⬇ ⬇Saxagliptin hydrochloride, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic agent.1,3
⬆ ⬇Saxagliptin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.1,2,3,10,25,31 Saxagliptin also is used in fixed combination with dapagliflozin (Qtern®) or with dapagliflozin and extended-release metformin hydrochloride (Qternmet® XR) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.55,101 The manufacturer states that the fixed combination of dapagliflozin, saxagliptin, and extended-release metformin hydrochloride (Qternmet® XR) is intended for use only in patients currently receiving metformin hydrochloride.101
Saxagliptin is used as initial therapy in combination with metformin (given separately or as the fixed combination of saxagliptin and extended-release metformin) as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate.1,27 Saxagliptin also is used in combination with other oral antidiabetic agents (e.g., 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.1,4,5,6,7,25,27,29,30
In pivotal clinical trials, glycemic efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus were evaluated at dosages of 2.5, 5, and 10 mg once daily as monotherapy or in combination with other antidiabetic agents.1,3,4,5,6,7,10 In these trials, the 10-mg daily dosage (currently not an FDA-labeled dosage) of saxagliptin did not demonstrate greater efficacy than the 5-mg daily dosage.1,5,27,32 (See Saxagliptin Monotherapy under Dosage: Type 2 Diabetes Mellitus, in Dosage and Administration.)
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 A1c; HbA1c], 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.25,698,704 Initiating antidiabetic therapy with 2 agents (e.g., metformin plus another drug) may be appropriate in patients with an initial HbA1c exceeding 7.5% or at least 1.5% above the target level.698,704 In metformin-intolerant patients with high initial HbA1c 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 HbA1c 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.25,698,704 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 HbA1c 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 saxagliptin is not indicated in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.1,2
Efficacy of saxagliptin as monotherapy in treatment-naive patients with type 2 diabetes mellitus is supported by results of 2 double-blind, placebo-controlled trials of 24 weeks' duration.1,3,10 In these trials, saxagliptin (2.5 or 5 mg once daily) improved glycemic control as evidenced by mean reductions in glycosylated hemoglobin (hemoglobin A1c; HbA1c) of about 0.4-0.7% (from a mean baseline HbA1c of 7.9%) compared with a mean increase in HbA1c of about 0.2-0.3% with placebo.1,3,10
Clinical trials evaluating the efficacy and safety of the fixed combination of saxagliptin and extended-release metformin hydrochloride (Kombiglyze® XR) in reducing HbA1c have not been conducted; unless otherwise specified, clinical trials of saxagliptin in combination with metformin discussed in this monograph were conducted using concomitantly administered saxagliptin and immediate-release metformin.27 Bioequivalence between the fixed combination of saxagliptin and extended-release metformin hydrochloride (Kombiglyze® XR) and each agent (saxagliptin and extended-release metformin hydrochloride) given concurrently as separate tablets has been demonstrated.27 (See Description.)
Efficacy of the combination of saxagliptin 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, active-controlled trial.1,4 In this trial, concurrent therapy with saxagliptin (5 or 10 mg once daily) and metformin hydrochloride (500 mg daily initially, titrated up to a maximum of 2 g daily given in 2 divided doses with meals) improved HbA1c, fasting plasma glucose, and 2-hour postprandial glucose values compared with saxagliptin or metformin monotherapy.1,4 Mean reductions in HbA1c from baseline were 2.5% in patients receiving saxagliptin 5 mg daily plus metformin, 2.5% in patients receiving saxagliptin 10 mg daily plus metformin, 2% with metformin plus placebo, and 1.7% with saxagliptin 10 mg daily plus placebo.1,4 The proportion of patients achieving an HbA1c less than 7% at week 24 was approximately 60% in patients receiving saxagliptin 5 or 10 mg daily plus metformin, 32% in patients receiving saxagliptin 10 mg daily plus placebo, and 41% in patients receiving metformin plus placebo.1,4
Efficacy of saxagliptin in combination with metformin, a sulfonylurea (glyburide), or a thiazolidinedione (pioglitazone or rosiglitazone) in patients with type 2 diabetes mellitus inadequately controlled on monotherapy with these drugs is supported by results of several long-term (24-52 weeks' duration), randomized, placebo- or active-controlled trials demonstrating improvements in HbA1c and fasting and/or 2-hour postprandial plasma glucose concentrations.1,4,5,6,7,27 In a trial in patients already receiving metformin hydrochloride (1.5-2.55 g daily), add-on therapy with saxagliptin (2.5 or 5 mg daily) resulted in a mean HbA1c decrease of about 0.6 or 0.7%, respectively, (from a mean baseline HbA1c of 8.1%) compared with a mean HbA1c increase of about 0.1% with add-on placebo.1,5 In patients receiving either pioglitazone (30-45 mg daily) or rosiglitazone (4-8 mg daily) therapy, addition of saxagliptin (2.5 or 5 mg daily) resulted in a mean HbA1c reduction of 0.7 or 0.9%, respectively, (from a mean baseline HbA1c of 8.3 or 8.4%, respectively) compared with a mean reduction of 0.3% (from a mean baseline HbA1c of 8.2%) with add-on placebo.1,7 In patients receiving a submaximal dosage of glyburide (7.5 mg daily as a fixed dosage), addition of saxagliptin (2.5 or 5 mg daily) resulted in a mean HbA1c reduction of 0.5 or 0.6%, respectively, (from a mean baseline HbA1c of 8.4 or 8.5%, respectively) compared with a mean increase of 0.1% with placebo added to glyburide 10 mg daily and titrated up to a maximum dosage of 15 mg daily (about 92% of patients had glyburide dosage titrated up to 15 mg daily within the initial 4 weeks of the trial).1,6
In a 24-week trial in patients already receiving metformin and a sulfonylurea, addition of saxagliptin (5 mg once daily) resulted in a mean HbA1c reduction of 0.7% (from a mean baseline HbA1c of 8.4%) compared with a mean reduction of 0.1% with placebo (from a mean baseline HbA1c of 8.2%).1
In another 24-week, placebo-controlled trial in patients with inadequate glycemic control while receiving metformin hydrochloride (at least 1.5 g daily for at least 8 weeks) and dapagliflozin (10 mg daily), addition of saxagliptin (5 mg daily) resulted in greater reductions in HbA1c from baseline compared with add-on placebo.27,103 A larger proportion of patients receiving saxagliptin add-on therapy (35.3%) achieved HbA1c values below 7 compared with those receiving add-on placebo (23.1%).1,27
In another trial comparing add-on therapy with saxagliptin versus add-on therapy with glipizide in patients already receiving metformin hydrochloride (1.5-3 g daily), addition of saxagliptin (5 mg daily) resulted in a mean HbA1c reduction of 0.6% (from a mean baseline HbA1c of 7.7%) versus a reduction of 0.7% (from a mean baseline HbA1c of 7.6%) with add-on glipizide therapy (initial glipizide dosage of 5 mg daily, titrated up to a mean final dosage of 15 mg daily).1,27
Efficacy of saxagliptin in combination with insulin in patients with type 2 diabetes mellitus inadequately controlled with insulin (with or without metformin) is supported by results of a 24-week, randomized, placebo-controlled trial.1 In this trial, addition of saxagliptin (5 mg once daily) to existing stable therapy with premixed insulin or intermediate- or long-acting insulin (insulin given in combination with metformin in some patients) resulted in improvements in HbA1c and 2-hour postprandial glucose concentrations at week 24 compared with addition of placebo.1 Mean reductions in HbA1c were similar for patients receiving saxagliptin as add-on therapy with insulin alone or insulin with metformin (0.4% in both groups).1 The mean reduction from baseline in 2-hour postprandial glucose at week 24 was 27 mg/dL with add-on saxagliptin and 4 mg/dL with add-on placebo.1 The mean change from baseline in daily insulin dosage at the end of the study was 2 or 5 units with saxagliptin or placebo, respectively.1
⬆ ⬇When saxagliptin is administered as monotherapy or in fixed combination with dapagliflozin, the drug should be administered orally once daily without regard to meals.1,2,21,55 The fixed-combination tablets with dapagliflozin should be swallowed whole; they should not be cut, chewed, or crushed.55,56 If a dose of saxagliptin alone or in fixed combination with dapagliflozin is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule.2,55,56 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.2,55,56
When saxagliptin is administered in fixed combination with extended-release metformin, the combination should be administered orally once daily with the evening meal; dosage should be titrated gradually to minimize adverse GI effects of the metformin component.27 The fixed-combination tablets with extended-release metformin should be swallowed whole; they should not be cut, chewed, or crushed.27,28 If a dose is missed, the next dose should be taken as prescribed unless a healthcare provider instructs otherwise; an extra dose should not be taken the next day.27,28
When saxagliptin is administered in fixed combination with extended-release metformin and dapagliflozin, the combination should be administered orally once daily in the morning with food; dosage should be individualized based on the patient's current drug regimen, effectiveness, and tolerability.101,102 The fixed-combination tablets with saxagliptin, extended-release metformin, and dapagliflozin should be swallowed whole; they should not be cut, chewed, or crushed.101,102 If a dose is missed and it is at least 12 hours before the next scheduled dose, the missed dose should be taken as soon as possible with food.101,102 If a dose is missed and it is less than 12 hours before the next scheduled dose, the missed dose should be skipped and the next dose taken at the usual time.101,102
Patient receiving saxagliptin in fixed combination with extended-release metformin hydrochloride (Kombiglyze® XR) or with extended-release metformin hydrochloride and dapagliflozin (Qternmet® XR) should be advised that occasionally, the inactive ingredients of the fixed-combination tablet will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.27,101
Dosage of saxagliptin hydrochloride (anhydrous) is expressed in terms of saxagliptin.1
The recommended dosage of saxagliptin for the management of type 2 diabetes mellitus in adults is 2.5 or 5 mg once daily.1 In clinical trials, dosages higher than 5 mg daily (e.g., 10 mg once daily) did not provide additional benefit and are not recommended by the manufacturer.1,5,27,32
When saxagliptin is used concomitantly with a potent inhibitor of cytochrome P-450 (CYP) isoenzymes 3A4/5 (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin), dosage of saxagliptin should be limited to 2.5 mg once daily.1,27 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)
Combination Therapy with Dapagliflozin
When the fixed-combination preparation containing saxagliptin and dapagliflozin is used in patients not already receiving dapagliflozin, the recommended initial dosage is 5 mg of saxagliptin and 5 mg of dapagliflozin once daily.55
If additional glycemic control is needed and the initial dosage is tolerated, the dosage may be increased to 5 mg of saxagliptin and 10 mg of dapagliflozin once daily.55
The fixed combination of saxagliptin and dapagliflozin should not be used in patients receiving a potent CYP3A4/5 inhibitor.55 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)
Combination Therapy with Metformin Hydrochloride
Dosage of saxagliptin hydrochloride in fixed combination with extended-release metformin hydrochloride should be individualized based on the patient's current antidiabetic regimen, clinical response, and tolerability.27 Any change in therapy should be undertaken with caution and appropriate monitoring because changes in glycemic control can occur.27
When the fixed-combination preparation containing saxagliptin and extended-release metformin hydrochloride is used in patients who have inadequate glycemic control on monotherapy with saxagliptin 5 mg daily, the recommended initial dosage of the fixed combination is 5 mg of saxagliptin and 500 mg of extended-release metformin hydrochloride once daily; dosage should be increased gradually to reduce adverse GI effects of metformin.27
When the fixed-combination preparation containing saxagliptin and extended-release metformin hydrochloride is used in patients who have inadequate glycemic control on monotherapy with extended-release metformin hydrochloride, dosage of the fixed combination 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, glycemic control should be closely monitored and dosage adjustments made accordingly.27
In patients who have inadequate glycemic control on monotherapy with saxagliptin 2.5 mg daily, the recommended initial dosage of saxagliptin in fixed combination with extended-release metformin hydrochloride is 2.5 mg of saxagliptin and 1 g of extended-release metformin hydrochloride daily. 27 Patients who require 2.5 mg of saxagliptin and who are either metformin naive or require a dose of metformin hydrochloride exceeding 1 g should use the individual components.27
The maximum recommended dosage of saxagliptin in fixed combination with extended-release metformin hydrochloride is 5 mg of saxagliptin and 2 g of extended-release metformin hydrochloride daily.27 When this fixed-combination preparation is used concomitantly with a potent CYP3A4/5 inhibitor (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin), dosage should be limited to 2.5 mg of saxagliptin and 1 g of extended-release metformin hydrochloride once daily.27 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)
Combination Therapy with Metformin Hydrochloride and Dapagliflozin
Dosage of saxagliptin hydrochloride in fixed combination with extended-release metformin hydrochloride and dapagliflozin should be individualized based on the patient's current antidiabetic regimen, clinical response, and tolerability.101
When the fixed-combination preparation containing saxagliptin, extended-release metformin hydrochloride, and dapagliflozin is used in patients who are not currently receiving dapagliflozin, the recommended initial dosage is 5 mg of saxagliptin, either 1 or 2 g of extended-release metformin hydrochloride, and 5 mg of dapagliflozin once daily.101
The maximum recommended dosage of saxagliptin in fixed combination with extended-release metformin hydrochloride and dapagliflozin is 5 mg of saxagliptin, 2 g of extended-release metformin hydrochloride, and 10 mg of dapagliflozin daily.101
The fixed combination of saxagliptin, extended-release metformin hydrochloride, and dapagliflozin should not be used in patients receiving a potent CYP3A4/5 inhibitor.101 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)
Assessment of renal function is recommended prior to initiation of saxagliptin and periodically thereafter.1 No dosage adjustment for saxagliptin is recommended in patients with creatinine clearance of 45 mL/minute per 1.73 m2 or greater.1 In patients with creatinine clearance less than 45 mL/minute (including patients with moderate or severe renal impairment or with end-stage renal disease requiring hemodialysis), the recommended dosage of saxagliptin is 2.5 mg once daily regardless of meals.1 In patients undergoing hemodialysis, saxagliptin should be administered following the dialysis procedure.1 Data are lacking regarding the use of saxagliptin in patients undergoing peritoneal dialysis.1
The manufacturer makes no recommendation regarding dosage adjustment of saxagliptin in patients with hepatic impairment.1
No dosage adjustment is recommended for geriatric patients based solely on a however, because of the greater frequency of decreased renal function in geriatric patients, dosage in geriatric patients should be selected with caution.1
⬆ ⬇Saxagliptin is contraindicated in patients with known serious hypersensitivity (e.g., anaphylaxis, angioedema, exfoliative skin reaction) to saxagliptin or any ingredient in the formulation.1,27
Pancreatitis and Pancreatic Precancerous Changes
Acute pancreatitis has been reported during postmarketing experience in patients receiving saxagliptin therapy.1,27,37 In a randomized, double-blind study (SAVOR) in 16,492 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease (ASCVD) or at high risk for the disease, acute pancreatitis was confirmed in 0.2 or 0.1% of patients receiving saxagliptin or placebo, respectively, in addition to standard care.1 Preexisting risk factors for pancreatitis were present in 88% of patients who developed pancreatitis while receiving saxagliptin and in 100% of those who developed pancreatitis while receiving placebo.1
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 saxagliptin-containing therapy should be monitored for manifestations of pancreatitis.1,27 (See Advice to Patients.) If pancreatitis is suspected, saxagliptin should be promptly discontinued and appropriate management instituted.1,27 Safety and efficacy of saxagliptin 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 saxagliptin therapy.1,27
Severe, disabling joint pain has been reported during postmarketing experience in patients receiving DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,27,41 Onset of such symptoms has ranged from 1 day to years following initiation of therapy.1,27,41 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.1,27,41 In some patients, symptoms recurred when the same or another DPP-4 inhibitor was restarted.1,27,41 DPP-4 inhibitors should be considered as a possible cause of severe joint pain and should be discontinued if appropriate.1,27,41 (See Advice to Patients.)
Saxagliptin may increase the risk of heart failure, particularly in patients who have a history of heart failure or renal impairment.1,27,42 In a randomized, double-blind study (SAVOR) in which saxagliptin or placebo was added to standard care in 16,492 patients with type 2 diabetes mellitus and established ASCVD or at high risk for the disease, more patients receiving saxagliptin were hospitalized for heart failure than patients receiving placebo (3.5 or 2.8%, respectively).1,27,38,39,42 After a median of 2 years of follow-up, treatment with saxagliptin was associated with a 27% increased risk of hospitalization for heart failure;1,27,42 however, therapy with the drug was not associated with increased or decreased rates of cardiovascular death or other ischemic events.39,40 Patients with a history of heart failure or renal impairment had a higher risk of hospitalization for heart failure in this study regardless of treatment (saxagliptin or placebo).1,27,42
The potential risks and benefits of saxagliptin therapy should be considered prior to use in patients at higher risk for heart failure (e.g., history of heart failure or renal impairment).1,27,42 Patients receiving saxagliptin-containing therapy should be monitored for manifestations of heart failure.1,27,42 (See Advice to Patients.) If heart failure develops, appropriate evaluation and management according to current standards of care should be instituted and consideration given to discontinuing saxagliptin.1,27,42
Concomitant Therapy with Hypoglycemic Agents
When saxagliptin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy.1,27,55,101 Therefore, patients receiving saxagliptin may require a reduced dosage of a concomitant insulin secretagogue (e.g., a sulfonylurea) or insulin to reduce the risk of hypoglycemia.1,27,55,101
Dose-related mean decreases in absolute lymphocyte count have been reported with saxagliptin dosages of 5 and 10 mg daily in clinical trials;1 clinical importance is not known.1 In most patients, recurrence of this effect was not observed with repeated exposure; however, some patients had reductions in lymphocyte count upon rechallenge that led to discontinuance of saxagliptin.1 Reductions in lymphocyte count were not associated with clinically relevant adverse effects.1,27 When clinically indicated (i.e., settings of unusual or prolonged infection), lymphocyte count should be measured.1
Dermatologic and Sensitivity Reactions
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use.1,27,55 The cases usually resolved after discontinuation of the DPP-4 inhibitor and treatment with topical or systemic immunosuppressive therapy.1,27,55 Patients should be advised to report the development of blisters or erosions while receiving saxagliptin.1,11,27,55 Saxagliptin should be discontinued if bullous pemphigoid is suspected, and referral of the patient to a dermatologist for diagnosis and appropriate treatment should be considered.1,27,55
In a pooled analysis of data from 5 studies, hypersensitivity reactions (e.g., urticaria, facial edema) were reported in 1.5% of patients receiving saxagliptin 2.5 or 5 mg daily.1 In addition, there have been postmarketing reports of serious allergic and hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative skin conditions).1,27 The onset of such reactions usually was within the first 3 months following treatment initiation; some reactions occurred after the first dose.1,27 (See Cautions: Contraindications.)
If a serious hypersensitivity reaction is suspected, saxagliptin should be promptly discontinued, other potential causes of the event should be investigated, appropriate treatment for the reaction should be provided, and alternative antidiabetic therapy should be instituted.1,27 (See Advice to Patients.) Saxagliptin should be used with caution in patients with a history of angioedema to other dipeptidyl peptidase-4 inhibitors because it is unknown whether such patients will be predisposed to angioedema with saxagliptin.1,27
In a pooled analysis of 8 randomized, phase 2 or 3 clinical trials (total of 4607 patients) designed to evaluate the relative risk of cardiovascular events (cardiovascular death, myocardial infarction, stroke) in patients receiving saxagliptin versus other antidiabetic agents (metformin, glyburide) or placebo, no increased cardiovascular risk was noted with saxagliptin therapy.13 The manufacturer states that evidence of macrovascular risk reduction with saxagliptin has not been conclusively demonstrated in clinical trials.1,27
When saxagliptin is used in fixed combination with metformin, dapagliflozin, and/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 saxagliptin.27,55,101
Data on the use of saxagliptin in pregnant women are insufficient to determine a drug-associated risk for major birth defects or miscarriage.1 Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications.1 In addition, poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.1
No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the prenatal and postnatal period.1
Saxagliptin is distributed into milk in rats at a milk-to-plasma ratio of approximately 1:1.1 Data are lacking regarding the presence of saxagliptin in human milk and on the effects of the drug on the breastfed infant or on milk production.1 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for saxagliptin and any potential adverse effects on the breastfed infant from saxagliptin or the underlying maternal condition.1
Safety and efficacy of saxagliptin have not been established in patients younger than 18 years of age.1
No substantial differences in safety and efficacy relative to younger adults have been observed, but increased sensitivity cannot be ruled out.1
Saxagliptin and its active metabolite are eliminated in part by the kidneys; renal function should be assessed periodically since geriatric patients are more likely to have decreased renal function.1
In patients with hepatic impairment (Child-Pugh class A, B, and C), mean peak concentrations and area under the plasma concentration-time curve (AUC) of saxagliptin were increased by up to 8 and 77%, respectively, compared with healthy individuals following a single 10-mg dose of the drug; peak concentrations and AUC of the active metabolite were increased by up to 59 and 33%, respectively.1 These differences were not considered clinically important.1
Renal function should be assessed prior to initiation of saxagliptin therapy and periodically thereafter.1 Adjustment of saxagliptin dosage is recommended when the drug is used in patients with moderate (eGFR 30 to less than 45 mL/minute per 1.73 m2) or severe renal impairment (eGFR 15 to less than 30 mL/minute per 1.73 m2) or end-stage renal disease requiring hemodialysis.1 The fixed combination of saxagliptin and extended-release metformin is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/minute per 1.73 m2).27
In clinical trials, the incidence of hypoglycemic adverse reactions in patients receiving saxagliptin was based on all reports of hypoglycemia, although a concurrent glucose measurement was not required or was normal in some patients with reported hypoglycemic reactions; therefore, it is not possible to determine conclusively whether all these reports represent true hypoglycemic events.1,27 In the clinical trial in which saxagliptin or placebo was added to insulin therapy (with or without metformin), (see Uses: Type 2 Diabetes Mellitus) the incidence of adverse effects (except for confirmed hypoglycemia) was similar with add-on saxagliptin and add-on placebo.1,27 However, the incidence of confirmed hypoglycemia (as determined by fingerstick blood glucose of 50 mg/dL or less) in this trial was higher with saxagliptin 5 mg daily (5.3%) than with placebo (3.3%).1,27
Adverse effects reported in at least 5% of patients in clinical trials receiving saxagliptin 5 mg daily as monotherapy or in combination with metformin, a thiazolidinedione (pioglitazone or rosiglitazone), or glyburide and more frequently than with placebo include upper respiratory tract infection, urinary tract infection, and headache.1,27
Adverse effects reported in at least 5% of patients in clinical trials receiving saxagliptin in combination with immediate-release metformin and more frequently than with metformin alone include headache and nasopharyngitis.27,28
⬆ ⬇Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes 
Saxagliptin and its active metabolite do not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 and do not induce CYP1A2, 2B6, 2C9, or 3A4 in vitro.1,27 Pharmacokinetic interactions with drugs metabolized by these isoenzymes are unlikely.1,27
Saxagliptin is metabolized principally via CYP3A4 and CYP3A5.1 Administration of a single dose of saxagliptin (100 mg) to healthy individuals receiving ketoconazole (200 mg every 12 hours for 9 days) decreased the peak steady-state plasma concentration and area under the plasma concentration-time curve (AUC) of ketoconazole by 16 and 13%, respectively, and increased the peak plasma concentration and AUC of saxagliptin by 62 and 145% (2.5-fold), respectively.1,24,27 Similar increases in saxagliptin plasma concentrations and AUC are anticipated with concomitant use of saxagliptin and other potent CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin).1,27 Saxagliptin dosage should be limited to 2.5 mg daily when the drug is used concomitantly with a potent CYP3A4/5 inhibitor.1,27
Inhibitors of P-glycoprotein Transport System
Saxagliptin is a substrate of the P-glycoprotein transport system but does not appreciably induce or inhibit P-glycoprotein.1,27
Concurrent administration of a single dose of saxagliptin (10 mg) and a single dose of liquid antacid containing aluminum hydroxide (2.4 g), magnesium hydroxide (2.4 g), and simethicone (240 mg) decreased peak plasma concentrations of saxagliptin by 26% and AUC by 3%.1,27 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Coadministration of saxagliptin (5-mg single dose) and dapagliflozin (10-mg single dose) decreased the AUC and peak plasma concentration of saxagliptin by 1 and 7%, respectively, and increased the AUC and peak plasma concentration of its active metabolite 5-hydroxy saxagliptin by 9 and 6%, respectively.1,27 The manufacturer states that no dosage adjustments are required with concomitant use.1,27
Concurrent administration of saxagliptin (10 mg once daily for 7 days) and digoxin (0.25 mg every 6 hours the first day, then 0.25 mg every 12 hours the second day, then 0.25 mg once daily for 5 days), a P-glycoprotein substrate, increased the AUC and peak plasma concentration of digoxin by 6 and 9%, respectively;1 the AUC of saxagliptin was increased by 5% and peak plasma saxagliptin concentrations decreased by 1%.1 The manufacturer states that no dosage adjustments are required with concurrent use.1
Concurrent administration of saxagliptin (10-mg single dose) and a long-acting formulation of diltiazem (360 mg daily for 9 days) increased the peak steady-state plasma concentration of diltiazem by 16% and the AUC by 10%; in addition, peak plasma saxagliptin concentrations increased by 63% and saxagliptin AUC was increased by 2.1-fold.1,27 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Administration of a single dose of saxagliptin (10 mg) concurrently with a single dose of famotidine (40 mg) increased the peak plasma concentration of saxagliptin by 14% and AUC by 3%.1,27 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Concurrent administration of saxagliptin (5 mg once daily for 21 days) and an estrogen-progestin combination contraceptive (ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.25 mg once daily for 21 days) did not appreciably alter the steady-state pharmacokinetics of ethinyl estradiol or the primary active progestin component, norelgestromin.1,27,33 The mean AUC and peak plasma concentration of norgestrel, an active metabolite of norelgestromin, were increased by 13 and 17%, respectively, which is not considered clinically important.1,27,33 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Concomitant administration of a single dose of saxagliptin (100 mg) and metformin hydrochloride (1 g) decreased the peak plasma concentration of saxagliptin by 21% and the AUC by 2%; metformin AUC and peak plasma concentration were increased by 20 and 9%, respectively.1,27 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Concurrent administration of saxagliptin (10 mg daily) and omeprazole (40 mg daily for 5 days) increased saxagliptin AUC by 13% and decreased peak plasma concentrations of the drug by 2%.1,27 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Concurrent administration of saxagliptin (10 mg once daily for 5 days) and pioglitazone (45 mg daily for 10 days) increased the peak plasma concentration of pioglitazone by 14% and the AUC by 8%.1,27 In addition, the AUC and peak plasma concentration of saxagliptin were each increased by 11%.1,27 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Concomitant administration of a single dose of saxagliptin (5 mg) with rifampin (600 mg daily for 6 days) decreased peak steady-state plasma concentrations and AUC of saxagliptin by 53 and 76%, respectively, while peak plasma concentration of the active metabolite was increased by 39%; there was no appreciable change in the AUC of the active metabolite of saxagliptin.1 The manufacturer states that no dosage adjustments are required with concurrent use.1,27
Concomitant administration of saxagliptin (10 mg once daily for 4 days) and simvastatin (40 mg once daily for 8 days) increased the peak plasma concentration and AUC of saxagliptin by 21 and 12%, respectively, while simvastatin peak plasma concentrations were reduced by 12% and AUC was increased by 4%.1,22,27 The manufacturer states that no dosage adjustments are required with concurrent use.1,22,27
Concomitant administration of single doses of saxagliptin (10 mg) and glyburide (5 mg) increased peak plasma concentrations of glyburide and saxagliptin by 16 and 8%, respectively; the AUC of glyburide was increased by 6% and that of saxagliptin was decreased by 2%.1,27 The manufacturer states that no dosage adjustments are required because of changes in systemic exposures when saxagliptin and glyburide are given concomitantly.1,27 However, in patients receiving saxagliptin concomitantly with a sulfonylurea antidiabetic agent, a reduced dosage of the sulfonylurea may be required to reduce the risk of hypoglycemia.1,27
⬆ ⬇Saxagliptin 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 Both saxagliptin and its active metabolite (5-hydroxy saxagliptin) are more selective for inhibition of DPP-4 than for DPP-8 or DPP-9.14 Saxagliptin increases circulating levels of GLP-1 and GIP in a glucose-dependent manner.1,8
GLP-1 and GIP stimulate insulin secretion 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, leading to reduced hepatic glucose production.1,8,9,25
Saxagliptin lowers fasting plasma glucose concentrations and reduces glucose excursions following a glucose load or meal in patients with type 2 diabetes mellitus. 1,25
Saxagliptin monotherapy usually is not associated with substantial changes in body weight.1,2,3,4,10,25
Saxagliptin did not produce a clinically meaningful prolongation of the QT interval corrected for rate (QTc) or heart rate at daily dosages up to 40 mg (8 times the maximum recommended human dose) in a randomized, double-blind, placebo-controlled, crossover active-comparator study using moxifloxacin in healthy individuals.1
Following oral administration of a single dose of saxagliptin under fasted conditions, the median time to peak plasma concentration was 2 hours for saxagliptin and 4 hours for 5-hydroxy saxagliptin.1 Administration of saxagliptin with a high-fat meal increased the area under the plasma concentration-time curve (AUC) by 27% and delayed the time to peak plasma concentration by approximately 20 minutes.1 In vitro binding of saxagliptin and 5-hydroxy saxagliptin to serum proteins is negligible.1,11 Metabolism of saxagliptin is principally mediated by cytochrome P-450 (CYP) 3A4 and 3A5 isoenzymes.1 Mean plasma half-life of saxagliptin or 5-hydroxy saxagliptin is 2.5 or 3.1 hours, respectively.1,11 Saxagliptin is eliminated by both renal and hepatic pathways; following administration of a single radiolabeled dose, 75% of the dose was excreted in urine (including 24% as unchanged drug and 36% as 5-hydroxy saxagliptin).1 A total of 22% of administered radioactivity was recovered in feces, representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the GI tract.1
Bioequivalence between the fixed combination of saxagliptin and extended-release metformin hydrochloride (Kombiglyze® XR) and each agent (saxagliptin and extended-release metformin hydrochloride) given concurrently as separate tablets has been demonstrated; however, the relative bioavailability of the fixed combination of saxagliptin and extended-release metformin hydrochloride (Kombiglyze® XR) and concomitantly administered saxagliptin and immediate-release metformin hydrochloride has not been established.27 Metformin immediate-release and extended-release tablets have a similar extent of absorption (AUC), but peak plasma concentrations of metformin following administration of the drug as extended-release tablets are approximately 20% lower than peak concentrations following administration of the same dose as immediate-release tablets.27
Importance of patients reading medication guide before initiating therapy and each time the drug is dispensed.1
Importance of informing patients of the potential risks and benefits of saxagliptin and of alternative therapies.1 Importance of not using saxagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.2
Importance of informing patients about the possibility of acute pancreatitis, which may be severe or fatal, with saxagliptin therapy.1,2,27 Importance of patients advising 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 patients of the possibility of severe and disabling joint pain with DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).1,41 Advise patients to contact a clinician promptly if severe and persistent joint pain occurs; patients should not discontinue the drug without consulting their clinician.1,2,41
Importance of promptly informing clinician if skin blisters or erosion (breakdown of the outer layer of skin) occurs.1,27
Importance of informing patients about possibility of heart failure with saxagliptin therapy.1,2,42 Importance of clinicians asking patients about a history of heart failure or renal impairment prior to initiating saxagliptin therapy.1,2,27,28,42,55,56 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.1,2,27,42,55
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 glycosylated hemoglobin (hemoglobin A1c; HbA1c) testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.1
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 their clinician if any unusual symptom develops or if any existing symptom persists or worsens.1
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.1,2 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 (e.g., antibiotics, antifungals, antiretrovirals) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., allergies, kidney disease).2,28
Importance of informing patients of other important precautionary information.1 (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.
⬆ ⬇Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 2.5 mg (of saxagliptin) | ||
5 mg (of saxagliptin) | Onglyza® | Astra Zeneca |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release | 2.5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g | Kombiglyze® XR | |
2.5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g and Dapagliflozin Propanediol 2.5 mg (of dapagliflozin) | Qternmet® XR | AstraZeneca | ||
2.5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g and Dapagliflozin Propanediol 5 mg (of dapagliflozin) | Qternmet® XR | AstraZeneca | ||
5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 500mg | Kombiglyze® XR | AstraZeneca | ||
5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g | Kombiglyze® XR | AstraZeneca | ||
5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g and Dapagliflozin Propanediol 5 mg (of dapagliflozin) | Qternmet® XR | AstraZeneca | ||
5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g and Dapagliflozin Propanediol 10 mg (of dapagliflozin) | Qternmet® XR | AstraZeneca | ||
Tablets, film-coated | 5 mg (of saxagliptin) with Dapagliflozin Propranediol 5 mg (of dapagliflozin) | Qtern® | AstraZeneca | |
5 mg (of saxagliptin) with Dapagliflozin Propranediol 10 mg (of dapagliflozin) | Qtern® | AstraZeneca |
⬆ ⬇AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
⬆1. AstraZeneca. Onglyza® (saxagliptin) tablets prescribing information. Wilmington, DE; 2019 Jun.
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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]
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