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The purpose of this study is to determine whether saxagliptin can reduce the risk of cardiovascular events when used alone or added to other diabetes medications. Detailed Description:. Drug Information available for: Saxagliptin. FDA Resources. Arms and Interventions.
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More Information. Related Info. J Am Coll Cardiol. Epub Aug Epub Jul JAMA Cardiol. DPP4 inhibitors and cardiovascular outcomes: safety on heart failure. Heart Fail Rev. Diabetes Care. Epub Oct Am J Med. In the subgroup analyses of adjudicated MACE for saxagliptin 2. In the study pool of saxagliptin add-on to metformin, the exposure time to a first MACE event or censoring was patient-years in the saxagliptin group versus patient-years in the control group.
A total of 23 patients who received saxagliptin had an adjudicated MACE versus 14 patients in the control group Figure 1. The IR per patient-years SE was similar for saxagliptin 0. In the study pool of saxagliptin add-on to metformin, IR estimates SE for saxagliptin versus control were 0. IRRs for these events ranged from 0. Heart failure was not defined as a component of MACE and was not adjudicated but was analyzed separately.
For heart failure study pool only , the IR SE was 0. IRRs for these individual events ranged between 0. In this pooled analysis of patients with T2DM from 20 phase 2 and 3 clinical trials, treatment with saxagliptin was not associated with an increased risk of CV events and heart failure compared with placebo or active comparator.
These results expand on previous findings on the CV safety of saxagliptin reported in a meta-analysis of 8 phase 2 and 3 trials [ 27 ]. In that analysis, a total of 40 MACE events in patients were reported. The present analysis expanded on the previous study and included patients who experienced 74 MACE events. Incidence rates for CV events for saxagliptin were not different from those for placebo or comparator in most analyses, with the exception of the lower IR for MACE in the saxagliptin 2.
However, it should be noted that only 7 of the 20 studies included patients who had received the 2. The present findings are also consistent with previously published meta-analyses of CV events from clinical trial programs for other DPP-4 inhibitors, including vildagliptin, sitagliptin, linagliptin, and alogliptin. Although these studies are not directly comparable because of different CV endpoints, study designs, adjudication procedures, patient populations and background medication, all supported the hypothesis that DPP-4 inhibitors do not increase CV risk and may possibly have CV benefits in patients with T2DM.
Results generally consistent with those were also reported from the alogliptin trial EXAMINE in patients after acute coronary syndrome [ 26 ]. The fact that SAVOR did not demonstrate superiority compared with placebo raises at least two alternative, though not mutually exclusive, interpretations: 1 evidence suggesting benefit from meta-analysis and preclinical evidence [ 16 , 54 ] was due to chance or 2 saxagliptin and likely other DPP-4 inhibitors are safe in all populations and trends to benefit occur only in the lower-risk general population studied in the phase 3 clinical development program.
SAVOR also demonstrated neutrality on the broader composite endpoint of CV death, MI, stroke, or hospitalization for unstable angina, heart failure, or coronary revascularization HR, 1.
The phase 3 data presented in this manuscript suggest that the observation of hospitalization for heart failure could not have been anticipated based on the phase 3 development program. Certain limitations of this analysis should be recognized and considered when interpreting the results.
To handle missing data as the result of premature discontinuation, analysis methods assumed similar event rates had the patient completed the study. However, patients treated with saxagliptin tended to be followed longer and had a lower rate of discontinuation compared with those who received control treatment.
Results using this assumption should be interpreted with caution. Both groups received a range of background medications, including metformin, sulfonylureas, and thiazolidinediones and the control group received both active medications and placebo. In several studies, a titration of background medication [ 22 , 41 , 46 — 48 ] or a titration of double-blind saxagliptin [ 19 , 29 , 30 , 39 , 40 ] was permitted.
In addition, in the majority of studies, rescue medication was permitted [ 19 — 23 , 32 , 36 , 38 — 43 ]. These factors complicate interpretation of the findings. The saxagliptin group was also heterogeneous and included patients treated with doses higher than the approved 2. Further, the analyses of the 2. It is important to recognize that the pooled patient population in these clinical trials was highly selected, which may have resulted in a lower event rate compared with that observed in clinical practice.
Finally, there was relatively limited experience beyond 18 months. Pooled data from 20 clinical trials involving patients with T2DM suggest that saxagliptin is safe and not associated with an increased CV risk. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States. Article PubMed Google Scholar. Diabetes Care. Article Google Scholar. Ann Intern Med. N Engl J Med.
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Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I: Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. Diabetes Res Clin Pract. Int J Diabetes Devel Countries. Diabet Med. Diab Vasc Dis Res.
Jadzinsky M, Pfutzner A, Paz-Pacheco E, Xu Z, Allen E, Chen R: Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Barnett AH, Charbonnel B, Donovan M, Fleming D: Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. White JL, Buchanan P, Li J, Frederich R: A randomized controlled trial of the efficacy and safety of twice-daily saxagliptin plus metformin combination therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy.
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Download references. Bristol-Myers Squibb and AstraZeneca funded this study. Medical writing support for the preparation of this manuscript was provided by Richard M. Edwards, PhD, and Janet E. You can also search for this author in PubMed Google Scholar. Correspondence to Nayyar Iqbal.
NI contributed to the conception and design of the study and the drafting and final approval of the manuscript.
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