Reply to the comment of Wilbrink et al. on Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes: The association between remaining β-cell function and the achievement of the HbA1c target 1 year after initiation.

We have reported that the HbA1c-lowering effects of liraglutide/basal insulin combination rely on remaining β-cell function and that the cut-off value of the C-peptide immunoreactivity index (CPI), a β-cell function-related index frequently used in Japanese clinical settings, is 1.103 for the achievement of HbA1c <7.0% at 54 weeks after initiating the liraglutide/basal insulin combination. Wilbrink et al claimed that glucose-lowering effects of glucagon-like peptide-1 receptor agonist liraglutide depend of duration of type 2 diabetes; while our resent study published in the Journal of Diabetes Investigation failed to detect such dependency. This discrepancy might be due to several reasons including co-administration of basal insulin with liraglutide in our study; ethnic difference in T2D pathophysiology between the two study; and difference in sample size (The Usui study on liraglutide/basal insulin, n = 38; the Usui study on liraglutide monotherapy or SU combination, n=88; and the Wilbrink study, n = 69).

We would like to thank Wilbrink et al.1 for their interest and comments on our recent article regarding the glycated hemoglobin (HbA1c)‐lowering effect of glucagon‐like peptide‐1 receptor agonist liraglutide with basal insulin among Japanese individuals with type 2 diabetes.

We have reported that the HbA1c‐lowering effects of liraglutide/basal insulin combination rely on remaining β‐cell function, and that the cut‐off value of the C‐peptide immunoreactivity index, a β‐cell function‐related index frequently used in Japanese clinical settings, is 1.103 for the achievement of HbA1c < 7.0% at 54 weeks after initiating the liraglutide/basal insulin combination2. In our study, we found that changes in HbA1c were not affected by type 2 diabetes duration, unlike the Wilbrink et al. study (Figure 1b). This discrepancy might be due to several reasons. First, we studied patients receiving liraglutide/basal insulin combination in replacement of multiple daily injection insulin therapy or basal insulin‐supported oral therapy, whereas Wilbrink et al. studied those receiving liraglutide in replacement of insulin therapy. We previously showed that discontinuation of liraglutide as a result of hyperglycemia after switching from insulin is affected by remaining β‐cell function and type 2 diabetes duration3. In addition, we also reported that the HbA1c‐lowering effects of liraglutide monotherapy and sulfonylurea combination rely on remaining β‐cell function and type 2 diabetes duration (Figure 1a) in a study in which 74% of the study patients had been taking insulin before initiating liraglutide4. Importantly, the C‐peptide immunoreactivity index cut‐off value for HbA1c < 7.0% achievement by liraglutide monotherapy and sulfonylurea combination was higher than that of liraglutide/basal combination (1.86 and 1.10, respectively)2, 4. It is widely accepted that β‐cell function progressively declines over time in type 2 diabetes patients, making it difficult to obtain appropriate glycemic control without insulin use5, 6. It is possible that basal insulin co‐administration compensated for the decline in β‐cell function associated with longer type 2 diabetes duration in our study2. Indeed, it was shown that the addition of basal insulin significantly improved HbA1c in individuals inadequately controlled by liraglutide7. Second, the discrepancy between our study and the Wilbrink et al. study might be due to ethnic difference in type 2 diabetes pathophysiology. Type 2 diabetes in East Asian patients is characterized primarily by non‐obesity and β‐cell dysfunction, unlike type 2 diabetes in Caucasian patients, which is characterized by obesity and insulin resistance8. As impaired β‐cell function is observed even in the early stage of type 2 diabetes in East Asian patients, type 2 diabetes duration might have less significance in predicting the HbA1c‐lowering effects of liraglutide. Third, the discrepancy might be due to limited sample size (the Usui study on liraglutide/basal insulin, n = 38; the Usui study on liraglutide monotherapy or sulfonylurea combination, n = 88; and the Wilbrink et al. study, n = 69). Dependence of HbA1c‐lowering effects of liraglutide/basal insulin combination on type 2 diabetes duration awaits further investigation by studies with larger sample sizes. Nevertheless, it is conceivable that liraglutide exerts greater HbA1c‐lowering effects in the early stage of type 2 diabetes when ample β‐cell function remains, and that addition of basal insulin or other antidiabetic drugs is required when β‐cell function becomes substantially reduced.

Figure 1

Changes of glycated hemoglobin (HbA1c) in Japanese patients with type 2 diabetes receiving (a) liraglutide monotherapy or sulfonylureas (SU) combination and (b) liraglutide/basal insulin combination. The patients were subdivided into two groups by medians of type 2 diabetes duration: (a) 10 years and (b) 16 years. Blue, those with type 2 diabetes duration below the median: (a) n = 37 and (b) n = 18); and red, those with type 2 diabetes duration with the median or above: (a) n = 51 and (b) n = 19). Time‐course curves were analyzed by mixed‐effects models including group, time, and the interaction of group and time, and the P‐values are shown. # P < 0.05 (vs patients with the median or above) by the Mann–Whitney U‐test. The statistical analysis was carried out using SPSS Statistics 24 software (IBM Corp., Armonk, New York, USA). Each value represents the mean ± standard error of the mean.

Disclosure

Daisuke Yabe received consulting or speaker fees from MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited and Taisho Toyama Pharmaceutical Co. Ltd. Daisuke Yabe also received clinically commissioned/joint research grants from Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly and Company, Taisho Toyama Pharmaceutical Co. Ltd., MSD K.K., Ono Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., Arklay Co. Ltd., and Takeda Pharmaceutical Company Limited. Yoshiyuki Hamamoto received consulting or speaker fees from Novo Nordisk Pharma Ltd. Takeshi Kurose received consulting or speaker fees from Sanofi K.K. Takeshi Kurose also received clinically commissioned/joint research grants from the Japan Vascular Disease Research Foundation. Yutaka Seino received consulting or speaker fees from Eli Lilly Japan K.K., Sanofi K.K., Novo Nordisk Pharma Inc., Glaxo‐Smith‐Kline, Taisho Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Astellas Pharma Inc., BD, Nippon Boehringer Ingelheim Co., Ltd., Johnson & Johnson and Takeda Pharmaceutical Company Limited. Yutaka Seino also received clinically commissioned/joint research grants from Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly and Company, Taisho Toyama Pharmaceutical Co. Ltd., MSD K.K., Ono Pharmaceutical Co. Ltd., Novo Nordisk Pharma Ltd., and Arklay Co. Ltd. R. The other authors declare no conflict of interest.