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Factors influencing the durability of the glucose-lowering effect of sitagliptin combined with a sulfonylurea Akira Kubota1,2*, Daisuke Yabe2, Akira Kanamori3, Akira Kuroe4, Nobuo Takahashi5, Tatsuhiko Saito6, Ikuro Matsuba7, Koichiro Nabe1, Takeshi Kurose2, Yutaka Seino2 1Kubota Clinic of Internal Medicine, 7Matsuba Clinic, Kawasaki city, 3Kanamori Diabetes Clinic, Sagamihara city, Kanagawa, 2Kansai Electric Power Hospital, Osaka city, Osaka, 4Hikone Municipal Hospital, Hikone city, Shiga, 5Takahashi Family Clinic, Nagoya city, Aichi, and 6Kobari General Hospital, Noda city, Chiba, Japan
Keywords Blood glucose, Sitagliptin, Sulfonylurea
*Correspondence Akira Kubota Tel.: +81-44-932-0161 Fax: +81-44-932-0253 E-mail address: kubota@sj8.so-net.ne.jp
J Diabetes Invest 2014; 5: 445–448
doi: 10.1111/jdi.12182
ABSTRACT We analyzed the changes of glycemic control over 12 months and the factors influencing blood glucose in 162 Japanese patients with type 2 diabetes having inadequate glycemic control despite sulfonylurea-based therapy who received add-on sitagliptin. Hemoglobin A1c (HbA1c) decreased significantly after 4 weeks of treatment, and this improvement was maintained for 1 year, although HbA1c was slightly higher in week 52 than in week 24. Comparison of the patients showing a ≥0.4% increase of HbA1c between weeks 24 and 52 (n = 57) with the others (n = 105) showed a significant difference in the change of bodyweight, as well as the dose of glibenclamide (both P < 0.01). Although combined therapy with sitagliptin and a sulfonylurea seems to be effective for at least 1 year, blood glucose levels are more likely to increase again in patients who show greater weight gain after 24 weeks of treatment and those receiving a higher dose of glibenclamide.
INTRODUCTION The goal of treating type 2 diabetes mellitus is to prevent complications caused by chronic hyperglycemia, and it is important to maintain good glycemic control over a long period1–5. Japanese patients with type 2 diabetes mellitus are characterized by lower early phase insulin secretion after meal ingestion, hence treatment of Japanese patients is focused on activation of insulin secretion with sulfonylureas (SUs)6,7. Before the introduction of dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas were most often used as monotherapy in Japan8. Sitagliptin is a new hypoglycemic agent9–13, which is often administered as add-on therapy to patients showing inadequate glycemic control with SU treatment14–22. In the present study, we investigated the hypoglycemic effect of sitagliptin, and its durability in patients receiving combination therapy with a SU and sitagliptin.
MATERIALS AND METHODS The present study enrolled 162 patients (Table 1) with type 2 diabetes mellitus who had inadequate glycemic control despite oral SU-based therapy (glimepiride n = 60, gliclazide n = 52 and glibenclamide n = 50) and received add-on treatment with sitagliptin for 1 year. Other concomitant drugs included metformin (n = 99), pioglitazone (n = 47) and an a-glucosi- dase inhibitor (n = 7). Patients were divided into a hemoglobin A1c (HbA1c)-ele-
vated group consisting of those with an increase of HbA1c by 0.4% or more in week 52 compared with week 24, and a HbA1c-non-elevated group consisting of the remaining patients. Logistic regression analysis was carried out to investigate the factors involved in the increase of blood glucose during the later part of the treatment period in the patients taking gliben- clamide, glimepiride or gliclazide. The factors assessed were the clinical characteristics of the patients (age, sex, body mass index, duration of diabetes), the change of bodyweight from week 24 to week 52, the dose of glibenclamide and the use of other medications.
Received 22 February 2013; revised 17 September 2013; accepted 26 September 2013
ª 2014 The Authors. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. 5 No. 4 July 2014 445 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
SHORT REPORT
The primary end-point was the HbA1c level. The values of HbA1c in the present study were converted and expressed by National Glycohemoglobin Standardization Program values23. All analyses were carried out using SPSS version 19 for Win-
dows (SPSS, Chicago, IL, USA). Data on HbA1c and body- weight were processed by one-way analysis of variance (ANOVA). The Mann–Whitney U-test was used for comparison of the HbA1c-elevated group with the non-elevated group. Results are presented as the mean – standard deviation, and P < 0.05 was considered significant. The present retrospective observational study was carried out
in accordance with the provisions of the Helsinki Declaration. Approval was obtained from the ethics committee of the Kan- sai Electric Power Hospital, and written informed consent was obtained from all patients.
RESULTS The mean HbA1c was 7.77 – 0.73% at the start of treatment with sitagliptin, and it decreased significantly to 7.45 – 0.71% after 4 weeks of treatment and to 7.25 – 0.75% in week 52, suggesting that the improvement of glycemic control was main- tained during 12 months of treatment (Figure 1a). However, the HbA1c level became slightly higher during the later part of the treatment period, and HbA1c was significantly higher in
week 52 than it was between weeks 16 and 44 (ANOVA, P < 0.01). The mean bodyweight showed no significant change during 12 months (Figure 1b). To analyze the factors related to the slight increase of HbA1c
in the later part of the treatment period, patients were divided into a HbA1c-elevated group (n = 57) and a HbA1c non-ele- vated group (n = 105; Figure 2). The characteristics of these two groups are compared in Table 1; there were significant differences regarding the change of bodyweight from week 24 to week 52 and the dose of glibenclamide. There was no signif- icant difference in the change of bodyweight from week 0 to week 24. There was no significant difference in the dose of the other SUs or in the use of medications other than SUs between the two groups. When logistic regression analysis was carried out in the glibenclamide group to determine the factors related to poor glycemic control, it was found that the difference of bodyweight between 24 and 52 weeks (DBW24_52 week) and the dose of glibenclamide were significant (Table 2). Thus, greater weight gain from week 24 to week 52 and a higher dose of glibenclamide were associated with a larger increase of HbA1c, but the age, sex and baseline body mass index were not significant factors. Logistic regression analysis carried out in the glimepiride or gliclazide groups showed that DBW24_52 week was the only significant factor in both groups, whereas the dose of glimepiride or gliclazide was not significant.
Table 1 | Clinical characteristics of the hemoglobin A1c elevated and hemoglobin A1c non-elevated groups and P-values
Total HbA1c- elevated group
HbA1c-non- elevated group
P-value
n 162 57 105 Age (years) 65.6 – 10.0 63.9 – 9.8 66.5 – 10.0 NS Sex (male/female) 98/64 30/27 68/37 NS Baseline BMI (kg/m2) 24.4 – 4.0 24.5 – 3.9 24.3 – 3.9 NS Duration of DM (years)
13.2 – 8.4 12.3 – 7.7 13.8 – 8.7 NS
DBW0_24 week (kg) 0.2 – 1.2 0.4 – 1.5 0.1 – 0.7 NS DBW24_52 week (kg)
0.3 – 1.4 0.9 – 1.8 0.0 – 0.9 <0.01
Glimepiride (mg/day)
1.7 – 1.2 1.6 – 1.0 1.8 – 1.2 NS
Gliclazide (mg/day) 34.4 – 19.4 33.1 – 17.6 35.0 – 20.1 NS Glibenclamide (mg/day)
3.5 – 2.2 4.6 – 2.1 2.9 – 1.9 <0.01
Metformin 99 37 (64.9%) 62 (59.0%) NS Pioglitazone 47 17 (29.8%) 30 (28.6%) NS a-Glucosidase inhibitor
7 3 (5.3%) 4 (3.8%) NS
DBW0_24 week, difference of bodyweight between 0 and 24 weeks; DBW24_52 week, difference of bodyweight between 24 and 52 weeks; BMI, body mass index; DM, diabetes mellitus; HbA1c, hemoglobin A1c; NS, not significant.
(a)
(b)
8.00
7.80
7.60
7.40
7.20
7.00
6.80
6.60
65.00
64.00
B W
(k g
) 63.6±12.1 (0 wk) 64.1±12.4 (52 wk)
63.00
62.00
0 4 8 12 16 20 24 28 (weeks)
32 36 40 44 48 52
0 4 8 12 16 20 24 28 (weeks)
32 36 40 44 48 52 H
b A
1c (%
) ** ††
††
†† †† †† †† †† †† †† ††
** ** ** ** ** ** ** **
** ** ** **
Figure 1 | Profile of (a) hemoglobin A1c (HbA1c) and (b) bodyweight (BW) over 52 weeks. Analysis of variance vs week 0 **P < 0.01, vs week 52 ††P < 0.01.
446 J Diabetes Invest Vol. 5 No. 4 July 2014 ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd
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DISCUSSION In the present study, a significant decrease of blood glucose was achieved that persisted throughout the study period with no significant change of bodyweight. Comparison between the groups of patients showing poorer and better durability of ther- apeutic efficacy showed a significant increase in bodyweight from week 24 to week 52 in the group with the elevated HbA1c. We also found that patients in the poorer durability group received a higher dose of glibenclamide. Thus, weight gain from week 24 to week 52 and the dose of glibenclamide were factors significantly related to poorer glycemic control. As previous reports have suggested that sitagliptin has no effect on bodyweight, the cause of the weight gain in the present study might be due to inadequate diet and/or exercise therapy11–13,20. Indeed, Tajiri et al.24 reported that blood glucose levels were likely to increase over time in patients on sitagliptin therapy with low lifestyle scores, which is consistent with our present results. Seasonal changes of glycemic control are often observed during the treatment of diabetes, and weight gain might have been related to such seasonal changes. Therefore, when sitaglip- tin is administered as add-on therapy to patients who have developed secondary failure of SU-based treatment, it is impor- tant to ensure that diet and exercise therapy are adequate to prevent weight gain in order to maintain glycemic control over a long period16,23. It is curious that only a higher dose of glibenclamide was
associated with poor glycemic control independently of weight gain. In contrast, the doses of glimepiride and gliclazide were
similar in both groups, and these drugs were used at relatively low doses compared with the glibenclamide-treated group. Logistic regression analysis showed that the dose of glimepiride or gliclazide was not a significant factor. The incidence of so- called secondary failure has been reported to differ among SU drugs25,26. Both Harrower25 and Satoh et al.26 reported that the incidence of secondary failure was higher for glibenclamide than gliclazide. The SU drugs show differences of various proper- ties27–30, and it is not yet clear which properties of SU drugs have an influence on the incidence of secondary failure25,26. The results of the present study are likely to have been influenced by differences in the rate of secondary failure among SU drugs. DPP-4 inhibitors reduce blood glucose levels by increasing
insulin secretion by an incretin effect. Accordingly, it is likely that endogenous insulin secretion was lower in the patients treated with higher doses of glibenclamide than in those receiving lower doses of this drug. Further studies are required to resolve these issues. In summary, we analyzed the profile of glycemic control in
patients receiving combination therapy with SUs and sitagliptin. The present results show that avoiding both weight gain and high-dose glibenclamide therapy can contribute to the mainte- nance of better glycemic control. However, it is unclear whether other factors also contributed
to the decrease in efficacy of DPP-4 inhibitor therapy or the secondary failure of DPP-4 inhibitor treatment in the present study, hence further investigations are required.
ACKNOWLEDGMENT The authors declare no conflicts of interest with regard to this report.
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Table 2 | Factors influencing the durability of combined sitagliptin and glibenclamide therapy according to logistic regression analysis
Independent variable Partial regression coefficient
P-value
DBW24_52 week -0.829 <0.05 Dose of glibenclamide -0.449 <0.05
DBW24_52 week, difference of bodyweight between 24 and 52 weeks.
0 6.40
6.90
7.40
H b
A 1c
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7.90
8.40 HbA1c non-elevated group HbA1c-elevated group
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ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd J Diabetes Invest Vol. 5 No. 4 July 2014 447
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448 J Diabetes Invest Vol. 5 No. 4 July 2014 ª 2014 The Authors. Journal of Diabetes Investigation published by AASD and Wiley Publishing Asia Pty Ltd
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