AHFS Class:

• Dipeptidyl Peptidase-4 (DPP-4) Inhibitors 68:20.05

Generic Name(s):

• SITagliptin Phosphate

• Ertugliflozin and Sitagliptin

• Sitagliptin and Metformin Hydrochloride

Chemical Name:

• 7-[(3 R )-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

Sitagliptin phosphate, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic agent.1,9

Type 2 Diabetes Mellitus

Sitagliptin is 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 Sitagliptin is used as initial therapy in combination with immediate- or extended-release metformin hydrochloride (given separately or as the fixed combination) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus1,11,21,45 when treatment with both sitagliptin and metformin is appropriate.11,45 Sitagliptin also is used in fixed combination with ertugliflozin L-pyroglutamic acid (Steglujan^®) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both drugs is appropriate.50 Sitagliptin also may be 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.1,2,5,9,11,45

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).698,704,705 (See Uses: Type 2 Diabetes Mellitus, in Metformin 68:20.04.) In patients with contraindications or intolerance to metformin (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA_1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA_1c levels, some experts suggest initiation of therapy with 2 agents from other antidiabetic drug classes with complementary mechanisms of action. 698,704

Because of the progressive nature of type 2 diabetes mellitus, patients initially receiving an oral antidiabetic agent will eventually require multiple oral and/or injectable noninsulin antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control.698,704 Patients who have inadequate glycemic control with initial (e.g., metformin) monotherapy should receive treatment with additional antidiabetic agents; data suggest that the addition of each noninsulin agent to initial therapy lowers HbA_1c by approximately 0.7-1%.704 In addition, early initiation of combination therapy may help to more rapidly attain glycemic goals and extend the time to treatment failure.704

Factors to consider when selecting additional antidiabetic agents for combination therapy in patients with inadequate glycemic control on metformin monotherapy include patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preference.698,699,704,705,706 Some experts recommend DPP-4 inhibitors as one of several classes of drugs for use in combination therapy, particularly in patients with both postprandial and fasting plasma glucose elevations.29,698,704 When the greater glucose-lowering effect of an injectable drug is needed in patients with type 2 diabetes mellitus, some experts currently state that an injectable GLP-1 receptor agonist is preferred over insulin in most patients because of beneficial effects on body weight and a lower risk of hypoglycemia, although adverse GI effects may diminish tolerability.698,704 While addition of a GLP-1 receptor agonist may successfully control hyperglycemia, many patients will eventually require insulin therapy.698 Early introduction of insulin therapy should be considered when hyperglycemia is severe (e.g., blood glucose of at least 300 mg/dL or HbA_1c exceeding 9-10%), especially in the presence of catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.698,704 For additional information regarding the initiation of insulin therapy in patients with diabetes mellitus, see Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.

The manufacturer states that sitagliptin should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.1,10,11,50

Sitagliptin Monotherapy

Efficacy of sitagliptin as monotherapy for the management of type 2 diabetes mellitus is supported by results of 2 controlled trials of 18 or 24 weeks' duration.1,3,4 Sitagliptin (100 or 200 mg once daily) improved glycemic control, as evidenced by reductions in glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) as well as fasting and 2-hour postprandial plasma glucose concentrations, compared with placebo.1,3,4 HbA_1c was reduced by 0.5-0.6% (from an average baseline value of about 8%) in patients receiving sitagliptin 100 mg daily, compared with an increase of 0.1-0.2% in those receiving placebo.1,3,4 Overall, use of a higher than recommended dosage of sitagliptin (200 mg daily) did not provide greater glycemic control than did the recommended dosage of 100 mg daily.1,3,4

Combination Therapy

Efficacy of the combination of sitagliptin and metformin as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise is supported by results of a 24-week randomized, placebo-controlled trial.1,21 In this trial, patients receiving initial therapy with sitagliptin (50 mg twice daily) in combination with metformin hydrochloride (500 mg or 1 g twice daily) had greater improvements in HbA_1c, fasting plasma glucose, and 2-hour postprandial glucose concentrations than those receiving placebo, metformin monotherapy, or sitagliptin monotherapy.1 Mean reductions in HbA_1c from baseline in patients not receiving an antihyperglycemic agent at trial entry were 1.1% with sitagliptin 100 mg once daily, 1.1% with metformin hydrochloride 500 mg twice daily, 1.2% with metformin hydrochloride 1 g twice daily, 1.6% with sitagliptin 50 mg twice daily in combination with metformin hydrochloride 500 mg twice daily, 1.9% with sitagliptin 50 mg twice daily in combination with metformin hydrochloride 1 g twice daily, and 0.2% with placebo.1 In the same study, patients with more severe hyperglycemia (HbA_1c exceeding 11% or blood glucose exceeding 280 mg/dL) who received sitagliptin (50 mg twice daily) in combination with metformin hydrochloride (1 g twice daily) on an open-label basis achieved mean reductions from baseline of 2.9% in HbA_1c, 127 mg/dL in fasting plasma glucose, and 208 mg/dL in 2-hour postprandial glucose by the end of the trial (at 24 weeks).1

In another 24-week, randomized trial in patients who had inadequate glycemic control with diet and exercise, initial therapy with the combination of sitagliptin (100 mg once daily) and pioglitazone (30 mg once daily) produced greater improvements in HbA_1c, fasting plasma glucose, and 2-hour postprandial glucose concentrations than pioglitazone monotherapy (30 mg once daily).1 In this trial, patients receiving the sitagliptin/pioglitazone combination achieved a 0.9% mean reduction in HbA_1c compared with those receiving pioglitazone monotherapy, and 60% of patients receiving sitagliptin/pioglitazone achieved a mean HbA_1c less than 7%, compared with 28% of those receiving pioglitazone monotherapy.1

Efficacy and safety of the fixed combination of sitagliptin and metformin have been established based on concurrent administration of the 2 agents given separately and extrapolations from clinical trials evaluating sitagliptin as add-on therapy to metformin.11,45 Bioequivalence has been demonstrated between the fixed combination of sitagliptin and metformin hydrochloride and the drugs administered concurrently as separate tablets.11,45

Efficacy of sitagliptin in combination with metformin, a sulfonylurea, and/or a thiazolidinedione in the management of type 2 diabetes mellitus (in patients inadequately controlled with metformin or thiazolidinedione monotherapy) is supported by results from several long-term (24 weeks' duration), randomized, placebo-controlled trials.1,2,5,11 In these trials, the addition of sitagliptin (100 mg once daily) to existing metformin and/or glimepiride therapy or to pioglitazone or rosiglitazone/metformin therapy improved glycemic control, as evidenced by reductions in HbA_1c as well as fasting and/or 2-hour postprandial plasma glucose concentrations, compared with placebo or existing therapy.1,2,5,9,11 In patients receiving metformin hydrochloride therapy (dosage of at least 1.5 g daily), the addition of sitagliptin resulted in a reduction of 0.7% in HbA_1c, while the addition of placebo resulted in no appreciable change in HbA_1c.1,5,9 In patients receiving glimepiride therapy (dosage of at least 4 mg daily), the addition of sitagliptin resulted in a reduction of 0.6% in HbA_1c compared with addition of placebo.1 In patients receiving glimepiride (dosage of at least 4 mg daily) in combination with metformin hydrochloride (dosage of at least 1.5 g daily), the addition of sitagliptin resulted in a reduction of 0.9% in HbA_1c compared with addition of placebo.1,11 In patients receiving pioglitazone therapy (30-45 mg daily), the addition of sitagliptin or placebo resulted in reductions of 0.9 or 0.2%, respectively, in HbA_1c.1,2,9 In patients receiving metformin and rosiglitazone therapy in a 54-week trial, addition of sitagliptin 100 mg once daily or placebo resulted in mean reductions in HbA_1c of 1 or 0.3%, respectively; sulfonylurea (e.g., glipizide) rescue therapy was used in 18 or 40% of patients receiving sitagliptin or placebo, respectively.11 In a 52-week noninferiority trial in patients receiving metformin hydrochloride (dosage of at least 1.5 g daily), add-on therapy with sitagliptin (100 mg once daily) or glipizide (5-20 mg once daily; mean 10 mg once daily) was associated with similar mean reductions from baseline in HbA_1c (intent-to-treat analysis); results may be applicable principally to patients with baseline HbA_1c values less than 8-9%, comparable to those of this study population.1,11

Efficacy and safety of the combination of sitagliptin and ertugliflozin (as initial or add-on therapy) for the management of type 2 diabetes mellitus have been established in several randomized, placebo-controlled and active comparator trials.50,55,57 In a 26-week, randomized, double-blind trial, concomitant therapy with sitagliptin (100 mg daily) and ertugliflozin (5 or 15 mg once daily) given as initial therapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise substantially improved glycemic control (as evidenced by reductions in HbA_1c) compared with placebo.50,57 Reductions in HbA_1c were 1.6 or 1.7% with ertugliflozin 5 or 15 mg once daily, respectively, plus sitagliptin and 0.4% with placebo.57 Additionally, a greater proportion of patients receiving sitagliptin and ertugliflozin combination therapy achieved an HbA_1c of less than 7%, and greater reductions in fasting plasma glucose were observed with ertugliflozin and sitagliptin combination therapy compared with placebo.50

In a trial evaluating the safety and efficacy of ertugliflozin in combination with sitagliptin in adults with type 2 diabetes mellitus inadequately controlled with metformin hydrochloride monotherapy (dosage of at least 1.5 g daily), the addition of ertugliflozin and sitagliptin combination therapy to existing metformin therapy substantially improved glycemic control compared with the addition of either ertugliflozin or sitagliptin alone.50,55 In this trial, patients received ertugliflozin 5 mg, ertugliflozin 15 mg, sitagliptin 100 mg, ertugliflozin 5 mg and sitagliptin 100 mg, or ertugliflozin 15 mg and sitagliptin 100 mg once daily.50,55 At week 26, patients who received concomitant therapy with ertugliflozin 5 or 15 mg and sitagliptin 100 mg had greater reductions in HbA_1c (reduction of 1.4%) compared with those receiving ertugliflozin or sitagliptin alone (reduction of 1%).50,55 Additionally, a higher proportion of patients who received ertugliflozin 5 or 15 mg and sitagliptin 100 mg as an add-on to existing metformin therapy achieved an HbA_1c of less than 7% (53 or 51%, respectively) compared with those who received ertugliflozin 5 or 15 mg or sitagliptin 100 mg alone (29, 34, or 39%, respectively).50

Efficacy of sitagliptin in combination with insulin (with or without metformin) in the management of type 2 diabetes mellitus in patients who have inadequate glycemic control with insulin is supported by results of a 24-week, randomized, placebo-controlled trial.1,11 In this trial, addition of sitagliptin (100 mg once daily) to existing stable insulin (premixed insulin or intermediate- or long-acting insulin) therapy with or without metformin hydrochloride (dosage of at least 1.5 g daily) resulted in improvements in HbA_1c, fasting plasma glucose, and 2-hour postprandial glucose concentrations compared with addition of placebo.1,11 In patients who received sitagliptin as add-on therapy to metformin and insulin, 14% had HbA_1c reductions to less than 7% compared with 5% of those receiving add-on placebo with metformin and insulin.11 Among patients also receiving metformin, the median daily dosage of insulin at baseline for patients treated with sitagliptin or placebo was 40 or 42 units, respectively;11 the median daily insulin dosage for both groups at the end of the study was unchanged.1,11 Patients in both treatment groups gained a mean of 0.1 kg of body weight over the study period; hypoglycemia was more common in patients receiving add-on sitagliptin therapy.1,11

General

The dosage of sitagliptin/metformin hydrochloride in fixed combination should be individualized according to clinician judgment based on the patient's current antidiabetic regimen, clinical response, and tolerability.11,45 Any change in therapy should be undertaken with care and appropriate monitoring because changes in glycemic control can occur.11,45

In patients receiving the fixed combination of sitagliptin and ertugliflozin, volume depletion should be corrected prior to initiating therapy.50

Administration

When sitagliptin is administered as monotherapy, the drug should be administered orally once daily with or without food.1,10 If a dose is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.1 If the missed dose is remembered at the time of the next dose, the missed dose should be skipped and the regular schedule resumed.1 The dose should not be doubled to replace a missed dose.1

When sitagliptin is administered in fixed combination with immediate-release metformin hydrochloride, the combination should be administered orally twice daily with meals, increasing dosage gradually to minimize the adverse GI effects of the metformin component.11,13 If a dose is missed, the missed dose should be taken with a meal23 as soon as it is remembered followed by resumption of the regular schedule.13 If a missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed.13 The dose should not be doubled to replace a missed dose.13

The manufacturer states that tablets of the fixed combination of sitagliptin and immediate- or extended-release metformin hydrochloride must not be split or divided before swallowing.11,45

The fixed combination of sitagliptin and ertugliflozin should be administered orally once daily in the morning with or without food.50 If a dose of the fixed combination of sitagliptin and ertugliflozin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.50 If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.50

Dosage

Sitagliptin phosphate is commercially available as the monohydrate; dosage is expressed in terms of sitagliptin.1,11,50

Type 2 Diabetes Mellitus

Sitagliptin Monotherapy

The recommended dosage of sitagliptin for the management of type 2 diabetes mellitus in adults is 100 mg once daily.1,10,23 In clinical trials, higher dosages of sitagliptin (200 mg daily) did not provide additional glycemic benefit,1 and the manufacturer states that 100 mg daily is the maximum recommended dosage.23

Sitagliptin/Immediate-release Metformin Hydrochloride Fixed-combination Therapy

Dosage of sitagliptin in fixed combination with immediate-release metformin hydrochloride should be individualized based on the patient's current antidiabetic regimen, effectiveness, and tolerability.11 In patients not currently receiving metformin hydrochloride, the recommended initial dosage is 50 mg of sitagliptin and 500 mg of immediate-release metformin hydrochloride twice daily as the fixed combination, with gradual dosage escalation to reduce adverse GI effects associated with the metformin hydrochloride component.11

When the fixed combination of sitagliptin and immediate-release metformin hydrochloride is used in patients currently receiving metformin hydrochloride, the recommended initial dosage is 50 mg of sitagliptin and 500 mg of metformin hydrochloride twice daily or 50 mg of sitagliptin and 1 g of metformin hydrochloride twice daily, depending on the patient's existing dosage of metformin hydrochloride.11 In patients currently receiving immediate-release metformin hydrochloride 850 mg twice daily, the recommended initial dosage is 50 mg of sitagliptin and 1 g of immediate-release metformin hydrochloride twice daily as the fixed combination.11

The maximum recommended daily dosage of the fixed combination containing sitagliptin and immediate-release metformin hydrochloride is 100 mg of sitagliptin and 2 g of immediate-release metformin hydrochloride.11,23

The same total daily dosage of sitagliptin and metformin hydrochloride should be maintained when transitioning between the fixed combination of sitagliptin and immediate-release metformin hydrochloride and the fixed combination of sitagliptin and extended-release metformin hydrochloride.45

Sitagliptin/Extended-release Metformin Hydrochloride Fixed-combination Therapy

Dosage of sitagliptin in fixed combination with extended-release metformin hydrochloride should be individualized based on the patient's current antidiabetic regimen, effectiveness, and tolerability.45 In patients not currently receiving metformin hydrochloride, the recommended initial dosage of the fixed combination is 100 mg of sitagliptin and 1 g of extended-release metformin hydrochloride once daily, with gradual dosage escalation to reduce adverse GI effects associated with the metformin hydrochloride component.45

When the fixed combination of sitagliptin and metformin hydrochloride is used in patients currently receiving metformin hydrochloride, the recommended initial dosage is 100 mg of sitagliptin and 1 g of extended-release metformin hydrochloride once daily or 100 mg of sitagliptin and 2 g of extended-release metformin hydrochloride once daily, depending on the patient's existing dosage of metformin hydrochloride.45 In patients currently receiving metformin hydrochloride 850 mg or 1 g twice daily, the recommended initial dosage of the fixed combination is 100 mg of sitagliptin and 2 g of metformin hydrochloride once daily.45

The maximum recommended daily dosage of the fixed combination containing sitagliptin and extended-release metformin hydrochloride is 100 mg of sitagliptin and 2 g of extended-release metformin hydrochloride.23,45

The same total daily dosage of sitagliptin and metformin hydrochloride should be maintained when transitioning between the fixed combination of sitagliptin and immediate-release metformin hydrochloride and the fixed combination of sitagliptin and extended-release metformin hydrochloride.45

Sitagliptin/Ertugliflozin Fixed-combination Therapy

The recommended initial dosage of the fixed combination of sitagliptin and ertugliflozin is 100 mg of sitagliptin and 5 mg of ertugliflozin once daily in the morning with or without food.50 If tolerated, the dosage may be increased to a maximum of 100 mg of sitagliptin and 15 mg of ertugliflozin once daily in patients who require additional glycemic control.50

In patients currently receiving ertugliflozin and switching to the fixed combination of sitagliptin and ertugliflozin, the current dosage of ertugliflozin can be maintained.50

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

When given in combination with metformin hydrochloride as separate tablets, a sitagliptin dosage of 100 mg once daily has been used.5,10,21,24

When given as separate tablets in combination with a sulfonylurea with or without metformin hydrochloride, a sitagliptin dosage of 100 mg once daily has been used.1,11,22 Dosage of the concomitant sulfonylurea may need to be reduced to decrease risk of hypoglycemia.1,11 For additional details, see Uses: Type 2 Diabetes Mellitus.

When given as separate tablets in combination with a thiazolidinedione antidiabetic agent (e.g., pioglitazone, rosiglitazone) with or without metformin hydrochloride, a sitagliptin dosage of 100 mg once daily has been used.1,2,10,11 For additional details, see Uses: Type 2 Diabetes Mellitus.

When given in combination with insulin with or without metformin hydrochloride, a sitagliptin dosage of 100 mg once daily has been used.1,11 Dosage of concomitant insulin may need to be reduced to decrease risk of hypoglycemia.1,11

Special Populations

Hepatic Impairment

Dosage adjustments of sitagliptin alone or in fixed combination with ertugliflozin are not necessary in patients with mild to moderate hepatic impairment (Child-Pugh score of 9 or less).1,10,23,50 Data are lacking on use of sitagliptin or the fixed combination of sitagliptin and ertugliflozin in patients with severe hepatic impairment (Child-Pugh score greater than 9), and the manufacturer states that such use is not recommended.1,10,50

The manufacturer states that the fixed combinations of sitagliptin and immediate- or extended-release metformin are not recommended in patients with hepatic impairment.11,45

Renal Impairment

Sitagliptin Monotherapy

Dosage adjustment is recommended for patients with an estimated glomerular filtration rate (eGFR) less than 45 mL/minute per 1.73 m².1,23,26 Caution should be used to ensure that the correct dosage of sitagliptin is prescribed for patients with moderate or severe renal impairment or end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis.1 (See Worsening of Renal Function under Cautions: Warnings/Precautions.) In patients with moderate renal impairment (creatinine clearance of 30 to less than 45 mL/minute per 1.73 m²), the recommended dosage of sitagliptin is 50 mg once daily.1,23,26 In patients with severe renal impairment (creatinine clearance less than 30 mL/minute per 1.73 m², corresponding to serum creatinine concentrations greater than 3 mg/dL in men or greater than 2.5 mg/dL in women), the recommended sitagliptin dosage is 25 mg once daily.1,26 Patients with ESRD requiring hemodialysis or peritoneal dialysis should receive a dosage of 25 mg once daily.1,26 Sitagliptin may be administered without regard to the timing of dialysis.1,10,26

Sitagliptin/Ertugliflozin Fixed-combination Therapy

No dosage adjustment or increased monitoring is needed in patients with mild renal impairment receiving the fixed combination of sitagliptin and ertugliflozin.50 The manufacturer states that initiation of therapy with the fixed combination of sitagliptin and ertugliflozin is not recommended in patients with an eGFR of 30 to less than 60 mL/minute per 1.73 m² and that continued use of the combination is not recommended when eGFR is persistently between 30 and less than 60 mL/minute per 1.73 m².50 Use of the fixed combination of sitagliptin and ertugliflozin is contraindicated in patients with eGFR less than 30 mL/minute per 1.73 m².50

Sitagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Renal function (eGFR) should be assessed prior to initiation of the fixed combination of sitagliptin and immediate- or extended-release metformin.11,45 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) The manufacturer states that the fixed combination of sitagliptin and immediate-release metformin hydrochloride is not recommended in patients with eGFR between 30 and less than 45 mL/minute per 1.73 m² because such patients require a lower dosage of sitagliptin than what is available in the fixed-combination preparation.11

The manufacturer states that initiation of the fixed combination of sitagliptin and extended-release metformin hydrochloride is not recommended in patients with eGFR of 30-45 mL/minute per 1.73 m².45 In patients taking the fixed combination of sitagliptin and extended-release metformin hydrochloride whose eGFR later decreases to less than 45 mL/minute per 1.73 m², the dosage of the sitagliptin component should be limited to 50 mg daily and the benefit versus risk of continuing therapy with the fixed combination should be assessed.45 The fixed combination should be discontinued in patients whose eGFR decreases to less than 30 mL/minute per 1.73 m².45

Use of the fixed combinations of sitagliptin and immediate- or extended-release metformin is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/minute per 1.73 m²).11,45

Geriatric Patients

Dosage should be selected with caution because of age-related decreases in renal function.1,11 (See Geriatric Use and also see Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) Dosage should be titrated carefully to the minimum dosage necessary for adequate glycemic control.11 The fixed combination of sitagliptin and ertugliflozin is expected to have diminished efficacy in geriatric patients with renal impairment.50

Contraindications

Sitagliptin is contraindicated in patients with known serious hypersensitivity (e.g., anaphylaxis, angioedema) to sitagliptin or to any ingredient in the formulation.1,11,50

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported during postmarketing experience in patients receiving sitagliptin with or without metformin.1,11,28 The most common manifestations associated with pancreatitis were abdominal pain, nausea, and vomiting.28 Hospitalization was required in 66% of 88 reported cases, including 2 cases of hemorrhagic or necrotizing pancreatitis that necessitated prolonged hospitalization and intensive-care unit (ICU) care.28 Pancreatitis occurred within 30 days of initiation of sitagliptin or sitagliptin/metformin therapy in 21% of cases; discontinuance of the drug led to resolution of pancreatitis in 53% of patients.28 At least one other risk factor (e.g., obesity, high cholesterol and/or triglyceride concentrations) was noted in 51% of cases.28

FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cell changes (pancreatic duct metaplasia) in patients with type 2 diabetes mellitus receiving incretin mimetics (e.g., exenatide, liraglutide, sitagliptin, saxagliptin, alogliptin, linagliptin).36,37 These findings are based on examination of a small number of pancreatic tissue specimens taken from patients who died from unspecified causes while receiving an incretin mimetic.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 has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.36 The manufacturer states that patients receiving sitagliptin-containing therapy should be monitored for manifestations of pancreatitis, such as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes radiating to the back;1,11,28 persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.1,11 If pancreatitis is suspected, sitagliptin should be promptly discontinued and appropriate management instituted.1,11,28 (e.g., including laboratory studies such as serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, and serum calcium, glucose, and lipase).28 Safety and efficacy of sitagliptin have not been established in patients with a history of pancreatitis and it is not known whether such patients are at increased risk for pancreatitis with sitagliptin therapy.1,11,45,50

Heart Failure Risk

In cardiovascular outcomes studies conducted with 2 other dipeptidyl peptidase-4 (DPP-4) inhibitors (alogliptin, saxagliptin) in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease (ASCVD), an association between DPP-4 inhibitor treatment and heart failure was observed.1,11,42,43,44,45,50 The potential risks and benefits of sitagliptin therapy should be considered prior to use in patients at higher risk for heart failure (e.g., history of heart failure or renal impairment).1,11,45,50 Patients receiving sitagliptin-containing therapy should be monitored for manifestations of heart failure.1,11,45,50 (See Advice to Patients.) If heart failure develops, appropriate evaluation and management should be instituted according to current standards of care and consideration given to discontinuing sitagliptin.1,11,45,50

Worsening of Renal Function

Renal function should be assessed prior to initiation of sitagliptin and periodically thereafter.1,11 Worsening of renal function, including acute renal failure that sometimes required dialysis, has been reported in some patients during postmarketing experience.1,11 A subset of these patients had renal insufficiency, some of whom were prescribed inappropriate dosages of sitagliptin.1 A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuance of potentially causative agents.1 Cautious reinitiation of sitagliptin can be considered if another etiology is deemed likely to have precipitated the acute worsening of renal function.1 The manufacturer states that sitagliptin has not been found to be nephrotoxic in clinical trials or in preclinical studies at clinically relevant dosages.1

Severe Arthralgia

Severe, disabling joint pain has been reported during postmarketing experience in patients receiving DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,41 Onset of such symptoms has ranged from 1 day to years following initiation of therapy.1,41 Fever, chills, rash, and swelling accompanied joint pain in some patients, suggesting an immunologic reaction; some patients have required hospitalization.41 Symptoms resolved upon discontinuance of the DPP-4 inhibitor, usually in less than a month.1,41 In some patients, symptoms recurred when the same or another DPP-4 inhibitor was restarted.1,41 DPP-4 inhibitors should be considered as a possible cause of severe joint pain and should be discontinued if appropriate.1,41 (See Advice to Patients.)

Concomitant Therapy with Hypoglycemic Agents

When sitagliptin was used in combination with a sulfonylurea or insulin, the incidence of hypoglycemia was greater than that in patients receiving placebo with a sulfonylurea or insulin.1,11 In a long-term (52-week) clinical noninferiority study, rates of hypoglycemia with sitagliptin/metformin combination therapy were lower than those observed with glipizide/metformin combination therapy.11,24 However, in a 24-week clinical study, rates of hypoglycemia in patients receiving sitagliptin and glimepiride with or without metformin were greater than those in patients receiving glimepiride and metformin.11,22 Patients receiving sitagliptin may require a lower dosage of a concomitant insulin secretagogue (e.g., sulfonylurea) or insulin to reduce the risk of hypoglycemia.1,11

Dermatologic and Sensitivity Reactions

There have been postmarketing reports of serious allergic and hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative skin conditions such as Stevens-Johnson syndrome) in patients receiving sitagliptin; rash, urticaria, and cutaneous vasculitis also have been reported.1,11 The onset of such reactions usually has been within the first 3 months following treatment initiation, but such reactions may occur after the first dose.1,11 (See Cautions: Contraindications.)

If hypersensitivity reactions occur, promptly discontinue the drug, assess for other potential causes of the event, institute appropriate monitoring and treatment, and initiate alternative antidiabetic therapy.1,11 (See Advice to Patients.) Use caution in patients with a history of angioedema with other dipeptidyl peptidase-4 (DPP-4) inhibitors because it is unknown whether such patients will be predisposed to angioedema with sitagliptin.1

Cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use during postmarketing experience.1 Patients in such cases usually recovered after discontinuation of the DPP-4 inhibitor and treatment with topical or systemic immunosuppressive therapy.1 Patients should be advised to report the development of blisters or erosions while receiving sitagliptin.1 If bullous pemphigoid is suspected, sitagliptin should be discontinued and consideration given to referring the patient to a dermatologist for diagnosis and appropriate treatment.1

Loss of Glycemic Control

Loss of glycemic control may occur 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 Sitagliptin therapy may be reinstituted after the acute episode of hyperglycemia has resolved.11

Macrovascular Outcomes

The manufacturer states that evidence of macrovascular risk reduction with sitagliptin has not been conclusively demonstrated in controlled clinical trials.1,11,45,50

Use of Fixed Combinations

When sitagliptin is used in fixed combination with metformin hydrochloride, ertugliflozin, or other drugs, the cautions, precautions, contraindications, and drug interactions associated with the concomitant agent(s) should be considered in addition to those associated with sitagliptin.11,45,50

Specific Populations

Pregnancy

Data are lacking on the use of sitagliptin in pregnant women.1 In embryofetal developmental studies, no adverse developmental effects were observed during organogenesis when sitagliptin was administered to pregnant rats and rabbits during organogenesis at doses of 250 and 125 mg/kg, respectively (up to 30 and 20 times, respectively, the 100-mg clinical dosage based on AUC).1 Pregnancy registry may be contacted at 800-986-8999.1,11,13

Lactation

Sitagliptin is distributed into milk in rats; data are lacking regarding the presence of the drug in human milk, the effects on the breastfed infant, or effects on milk production.1,11 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for sitagliptin and any potential adverse effects on the breastfed infant from sitagliptin or the underlying maternal condition.1,11

Pediatric Use

Safety and efficacy of sitagliptin alone or in fixed combination with metformin or ertugliflozin have not been established in children younger than 18 years of age.1,11,13,23,45,50

Geriatric Use

No substantial differences in safety and efficacy of sitagliptin relative to younger adults, but increased sensitivity cannot be ruled out.1 Renal function should be assessed more frequently in geriatric patients.1,11,45,50 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

Sitagliptin is substantially eliminated by the kidneys; renal function should be assessed prior to initiation of therapy and periodically thereafter.1,11 (See Worsening of Renal Function under Cautions: Warnings/Precautions.) Sitagliptin exposure is increased in patients with renal impairment;1 lower dosages of the drug are recommended in patients with eGFR less than 45 mL/minute per 1.73 m² and those with end-stage renal disease requiring dialysis.1 (See Renal Impairment under Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in at least 5% of patients receiving sitagliptin as monotherapy or add-on therapy with metformin and/or a thiazolidinedione or glimepiride and more commonly than with placebo include nasopharyngitis,1,3,4,10 upper respiratory tract infection,1,10 peripheral edema,1 and headache.1,10

Adverse effects reported in at least 5% of patients receiving sitagliptin concomitantly with immediate-release metformin and more commonly than with placebo include diarrhea, upper respiratory infection, and headache.11

Adverse effects reported in at least 5% of patients receiving sitagliptin given concomitantly with metformin and a sulfonylurea (glimepiride) and more commonly than with placebo include hypoglycemia and headache.11

Adverse effects reported in clinical trials of sitagliptin given concomitantly with ertugliflozin were similar in type and incidence to those reported with ertugliflozin alone.50

Adverse effects reported in at least 5% of patients receiving sitagliptin in combination with insulin and more commonly than with placebo include hypoglycemia.11

Drugs Metabolized by Hepatic Microsomal Enzymes

Sitagliptin is metabolized to a limited extent by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C8 to inactive metabolites.1,10,12 Sitagliptin 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 are unlikely.1

Drugs Secreted by Renal Tubular Cationic Transport

Sitagliptin is a substrate of the organic anion transport system; pharmacokinetic interactions are unlikely with substrates of the organic cationic transport system.1

Inhibitors of P-glycoprotein Transport System

Sitagliptin is a substrate of the P-glycoprotein transport system.1,12 There is a 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 appear to be unlikely.1,12,23 Sitagliptin does not appear to inhibit the P-glycoprotein transport system.1,12

Protein-bound Drugs

Pharmacokinetic interactions between sitagliptin and protein-bound drugs are unlikely.1

Cyclosporine

Concomitant administration of cyclosporine and sitagliptin may increase absorption and plasma concentrations of sitagliptin.1,12 However, this interaction is not considered clinically important and dosage adjustments are not required.1,12

Digoxin

Concomitant administration of sitagliptin (100 mg daily for 10 days) with digoxin (0.25 mg once daily for 10 days) resulted in a slight increase in plasma concentrations and area under the concentration-time curve (AUC) of digoxin (18 and 11%, respectively).1,23 While these increases are not considered clinically important, patients receiving digoxin should be monitored appropriately; however, no digoxin or sitagliptin dosage adjustment is needed.1,23

Hormonal Contraceptives, Oral

Sitagliptin has no clinically important effect on the pharmacokinetics of norethindrone or ethinyl estradiol.1

Metformin

Sitagliptin and metformin have a potential additive effect on active glucagon-like peptide (GLP-1) concentrations.1,11,21,22 Pharmacokinetic interactions are unlikely.1,10,11,27

The relevance of these effects to glycemic control in patients with type 2 diabetes mellitus is unclear.11,23

Simvastatin

Pharmacokinetic interactions between sitagliptin and simvastatin are unlikely.1

Insulin Secretagogues or Insulin

The incidence of hypoglycemia was increased compared with placebo when sitagliptin was added to therapy with an insulin secretagogue (e.g., sulfonylurea) or insulin.1,22 (See Concomitant Therapy with Hypoglycemic Agents under Cautions: Warnings/Precautions.) Clinically important pharmacokinetic interactions between sitagliptin and sulfonylureas (e.g., glimepiride, glipizide, glyburide, tolbutamide) are unlikely.1,23

Thiazolidinediones

Pharmacokinetic interactions between sitagliptin and thiazolidinediones (e.g., rosiglitazone) are unlikely.1

Warfarin

Pharmacokinetic interactions between sitagliptin and warfarin are unlikely.1

Pharmacokinetics

Absorption

Bioavailability

The absolute bioavailability of sitagliptin is approximately 87%.1,23 The drug is rapidly absorbed following oral administration; at steady state (within 3 days of therapy initiation), peak plasma concentrations generally are attained within 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

Pharmacokinetics of fixed-combination tablet containing sitagliptin and ertugliflozin L-pyroglutamic acid (Steglujan^®) administered with high-fat meal comparable to those reported for individual tablets.50

Administration of sitagliptin-ertugliflozin fixed combination with food decreased peak plasma ertugliflozin concentrations by 29%; no meaningful effect on area under the concentration-time curve (AUC) of ertugliflozin or on peak plasma concentrations or AUC of sitagliptin.50

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 (ESRD) 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

Based on a population or composite pharmacokinetic analysis of available data, body mass index, sex, and race do not have a clinically meaningful effect on sitagliptin pharmacokinetics.1

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

Description

Sitagliptin inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are incretin hormones.1,7,8,9,11,21,24 The drug inhibits DPP-4 selectively with no effect on DPP-8 or DDP-9 in vitro at concentrations approximating those from therapeutic dosage.1,11 Sitagliptin 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

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

Peak plasma sitagliptin concentration is achieved within 3 hours following oral administration.1,23,25 Absolute bioavailability is approximately 87%.1,23 Administration of sitagliptin with a high-fat meal had no effect on the pharmacokinetics of the drug1 Sitagliptin is metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.1,12 Terminal half-of sitagliptin is 12.4 hours following oral administration of a 100 mg oral dose.1 Following administration of a single radiolabeled dose, 87% of the dose was excreted in the urine (mainly as unchanged drug) and 13% was excreted in the feces.1,10

Advice to Patients

Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1,6,13

Importance of informing patients of potential risks and benefits of sitagliptin-containing therapy and of alternative therapies.1,6,11,13 Importance of not using sitagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1,6

Importance of informing patient about the possibility of acute pancreatitis, which may be severe or fatal, with sitagliptin therapy.1,6,13,28 Importance of patients advising clinicians about a history of pancreatitis, gallstones, alcoholism, high triglyceride levels, or kidney problems.1,6,13,45,51 Importance of advising 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 sitagliptin and promptly notifying clinician if such signs or symptoms are present.1,6,13,28,45,50

Importance of informing patients of the possibility of severe and disabling joint pain with DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,6,41 Advise patients to contact a clinician promptly if severe and persistent joint pain occurs; patients should not discontinue the DPP-4 inhibitor without consulting their clinician.1,6,41

Importance of informing patients about possibility of heart failure with sitagliptin therapy.1,6 Importance of clinicians asking patients about a history of heart failure or renal impairment prior to initiating sitagliptin therapy.1,6 Importance of informing patients about signs and symptoms of heart failure (e.g., shortness of breath, unusual tiredness, rapid weight gain, edema especially in the feet, ankles, or legs); importance of patients immediately contacting a clinician if manifestations of heart failure occur.1,6

Importance of informing patients that bullous pemphigoid may occur with the use of a DPP-4 inhibitor.1,6,11,45,50 Advise patients to promptly inform clinician if skin blisters or erosion (breakdown of the outer layer of skin) occurs.1,6,11,45,50

Importance of patient 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.1,6,11,13

Importance of instructing patients regarding self-monitoring of blood glucose, periodic HbA_1c monitoring, adherence to meal planning, regular physical exercise, and management of hypoglycemia and hyperglycemia.1,6,11,13

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.1,6,13 (See Loss of Glycemic Control under Cautions: Warnings/Precautions.)

Risk of allergic reactions (e.g., rash; hives; swelling of face, lips, tongue, throat that may cause difficulty in breathing or swallowing).1,6,11 If such reactions occur, importance of discontinuing sitagliptin and informing clinicians promptly.1,6,11,13 (See Dermatologic and Sensitivity Reactions under Cautions: Warnings/Precautions.)

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, history of pancreatitis).1,13,28

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

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Merck. Januvia^® (sitagliptin) tablets prescribing information. Whitehouse Station, NJ; 2018 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; 2018 Feb.

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 and metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2015 Aug.

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; 2015 Aug.

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. [PubMed 10764847]

17. Florence JA, Yeager BF. Treatment of type 2 diabetes mellitus. Am Fam Physician . 1999; 59:2835-44. [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. [PubMed 10566566]

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

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. [PubMedCentral][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.[Web]

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]

41. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Rockville, MD; 2015 Aug 28. From FDA website. [Web]

42. Food and Drug Administration. FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. Silver Spring, MD; 2016 April 5. From FDA website. [Web]

43. Scirica BM, Braunwald E, Raz I et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation . 2014; 130:1579-88. [PubMed 25189213]

44. Zannad F, Cannon CP, Cushman WC et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet . 2015; 385:2067-76. [PubMed 25765696]

45. Merck. Janumet^® XR (sitagliptin and extended-release metformin hydrochloride) tablets prescribing information. Whitehouse Station, NJ; 2020 Dec.

50. Merck. Steglujan^® (ertugliflozin and sitagliptin) tablets prescribing information. Whitehouse Station, NJ; 2020 Jan.

51. Merck. Steglujan^® (ertugliflozin and sitagliptin) tablets medication guide. Whitehouse Station, NJ; 2020 Jan.

55. Pratley RE, Eldor R, Raji A et al. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes Metab . 2018; 20:1111-1120. [PubMed 29266675]

56. Dagogo-Jack S, Liu J, Eldor R et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab . 2018; 20:530-540. [PubMed 28921862]

57. Miller S, Krumins T, Zhou H et al. Ertugliflozin and Sitagliptin Co-initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study. Diabetes Ther . 2018; 9:253-268. [PubMed 29313282]

698. Garber AJ, Handelsman Y, Grunberger G et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2020 executive summary. Endocr Pract . 2020; 26:107-139. [PubMed 32022600]

699. Zelniker TA, Wiviott SD, Raz I et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation . 2019; 139(17):2022-2031. [PubMed 30786725]

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