In treatment-naïve patients with T2DM, once-daily saxagliptin lowered blood glucose concentrations relative to baseline after 24 weeks and was generally well tolerated through week 76 in all treatment groups. These findings were largely similar to those reached in the previously published saxagliptin monotherapy trial . However, it is noteworthy that this study also explored the effects of dose titration and P.M. versus A.M. dosing, and that the patient populations differed with respect to important baseline characteristics (including baseline CV risk, HbA1c, and FPG).
At week 24, adjusted mean changes from baseline HbA1c demonstrated in the 4 saxagliptin treatment groups (−0.61% to −0.71%) were comparable and consistent. The adjusted mean change from baseline HbA1c of −0.26% in the placebo group was larger, however, than that seen in the previous study of saxagliptin as monotherapy (+0.19%) . Per study protocol, patients received exercise and dietary instruction throughout the study. The reduction in HbA1c observed in the placebo group, and the reduction in body weight in all groups, largest in placebo (−1.3 kg [0.40]), supports the notion that the dietary and exercise interventions (as per local guidelines) were followed by patients in this group. Adherence to diet and exercise interventions in the context of low HbA1c and FPG (at baseline 7.9% and 162 mg/dL, respectively) may have also lessened the placebo-subtracted HbA1c reduction observed, particularly given the glucose-dependent mechanism of action of DPP-4 inhibitors .
The reduction in HbA1c from baseline to week 24 observed in all treatment groups was sustained through week 76 in the saxagliptin 2.5 mg q.A.M. and 2.5/5 mg q.A.M. treatment groups. The saxagliptin 5 mg q.A.M. and 5 mg q.P.M. groups, which maintained a higher proportion of patients who completed without titration (17.9%–26.4%) than the saxagliptin 2.5 mg groups (9.3%–13.7%), showed reductions from baseline HbA1c at week 76 that were smaller than those at week 24. The control group, which started metformin treatment at week 24, showed an expected HbA1c reduction from week 24 to week 30 likely due to the addition of active medication but this effect attenuated thereafter. The small number of patients per treatment group and the decreasing amount of available data prior to rescue over time limits the ability to draw definitive conclusions about efficacy results at the end of the long-term period. The reason for the upward HbA1c trend in the arms randomized to saxagliptin 5 mg or placebo is not clear; we can only speculate that it may represent attenuation of the diet and exercise effect documented in the placebo arm during the first 24 weeks and/or natural progression of type 2 diabetes . The fact this trend was not obvious in the 2 arms randomized to 2.5 mg may represent the small effect of titration to 5 mg (Additional file1).
The 2010 European Medicines Agency draft guidance for drugs for the treatment of diabetes recommends that new therapies be studied in a titration design . In this study, saxagliptin was given as a fixed dose as well as in titration in the first 24 weeks, with all patients eligible for titration in the long-term extension. Decreases in HbA1c were seen in all saxagliptin treatment groups at both the 2.5 and 5 mg doses, and regardless of whether saxagliptin was given in the morning or evening or in a titrated fashion. A small, additional HbA1c reduction was identified with titration of saxagliptin from 2.5 to 5 mg; however, no additional HbA1c reductions were observed with titration of saxagliptin from 5 to 10 mg in the long-term extension. This finding is consistent with other studies, which demonstrated similar efficacy for saxagliptin doses of 5 and 10 mg [4, 13]. Dosing saxagliptin 5 mg in the morning resulted in the highest rates of completion and completion without rescue of any treatment group, factors which are likely to be most attractive for many physicians. Importantly, treatment with saxagliptin 2.5 mg with eligibility for early titration to 5 mg did not appear to confer any benefit on safety or tolerability. We found that saxagliptin is generally well tolerated and effective given in titration, but this study does not suggest any advantages to early titration over an initial 5 mg fixed dose.
This study also examined dosing of saxagliptin at different times of the day. The treatment groups initially given saxagliptin 5 mg in the evening showed a decrease from baseline HbA1c that was similar to that in the group initially treated with saxagliptin 5 mg q.A.M., by repeated-measures analysis at weeks 24 and 76. While the FPG results with evening dosing did not reach statistical significance, the magnitude of effect was generally similar to those in the other active treatment groups, and the lack of significance may reflect the relatively small numbers of patients per treatment group. Overall, patients in the saxagliptin 5 mg q.P.M. group had a disposition and safety profile very similar to the other saxagliptin treatment groups.
Saxagliptin was well tolerated. While the proportion of patients experiencing AEs was numerically higher in the saxagliptin groups compared with control the rates of SAEs and AEs leading to discontinuation were similar between saxagliptin-treated and control patients. The overall AE profile observed at week 76 was similar to that seen at week 24. It is important to note that the relatively modest numbers of patients within each treatment group likely contributed to some variability in AE incidence rates.
Trials with lower CV risk patients such as the UK Prospective Diabetes Study (UKPDS)  and the Kumamoto study , and those with higher risk patients such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD)  and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) studies , have consistently shown a benefit of lower glucose on microvascular complications. However, the anticipated benefit on macrovascular events based on UKPDS lower risk patients  was not observed in these studies enriched in patients at higher CV risk. The American Association of Clinical Endocrinologists/American College of Endocrinology , ADA , and ADA/European Association for the Study of Diabetes  guidelines have recently been updated in response, and each emphasizes that hypoglycemia may be a greater risk than previously appreciated, especially in patients at high CV risk. They also suggest that the risk profile of drugs and glycemic targets may be different for populations at higher CV risk. For saxagliptin, the results of this trial in a population at higher baseline CV risk are consistent with the earlier reported monotherapy trial, in which the patient population had a lower baseline CV risk. The overall saxagliptin registrational program did not suggest that saxagliptin was associated with increased CV risk . A large CV outcome trial to investigate the possible benefit of saxagliptin on CV events is currently ongoing (ClinicalTrials.gov Identifier: NCT01107886).
Study limitations include the relatively modest size of the treatment groups, which introduces a greater risk that apparent differences between groups are due to chance. Use of rescue therapy ensured that patients received needed glycemic control. However, it complicates the interpretation of efficacy findings. To avoid the confounding effects of rescue therapy efficacy results included only data collected up to the time of rescue, such that fewer patients were able to contribute data for efficacy analyses at later time points in the study. Because of the small number of patients with available efficacy data at later time points, the long-term efficacy results should be interpreted with caution. The long-term extension control group included patients who received blinded metformin to ensure that patients in the study did not experience overly prolonged periods without antihyperglycemic medication. While necessary for patient well-being, this addition limits the ability to draw firm, placebo-based conclusions with respect to efficacy in the long-term. Finally, there was reduced ability to draw conclusions regarding the PPG-AUC analysis, due to an error in OGTT administration to several participants.