ONGLYZA (Page 11 of 14)

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 *

Efficacy Parameter	ONGLYZA 5 mg + Insulin (+/− Metformin) N=304	Placebo + Insulin (+/− Metformin) N=151
* 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.
Hemoglobin A1C (%)	N=300	N=149
Baseline (mean)	8.7	8.7
Change from baseline (adjusted mean †)	−0.7	−0.3
Difference from placebo (adjusted mean †)	−0.4‡
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 †)	−23§
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.

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 *

Efficacy Parameter	ONGLYZA 5 mg + Metformin plus Sulfonylurea N=129	Placebo + Metformin plus Sulfonylurea N=128
* 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
Hemoglobin A1C (%)	N=127	N=127
Baseline (mean)	8.4	8.2
Change from baseline (adjusted mean †)	−0.7	−0.1
Difference from placebo (adjusted mean †)	−0.7‡
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 †)	−17§
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 plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.

Add-on Combination Therapy with Metformin plus an SGLT2 Inhibitor

A total of 315 patients with type 2 diabetes 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 in patients with a baseline of HbA1c ≥7% to ≤10.5%. The mean age of these subjects 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 race. At baseline the population had diabetes 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 (≥1500 mg per day) for at least 8 weeks prior to enrollment. Eligible subjects who completed the screening period entered the lead in treatment period, which included open-label metformin 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).

Table 12: HbA1c Change from Baseline at Week 24 in a Placebo-Controlled Trial of ONGLYZA as Add-on to Dapagliflozin and Metformin *

* There were 6.5% (n=10) of randomized subjects in the saxagliptin arm and 3.1% (n=5) in the placebo arm for whom change from baseline HbA1c data was missing at week 24. Of the subjects who discontinued study medication early, 9.1% (1 of 11) in the saxagliptin arm and 16.7% (1 of 6) in the placebo arm had HbA1c measured at week 24. † Number of randomized and treated patients. ‡ 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 subjects having missing week 24 data. § Least squares mean adjusted for baseline value. ¶ p-value <0.0001
	ONGLYZA 5 mg (N=153) †	Placebo (N=162) †
	In combination with Dapagliflozin and Metformin
Hemoglobin A1C (%) ‡
Baseline (mean)	8.0	7.9
Change from baseline (adjusted mean §) 95% Confidence Interval	−0.5 (−0.6, −0.4)	−0.2 (−0.3, −0.1)
Difference from placebo (adjusted mean) 95% Confidence Interval	−0.4¶ (−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.