Results from an investigational hhase 3b clinical study have shown that the addition of Saxagliptin ( Onglyza ) 5 mg to ongoing Insulin therapy ( with or without Metformin ) maintained reductions of glycosylated hemoglobin levels ( HbA1c ) in adult patients with type 2 diabetes compared to the addition of placebo ( with or without Metformin ) from 24 to 52 weeks.
These results are from an extension of a 24-week trial, the results of which were presented at the 71st American Diabetes Association ( ADA ) Scientific Sessions in San Diego, CA in June 2011.

In the 52-week analysis, change from baseline in HbA1c in patients taking Saxagliptin 5 mg added to Insulin ( with or without Metformin ) was -0.75% compared to -0.38% for those taking placebo added to Insulin ( with or without Metformin ). There was also a greater increase from baseline mean daily Insulin dose in patients who received placebo compared to patients who received Saxagliptin 5 mg ( with or without Metformin ). 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 primary endpoint at 24 weeks was mean change in HbA1c from baseline of Saxagliptin 5 mg added to Insulin ( with or without Metformin ) compared to placebo added to Insulin ( with or without Metformin ). The study met the primary endpoint, demonstrating that Saxagliptin 5 mg added to Insulin ( with or without Metformin ) achieved a statistically significant HbA1c reduction from baseline of -0.75% compared to -0.38% ( p-value less than 0.0001 ) for those receiving placebo added to insulin ( with or without Metformin ). The overall objective of the extension was to assess the long-term safety and efficacy of Saxagliptin over 52 weeks. Efficacy measures included: changes from baseline of HbA1c, mean total daily dose of insulin ( MTDDI ), percent of patients achieving glycemic response of HbA1c less than 7%, and body weight. Given the exploratory nature of these analyses, statistical significance testing was not pre-specified in the statistical analysis plan; however, for the primary efficacy measure ( HbA1c change from baseline ), a post-hoc analysis of significance was conducted.

The study included 455 individuals with type 2 diabetes ( ages 18-78 ) with inadequate glycemic control ( HbA1c levels greater than or equal 7.5% and less than or equal 11%; mean baseline HbA1c = 8.7% ) who were receiving a stable dose of Insulin ( with or without Metformin ). Patients were randomly assigned to receive Saxagliptin 5 mg added to Insulin ( n=304 ) or placebo added to Insulin ( n=151 ) once-daily for 52 weeks. During the initial 24-week period, patients were advised to maintain stable Insulin doses, which could be decreased to reduce the 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. During the extension period, all patients were able to adopt a flexible Insulin regimen. Sixty-nine percent of patients were treated with Metformin, and the dose could not be changed in the study.

Of the 455 patients initially randomized and treated in the study, 371 patients completed the extension ( 81% of patients in the Saxagliptin added to Insulin group and 83% of patients in the placebo added to Insulin group, of those originally treated ).

Over 52 weeks, patients receiving Saxagliptin 5 mg added to Insulin ( with or without Metformin ) compared to patients receiving placebo added to Insulin ( with or without Metformin ) showed the following:

a) maintained reductions of blood sugar levels over 52 weeks in HbA1c from baseline: -0.75% vs -0.38% ( p less than or equal to 0.0001, n=244, baseline 8.67% for Saxagliptin 5 mg added to Insulin; n=124, baseline 8.66% for placebo added to Insulin ); similar HbA1c reduction was reported for patients with or without Metformin use at baseline;

b) increase in mean total daily dose of Insulin from baseline of +5.67 units/day vs +6.67 units/day;

c) of patients on Saxagliptin 5 mg, 21.3% achieved a therapeutic glycemic response of HbA1c less than 7%, and of patients on placebo, 8.7% achieved a therapeutic glycemic response of HbA1c less than 7%;

d) increases in mean change in body weight from baseline of 0.8 kg for Saxagliptin 5 mg vs. 0.5 kg for placebo ( 95% CI: –0.3, 0.9; n=246, baseline 87.7 kg for Saxagliptin 5 mg added to Insulin; n=125, baseline 86.2 kg for placebo added to Insulin ).

Most patients completed the study through week 52 ( 81% and 83% of patients in the Saxagliptin and placebo groups, respectively ).

Over the 52-week treatment period, 66.4% of patients in the Saxagliptin 5 mg added to Insulin group had at least one adverse event compared to 71.5% in the placebo added to Insulin group.

Hypoglycemia was reported in 22.7% of patients in the Saxagliptin 5 mg added to Insulin group compared to 26.5% in the placebo added to Insulin group, with confirmed hypoglycemia of 7.6% and 6.6%, respectively. Confirmed hypoglycemia was defined as hypoglycemic symptoms associated with a fingerstick glucose measurement of less than or equal to 50 mg/dL at the time of the event.
The other most common adverse events ( incidence greater than or equal to 5% for Saxagliptin 5 mg ) were as follows for Saxagliptin 5 mg added to Insulin ( with or without Metformin ) compared to placebo added to Insulin ( with or without Metformin ) respectively: urinary tract infections ( 7.9% vs 7.9% ), nasopharyngitis ( 6.3% vs 6.6% ), upper respiratory tract infections ( 6.3% vs 7.3% ), headache ( 5.9% vs 4.0% ), bronchitis ( 5.3% vs 3.3% ).
Twenty-five ( 8.2% ) patients in the Saxagliptin 5 mg added to Insulin group reported at least one serious adverse event, as compared to 13 ( 8.6% ) patients in the placebo added to Insulin group. Treatment-related serious adverse event were reported in three patients in the Saxagliptin 5 mg added to Insulin group versus zero in the placebo added to Insulin group. In the Saxagliptin 5 mg added to Insulin group, nine ( 3.0% ) patients discontinued the study due to adverse events, of which four were considered serious adverse events. In the placebo added to Insulin group, three ( 2.0% ) patients discontinued due to adverse events, of which zero were considered serious adverse events. There were also two deaths in the Saxagliptin added to Insulin group, in which both events were considered unrelated to treatment.

Source: 47th European Association for the Study of Diabetes ( EASD ) Annual Meeting, 2011

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