Saxagliptin Efficacy and Safety in Patients With Type 2 Diabetes and Moderate Renal Impairment

Shira Perl, William Cook, Cheryl Wei, Nayyar Iqbal, Boaz Hirshberg, Shira Perl, William Cook, Cheryl Wei, Nayyar Iqbal, Boaz Hirshberg

Abstract

Introduction: Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). The recommended dose of the dipeptidyl peptidase-4 inhibitor saxagliptin is 2.5 mg in patients with moderate or severe renal impairment (creatinine clearance ≤50 mL/min). In this post hoc analysis, we assessed the effect of saxagliptin 2.5 and 5 mg/day versus placebo on glycemic measures in patients with T2D and estimated glomerular filtration rate 45-60 mL/min/1.73 m(2).

Methods: Efficacy and safety data were pooled from nine 24-week, randomized, placebo-controlled clinical trials.

Results: The majority (56-61%) of patients were women aged <65 years with glycated hemoglobin (A1C) 8.1-8.2%; half of the patients had a T2D duration ≥5 years. Mean change from baseline in A1C was significantly greater with saxagliptin 2.5 (-0.6%, P = 0.036 vs placebo) and 5 mg/day (-0.9%, P < 0.001 vs placebo) compared with placebo (-0.2%). There were numerically greater reductions in fasting plasma glucose and 2-h postprandial glucose, and a significantly greater proportion of patients achieved A1C <7% with saxagliptin 5 mg/day (44.8%) compared with placebo (20.0%, P = 0.004 vs placebo). The incidence of hypoglycemia was not significantly different across groups (16.2% in the saxagliptin 5-mg/day, 12.2% in the saxagliptin 2.5-mg/day, and 11.3% in the placebo groups).

Conclusion: These results suggest that saxagliptin 2.5 and 5 mg/day improve glycemic control and are generally well tolerated in patients with T2D and moderate CKD.

Trial registration: ClinicalTrials.gov identifier, NCT00121641, NCT00316082, NCT00698932, NCT00918879, NCT00121667, NCT00661362, NCT00313313, NCT00295633, NCT00757588.

Funding: AstraZeneca, Gaithersburg, MD, USA.

Keywords: Chronic kidney disease; Dipeptidyl peptidase-4 inhibitor; Estimated glomerular filtration rate; Saxagliptin; Type 2 diabetes.

Figures

Fig. 1
Fig. 1
Mean change from baseline to week 24 in a A1C, b FPG, and c 2-h PPG. A1C glycated hemoglobin, FPG fasting plasma glucose, NS nonsignificant, PPG 2-h postprandial glucose, SAXA saxagliptin, SD standard deviation
Fig. 2
Fig. 2
Proportion of patients achieving A1C A1C glycated hemoglobin, NS nonsignificant, SAXA saxagliptin
Fig. 3
Fig. 3
Mean eGFR at baseline and 24 weeks. Mean (SD) change from baseline is shown above the bars. eGFR estimated glomerular filtration rate, SAXA saxagliptin, SD standard deviation

References

    1. Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382:260–272. doi: 10.1016/S0140-6736(13)60687-X.
    1. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3(1):1–150.
    1. Saran R, Li Y, Robinson B, et al. US renal data system 2014 annual data report: epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2015;65:A7. doi: 10.1053/j.ajkd.2015.05.001.
    1. Bailey RA, Wang Y, Zhu V, Rupnow MF. Chronic kidney disease in US adults with type 2 diabetes: an updated national estimate of prevalence based on Kidney Disease: improving Global Outcomes (KDIGO) staging. BMC Res Notes. 2014;7:415. doi: 10.1186/1756-0500-7-415.
    1. Arnouts P, Bolignano D, Nistor I, et al. Glucose-lowering drugs in patients with chronic kidney disease: a narrative review on pharmacokinetic properties. Nephrol Dial Transplant. 2014;29:1284–1300. doi: 10.1093/ndt/gft462.
    1. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401–2411. doi: 10.1185/03007990903178735.
    1. Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr. 2012;4:36. doi: 10.1186/1758-5996-4-36.
    1. Pan CY, Yang W, Tou C, Gause-Nilsson I, Zhao J. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev. 2012;28:268–275. doi: 10.1002/dmrr.1306.
    1. Kumar KMP, Jain SM, Tou C, Schützer K-M. Saxagliptin as initial therapy in treatment-naive Indian adults with type 2 diabetes mellitus inadequately controlled with diet and exercise alone: a randomized, double-blind, placebo-controlled, phase IIIb clinical study. Int J Diabetes Dev Ctries. 2014;34:201–209. doi: 10.1007/s13410-014-0191-1.
    1. DeFronzo RA, Hissa MN, Garber AJ, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32:1649–1655. doi: 10.2337/dc08-1984.
    1. Yang W, Pan CY, Tou C, Zhao J, Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract. 2011;94:217–224. doi: 10.1016/j.diabres.2011.07.035.
    1. Chacra AR, Tan GH, Apanovitch A, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract. 2009;63:1395–1406. doi: 10.1111/j.1742-1241.2009.02143.x.
    1. Hollander P, Li J, Allen E, Chen R, CV181-013 Investigators Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009;94:4810–4819. doi: 10.1210/jc.2009-0550.
    1. 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. Curr Med Res Opin. 2012;28:513–523. doi: 10.1185/03007995.2012.665046.
    1. Boulton DW, Li L, Frevert EU, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet. 2011;50:253–265. doi: 10.2165/11584350-000000000-00000.
    1. Onglyza® (saxagliptin). Full Prescribing Information. Wilmington, DE: AstraZeneca; 2015.
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70.
    1. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24:302–308. doi: 10.1681/ASN.2012070718.
    1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296–1305. doi: 10.1056/NEJMoa041031.
    1. Abaterusso C, Lupo A, Ortalda V, et al. Treating elderly people with diabetes and stages 3 and 4 chronic kidney disease. Clin J Am Soc Nephrol. 2008;3:1185–1194. doi: 10.2215/CJN.00410108.
    1. Nowicki M, Rychlik I, Haller H, Warren L, Suchower L, Gause-Nilsson I. Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes Obes Metab. 2011;13:523–532. doi: 10.1111/j.1463-1326.2011.01382.x.
    1. Nowicki M, Rychlik I, Haller H, et al. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J Clin Pract. 2011;65:1230–1239. doi: 10.1111/j.1742-1241.2011.02812.x.
    1. Udell JA, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care. 2015;38:696–705.

Source: PubMed

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