insulin with or without metformin hydrochloride: 100 mg of sitagliptin once daily has been used.1 11 Reduced dosage of concomitant insulin may be needed to decrease risk of hypoglycemia.1

Prescribing Limits

Adults

Diabetes Mellitus
Oral

Sitagliptin monotherapy: Maximum 100 mg daily.23

Fixed combination with metformin hydrochloride: Maximum 100 mg of sitagliptin and 2 g of metformin hydrochloride daily (in divided doses).11 23

Special Populations

Hepatic Impairment

No dosage adjustments necessary in patients with mild to moderate hepatic impairment (Child-Pugh score ≤9).1 10 23 Efficacy and safety not established in patients with severe hepatic impairment (Child-Pugh score >9).1 10

Renal Impairment

Sitagliptin Monotherapy
Oral

Moderate renal impairment (Clcr of 30 to <50 mL/minute, corresponding to Scr of >1.7–3 mg/dL in men or >1.5–2.5 mg/dL in women): 50 mg once daily.1 23 26

Severe renal impairment (Clcr <30 mL/minute, corresponding to Scr of >3 mg/dL in men or >2.5 mg/dL in women): 25 mg once daily.1 26

End-stage renal disease requiring hemodialysis or peritoneal dialysis: 25 mg once daily.1 26

May administer without regard to timing of dialysis.1 10 26 (See Absorption: Special Populations, under Pharmacokinetics.)

Sitagliptin/Metformin Hydrochloride Fixed-combination Therapy
Oral

Patients with renal impairment receiving reduced dosages of sitagliptin should not be switched to the fixed combination of sitagliptin and metformin hydrochloride.11 (See Renal Impairment under Cautions.)

Geriatric Patients

Sitagliptin monotherapy: Select dosage with caution because of age-related decreases in renal function.1 11 (See Geriatric Use and also see Renal Impairment under Cautions.)

Sitagliptin in fixed combination with metformin hydrochloride: Select dosage with caution because of age-related decreases in renal function.11 (See Geriatric Use and also see Renal Impairment under Cautions.) Carefully titrate dosage to minimum dosage necessary for adequate glycemic control.11

Cautions for Januvia

Contraindications

  • Known serious hypersensitivity (e.g., anaphylaxis, angioedema) to sitagliptin or any ingredient in formulation.1 11

Warnings/Precautions

Pancreatitis and Precancerous Changes

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, reported during postmarketing experience with sitagliptin or sitagliptin/metformin.1 11 28

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 the agency has 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 receiving sitagliptin or sitagliptin/metformin for manifestations of pancreatitis, such as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes radiating to the back.1 11 28

Promptly discontinue sitagliptin and initiate appropriate management (e.g., obtain serum and urine amylase, amylase/creatinine clearance ratio, serum electrolytes, calcium, glucose, lipase) if pancreatitis suspected.1 11 28

Unknown whether history of pancreatitis increases risk for pancreatitis with sitagliptin therapy.1 11

Worsening of Renal Function

Worsening of renal function, including acute renal failure that sometimes required dialysis, reported in some patients during postmarketing experience.1 11

Assess renal function prior to initiation of sitagliptin and periodically thereafter.1 11

Concomitant Therapy with Hypoglycemic Agents

Greater incidence of hypoglycemia when sitagliptin used in combination with a sulfonylurea or insulin.1 11 May require lower dosage of concomitant insulin secretagogue (e.g., sulfonylurea) or insulin to reduce risk of hypoglycemia.1 11

Sensitivity Reactions

Risk of hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative dermatitis, Stevens-Johnson syndrome).1 11 Onset usually within first 3 months of treatment initiation, but may occur after first dose.1 11 (See Contraindications under Cautions.)

If hypersensitivity reactions occur, promptly discontinue drug, assess other potential causes for event, and institute alternative antidiabetic therapy.1 11 (See Advice to Patients.)

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

Loss of Glycemic Control

Possible loss of glycemic control during periods of stress (e.g., fever, trauma, infection, surgery).1 11 (See Advice to Patients.)

Temporary discontinuance of sitagliptin and administration of insulin may be required.11 May reinstitute sitagliptin therapy after acute episode of hyperglycemia has resolved.11

Macrovascular Outcomes

Evidence of macrovascular risk reduction with sitagliptin or any other antidiabetic agent not conclusively demonstrated in controlled clinical trials.1

Use of Fixed Combinations

When used in fixed combination with metformin, consider the cautions, precautions, and contraindications associated with metformin.11

Specific Populations

Pregnancy

Category B.1 11 Pregnancy registry at 800-986-8999.1 11 13

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 11 Use caution.1 11

Pediatric Use

Safety and efficacy of sitagliptin alone or in fixed combination with metformin not established in children <18 years of age.1 11 13 23

Geriatric Use

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

Substantially eliminated by kidneys; assess renal function prior to initiation of therapy and periodically thereafter because geriatric patients more likely to have decreased renal function.1

Renal Impairment

Substantially eliminated by kidneys; assess renal function prior to initiation of therapy and periodically thereafter.1

Common Adverse Effects

Sitagliptin monotherapy or add-on therapy with metformin and/or a thiazolidinedione or glimepiride: Nasopharyngitis,1 3 4 10 upper respiratory tract infection,1 10 peripheral edema,1 headache.1 10

Sitagliptin/metformin fixed combination: Diarrhea, upper respiratory infection, headache.11

Sitagliptin in combination with metformin and glimepiride: Hypoglycemia, headache.11

Sitagliptin in combination with insulin: Hypoglycemia.11

Interactions for Januvia

Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.1 10 12

Drugs Metabolized by Hepatic Microsomal Enzymes

Does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro or induce CYP3A4.1 11 Pharmacokinetic interactions with drugs metabolized by these isoenzymes unlikely.1

Inhibitors of P-glycoprotein Transport System

Substrate of p-glycoprotein transport system.1 12 Potential pharmacokinetic interaction (increased absorption and renal clearance of sitagliptin) with p-glycoprotein inhibitors.1 12 23

Clinically important pharmacokinetic interactions with p-glycoprotein inhibitors unlikely.1 12 23 Does not appear to inhibit p-glycoprotein transport system.1 12

Drugs Secreted by Renal Tubular Cationic Transport

Substrate of organic anion transport system; pharmacokinetic interaction unlikely with substrates of organic cationic transport system.1

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1

Specific Drugs

Drug

Interaction

Comments

Cyclosporine

Increased absorption and plasma concentrations of sitagliptin1 12

Not considered clinically important1 12

Digoxin

Slight increase in plasma concentrations and AUC of digoxin 1 23

Not considered clinically important; no dosage adjustment needed but monitor digoxin appropriately1 23

Hormonal contraceptives, oral

No clinically meaningful effect on pharmacokinetics of norethindrone or ethinyl estradiol1

Insulin

Risk of hypoglycemia increased when sitagliptin added to insulin therapy1 11

Reduced dosage of insulin may be required to reduce risk of hypoglycemia1

Metformin

Potential additive effect on active GLP-1 concentrations1 11 21 22

Pharmacokinetic interactions unlikely1 10 11 27

Relevance of these effects to glycemic control in patients with type 2 diabetes mellitus unclear11 23

Simvastatin

Pharmacokinetic interactions unlikely1

Sulfonylureas

Risk of hypoglycemia increased when sitagliptin added to glimepiride therapy1 22

Pharmacokinetic interactions unlikely1 23

Reduced dosage of sulfonylurea may be required to reduce risk of hypoglycemia1 23

Thiazolidinediones

Pharmacokinetic interactions unlikely1

Warfarin

Pharmacokinetic interactions unlikely1

Januvia Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability 87%.1 23

Rapidly absorbed following oral administration; at steady state (within 3 days of therapy initiation), peak plasma concentrations generally attained ≤3 hours following administration of recommended doses.1 23 25

Fixed-combination tablet containing sitagliptin 50 mg and metformin hydrochloride 500 mg or 1 g (Janumet) bioequivalent to one 50-mg tablet of sitagliptin and one 500-mg or 1-g tablet of metformin hydrochloride, respectively, given simultaneously.11

Onset

Reduction in postprandial plasma glucose excursion: Approximately 60 minutes.4 7 23

Duration

Approximately 80% inhibition of DPP-4 activity persists for 12 or 24 hours following administration of ≥50 or ≥100 mg, respectively, of sitagliptin.1 9 23 25

Food

Food does not appear to affect absorption.1

Special Populations

Renal impairment results in increased plasma AUC.1 Removed modestly by hemodialysis; time to peak plasma drug concentration increased in a limited number of patients with end-stage renal disease requiring hemodialysis.1 26

Moderate hepatic impairment results in increased peak plasma concentrations and AUC; not considered clinically important.1 23

In geriatric patients, modest increases in plasma concentrations compared with younger adults.1 11

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1 11

Plasma Protein Binding

38%.1

Elimination

Metabolism

Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.1 12

Elimination Route

Eliminated principally by kidneys via active tubular secretion.1 25 26 Excreted in urine (87%) mainly as unchanged drug and in feces (13%).1 10

Half-life

12.4 hours.1

Special Populations

Renal impairment results in increased terminal elimination half-life.26

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1 11 13

Actions

  • Inhibits DPP-4, an enzyme that inactivates incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 7 8 9 11 21 24

  • Inhibits DPP-4 selectively with no effect on DPP-8 or DDP-9 in vitro at concentrations approximating those from therapeutic dosage.1 11

  • Increases circulating concentrations of GIP and GLP-1 in a glucose-dependent manner.1 2 3 7 8 9 10 21 Coadministration of sitagliptin and metformin has an additive effect on active GLP-1 concentrations.1 11 21

  • 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) by intracellular signaling pathways involving cyclic 3′,5′-adenosine monophosphate (cAMP).1 8 21 24

  • GLP-1 also decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, leading to reduced hepatic glucose production.1 2 3 7 21 24

  • Lowers fasting plasma glucose concentrations and reduces glucose excursions following glucose load or meal in patients with type 2 diabetes mellitus.1 4 7 11

  • Sitagliptin usually not associated with hypoglycemia or substantial changes in body weight.1 3 4 5 8 9

Advice to Patients

  • Inform patients of potential risks and advantages of sitagliptin-containing therapy and of alternative therapies.1 11

  • Importance of not using sitagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1

  • 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 11 13

  • Risk of acute pancreatitis, which may be severe or fatal.1 13 28 Importance of advising clinicians about a history of pancreatitis, gallstones, alcoholism, high triglyceride levels, or kidney problems.1 13 Importance of discontinuing sitagliptin and promptly notifying clinician if signs or symptoms of pancreatitis (e.g., nausea, vomiting, anorexia, persistent severe abdominal pain sometimes radiating to the back) are present.1 13 28

  • Importance of patient reading medication guide before initiating therapy and each time drug is dispensed.1 13

  • Importance of instructing patients regarding self-monitoring of blood glucose, periodic HbA1c monitoring, adherence to meal planning, regular physical exercise, and management of hypoglycemia and hyperglycemia.1 11 13

  • Discuss potential for alterations in dosage requirements in special situations (e.g., fever, trauma, infection, surgery, changes in renal function); importance of informing clinician promptly if such situations occur.1 13 (See Loss of Glycemic Control under Cautions.)

  • Risk of allergic reactions (e.g., rash; hives; swelling of face, lips, tongue, throat that may cause difficulty in breathing or swallowing).1 11 If such reactions occur, importance of discontinuing sitagliptin and informing clinicians promptly.1 11 13 (See Sensitivity Reactions under Cautions.)

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 13

  • 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 problems).1 13

  • Importance of informing patients of other important precautionary information.1 13 (See Cautions.)

Preparations

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

Sitagliptin Phosphate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

25 mg (of sitagliptin)

Januvia

Merck

50 mg (of sitagliptin)

Januvia

Merck

100 mg (of sitagliptin)

Januvia

Merck

Sitagliptin Phosphate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg (of sitagliptin) with Metformin Hydrochloride 500 mg

Janumet

Merck

50 mg (of sitagliptin) with Metformin Hydrochloride 1 g

Janumet

Merck

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.

Janumet 50-1000MG Tablets (MERCK SHARP &amp; DOHME): 60/$224.99 or 180/$645.95

Janumet 50-500MG Tablets (MERCK SHARP &amp; DOHME): 60/$220.99 or 180/$639.96

Januvia 100MG Tablets (MERCK SHARP &amp; DOHME): 30/$235.00 or 90/$672.99

Januvia 25MG Tablets (MERCK SHARP &amp; DOHME): 90/$645.98 or 270/$1,825.92

Januvia 50MG Tablets (MERCK SHARP &amp; DOHME): 30/$228.98 or 90/$659.99

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. Merck. Januvia (sitagliptin) tablets prescribing information. Whitehouse Station, NJ; 2013 Feb.

2. Rosenstock J, Brazg R, Andryuk PJ et al. Efficacy and safety of dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006; 28:1556-68. [PubMed 17157112]

3. Raz I, Hanefeld M, Xu L et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006; 49:2564-71. [PubMed 17001471]

4. Aschner P, Kipnes MS, Lunceford JK et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006; 29:2632-7. [PubMed 17130196]

5. Charbonnel B, Karasik A, Liu J et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006; 29:2638-43. [PubMed 17130197]

6. Merck. Januvia (sitagliptin phosphate) tablets medication guide. Whitehouse Station, NJ; 2012 Apr.

7. Herman GA, Bergman A, Stevens C et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006; 91:4612-9. [PubMed 16912128]

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

9. Anon. Sitagliptin (Januvia) for type 2 diabetes. Med Lett Drugs Ther. 2007; 49:1-3.

10. Merck. Product information form for AHFS drug information: Januvia (sitagliptin phosphate) tablets. Whitehouse Station, NJ; 2006.

11. Merck. Janumet (sitagliptin/metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2012 Apr.

12. Krishna R, Bergman A, Larson P et al. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol. 2007; 47:165-74. [PubMed 17244767]

13. Merck. Janumet (sitagliptin phosphate) tablets medication guide. Whitehouse Station, NJ; 2012 Apr.

14. Nathan DM, Buse JB, Davidson MB et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006; 29:1963-72. [PubMed 16873813]

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. American Diabetes Association. Hyperglycemic crises in patients with diabetes mellitus. Diabetes Care. 2004; 27(Suppl 1):S94-102.

21. Goldstein BJ, Feinglos MN, Lunceford JK et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007; 30:1979-87. [PubMed 17485570]

22. Hermansen K, Kipnes M, Luo E et al. Efficacy and safety of the didpeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007; 9:733-45. [PubMed 17593236]

23. Merck, North Wales, PA: personal communication.

24. Nauck MA, Meininger G, Sheng G et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007; 9:194-205. [PubMed 17300595]

25. Bergman A, Stevens C, Zhou YY et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a didpeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006; 28:55-72. [PubMed 16490580]

26. Bergman AJ, Cote J, Yi B et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007; 30:1862-4. [PubMed 17468348]

27. Herman GA, Bergman A, Yi B et al. Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes. Curr Med Res Opin. 2006; 22:1939-47. [PubMed 17022853]

28. Food and Drug Administration, Center for Drug Evaluation and Research. FDA alert: Information for healthcare professionals—acute pancreatitis and sitagliptin (marketed as Januvia and Janumet). Rockville MD: Food and Drug Administration; 2009 Sep 25. Available from FDA website. Accessed 2009 Dec 4.

29. Rodbard Hw, Jellinger PS, Davidson JA. 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.

30. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009; 32:193-203. [PubMed 18945920]

31. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus.Ann Intern Med. 2007; 147:386-99. [PubMed 17638715]

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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