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. 2018 Jan 12;9(3):168-178.
doi: 10.1007/s13340-017-0341-z. eCollection 2018 Jul.

Efficacy and safety of nateglinide plus sitagliptin combination therapy in type 2 diabetes patients inadequately controlled by sitagliptin monotherapy: a phase 3, multicenter, open-label, long-term study

Takahisa Hirose  1 , Chihiro Saitoh  2 , Ichiro Oikawa  2 , Nobuo Kondo  2   3
Affiliations

Efficacy and safety of nateglinide plus sitagliptin combination therapy in type 2 diabetes patients inadequately controlled by sitagliptin monotherapy: a phase 3, multicenter, open-label, long-term study

Takahisa Hirose et al. Diabetol Int. .

Abstract

Background: Combination therapies of drugs with distinct mechanisms of action are emerging as ways to achieve strict glycemic control, thus preventing the onset and progression of diabetic complications in type 2 diabetes patients. A rapid-acting insulin secretagog, nateglinide, and a potent dipeptidyl peptidase-4 inhibitor, sitagliptin, meet such criteria.

Methods: A total of 121 patients inadequately controlled with sitagliptin monotherapy received 52-week combination therapy (nateglinide + sitagliptin). The primary endpoint was the safety of the therapy, and its efficacy was also evaluated. A meal tolerance test was performed 4 weeks before the start of combination therapy (week -4) and at week 24 and week 52 after the start of combination therapy.

Results: HbA1c levels were lower at week 52 than at week 0 [-0.42% (95% confidence interval -0.53, -0.31)]. Fasting plasma glucose levels tended to decrease from baseline (week 0) to week 52 [-4.8 mg/dl (-9.4, -0.2)]. In the meal tolerance test, postprandial plasma glucose levels and area under the curve of glucose from before to 2 h after the meal load were lower at week 24 and week 52 than at week -4. In addition, the levels of insulin and active glucagon-like peptide-1 were higher at week 52 than at week -4. Furthermore, the incidence of adverse events in combination therapy with sitagliptin was similar to those previously shown in nateglinide monotherapy.

Conclusion: Compared with sitagliptin monotherapy, the combination therapy of nateglinide plus sitagliptin was more effective in type 2 diabetes patients at improving glycemic control while showing similar safety.

Keywords: Combination therapy; DPP-4 inhibitor; Diabetes; Long-term study; Nateglinide; Safety.

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Conflict of interest statement

T. Hirose received consultancy fees from EA Pharma Co., Ltd.; lecture fees from MSD K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Ltd., Novo Nordisk Pharma Ltd, Sanofi K.K., AstraZeneca K.K., and Daiichi Sankyo Co., Ltd.; and research funds from MSD K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd, Kissei Pharmaceutical Co., Ltd., Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma Co., Ltd., Sanofi K.K., Ono pharmaceutical Co., Ltd., AstraZeneca K.K., and Daiichi Sankyo Co., Ltd. C. Saitoh and I. Oikawa are employees of EA Pharma Co., Ltd. N. Kondo was an employee of EA Pharma Co., Ltd.This research involves human participants. The study protocol was approved by the Sakayori Clinic Institutional Review Board on July 23, 2012 (approval number is not applicable).All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.Informed consent was obtained from all patients for being included in the study.

Figures

Fig. 1
Fig. 1
Study design. The study period was composed of the observation (4 weeks) and combination therapy period (52 weeks). The detailed daily doses of nateglinide and sitagliptin are shown. The following abbreviations were used: t.i.d. for three times daily, stat. a.c. for just before each meal, q.d. for once daily, and a.j. for before breakfast
Fig. 2
Fig. 2
Disposition of patients. Disposition of 122 enrolled patients in this study is detailed here
Fig. 3
Fig. 3
Changes in HbA1c levels during combination therapy. a HbA1C levels over the duration of combination therapy. Data are presented as the mean ± standard deviation. b Changes in HbA1C level from baseline (week 0). Data are presented as the mean and 95% confidence intervals
Fig. 4
Fig. 4
Changes in postprandial plasma glucose levels. a Postprandial plasma glucose levels at weeks −4, 24, and 52. The values were obtained from the samples before (0 h) and 0.5, 1, and 2 h after meal load. Data are presented as the mean ± standard deviation. b Changes in AUC0–2h glucose at weeks 24 and 52 from baseline (week −4). Data are presented as the mean and 95% confidence intervals
Fig. 5
Fig. 5
Changes in plasma insulin levels. a Postprandial plasma insulin levels at weeks −4, 24, and 52. The values were obtained from the samples before (0 h) and 0.5, 1, and 2 h after meal load. Data are presented as the mean ± standard deviation. b Changes in AUC0–2h insulin at weeks 24 and 52 from baseline (week −4). Data are presented as the mean and 95% confidence intervals
Fig. 6
Fig. 6
Changes in plasma active GLP-1 levels. a Postprandial plasma active GLP-1 levels at weeks −4, 24, and 52. The values were obtained from the samples before (0 h) and 0.5, 1, and 2 h after meal load. Data are presented as the mean ± standard deviation. b Changes in AUC0–2h active GLP-1 at weeks 24 and 52 from baseline (week −4). Data are presented as the mean and 95% confidence intervals
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