Onglyza (Saxagliptin)
Dosage & administration
By using PrescriberAI, you agree to the AI Terms of Use.
Onglyza prescribing information
ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [
ONGLYZA has been studied as monotherapy and in combination with metformin HCl, 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 administered orally. 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 White, 16% were Asian, 4% were Black or African American, and 9% were of other racial groups. An additional 423 patients, including 315 who received ONGLYZA, participated in a placebo-controlled, dose-ranging trial 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 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 five additional trials in patients with type 2 diabetes mellitus: an active-controlled trial comparing add-on therapy with ONGLYZA to glipizide in 858 patients inadequately controlled on metformin HCl alone, a trial comparing ONGLYZA to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin HCl, a trial comparing ONGLYZA to placebo in 257 patients inadequately controlled on metformin HCl plus a sulfonylurea, a trial comparing ONGLYZA to placebo in 315 patients inadequately controlled on dapagliflozin and metformin HCl, and a trial comparing ONGLYZA to placebo in 170 patients with type 2 diabetes mellitus and moderate or severe renal impairment or ESRD.
A total of 766 patients with type 2 diabetes mellitus 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 trial were treated with metformin HCl 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.
Efficacy Parameter | ONGLYZA 2.5 mg N=102 | ONGLYZA 5 mg N=106 | Placebo N=95 |
Hemoglobin A1C (%) | N=100 | N=103 | N=92 |
Baseline (mean) | 7.9 | 8.0 | 7.9 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) | −0.4 | −0.5 | +0.2 |
Difference from placebo (adjusted mean ) | −0.6p-value <0.0001 compared to placebo. | −0.6 | |
95% Confidence Interval | (−0.9, −0.3) | (−0.9, −0.4) | |
Percent of patients achieving A1C <7% | 35% (35/100) | 38%p-value <0.05 compared to placebo.(39/103) | 24% (22/92) |
Fasting Plasma Glucose (mg/dL) | N=101 | N=105 | N=92 |
Baseline (mean) | 178 | 171 | 172 |
Change from baseline (adjusted mean ) | −15 | −9 | +6 |
Difference from placebo (adjusted mean ) | −21 | −15 | |
95% Confidence Interval | (−31, −10) | (−25, −4) | |
2-hour Postprandial Glucose (mg/dL) | N=78 | N=84 | N=71 |
Baseline (mean) | 279 | 278 | 283 |
Change from baseline (adjusted mean ) | −45 | −43 | −6 |
Difference from placebo (adjusted mean ) | −39Significance was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA. | −37 | |
95% Confidence Interval | (−61, −16) | (−59, −15) |
A second 24-week monotherapy trial was conducted to assess a range of dosing regimens for ONGLYZA.
Treatment-naive patients with inadequately controlled type 2 diabetes mellitus (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 trial were treated with metformin HCl 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%).
A total of 743 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin HCl 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 HCl (1,500-2,550 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 HCl at their pre-trial dose, up to 2,500 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 HCl. The 10 mg dosage of ONGLYZA is not an approved dosage. Patients who failed to meet specific glycemic goals during the trial were treated with pioglitazone rescue therapy, added on to existing trial medications. Dose titrations of ONGLYZA and metformin HCl 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.
Efficacy Parameter | ONGLYZA 2.5 mg + Metformin HCl N=192 | ONGLYZA 5 mg + Metformin HCl N=191 | Placebo + Metformin HCl N=179 |
|---|---|---|---|
Hemoglobin A1C (%) | N=186 | N=186 | N=175 |
Baseline (mean) | 8.1 | 8.1 | 8.1 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) | −0.6 | −0.7 | +0.1 |
Difference from placebo (adjusted mean ) | −0.7p-value <0.0001 compared to placebo + metformin HCl. | −0.8 | |
95% Confidence Interval | (−0.9, −0.5) | (−1.0, −0.6) | |
Percent of patients achieving A1C <7% | 37%p-value <0.05 compared to placebo + metformin HCl.(69/186) | 44% (81/186) | 17% (29/175) |
Fasting Plasma Glucose (mg/dL) | N=188 | N=187 | N=176 |
Baseline (mean) | 174 | 179 | 175 |
Change from baseline (adjusted mean ) | −14 | −22 | +1 |
Difference from placebo (adjusted mean ) | −16 | −23 | |
95% Confidence Interval | (−23, −9) | (−30, −16) | |
2-hour Postprandial Glucose (mg/dL) | N=155 | N=155 | N=135 |
Baseline (mean) | 294 | 296 | 295 |
Change from baseline (adjusted mean ) | −62 | −58 | −18 |
Difference from placebo (adjusted mean ) | −44 | −40 | |
95% Confidence Interval | (−60, −27) | (−56, −24) |
*Includes patients with a baseline and week 24 value.
Week 24 (LOCF) includes intent-to-treat population using last observation on trial prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.
A total of 565 patients with type 2 diabetes mellitus 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-trial 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 trial were treated with metformin HCl rescue, added on to existing trial medications. Dose titration of ONGLYZA or TZD was not permitted during the trial. 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.
Efficacy Parameter | ONGLYZA 2.5 mg + TZD N=195 | ONGLYZA 5 mg + TZD N=186 | Placebo + TZD N=184 |
|---|---|---|---|
Hemoglobin A1C (%) | N=192 | N=183 | N=180 |
Baseline (mean) | 8.3 | 8.4 | 8.2 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value) | −0.7 | −0.9 | −0.3 |
Difference from placebo (adjusted mean ) | −0.4p-value <0.0001 compared to placebo + TZD | −0.6p-value <0.05 compared to placebo + TZD | |
95% Confidence Interval | (−0.6, −0.2) | (−0.8, −0.4) | |
Percent of patients achieving A1C <7% | 42% (81/192) | 42% (77/184) | 26% (46/180) |
Fasting Plasma Glucose (mg/dL) | N=193 | N=185 | N=181 |
Baseline (mean) | 163 | 160 | 162 |
Change from baseline (adjusted mean ) | −14 | −17 | −3 |
Difference from placebo (adjusted mean ) | −12 | −15 | |
95% Confidence Interval | (−20, −3) | (−23, −6) | |
2-hour Postprandial Glucose (mg/dL) | N=156 | N=134 | N=127 |
Baseline (mean) | 296 | 303 | 291 |
Change from baseline (adjusted mean ) | −55 | −65 | −15 |
Difference from placebo (adjusted mean ) | −40 | −50 | |
95% Confidence Interval | (−56, −24) | (−66, −34) |
A total of 768 patients with type 2 diabetes mellitus 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 trial, 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 trial 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 trial period. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue, added on to existing trial medication. Dose titration of ONGLYZA was not permitted during the trial.
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.
Efficacy Parameter | ONGLYZA 2.5 mg + Glyburide 7.5 mg N=248 | ONGLYZA 5 mg + Glyburide 7.5 mg N=253 | Placebo + Up-Titrated Glyburide N=267 |
|---|---|---|---|
Hemoglobin A1C (%) | N=246 | N=250 | N=264 |
Baseline (mean) | 8.4 | 8.5 | 8.4 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) | −0.5 | −0.6 | +0.1 |
Difference from up-titrated glyburide (adjusted mean ) | −0.6p-value <0.0001 compared to placebo + up-titrated glyburide. | −0.7 | |
95% Confidence Interval | (−0.8, −0.5) | (−0.9, −0.6) | |
Percent of patients achieving A1C <7% | 22%p-value <0.05 compared to placebo + up-titrated glyburide.(55/246) | 23% (57/250) | 9% (24/264) |
Fasting Plasma Glucose (mg/dL) | N=247 | N=252 | N=265 |
Baseline (mean) | 170 | 175 | 174 |
Change from baseline (adjusted mean ) | −7 | −10 | +1 |
Difference from up-titrated glyburide (adjusted mean ) | −8 | −10 | |
95% Confidence Interval | (−14, −1) | (−17, −4) | |
2-hour Postprandial Glucose (mg/dL) | N=195 | N=202 | N=206 |
Baseline (mean) | 309 | 315 | 323 |
Change from baseline (adjusted mean ) | −31 | −34 | +8 |
Difference from up-titrated glyburide (adjusted mean ) | −38 | −42 | |
95% Confidence Interval | (−50, −27) | (−53, −31) |
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 HCl 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 trial.
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 HCl 500 mg, saxagliptin 10 mg + metformin HCl 500 mg, saxagliptin 10 mg + placebo, or metformin HCl 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 HCl, the metformin HCl dose was up-titrated weekly in 500 mg per day increments, as tolerated, to a maximum of 2,000 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 HCl provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin (Table 8).
Efficacy Parameter | ONGLYZA 5 mg + Metformin HCl N=320 | Placebo + Metformin HCl N=328 |
|---|---|---|
Hemoglobin A1C (%) | N=306 | N=313 |
Baseline (mean) | 9.4 | 9.4 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) | −2.5 | −2.0 |
Difference from placebo + metformin HCl (adjusted mean ) | −0.5p-value <0.0001 compared to placebo + metformin HCl. | |
95% Confidence Interval | (−0.7, −0.4) | |
Percent of patients achieving A1C <7% | 60%p-value <0.05 compared to placebo + metformin HCl.(185/307) | 41% (129/314) |
Fasting Plasma Glucose (mg/dL) | N=315 | N=320 |
Baseline (mean) | 199 | 199 |
Change from baseline (adjusted mean ) | −60 | −47 |
Difference from placebo + metformin HCl (adjusted mean ) | −13 | |
95% Confidence Interval | (−19, −6) | |
2-hour Postprandial Glucose (mg/dL) | N=146 | N=141 |
Baseline (mean) | 340 | 355 |
Change from baseline (adjusted mean ) | −138 | −97 |
Difference from placebo + metformin HCl (adjusted mean ) | −41 | |
95% Confidence Interval | (−57, −25) |
In this 52-week, active-controlled trial, a total of 858 patients with type 2 diabetes mellitus and inadequate glycemic control (A1C >6.5% and ≤10%) on metformin HCl alone were randomized to double-blind add-on therapy with ONGLYZA or glipizide. Patients were required to be on a stable dose of metformin HCl (at least 1,500 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 HCl (1,500-3,000 mg based on their pre-trial 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 HCl. Patients in the glipizide plus metformin HCl 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 HCl 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).
Efficacy Parameter | ONGLYZA 5 mg + Metformin HCl N=428 | Titrated Glipizide + Metformin HCl N=430 |
|---|---|---|
Hemoglobin A1C (%) | N=423 | N=423 |
Baseline (mean) | 7.7 | 7.6 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) | −0.6 | −0.7 |
Difference from glipizide + metformin HCl (adjusted mean ) | 0.1 | |
95% Confidence Interval | (−0.02, 0.2)ONGLYZA + metformin HCl is considered non-inferior to glipizide + metformin HCl because the upper limit of this confidence interval is less than the prespecified non-inferiority margin of 0.35%. | |
Fasting Plasma Glucose (mg/dL) | N=420 | N=420 |
Baseline (mean) | 162 | 161 |
Change from baseline (adjusted mean ) | −9 | −16 |
Difference from glipizide + metformin HCl (adjusted mean ) | 6 | |
95% Confidence Interval | (2, 11)Significance not tested. |
A total of 455 patients with type 2 diabetes mellitus 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 HCl (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 HCl 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 HCl (−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.
Efficacy Parameter | ONGLYZA 5 mg + Insulin (+/− Metformin HCl) N=304 | Placebo + Insulin (+/− Metformin HCl) N=151 |
Hemoglobin A1C (%) | N=300 | N=149 |
Baseline (mean) | 8.7 | 8.7 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value and metformin HCl use at baseline.) | −0.7 | −0.3 |
Difference from placebo (adjusted mean ) | −0.4p-value <0.0001 compared to placebo + insulin. | |
95% Confidence Interval | (−0.6, −0.2) | |
2-hour Postprandial Glucose (mg/dL) | N=262 | N=129 |
Baseline (mean) | 251 | 255 |
Change from baseline (adjusted mean ) | −27 | −4 |
Difference from placebo (adjusted mean ) | −23p-value <0.05 compared to placebo + insulin. | |
95% Confidence Interval | (−37, −9) |
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 17% (52/300) with ONGLYZA in combination with insulin compared to 7% (10/149) with placebo. Significance was not tested.
A total of 257 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin HCl plus a sulfonylurea in patients with inadequate glycemic control (A1C ≥7% and ≤10%). Patients were to be on a stable combined dose of metformin HCl extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1,500 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 HCl 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 trial medication during the treatment period was prohibited.
ONGLYZA in combination with metformin HCl plus a sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin HCl 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.
Efficacy Parameter | ONGLYZA 5 mg + Metformin HCl plus Sulfonylurea N=129 | Placebo + Metformin HCl plus Sulfonylurea N=128 |
Hemoglobin A1C (%) | N=127 | N=127 |
Baseline (mean) | 8.4 | 8.2 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value) | −0.7 | −0.1 |
Difference from placebo (adjusted mean ) | −0.7p-value <0.0001 compared to placebo + metformin HCl plus sulfonylurea | |
95% Confidence Interval | (−0.9, −0.5) | |
2-hour Postprandial Glucose (mg/dL) | N=115 | N=113 |
Baseline (mean) | 268 | 262 |
Change from baseline (adjusted mean ) | −12 | 5 |
Difference from placebo (adjusted mean ) | −17p-value <0.05 compared to placebo + metformin HCl plus sulfonylurea | |
95% Confidence Interval | (−32, −2) |
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 HCl plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.
A total of 315 patients with type 2 diabetes mellitus participated in this 24-week randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA added to dapagliflozin (an SGLT2 inhibitor) and metformin HCl in patients with a baseline of HbA1c ≥7% to ≤10.5%. The mean age of these patients was 54.6 years, 1.6% were 75 years or older and 52.7% were female. The population was 87.9% White, 6.3% Black or African American, 4.1% Asian, and 1.6% other races. At baseline the population had diabetes mellitus for an average of 7.7 years and a mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were required to be on a stable dose of metformin HCl (≥1,500 mg per day) for at least 8 weeks prior to enrollment. Eligible patients who completed the screening period entered the lead in treatment period, which included open-label metformin HCl and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to ONGLYZA 5 mg (N=153) or placebo (N =162).
The group treated with add-on ONGLYZA had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo (see Table 12).
ONGLYZA 5 mg (N=153) Number of randomized and treated patients. | Placebo (N=162) | |
In combination with Dapagliflozin and Metformin HCl | ||
Hemoglobin A1C (%) Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using placebo data for all patients having missing Week 24 data. | ||
Baseline (mean) | 8.0 | 7.9 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) 95% Confidence Interval | −0.5 (−0.6, −0.4) | −0.2 (−0.3, −0.1) |
Difference from placebo (adjusted mean) 95% Confidence Interval | −0.4p-value <0.0001 (−0.5, −0.2) | |
The known proportion of patients achieving HbA1c <7% at Week 24 was 35.3% in the saxagliptin treated group compared to 23.1% in the placebo treated group.
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 mellitus 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 13). 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.
Efficacy Parameter | ONGLYZA 2.5 mg N=85 | Placebo N=85 |
|---|---|---|
Hemoglobin A1C (%) | N=81 | N=83 |
Baseline (mean) | 8.4 | 8.1 |
Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) | −0.9 | −0.4 |
Difference from placebo (adjusted mean ) | −0.4p-value <0.01 compared to placebo. | |
95% Confidence Interval | (−0.7, −0.1) |
The cardiovascular risk of ONGLYZA was evaluated in SAVOR, a multicenter, multinational, randomized, double-blind trial comparing ONGLYZA (N=8280) to placebo (N=8212), both administered in combination with standard of care, in adult patients with type 2 diabetes mellitus at high risk for atherosclerotic cardiovascular disease. Of the randomized trial patients, 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.
Patients were at least 40 years of age, had A1C ≥6.5%, and multiple risk factors (21% of randomized patients) 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 patients) cardiovascular disease defined as a history of ischemic heart disease, peripheral vascular disease, or ischemic stroke. Overall, the use of diabetes medications was balanced across treatment groups (metformin HCl 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications was also balanced (angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) 79%, statins 78%, aspirin 75%, beta-blockers 62%, and non-aspirin antiplatelet medications 24%).
The majority of patients were male (67%) and White (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/1.73 m2) to severe (eGFR <30 mL/min/1.73 m2) renal impairment, and 13% had a prior history of heart failure. Patients 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 patients were treated with diet and exercise only at baseline. Overall, the use of diabetes medications was balanced across treatment groups (metformin HCl 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 trial 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 14. 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.
ONGLYZA | Placebo | Hazard Ratio | |||
|
|
|
|
| |
Composite of first event of CV death, non-fatal MI or non-fatal ischemic stroke (MACE) |
|
|
|
| |
613 (7.4) | 3.8 | 609 (7.4) | 3.8 | 1.00 (0.89, 1.12) | |
CV death | 245 (3.0) | 1.5 | 234 (2.8) | 1.4 | |
Non-fatal MI | 233 (2.8) | 1.4 | 260 (3.2) | 1.6 | |
Non-fatal ischemic stroke | 135 (1.6) | 0.8 | 115 (1.4) | 0.7 | |
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.
Vital status was obtained for 99% of patients 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 15) was not statistically different between the treatment groups (HR: 1.11; 95.1% CI: 0.96, 1.27).
ONGLYZA | Placebo | Hazard Ratio | |||
Number of Patients (%) | Rate per 100 PY | Number of Patients (%) | Rate per 100 PY | (95.1% CI) | |
N=8280 | PY=16645.3 | N=8212 | PY=16531.5 | ||
All-cause mortality | 420 (5.1) | 2.5 | 378 (4.6) | 2.3 | 1.11 (0.96, 1.27) |
CV death | 269 (3.2) | 1.6 | 260 (3.2) | 1.6 | |
Non-CV death | 151 (1.8) | 0.9 | 118 (1.4) | 0.7 | |
• Recommended dosage is 2.5 mg or 5 mg orally once daily taken regardless of meals.2.1 Recommended DosageThe recommended dosage of ONGLYZA is 2.5 mg or 5 mg orally once daily taken regardless of meals. Do not cut, crush, or chew ONGLYZA tablets.
If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
• Patients with an eGFR <45 mL/min/1.73 m2 (moderate or severe renal impairment, or end-stage renal disease): Recommended dosage is 2.5 mg once daily regardless of meals.2.2 Dosage in Patients with Renal ImpairmentAssess renal function prior to initiation of ONGLYZA and then as clinically indicated [see
Use in Specific Populations (8.6)].The recommended dosage of ONGLYZA in patients with an eGFR greater than or equal to 45 mL/minute/1.73 m2is the same as the recommended dosage in patients with normal renal function [
seeDosage and Administration (2.1)].The dosage of ONGLYZA is 2.5 mg orally once daily for patients with eGFR <45 mL/min/1.73 m2[which includes a subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis] [
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.• Assess renal function before starting ONGLYZA and periodically thereafter.2.2 Dosage in Patients with Renal ImpairmentAssess renal function prior to initiation of ONGLYZA and then as clinically indicated [see
Use in Specific Populations (8.6)].The recommended dosage of ONGLYZA in patients with an eGFR greater than or equal to 45 mL/minute/1.73 m2is the same as the recommended dosage in patients with normal renal function [
seeDosage and Administration (2.1)].The dosage of ONGLYZA is 2.5 mg orally once daily for patients with eGFR <45 mL/min/1.73 m2[which includes a subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis] [
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.• Limit the dosage of ONGLYZA to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole).2.3 Dosage Modification with Concomitant Use of Strong CYP3A4/5 InhibitorsThe dosage of ONGLYZA is 2.5 mg orally once daily when used concomitantly 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)].
Tablets:
• 5 mg: pink, biconvex, round, film-coated tablets with “5” printed on one side and “4215” printed on the reverse side, in blue ink.• 2.5 mg: 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.
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.
ONGLYZA is contraindicated in patients with a history of a serious hypersensitivity reaction to saxagliptin or any of the ingredients in ONGLYZA. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported with ONGLYZA [
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 [
Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with ONGLYZA.
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.
• Gastrointestinal Disorders:Pancreatitis• Immune System Disorders:Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions• Musculoskeletal and Connective Tissue Disorders:Rhabdomyolysis, Severe and disabling arthralgia• Skin and Subcutaneous Tissue Disorders:Bullous pemphigoid
• Pancreatitis:There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue ONGLYZA.5.1 PancreatitisThere 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.
• 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 Heart FailureIn 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). Patients with a prior history of heart failure and patients 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.
• Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues:Consider a lower dosage of insulin or insulin secretagogue when used in combination wtih ONGLYZA.5.3 Hypoglycemia with Concomitant Use of Insulin or Insulin SecretagoguesWhen ONGLYZA was used in combination with insulin or an insulin secretagogue, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with insulin or an insulin secretagogue [
see Adverse Reactions (6.1)]. Therefore, a lower dosage of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with ONGLYZA [see Drug Interactions (7.2)]. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.• Hypersensitivity-Related EventsThere have been postmarketing reports of serious hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative skin conditions. If hypersensitivity reactions occur, discontinue ONGLYZA, treat promptly, and monitor until signs and symptoms resolve.5.4 Hypersensitivity ReactionsThere 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 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with ONGLYZA.
• Arthralgia:Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.5.5 Severe and Disabling ArthralgiaThere have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 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 DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
• Bullous Pemphigoid:There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue ONGLYZA.5.6 Bullous PemphigoidPostmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP‑4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving ONGLYZA. If bullous pemphigoid is suspected, ONGLYZA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.