Results from an investigational phase 3b clinical study have shown that Onglyza ( Saxagliptin ) 5 mg added to Insulin ( with or without Metformin ) significantly reduced glycosylated hemoglobin levels ( HbA1c ) in adult patients with type 2 diabetes compared to treatment with placebo added to Insulin ( with or without Metformin ) at 24 weeks.
The results showed that the study met its primary endpoint of mean change in HbA1c from baseline to week 24.

Secondary endpoint results included a statistically significant reduction in post-prandial glucose ( PPG ) in patients who received Saxagliptin 5 mg added to Insulin ( with or without Metformin ). In addition, there was a numerical reduction ( not statistically significant ) in fasting plasma glucose ( FPG ) and a greater proportion of patients achieving a therapeutic glycemic response of HbA1c less than 7% ( significance not tested ) in patients who received Saxagliptin 5 mg added to Insulin compared to patients who received placebo added to Insulin ( with or without Metformin ). There was also a smaller increase from baseline in mean daily Insulin dose ( significance not tested ) in patients who received Saxagliptin 5 mg ( with or without Metformin ). Although patients were advised not to change insulin dose, adjustments were made. It is unknown whether increased Insulin doses by patients in the placebo group could have affected the magnitude of differences seen between the two treatment groups in the efficacy analyses.

The study was a 24-week multicenter, randomized, placebo-controlled, double-blind study, which evaluated the efficacy and safety of Saxagliptin when added to Insulin with or without Metformin compared to placebo when added to insulin with or without Metformin. The study included 455 individuals with type 2 diabetes ( ages 18 – 78 ) with inadequate glycemic control ( HbA1c levels greater than or equal to 7.5% and less than or equal to 11%; mean baseline HbA1c = 8.7% ) currently on a stable dose of Insulin ( 30-150 units/day with less than or equal to 20% variation per day ) alone or with a stable dose of Metformin for at least 8 weeks. Patients were randomly assigned to receive Saxagliptin 5 mg added to Insulin ( n=304 ) or placebo added to Insulin ( n=151 ) once daily for 24 weeks. A similar proportion of patients in both groups completed the study: 88.2% for the Saxagliptin added to Insulin group and 88.7% for the placebo added to Insulin group. Patients were advised to maintain stable insulin doses, which could be decreased to reduce risk of hypoglycemia. Patients with hyperglycemia or with substantially increased Insulin had a rescue visit and remained in the study on a flexible Insulin regimen. Sixty-nine percent of patients were treated with Metformin, the dose of which could not be changed in the study.

Although patients were advised not to change Insulin dose, adjustments were made and increased Insulin doses by patients in the placebo group may have decreased the magnitude of differences seen between the two treatment groups in the efficacy analyses. After 24 weeks, individuals receiving Saxagliptin 5 mg added to insulin demonstrated the following, compared to placebo added to Insulin:

a) statistically significant reduction in HbA1c from baseline, the primary endpoint of the study: -0.73% vs -0.32% ( p-value less than 0.0001, n=300, baseline 8.67% for Saxagliptin 5 mg added to Insulin; n=149, baseline 8.66% for placebo added to Insulin );

b) similar HbA1c reduction was reported for patients receiving Saxagliptin added to insulin alone and Saxagliptin added to Insulin in combination with Metformin ( pre-specified test of interaction, P=0.99 );

c) statistically significant reduction in change from baseline in PPG ( 120 min PPG value in response to a meal tolerance test ): -27.2 mg/dL vs -4.2 mg/dL ( p-value = 0.0016, n=262, baseline 251.2 mg/dL for Saxagliptin 5 mg added to Insulin; n=129, baseline 255.1 mg/dL for placebo added to Insulin );

d) numerically greater decrease in FPG from baseline: -10.08 mg/dL vs -6.06 mg/dL ( not significant p-value = 0.3958, n=300, baseline 173.43 mg/dL for Saxagliptin 5 mg added to Insulin; n=149, baseline 173.07 mg/dL for placebo added to Insulin ) ;

e) a greater proportion of patients achieving a therapeutic glycemic response of HbA1c less than 7%: 17.3% ( 52/300 ) vs 6.7% ( 10/149; statistical significance not tested );

f) Patients had an adjusted mean change from baseline in Insulin of +1.7 units/day in the Saxagliptin 5 mg added to Insulin group compared to an increase of +5.0 units/day for the placebo added to Insulin group ( statistical significance not tested; n=299, baseline 53.4 U for Saxagliptin 5 mg added to Insulin; n=151, baseline 55.3 U for placebo added to Insulin ).

At week 24, 22.7% and 31.8% of patients in the Saxagliptin and placebo groups, respectively, had been rescued or discontinued due to lack of glycemic control.

A similar proportion of patients had at least one adverse event over the 24-week treatment period ( 56.9% in the Saxagliptin 5 mg added to Insulin group vs 59.6% in the placebo added to Insulin group ).
The most common adverse events for Saxagliptin 5 mg added to Insulin compared to placebo added to Insulin ( incidence greater than or equal to 5% ) were as follows: hypoglycemia ( 18.4% vs 19.9% ), confirmed hypoglycemia with associated symptoms, with fingerstick glucose measurement of less than or equal 50 mg/dL at the time of the event ( 5.3% vs 3.3% ), urinary tract infection ( 5.9% vs 6.0% ), influenza ( 3.0% vs 6.6% ), pain in extremity ( 1.6% vs 6.0% ).
Twelve ( 3.9% ) patients in the Saxagliptin 5 mg added to Insulin group reported at least one serious adverse event, as compared to six ( 4.0% ) patients in the placebo added to insulin group. Treatment-related serious adverse event were reported in two ( 0.7% ) patients in the Saxagliptin 5 mg added to Insulin group vs zero in the placebo added to Insulin group.

Source: 71st American Diabetes Association (ADA) Scientific Sessions, 2011

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