英文药名: Onglyza(Saxagliptin Tablets) 中文药名: 沙格列汀片 生产厂家: 百时美施贵宝/阿斯利康 药品介绍 2009年7月31日，降糠新药ONGLYZA(saxagliptin沙格列汀片，一种二肽基肽酶-4(DPP4)抑制剂）获得了美国食品药品监督管理局FDA批准上市。 ONGLYZA可作为饮食和锻炼的辅助治疗，改善2型糖尿病成人患者的血糖控制情况。ONGLYZA?每日服用1次，可与常用处方口服降糖药：二甲双胍、磺脲类或噻唑烷二酮类（TZD）药物联用，也可单用，可显著降低糖化血红蛋白（A1C）水平。 ONGLYZA不应用于治疗1型糖尿病或糖尿病酮症酸中毒（某些酸的水平升高，如血液或尿液中的酮体水平升高）。目前尚未研究ONGLYZA?和胰岛素的联用。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ONGLYZA safely and effectively. See full prescribing information for ONGLYZA. ONGLYZA(saxagliptin) tablets, for oral use Initial U.S. Approval: 2009 RECENT MAJOR CHANGES Warnings and Precautions Pancreatitis ( 5.1) 4/2016 Heart Failure ( 5.2) 4/2016 INDICATIONS AND USAGE ONGLYZA is a dipeptidyl peptidase-4 (DPP4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1.1, 14) Limitations of Use: Not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1.2) DOSAGE AND ADMINISTRATION Recommended dosage is 2.5 mg or 5 mg once daily taken regardless of meals. (2.1) Patients with moderate or severe renal impairment, or end-stage renal disease (CrCl ≤50 mL/min): Recommended dosage is 2.5 mg once daily regardless of meals. (2.2) Assess renal function before starting ONGLYZA and periodically thereafter. (2.2) 2.5 mg daily is recommended for patients also taking strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1) DOSAGE FORMS AND STRENGTHS Tablets: 5 mg and 2.5 mg ( 3) CONTRAINDICATIONS History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to ONGLYZA. ( 4) WARNINGS AND PRECAUTIONS Pancreatitis: If pancreatitis is suspected, promptly discontinue ONGLYZA. (5.1) Heart Failure: Consider the risks and benefits of ONGLYZA in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. (5.2) Hypoglycemia: In add-on to sulfonylurea, add-on to insulin, and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia was more common in patients treated with ONGLYZA compared to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, a lower dose of insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. ( 5.3, 6.1) Hypersensitivity-Related Events (e.g., urticaria, facial edema): More common in patients treated with ONGLYZA than in patients treated with placebo; and postmarketing reports of serious hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative skin conditions. Promptly discontinue ONGLYZA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. ( 5.4, 6.1, 6.2) Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.5) There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug. (5.6) Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug. (5.6) ADVERSE REACTIONS Adverse reactions reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients treated with placebo are upper respiratory tract infection, urinary tract infection, and headache. (6.1) Peripheral edema was reported more commonly in patients treated with the combination of ONGLYZA and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with ONGLYZA significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA dosage to 2.5 mg once daily. (2.3, 7.1) USE IN SPECIFIC POPULATIONS No adequate and well-controlled studies in pregnant women. (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 4/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Monotherapy and Combination Therapy ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)]. 1.2 Limitation of Use ONGLYZA is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless of meals. ONGLYZA tablets must not be split or cut. 2.2 Dosage in Patients with Renal Impairment No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment (creatinine clearance [CrCl] >50 mL/min). The dosage of ONGLYZA is 2.5 mg once daily (regardless of meals) for patients with moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis. Because the dosage of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula [see Clinical Pharmacology (12.3)]. 2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors The dosage of ONGLYZA is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When ONGLYZA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia [see Warnings and Precautions (5.3)]. 3 DOSAGE FORMS AND STRENGTHS ONGLYZA (saxagliptin) 5 mg tablets are pink, biconvex, round, film-coated tablets with “5” printed on one side and “4215” printed on the reverse side, in blue ink ONGLYZA (saxagliptin) 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets with “2.5” printed on one side and “4214” printed on the reverse side, in blue ink  4 CONTRAINDICATIONS ONGLYZA is contraindicated in patients with a history of a serious hypersensitivity reaction to ONGLYZA, such as anaphylaxis, angioedema, or exfoliative skin conditions. [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)]. 5 WARNINGS AND PRECAUTIONS 5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. In a cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving ONGLYZA compared to 9 of 8173 (0.1%) receiving placebo. Preexisting risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving ONGLYZA and in 100% (9/9) of those patients receiving placebo. After initiation of ONGLYZA, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue ONGLYZA and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using ONGLYZA. 5.2 Heart Failure In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to ONGLYZA (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitalization for heart failure was higher in the ONGLYZA group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of ONGLYZA prior to initiating treatment in patients at a higher risk for heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of ONGLYZA. 5.3 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin When ONGLYZA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [see Adverse Reactions (6.1)]. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA [see Dosage and Administration (2.4)]. 5.4 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for other potential causes for the event, and institute alternative treatment for diabetes [see Adverse Reactions (6.2)]. Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with ONGLYZA. 5.5 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate. 5.6 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug. 6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis [see Warnings and Precautions (5.1)] Heart Failure [see Warnings and Precautions (5.2)] Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Efficacy Trials The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies (14)]. These data shown in the table reflect exposure of 882 patients to ONGLYZA and a mean duration of exposure to ONGLYZA of 21 weeks. The mean age of these patients was 55 years, 1.4 % were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, Other 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR≥60mL/min/1.73m2) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of ONGLYZA. These adverse reactions occurred more commonly on ONGLYZA than on placebo and occurred in at least 5% of patients treated with ONGLYZA. Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with ONGLYZA 5 mg and More Commonly than in Patients Treated with Placebo  The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. In patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for ONGLYZA 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for ONGLYZA 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in study drug discontinuation. Rates of peripheral edema for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for ONGLYZA (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incidence rate of fracture events in patients who received ONGLYZA did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of ONGLYZA on bone. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to ONGLYZA is not known. Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of subjects receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 subjects treated with ONGLYZA 2.5 mg or at least 2 subjects treated with ONGLYZA 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). Adverse Reactions with Concomitant Use with Insulin In the add-on to insulin trial [see Clinical Studies (14.1)], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between ONGLYZA and placebo, except for confirmed hypoglycemia [see Adverse Reactions (6.1)]. Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. In the add-on to glyburide study, the overall incidence of reported hypoglycemia was higher for ONGLYZA 2.5 mg and ONGLYZA 5 mg (13.3% and 14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this study, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL, was 2.4% and 0.8% for ONGLYZA 2.5 mg and ONGLYZA 5 mg and 0.7% for placebo [see Warnings and Precautions (5.3)]. The incidence of reported hypoglycemia for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive patients given ONGLYZA 5 mg plus metformin and 4% in patients given metformin alone. In the active-controlled trial comparing add-on therapy with ONGLYZA 5 mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with ONGLYZA 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was reported in none of the ONGLYZA-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001). In the add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for ONGLYZA 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was higher with ONGLYZA 5 mg (5.3%) versus placebo (3.3%). In the add-on to metformin plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for ONGLYZA 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the ONGLYZA-treated patients and in none of the placebo-treated patients [see Warnings and Precautions (5.3)]. Hypersensitivity Reactions Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively. None of these events in patients who received ONGLYZA required hospitalization or were reported as life-threatening by the investigators. One ONGLYZA-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema. Renal Impairment In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e., doubling of serum creatinine compared with baseline and serum creatinine >6 mg/dL), were reported in 5.8% (483/8280) of ONGLYZA-treated subjects and 5.1% (422/8212) of placebo-treated subjects. The most frequently reported adverse reactions included renal impairment (2.1% vs. 1.9%), acute renal failure (1.4% vs. 1.2%), and renal failure (0.8% vs. 0.9%), in the ONGLYZA versus placebo groups, respectively. From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5 mL/min/1.73m2 for ONGLYZA-treated patients and a mean decrease of 2.4 mL/min/1.73m2 for placebo-treated patients. More subjects randomized to ONGLYZA (421/5227, 8.1%) compared to subjects randomized to placebo (344/5073, 6.8%) had downward shifts in eGFR from >50 mL/min (i.e., normal or mild renal impairment) to ≤50 mL/min (i.e., moderate or severe renal impairment). The proportions of subjects with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment. Infections In the unblinded, controlled, clinical trial database for ONGLYZA to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 ONGLYZA-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with ONGLYZA until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of ONGLYZA that remained stable throughout ONGLYZA treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with ONGLYZA use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to ONGLYZA use. There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in an ONGLYZA-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of ONGLYZA therapy. There have been no spontaneous reports of opportunistic infections associated with ONGLYZA use. Vital Signs No clinically meaningful changes in vital signs have been observed in patients treated with ONGLYZA. Laboratory Tests Absolute Lymphocyte Counts There was a dose-related mean decrease in absolute lymphocyte count observed with ONGLYZA. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with ONGLYZA 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical studies. Similar effects were observed when ONGLYZA 5 mg was given in initial combination with metformin compared to metformin alone. There was no difference observed for ONGLYZA 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the ONGLYZA 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to ONGLYZA although some patients had recurrent decreases upon rechallenge that led to discontinuation of ONGLYZA. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg dosage is not an approved dosage. In the SAVOR trial mean decreases of approximately 84 cells/microL with ONGLYZA relative to placebo was observed. The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on ONGLYZA and placebo respectively. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of ONGLYZA on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of ONGLYZA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions [ see Contraindications (4) and Warnings and Precautions (5.4)]. Acute pancreatitis [ see Warnings and Precautions (5.1)]. Severe and disabling arthralgia [ see Warnings and Precautions (5.5)]. 7 DRUG INTERACTIONS 7.1 Strong Inhibitors of CYP3A4/5 Enzymes Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of ONGLYZA should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ONGLYZA, like other antidiabetic medications, should be used during pregnancy only if clearly needed. Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental delay, occurred in rats at a dose of 240 mg/kg, or approximately 1503 and 66 times human exposure to saxagliptin and the active metabolite, respectively, at the maximum recommended human dose (MRHD) of 5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD. Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the MRHD (saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid. Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (exposures ≥1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. 8.3 Nursing Mothers Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when ONGLYZA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ONGLYZA in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of ONGLYZA in pediatric patients have not been performed. 8.5 Geriatric Use In the seven, double-blind, controlled clinical safety and efficacy trials of ONGLYZA, a total of 4751 (42.0%) of the 11301 patients randomized to ONGLYZA were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects ≥65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.6 Renal Impairment In a 12-week randomized placebo-controlled trial, ONGLYZA 2.5 mg was administered to 85 subjects with moderate (n=48) or severe (n=18) renal impairment or end-stage renal disease (ESRD) (n=19) [see Clinical Studies (14)]. The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between ONGLYZA and placebo. The overall incidence of reported hypoglycemia was 20% among subjects treated with ONGLYZA 2.5 mg and 22% among subjects treated with placebo. Four ONGLYZA-treated subjects (4.7%) and three placebo-treated subjects (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤50 mg/dL). 10 OVERDOSAGE In a controlled clinical trial, once-daily, orally-administered ONGLYZA in healthy subjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours). 11 DESCRIPTION Saxagliptin is an orally-active inhibitor of the DPP4 enzyme. Saxagliptin monohydrate is described chemically as (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate or (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is C18H25N3O2?H2O and the molecular weight is 333.43. The structural formula is: Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400). Each film-coated tablet of ONGLYZA for oral use contains either 2.79 mg saxagliptin hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin hydrochloride (anhydrous) equivalent to 5 mg saxagliptin and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, and iron oxides. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. 12.2 Pharmacodynamics In patients with type 2 diabetes mellitus, administration of ONGLYZA inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal. Cardiac Electrophysiology In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, ONGLYZA was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the MRHD). 12.3 Pharmacokinetics The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng?h/mL and 214 ng?h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%. No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg. Absorption The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. ONGLYZA may be administered with or without food. Distribution The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. Metabolism The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1)]. Excretion Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of ONGLYZA 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Specific Populations Renal Impairment A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment (N=8 per group) compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (>50 to ≤80 mL/min), moderate (30 to ≤50 mL/min), and severe (<30 mL/min), as well as patients with end-stage renal disease on hemodialysis. Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula: The degree of renal impairment did not affect the Cmax of saxagliptin or its active metabolite. In subjects with mild renal impairment, the AUC values of saxagliptin and its active metabolite were 20% and 70% higher, respectively, than AUC values in subjects with normal renal function. Because increases of this magnitude are not considered to be clinically relevant, dosage adjustment in patients with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment, the AUC values of saxagliptin and its active metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. To achieve plasma exposures of saxagliptin and its active metabolite similar to those in patients with normal renal function, the recommended dose is 2.5 mg once daily in patients with moderate and severe renal impairment, as well as in patients with end-stage renal disease requiring hemodialysis. Saxagliptin is removed by hemodialysis. Hepatic Impairment In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful. No dosage adjustment is recommended for patients with hepatic impairment. Body Mass Index No dosage adjustment is recommended based on body mass index (BMI) which was not identified as a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis. Gender No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Geriatric No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Race and Ethnicity No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 Caucasian subjects with 105 non-Caucasian subjects (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations. Drug Interaction Studies In Vitro Assessment of Drug Interactions The metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp. In Vivo Assessment of Drug Interactions Table 2: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses Results exclude one subject The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting Table 3: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs Single dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses Results include all subjects ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Saxagliptin did not induce tumors in either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg) at the highest doses evaluated. The highest doses evaluated in mice were equivalent to approximately 870 (males) and 1165 (females) times the human exposure at the MRHD of 5 mg/day. In rats, exposures were approximately 355 (males) and 2217 (females) times the MRHD. Mutagenesis Saxagliptin was not mutagenic or clastogenic with or without metabolic activation in an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes. The active metabolite was not mutagenic in an in vitro Ames bacterial assay. Impairment of Fertility In a rat fertility study, males were treated with oral gavage doses for 2 weeks prior to mating, during mating, and up to scheduled termination (approximately 4 weeks total) and females were treated with oral gavage doses for 2 weeks prior to mating through gestation day 7. No adverse effects on fertility were observed at exposures of approximately 603 (males) and 776 (females) times the MRHD. Higher doses that elicited maternal toxicity also increased fetal resorptions (approximately 2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility, ovulation, and implantation were observed at approximately 6138 times the MRHD. 13.2 Animal Toxicology and/or Pharmacology Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible at ≥20 times the MRHD but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1 to 3 times) the MRHD of 5 mg. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin. 14 CLINICAL STUDIES 14.1 Glycemic Efficacy Trials ONGLYZA has been studied as monotherapy and in combination with metformin, glyburide, and thiazolidinedione (pioglitazone and rosiglitazone) therapy. A total of 4148 patients with type 2 diabetes mellitus were randomized in six, double-blind, controlled clinical trials conducted to evaluate the safety and glycemic efficacy of ONGLYZA. A total of 3021 patients in these trials were treated with ONGLYZA. In these trials, the mean age was 54 years, and 71% of patients were Caucasian, 16% were Asian, 4% were black, and 9% were of other racial groups. An additional 423 patients, including 315 who received ONGLYZA, participated in a placebo-controlled, dose-ranging study of 6 to 12 weeks in duration. In these six, double-blind trials, ONGLYZA was evaluated at doses of 2.5 mg and 5 mg once daily. Three of these trials also evaluated an ONGLYZA dose of 10 mg daily. The 10 mg daily dose of ONGLYZA did not provide greater efficacy than the 5 mg daily dose. The 10 mg dosage is not an approved dosage. Treatment with ONGLYZA 5 mg and 2.5 mg doses produced clinically relevant and statistically significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following a standard oral glucose tolerance test (OGTT), compared to control. Reductions in A1C were seen across subgroups including gender, age, race, and baseline BMI. ONGLYZA was not associated with significant changes from baseline in body weight or fasting serum lipids compared to placebo. ONGLYZA has also been evaluated in four additional trials in patients with type 2 diabetes: an active-controlled trial comparing add-on therapy with ONGLYZA to glipizide in 858 patients inadequately controlled on metformin alone, a trial comparing ONGLYZA to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin, a trial comparing ONGLYZA to placebo in 257 patients inadequately controlled on metformin plus a sulfonylurea, and a trial comparing ONGLYZA to placebo in 170 patients with type 2 diabetes and moderate or severe renal impairment or ESRD. Monotherapy A total of 766 patients with type 2 diabetes inadequately controlled on diet and exercise (A1C ≥7% to ≤10%) participated in two 24-week, double-blind, placebo-controlled trials evaluating the efficacy and safety of ONGLYZA monotherapy. In the first trial, following a 2-week single-blind diet, exercise, and placebo lead-in period, 401 patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo. The 10 mg dosage is not an approved dosage. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy, added on to placebo or ONGLYZA. Efficacy was evaluated at the last measurement prior to rescue therapy for patients needing rescue. Dose titration of ONGLYZA was not permitted. Treatment with ONGLYZA 2.5 mg and 5 mg daily provided significant improvements in A1C, FPG, and PPG compared to placebo (Table 4). The percentage of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 16% in the ONGLYZA 2.5 mg treatment group, 20% in the ONGLYZA 5 mg treatment group, and 26% in the placebo group. Table 4: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA Monotherapy in Patients with Type 2 Diabetes* Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue. Least squares mean adjusted for baseline value. p-value <0.0001 compared to placebo p-value <0.05 compared to placebo Significance was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA A second 24-week monotherapy trial was conducted to assess a range of dosing regimens for ONGLYZA. Treatment-naive patients with inadequately controlled diabetes (A1C ≥7% to ≤10%) underwent a 2-week, single-blind diet, exercise, and placebo lead-in period. A total of 365 patients were randomized to 2.5 mg every morning, 5 mg every morning, 2.5 mg with possible titration to 5 mg every morning, or 5 mg every evening of ONGLYZA, or placebo. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy added on to placebo or ONGLYZA; the number of patients randomized per treatment group ranged from 71 to 74. Treatment with either ONGLYZA 5 mg every morning or 5 mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of 0.4% and 0.3%, respectively). Treatment with ONGLYZA 2.5 mg every morning also provided significant improvement in A1C versus placebo (mean placebo-corrected reduction of 0.4%). Combination Therapy Add-On Combination Therapy with Metformin A total of 743 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin in patients with inadequate glycemic control (A1C ≥7% and ≤10%) on metformin alone. To qualify for enrollment, patients were required to be on a stable dose of metformin (1500-2550 mg daily) for at least 8 weeks. Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin at their pre-study dose, up to 2500 mg daily. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo in addition to their current dose of open-label metformin. The 10 mg dosage is not an approved dosage. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue therapy, added on to existing study medications. Dose titrations of ONGLYZA and metformin were not permitted. ONGLYZA 2.5 mg and 5 mg add-on to metformin provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin (Table 5). Mean changes from baseline for A1C over time and at endpoint are shown in Figure 1. The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 15% in the ONGLYZA 2.5 mg add-on to metformin group, 13% in the ONGLYZA 5 mg add-on to metformin group, and 27% in the placebo add-on to metformin group. Table 5: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA as Add-On Combination Therapy with Metformin* Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue. Least squares mean adjusted for baseline value. p-value <0.0001 compared to placebo + metformin p-value <0.05 compared to placebo + metformin Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin* Includes patients with a baseline and week 24 value. Week 24 (LOCF) includes intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value. Add-On Combination Therapy with a Thiazolidinedione A total of 565 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with a thiazolidinedione (TZD) in patients with inadequate glycemic control (A1C ≥7% to ≤10.5%) on TZD alone. To qualify for enrollment, patients were required to be on a stable dose of pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or 8 mg either once daily or in two divided doses of 4 mg) for at least 12 weeks. Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received TZD at their pre-study dose. Following the lead-in period, eligible patients were randomized to 2.5 mg or 5 mg of ONGLYZA or placebo in addition to their current dose of TZD. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue, added on to existing study medications. Dose titration of ONGLYZA or TZD was not permitted during the study. A change in TZD regimen from rosiglitazone to pioglitazone at specified, equivalent therapeutic doses was permitted at the investigator’s discretion if believed to be medically appropriate. ONGLYZA 2.5 mg and 5 mg add-on to TZD provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to TZD (Table 6). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 10% in the ONGLYZA 2.5 mg add-on to TZD group, 6% for the ONGLYZA 5 mg add-on to TZD group, and 10% in the placebo add-on to TZD group. Table 6: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA as Add-On Combination Therapy with a Thiazolidinedione* Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue. Least squares mean adjusted for baseline value. p-value <0.0001 compared to placebo + TZD p-value <0.05 compared to placebo + TZD Add-On Combination Therapy with Glyburide A total of 768 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with a sulfonylurea (SU) in patients with inadequate glycemic control at enrollment (A1C ≥7.5% to ≤10%) on a submaximal dose of SU alone. To qualify for enrollment, patients were required to be on a submaximal dose of SU for 2 months or greater. In this study, ONGLYZA in combination with a fixed, intermediate dose of SU was compared to titration to a higher dose of SU. Patients who met eligibility criteria were enrolled in a single-blind, 4-week, dietary and exercise lead-in period, and placed on glyburide 7.5 mg once daily. Following the lead-in period, eligible patients with A1C ≥7% to ≤10% were randomized to either 2.5 mg or 5 mg of ONGLYZA add-on to 7.5 mg glyburide or to placebo plus a 10 mg total daily dose of glyburide. Patients who received placebo were eligible to have glyburide up-titrated to a total daily dose of 15 mg. Up-titration of glyburide was not permitted in patients who received ONGLYZA 2.5 mg or 5 mg. Glyburide could be down-titrated in any treatment group once during the 24-week study period due to hypoglycemia as deemed necessary by the investigator. Approximately 92% of patients in the placebo plus glyburide group were up-titrated to a final total daily dose of 15 mg during the first 4 weeks of the study period. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue, added on to existing study medication. Dose titration of ONGLYZA was not permitted during the study. In combination with glyburide, ONGLYZA 2.5 mg and 5 mg provided significant improvements in A1C, FPG, and PPG compared with the placebo plus up-titrated glyburide group (Table 7). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 18% in the ONGLYZA 2.5 mg add-on to glyburide group, 17% in the ONGLYZA 5 mg add-on to glyburide group, and 30% in the placebo plus up-titrated glyburide group. Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA as Add-On Combination Therapy with Glyburide Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue Least squares mean adjusted for baseline value p-value <0.0001 compared to placebo + up-titrated glyburide p-value <0.05 compared to placebo + up-titrated glyburide Coadministration with Metformin in Treatment-Naive Patients A total of 1306 treatment-naive patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, active-controlled trial to evaluate the efficacy and safety of ONGLYZA coadministered with metformin in patients with inadequate glycemic control (A1C ≥8% to ≤12%) on diet and exercise alone. Patients were required to be treatment-naive to be enrolled in this study. Patients who met eligibility criteria were enrolled in a single-blind, 1-week, dietary and exercise placebo lead-in period. Patients were randomized to one of four treatment arms: ONGLYZA 5 mg + metformin 500mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin 10 mg + placebo, or metformin 500 mg + placebo. The 10 mg saxagliptin dosage is not an approved dosage. ONGLYZA was dosed once daily. In the 3 treatment groups using metformin, the metformin dose was up-titrated weekly in 500 mg per day increments, as tolerated, to a maximum of 2000 mg per day based on FPG. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue as add-on therapy. Coadministration of ONGLYZA 5 mg plus metformin provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin (Table 8). Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA Coadministration with Metformin in Treatment-Naive Patients* Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue. Least squares mean adjusted for baseline value. p-value <0.0001 compared to placebo + metformin p-value <0.05 compared to placebo + metformin Add-On Combination Therapy with Metformin versus Glipizide Add-On Combination Therapy with Metformin In this 52-week, active-controlled trial, a total of 858 patients with type 2 diabetes and inadequate glycemic control (A1C >6.5% and ≤10%) on metformin alone were randomized to double-blind add-on therapy with ONGLYZA or glipizide. Patients were required to be on a stable dose of metformin (at least 1500 mg daily) for at least 8 weeks prior to enrollment. Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin (1500-3000 mg based on their pre-study dose). Following the lead-in period, eligible patients were randomized to 5 mg of ONGLYZA or 5 mg of glipizide in addition to their current dose of open-label metformin. Patients in the glipizide plus metformin group underwent blinded titration of the glipizide dose during the first 18 weeks of the trial up to a maximum glipizide dose of 20 mg per day. Titration was based on a goal FPG ≤110 mg/dL or the highest tolerable glipizide dose. Fifty percent (50%) of the glipizide-treated patients were titrated to the 20-mg daily dose; 21% of the glipizide-treated patients had a final daily glipizide dose of 5 mg or less. The mean final daily dose of glipizide was 15 mg. After 52 weeks of treatment, ONGLYZA and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin therapy (Table 9). This conclusion may be limited to patients with baseline A1C comparable to those in the trial (91% of patients had baseline A1C <9%). From a baseline mean body weight of 89 kg, there was a statistically significant mean reduction of 1.1 kg in patients treated with ONGLYZA compared to a mean weight gain of 1.1 kg in patients treated with glipizide (p<0.0001). Table 9: Glycemic Parameters at Week 52 in an Active-Controlled Trial of ONGLYZA versus Glipizide in Combination with Metformin Intent-to-treat population using last observation on study Least squares mean adjusted for baseline value ONGLYZA + metformin is considered non-inferior to glipizide + metformin because the upper limit of this confidence interval is less than the prespecified non-inferiority margin of 0.35% Significance not tested. Add-On Combination Therapy with Insulin (with or without metformin) A total of 455 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with insulin in patients with inadequate glycemic control (A1C ≥7.5% and ≤11%) on insulin alone (N=141) or on insulin in combination with a stable dose of metformin (N=314). Patients were required to be on a stable dose of insulin (≥30 units to ≤150 units daily) with ≤20% variation in total daily dose for ≥8 weeks prior to screening. Patients entered the trial on intermediate- or long-acting (basal) insulin or premixed insulin. Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a premixed insulin. Patients who met eligibility criteria were enrolled in a single-blind, four-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either ONGLYZA 5 mg or placebo. Doses of the antidiabetic therapies were to remain stable but patients were rescued and allowed to adjust the insulin regimen if specific glycemic goals were not met or if the investigator learned that the patient had self-increased the insulin dose by >20%. Data after rescue were excluded from the primary efficacy analyses. Add-on therapy with ONGLYZA 5 mg provided significant improvements from baseline to Week 24 in A1C and PPG compared with add-on placebo (Table 10). Similar mean reductions in A1C versus placebo were observed for patients using ONGLYZA 5 mg add-on to insulin alone and ONGLYZA 5 mg add-on to insulin in combination with metformin (0.4% and ?0.4%, respectively). The percentage of patients who discontinued for lack of glycemic control or who were rescued was 23% in the ONGLYZA group and 32% in the placebo group. The mean daily insulin dose at baseline was 53 units in patients treated with ONGLYZA 5 mg and 55 units in patients treated with placebo. The mean change from baseline in daily dose of insulin was 2 units for the ONGLYZA 5 mg group and 5 units for the placebo group. Table 10: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Insulin* Intent-to-treat population using last observation on study or last observation prior to insulin rescue therapy for patients needing rescue Least squares mean adjusted for baseline value and metformin use at baseline p-value <0.0001 compared to placebo + insulin p-value <0.05 compared to placebo + insulin Add-On Combination Therapy with Metformin plus Sulfonylurea A total of 257 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin plus a sulfonylurea in patients with inadequate glycemic control (A1C ≥7% and ≤10%). Patients were to be on a stable combined dose of metformin extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1500 mg) and a sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being ≥50% of the maximum recommended dose) for ≥8 weeks prior to enrollment. Patients who met eligibility criteria were entered in a 2-week enrollment period to allow assessment of inclusion/exclusion criteria. Following the 2-week enrollment period, eligible patients were randomized to either double-blind ONGLYZA (5 mg once daily) or double-blind matching placebo for 24 weeks. During the 24-week double-blind treatment period, patients were to receive metformin and a sulfonylurea at the same constant dose ascertained during enrollment. Sulfonylurea dose could be down titrated once in the case of a major hypoglycemic event or recurring minor hypoglycemic events. In the absence of hypoglycemia, titration (up or down) of study medication during the treatment period was prohibited. ONGLYZA in combination with metformin plus a sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin plus a sulfonylurea (Table 11). The percentage of patients who discontinued for lack of glycemic control was 6% in the ONGLYZA group and 5% in the placebo group. Table 11: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin plus Sulfonylurea* Intent-to-treat population using last observation prior to discontinuation Least squares mean adjusted for baseline value p-value <0.0001 compared to placebo + metformin plus sulfonylurea p-value <0.05 compared to placebo + metformin plus sulfonylurea The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C <7% was 31% (39/127) with ONGLYZA in combination with metformin plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested. 14.2 Renal Impairment A total of 170 patients participated in a 12-week, randomized, double-blind, placebo-controlled trial conducted to evaluate the efficacy and safety of ONGLYZA 2.5 mg once daily compared with placebo in patients with type 2 diabetes and moderate (n=90) or severe (n=41) renal impairment or ESRD (n=39). In this trial, 98% of the patients were using background antidiabetic medications (75% were using insulin and 31% were using oral antidiabetic medications, mostly sulfonylureas). After 12 weeks of treatment, ONGLYZA 2.5 mg provided significant improvement in A1C compared to placebo (Table 12). In the subgroup of patients with ESRD, ONGLYZA and placebo resulted in comparable reductions in A1C from baseline to Week 12. This finding is inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment. After 12 weeks of treatment, the mean change in FPG was 12 mg/dL with ONGLYZA 2.5 mg and  13 mg/dL with placebo. Compared to placebo, the mean change in FPG with ONGLYZA was ?12 mg/dL in the subgroup of patients with moderate renal impairment, 4 mg/dL in the subgroup of patients with severe renal impairment, and +44 mg/dL in the subgroup of patients with ESRD. These findings are inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment. Table 12: A1C at Week 12 in a Placebo-Controlled Trial of ONGLYZA in Patients with Renal Impairment* Intent-to-treat population using last observation on study. Least squares mean adjusted for baseline value. p-value <0.01 compared to placebo 14.3 Cardiovascular Safety Trial The cardiovascular risk of ONGLYZA was evaluated in SAVOR, a multicenter, multinational, randomized, double-blind study comparing ONGLYZA (N=8280) to placebo (N=8212), both administered in combination with standard of care, in adult patients with type 2 diabetes at high risk for atherosclerotic cardiovascular disease. Of the randomized study subjects, 97.5% completed the trial, and the median duration of follow-up was approximately 2 years. The trial was event-driven, and patients were followed until a sufficient number of events were accrued. Subjects were at least 40 years of age, had A1C ≥6.5%, and multiple risk factors (21% of randomized subjects) for cardiovascular disease (age ≥55 years for men and ≥60 years for women plus at least one additional risk factor of dyslipidemia, hypertension, or current cigarette smoking) or established (79% of the randomized subjects) cardiovascular disease defined as a history of ischemic heart disease, peripheral vascular disease, or ischemic stroke. The majority of subjects were male (67%) and Caucasian (75%) with a mean age of 65 years. Approximately 16% of the population had moderate (estimated glomerular filtration rate [eGFR] ≥30 to ≤50 mL/min) to severe (eGFR <30 mL/min) renal impairment, and 13% had a prior history of heart failure. Subjects had a median duration of type 2 diabetes mellitus of approximately 10 years, and a mean baseline A1C level of 8.0%. Approximately 5% of subjects were treated with diet and exercise only at baseline. Overall, the use of diabetes medications was balanced across treatment groups (metformin 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications was also balanced (ACE inhibitors or ARBs 79%, statins 78%, aspirin 75%, beta-blockers 62%, and non-aspirin antiplatelet medications 24%). The primary analysis in SAVOR was time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event in SAVOR was defined as a cardiovascular death or a nonfatal myocardial infarction (MI) or a nonfatal ischemic stroke. The study was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of MACE and was also powered for a superiority comparison if non-inferiority was demonstrated. The results of SAVOR, including the contribution of each component to the primary composite endpoint, are shown in Table 13. The incidence rate of MACE was similar in both treatment arms: 3.8 MACE per 100 patient-years on placebo vs. 3.8 MACE per 100 patient-years on ONGLYZA. The estimated hazard ratio of MACE associated with ONGLYZA relative to placebo was 1.00 with a 95.1% confidence interval of (0.89, 1.12). The upper bound of this confidence interval, 1.12, excluded a risk margin larger than 1.3. Table 13 : Major Adverse Cardiovascular Events (MACE) by Treatment Group in the SAVOR Trial The Kaplan-Meier-based cumulative event probability is presented in Figure 2 for time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for both ONGLYZA and placebo arms are close together throughout the duration of the trial. The estimated cumulative event probability is approximately linear for both arms, indicating that the incidence of MACE for both arms was constant over the trial duration. Figure 2: Cumulative Percent of Time to First MACE Vital status was obtained for 99% of subjects in the trial. There were 798 deaths in the SAVOR trial. Numerically more patients (5.1%) died in the ONGLYZA group than in the placebo group (4.6%). The risk of deaths from all cause (Table 14) was not statistically different between the treatment groups (HR: 1.11; 95.1% CI: 0.96, 1.27). Table 14: All-cause mortality by Treatment Group in the SAVOR Study 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ONGLYZA (saxagliptin) tablets have markings on both sides and are available in the strengths and packages listed in Table 15. Table 15: ONGLYZA Tablet Presentations Storage and Handling Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION Advise the patient to read FDA-approved patient labeling (Medication Guide). Medication Guide Healthcare providers should instruct their patients to read the Medication Guide before starting ONGLYZA therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom or if any existing symptom persists or worsens. Patients should be informed of the potential risks and benefits of ONGLYZA and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly. Pancreatitis Patients should be informed that acute pancreatitis has been reported during postmarketing use of ONGLYZA. Before initiating ONGLYZA, patients should be questioned about other risk factors for pancreatitis, such as a history of pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should also be informed that 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. Patients should be instructed to promptly discontinue ONGLYZA and contact their healthcare provider if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)]. Heart Failure Patients should be informed of the signs and symptoms of heart failure. Before initiating ONGLYZA, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Patients should be instructed to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.2)]. Hypersensitivity Reactions Patients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during postmarketing use of ONGLYZA. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking ONGLYZA and seek medical advice promptly. Severe and Disabling Arthralgia Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.5)]. Missed Dose Patients should be informed that if they miss a dose of ONGLYZA they should take the next dose as prescribed, unless otherwise instructed by their healthcare provider. Patients should be instructed not to take an extra dose the next day. Administration Instructions Patients should be informed that ONGLYZA tablets must not be split or cut. Laboratory Tests Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C, with a goal of decreasing these levels toward the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust their dose based on changes in renal function tests over time. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c5116390-e0fe-4969-94cb-e9de5165fbab 百时美施贵宝公司(NYSE: BMY)和阿斯利康公司(NYSE: AZN)今天发布了一项3b期临床研究的结果，该研究比较2型糖尿病成人患者中持续胰岛素疗法(联合或不联合二甲双胍)基础上添加ONGLYZATM (沙格列汀) 5毫克与添加安慰剂(联合或不联合二甲双胍)维持血糖水平(糖化血红蛋白水平，或称HbA1c)降低的效应，疗程介于24~52周。该结果在葡萄牙里斯本的欧洲糖尿病研究学会(EASD)第47届年会上呈报，该结果来自一项为期24周的试验的延伸期，该24周试验的结果于2011年6月在加州圣迭戈的美国糖尿病学会(ADA)第71届科学会议上呈报。 52周结果分析显示，胰岛素(联合或不联合二甲双胍)基础上添加ONGLYZA 5毫克患者的HbA1c基线后变化为-0.75%，而胰岛素(联合或不联合二甲双胍)基础上添加安慰剂患者为-0.38%。安慰剂组的胰岛素日均剂量基线后增幅也大于ONGLYZA 5毫克 (联合或不联合二甲双胍)组。有效性分析中，安慰剂组胰岛素剂量增加能否影响这两个治疗组间的差值幅度尚属未知。 52周治疗期间，各治疗组出现至少一次不良事件的患者比例是相似的。最常见事件包括低血糖、尿路感染、鼻咽炎、上呼吸道感染、头痛和支气管炎。 该研究的主要研究者-伯明翰大学、Heart of England NHS Foundation Trust的Anthony Barnett， MD说："由于众多2型糖尿病患者最终需要用胰岛素，若要采用某种化合物来控制血糖，那么，评估其能否与胰岛素长期联合使用是至关重要的。本研究是首次报道ONGLYZA 5毫克与胰岛素联合用药24~52周可维持2型糖尿病成人患者血糖控制改善的长期研究。" 临床开发 ONGLYZA(saxagliptin　沙格列汀片)　临床开发项目 ONGLYZA的获批基于一个临床开发项目，该项目包括约5000名受试者，其中4000多名使用了ONGLYZA。在控制饮食和锻炼基础上，该开发项目的组成包括：将ONGLYZA加用于其他口服降糖药（包括二甲双胍、磺脲类中的格列苯脲和TZDs）的研究；在初次接受治疗的成人糖尿病患者中，开始便联合使用二甲双胍和ONGLYZA?的研究；以及单药治疗研究。 整个III期开发项目中，所有剂量水平的ONGLYZA与其他常用口服降糖药（二甲双胍，磺脲类和TZDs）联用，或作为单药使用时，都令所研究的3个血糖控制关键指标：糖化血红蛋白（AIC）、空腹血糖（FPG）和餐后血糖（PPG）出现了具有临床相关性与统计学意义的下降。与安慰剂相比，ONGLYZAA对体重和血脂没有影响。 作用机理 ONGLYZA通过作用于空腹血糖（FPG）和餐后血糖（PPG）来控制糖化血红蛋白（A1C） 肠促胰岛素通过影响胰腺分泌胰岛素和胰高血糖素，帮助机体调节餐后血糖的水平。ONGLYZA可抑制DPP4酶（这种酶通常可在几分钟内降解肠促胰岛素），从而增加并延长肠促胰岛素的作用。 ONGLYZA对DPP4酶的抑制使胰腺增加了胰岛素的分泌，降低了胰高血糖素的分泌。这些作用是葡萄糖依赖性的，可增强机体对食物的自然反应，降低餐前和餐后血糖水平。 加州大学圣地亚哥分校内分泌和代谢系主任医学博士罗伯特亨利（Robert Henry）说道：“我在临床工作中发现一些糖尿病成人患者虽然接受了治疗，但仍有较高的空腹血糖或餐后血糖，而这两者都是促成糖化血红蛋白升高的重要因素。沙格列汀（Saxagliptin）的获批为2型糖尿病成人患者提供了一种新的治疗方法，该药可用于控制各项关键的血糖指标，改善血糖，从而降低糖化血红蛋白水平。” 适应症 1. 在二甲双胍治疗不能控制血糖时加用，ONGLYZA使糖化血红蛋白（A1C）出现具有统计学意义的下降 研究者对ONGLYZA和二甲双胍（最常用的口服降糖药）的联用作了大量的研究。在二甲双胍未能充分控制血糖的成人患者中，加用ONGLYZA 2.5mg（n=192,基线A1C 8.1%）和5mg（n=191,基线A1C8.1%）每天1次，到第24周时可使糖化血红蛋白水平从基线分别下降0.6%和0.7%，而安慰剂则使其升高0.1%（与安慰剂相比，p<0.0001，n=179，基线A1C8.1%）。服用ONGLYZA 2.5mg和5mg报告的低血糖发生率分别为7.8%、5.8%，而服用安慰剂则为5%。 对于初次使用糖尿病治疗药物的患者来说ONGLYZA 5mg加二甲双胍（n=320，基线A1C 为9.4%）作为初始治疗，到第24周时可使A1C从基线下降了2.5%，而二甲双胍加安慰剂则使其下降了2%（p<0.0001,n=313，基线A1C9.4%）。ONGLYZA 加二甲双胍组患者达到了美国糖尿病协会推荐的A1C水平<7%的患者人数明显多于二甲双胍加安慰剂组（60% 比41%，p<0.05)。在ONGLYZA 5mg加二甲双胍组的成人患者中，低血糖的发生率为3.4%，单用二甲双胍组的发生率为4%。而由其引起的，发生率≥5%，且高于单用二甲双胍组的不良反应为头痛（7.5%相对于5.2%）和鼻咽炎（6.9%相对于4%）。 2. 在格列苯脲或TZDs治疗不能控制血糖时加用，糖化血红蛋白（A1C）出现进一步的、具有统计学意义的下降 对于用格列苯脲未能控制血糖的成人患者，ONGLYZA能够改善其血糖控制。在低于每日最大剂量格列苯脲7.5mg的治疗中加入ONGLYZA 2.5mg (n=248, 基线 A1C 8.4%) 或5 mg (n=253, 基线 A1C 8.5%) 可使A1C水平从基线到第24周时分别下降了0.5%和0.6%，而每日总剂量约增加1倍的格列苯脲与安慰剂联用时，A1C则升高了0.1%（相比调高剂量的格列苯脲，p<0.0001 n=267，基线 A1C 8.4 %）。ONGLYZA 2.5mg或5mg加用组报告的低血糖发生率分别为13.3%、14.6%，而高剂量格列苯脲组为10.1%；ONGLYZA 2.5mg或5mg确认的低血糖发生率分别为2.4%、0.8%，而高剂量格列苯脲组为0.7%（定义为：有低血糖症状，同时指尖测得的血糖水平≤50 mg/dL)。与磺脲类联用时，为了降低发生低血糖的风险，需要减少磺脲类的用量。 在TZDs（吡格列酮或罗格列酮）的治疗中加用ONGLYZA(沙格列汀saxagliptin)，可进一步控制血糖。加入ONGLYZA 2.5mg (n=195, 基线 A1C 8.3%) 或5 mg (n=186, 基线 A1C 8.4%) 可使A1C水平从基线到第24周时分别下降0.7%和0.9%，而加用安慰剂时，A1C的下降幅度为0.3%（与安慰剂相比，p<0.05， n=184，基线 A1C 8.2 %）。ONGLYZA 2.5mg或5mg报告的低血糖发生率分别为4.1%、2.7%，而安慰剂组为3.8%。外周性水肿的发生率分别为3.1%、8.1%，而安慰剂组为4.3%；均未导致治疗中止。 3. ONGLYZA作为单药治疗时可显著降低糖化血红蛋白（A1C） 作为单药治疗进行研究时，ONGLYZA可明显改善血糖控制。第24周时，ONGLYZA 2.5mg组（n=102,基线A1C7.9%）和5mg组（n=106,基线A1C8.0%）的A1C与基线相比下降了0.4%和0.5%，而安慰剂组则升高了0.2%（与安慰剂相比，p<0.0001,n=95，基线A1C7.9%）。ONGLYZA组报告的低血糖发生率分别为4%、5.6%，而安慰剂组为4.1%。 不良反应 ONGLYZA副作用的总体发生率与安慰剂相似 在临床试验中，ONGLYZA?2.5mg和5mg的副作用总体发生率与安慰剂的70.6%相似，分别为72%、72.2%。ONGLYZA 5mg组最常见的不良事件（发生率≥5%且高于安慰剂组）为上呼吸道感染（7.7%，安慰剂组为7.6%）、尿路感染（6.8%，安慰剂组为6.1%）和头痛（6.5%，安慰剂组为5.9%）。 在ONGLYZA 2.5mg治疗的成人患者中，只有头痛的发生率≥5%（6.5%），而且比安慰剂组更常见。ONGLYZA 2.5mg组、5mg组和安慰剂组分别有2.2%、3.3%和1.8%患者因为发生不良事件而中止治疗。ONGLYZA?组观察到白细胞绝对数均值出现与剂量相关性的下降。 用法用量 ONGLYZA(saxagliptin)每日1次，服用方便 ONGLYZA2.5mg或5mg每日1次，服用方便，用药时间不受进餐影响。 ONGLYZA2.5mg被推荐用于中度或重度肾功能不全或需要血液透析的终末期肾病（肌酐清除率≤50mL/min）成人患者中。目前尚未在接受腹膜透析治疗的患者中对ONGLYZA进行研究。开始ONGLYZA治疗前及治疗开始后应定期评估肾功能。与强效细胞色素P450 3A4/5(CYP 3A4/5)抑制剂（如酮康唑）合用时，应将ONGLYZA的剂量限制为2.5mg。 无需根据性别、种族、体重或肝功能不全来调整剂量。 重要信息 (1) 适应症和重要的应用限制 ONGLYZA可作为饮食和锻炼的辅助治疗，改善2型糖尿病成人患者的血糖控制。 ONGLYZA不应用于治疗1型糖尿病或糖尿病酮症酸中毒。 目前尚未对ONGLYZA和胰岛素的联用进行研究。 (2) 重要的安全性信息 与已知会引起低血糖的药物合用：胰岛素促泌剂，如磺脲类，会引起低血糖。因此，与ONGLYZA?合用时，需减少胰岛素促泌剂的剂量，以降低发生低血糖的风险。 大血管风险终点事件研究：目前尚无此类结论性的临床研究证明ONGLYZA(saxagliptin)或其他任何糖尿病治疗药物可降低大血管并发症的风险。 (3) 最常见的不良反应（无论研究者对因果关系的评估如何）：ONGLYZA治疗的患者中，发生率≥5%且高于对照组患者发生率的不良反应为上呼吸道感染（7.7%，7.6%）、头痛（7.5%，5.2%）、鼻咽炎（6.9%，4.0%）和尿路感染（6.8%，6.1%）。噻唑烷二酮类联用治疗时，ONGLYZA2.5mg、5mg和安慰剂的外周性水肿发生率分别为3.1%、8.1%和4.3%。 (4) 药物相互作用：由于CYP 3A4/5强抑制剂酮康唑可增加沙格列汀（saxagliptin）暴露量，当ONGLYZA与CYP 3A4/5强抑制剂（如阿扎那韦、克拉霉素、茚地那韦、伊曲康唑、酮康唑、奈法唑酮、奈非那韦、利托那韦、沙奎那韦和泰利霉素）合用时，应限制剂量为2.5mg。 (5) 肾功能不全患者：为中度或重度肾功能不全患者或需要血液透析的终末期肾病（肌酐清除率≤50mL/min）患者每日给予ONGLYZA2.5mg 1次，应在血液透析后给药。目前尚未在接受腹膜透析治疗的患者中对ONGLYZA进行研究。开始ONGLYZA?治疗前及治疗开始后应定期评估肾功能。 (6) 孕妇及哺乳期妇女：没有在孕妇中开展充分且良好对照的研究。与其它糖尿病治疗药物一样，ONGLYZA?只有在明显需要时才能用于孕妇。目前尚不清楚沙格列汀（saxagliptin）是否会通过人类母乳分泌。由于很多药物都通过人类母乳分泌，因此，对于哺乳期妇女，ONGLYZA?应慎用。 (7) 儿童患者：尚未开展ONGLYZA（沙格列汀saxagliptin）在儿童患者中的安全性和有效性研究。 独特机制 格列汀应用灵活且持久降糖探讨独特机制介导的降糖效应 近年来，基于肠促胰素的治疗逐渐走入临床，其独特的作用机制及良好的疗效使其逐渐为广大临床医生和2型糖尿病患者所接受。沙格列汀（Saxagliptin）是这类药物中的一个成员，作为高效的选择性二肽基肽酶4（DPP-4）抑制剂，其通过升高内源性肠促胰素——胰高血糖素样肽1（GLP-1）和葡萄糖依赖性促胰岛素释放多肽（GIP）水平，发挥血糖调节作用。大量临床试验证据显示，沙格列汀可单药或与其他降糖药物联用安全有效降糖。据此，美国食品与药物管理局（FDA）于今年8月批准其上市，以改善2型糖尿病成人患者的血糖控制。不久前，沙格列汀用于2型糖尿病治疗的总观察期为102周的研究结果发布，进一步证实了其改善血糖控制的持久性。这些研究证据和日益丰富的临床应用经验都显示，沙格列汀作为口服DPP-4抑制剂，以基于肠促胰素的独特作用机制带来了安全、有效且持久的降糖效应。 (1) 应用灵活 a. 单药或联合治疗均有效降糖 作为基于肠促胰素的治疗方式，沙格列汀的降糖机制完全不同于传统口服降糖药，且每日口服1次方便易行，使其可在现有降糖策略中灵活应用。一系列为期24周的随机对照临床试验已经证实，沙格列汀无论是单药使用还是与其他药物联合治疗，都可以安全、有效改善血糖控制。 b. 单药起始 对于初治2型糖尿病患者，无论血糖水平如何[糖化血红蛋白（HbA1c）为7%~10%或10%~12%]，沙格列汀每日1次单药治疗均有有效控制血糖（与安慰剂相比，P<0.001），且未发现症状性低血糖，患者体重无增加。 c. 与二甲双胍联合起始 对于初治2型糖尿病患者，沙格列汀与二甲双胍联用的降糖效果显著优于两药分别单用，而且基线HbA1c水平高者HbA1c降幅也更大，不良事件发生率相似。 d. 其他口服降糖药降糖不佳时加用 二甲双胍、磺脲类或噻唑烷二酮类药物降糖不佳时，加用沙格列汀可更好地控制血糖（如与加用安慰剂相比，沙格列汀5 mg+二甲双胍使HbA1c进一步降低0.8%，沙格列汀5 mg+格列本脲使HbA1c进一步降低0.7%，沙格列汀5 mg+吡格列酮或罗格列酮使HbA1c进一步降低0.6%，均为P<0.0001）。 (2) 疗效持久 最新研究显示102周持续降糖 在2009年欧洲糖尿病研究会（EASD）年会上，美国拉维奇安德兰（Ravichandran）教授报告了一项最新的在24周随机对照研究基础上延长到102周的长期观察结果，显示对于二甲双胍单药治疗血糖控制不佳（HbA1c为7.0%~10.0%）的2型糖尿病患者，加服每日1次沙格列汀可持续有效降糖且安全耐受性良好。 在这项研究中，743例2型糖尿病患者在接受稳定剂量二甲双胍（1500~2500 mg/d）基础上，加用沙格列汀（2.5、5或10 mg）或安慰剂治疗24周，随后仍盲法使用沙格列汀并按预设标准进行吡格列酮补救治疗，进行为期42个月的延长期观察。102周时的结果显示，沙格列汀组患者血糖仍明显低于基线值，即二甲双胍降糖不佳时加用沙格列汀可持续有效控制血糖（图1）。而且，沙格列汀各治疗组的确证低血糖事件发生率均很低（<1.1%），患者平均体重自基线有小幅降低，提示其良好的长期耐受性。 (3) 机制探索 a. β细胞保护效应延缓病情进展 作为DPP-4抑制剂，沙格列汀通过升高2型糖尿病患者肠促胰素水平发挥降糖作用。其中，GLP-1作为重要的肠促胰素，已被众多研究证实有多效性特点。 就降糖相关作用而言，GLP-1可呈葡萄糖浓度依赖性刺激胰岛素分泌和抑制胰高血糖素分泌，而且更重要的是，GLP-1还具有改善β细胞功能的潜力。 动物和体外研究显示，GLP-1可增强胰岛素生物合成，刺激胰岛素基因转录，增加胰岛素生成量，还可促进β细胞增殖，抑制β细胞凋亡，从而增加β细胞数量。 b. 研究提示沙格列汀具β细胞保护效应 使用DPP-4抑制剂沙格列汀是否能为2型糖尿病患者提供β细胞保护作用呢？亨利（Henry）等在EASD年会上发布的一项研究为此提供了证据。这项在2型糖尿病患者中进行的研究，通过高糖钳夹（HC）方法观察沙格列汀对β细胞的影响。研究中20例患者每日1次口服沙格列汀5 mg，16例患者服用安慰剂治疗12周。高糖钳夹试验在基线和12周时进行，包括空腹状态（0~180 min，静脉HC）以及口服75 g葡萄糖刺激肠促胰素分泌后（180~480 min，静脉-口服HC）。结果显示，沙格列汀治疗12周后，空腹及餐后状态下胰岛素分泌量均显著增加，从而证实了其改善胰岛β细胞功能的作用。 c. β细胞保护效应意义探讨 沙格列汀的这种β细胞保护效应究竟有何意义？不妨从2型糖尿病病生理基础和目前的治疗现状说起。众所周知，β细胞功能障碍和胰岛素抵抗是2型糖尿病的重要病理生理基础，对于亚洲人群而言，尤其是前者更加明显。β细胞功能障碍具有发生早、进行性恶化的特点，这也是2型糖尿病随患者病程延长持续进展，须不断强化治疗才能控制血糖的重要原因。因此，如果降糖药物能保护β细胞，就意味着能延缓（也许甚至是逆转）疾病进展，在治疗中则表现为持续、稳定地控制血糖。对于沙格列汀，上述研究中所显示的持久良好的降糖作用，可能即与其所具有的β细胞保护作用密切相关。 d. 早期治疗提高β细胞干预获益 β细胞保护效应的存在还提示了早期干预的重要性。万奇伯格（Wajchenberg）教授在2007年发表的对可能保护β细胞的各种治疗策略的分析中已指出，“受损的β细胞功能及减少的β细胞数量都有可能逆转，尤其是在疾病早期，可能尚未超过对降低的β细胞量逆转可能性阈值限制的时候”。到底β细胞功能不可逆转的阈值为多少，人们并不清楚，但可以明确的是，越早干预患者获益越多。据此，针对沙格列汀的多种使用方式（单药或联合），就β细胞保护而言，对初诊患者就使用沙格列汀干预似乎能带来更多益处。 总之，根据现有临床证据，沙格列汀作为高选择性DPP-4抑制剂，提高内源性肠促胰素水平，可通过保护β细胞、刺激胰岛素分泌等多种途径实现有效、长期降糖。我们也期待更长期、深入的研究，验证其独特机制下的降糖作用，并为其临床使用提供更加丰富的证据。