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Efficacy of Initial Basal-Supported Oral Therapy with Sitagliptin in Untreated Type 2 Diabetes

Introduction The present study assessed the efficacy of initial basal-supported oral therapy (BOT) with sitagliptin for achievement of glycemic control and subsequent switching from BOT to sitagliptin-based oral therapy. Methods Nineteen recently diagnosed type 2 diabetic patients who had received no antidiabetic medication in the previous 2 years were sequentially examined for the 24-week study. Patients were initially treated with a combination of insulin glargine and sitagliptin. Sitagliptin was initiated and maintained at a dose of 50 mg/day, and insulin glargine was started at a dose of 4 U at bedtime and adjusted if needed. Results During the 24-week treatment period, 12 patients (63%) achieved HbA1c levels <7% (mean BOT duration 13.7 ± 5.6 weeks) and switched from BOT to sitagliptin monotherapy or in combination with metformin (achievers). The remaining seven patients (37%) failed to achieve HbA1c levels <7% (non-achievers) and continued on BOT. Both FPG and HbA1c in achievers significantly dropped at 4, 8, 12 and 24 weeks from baseline, while those in non-achievers significantly decreased at 12 and 24 weeks from baseline, but failed to reach target glycemic control. There were statistically significant differences in FPG at 4, 8, 12 and 24 weeks and in HbA1c at 8, 12 and 24 weeks between achievers and non-achievers. Body weight and BMI in achievers were significantly reduced at 12 and 24 weeks, but those in non-achievers did not change significantly. Dosage of concomitant insulin during BOT was significantly lower in achievers compared to non-achievers. Non-achievers had a similar CPI, a measure of insulin secretion capacity, to achievers, but significantly showed an insulin resistance index (value of 20/[fasting CPR × FPG]), in comparison to achievers. Conclusion Initiating BOT with sitagliptin followed by sitagliptin-based oral therapy is a useful option in untreated and poorly controlled patients with type 2 diabetes.


INTRODUCTION
Short-term intensive insulin therapy prescribed early on in the course of type 2 diabetes can improve b-cell function and insulin resistance by eliminating glucotoxicity and lead to drugfree glycemic remission for up to 2 years [1,2]. However, intensive insulin therapy is not generally suitable for outpatients who are often unable to undergo multiple insulin injections; as a result many patients are prescribed oral hypoglycemic agents (OHAs) when they are no longer in glycemic remission. Basal-supported oral therapy (BOT), comprising a basal insulin and OHAs, is an alternative option in this clinical setting [3][4][5].
However, conventional BOT using sulfonylureas (SUs) mainly controls fasting plasma glucose (FPG) and does not necessarily correct post-prandial glycemia; as a consequence, adequate glycemic control is not always achieved and frequent hypoglycemic episodes may occur [6]. Thus, achieving target glycemic control using conventional BOT is limited.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are used in clinical practice for the treatment of type 2 diabetes [7,8]. These agents have an advantage over SUs as they regulate insulin secretion in a glucose-dependent manner [9,10], thereby minimizing the risk of hypoglycemia [11] and reducing glycemic fluctuations [12,13]. A few studies evaluating BOT using DPP-4 inhibitors have demonstrated a glucose-lowering effect when used in conjunction with ongoing insulin therapy in patients with type 2 diabetes [14][15][16]. The aim of the present study was to evaluate whether starting BOT with sitagliptin, a DPP-4 inhibitor, achieves adequate glycemic control and allows subsequent switching from BOT to sitagliptinbased oral therapy.

Patients
Patients aged between 30 and 70 years were enrolled in the study if they had a new or recent diagnosis of type 2 diabetes, had not been treated with an antidiabetic agent in the previous 2 years, and had poor glycemic control (hemoglobin A1c [HbA1c] C9.0%).
Patients were excluded if they had type 1 diabetes, chronic liver disease, advanced kidney disease, were taking corticosteroids, or were diagnosed with diabetic ketoacidosis.

Treatment
Patients were educated in diet therapy [25 kcal 9 ideal body weight (kg) per day] by a dietician and instructed to take 12,000 steps per day as exercise, according to the Japanese treatment guide for diabetes [17]. Adherence to diet and exercise therapy was evaluated by the proportion of patients attaining at least 80% of the instructed levels using self-dietary records and pedometer, respectively.
Patients were treated with a combination of sitagliptin and insulin glargine for 24 weeks.
Sitagliptin was initiated and maintained at a dose of 50 mg/day, and insulin glargine was initiated at a dose of 4 U at bedtime and adjusted if needed at monthly clinic visit (increased by 1 unit when FPG [180 mg/dL, and decreased by 1 unit when FPG \90 mg/dL). Patients who achieved an HbA1c of \7% during the 24-week treatment period were referred to as achievers and discontinued their basal insulin therapy. They were then maintained on sitagliptin (50 mg/day) monotherapy or on a combination of sitagliptin with metformin (500-1,500 mg/day). Patients who did not achieve an HbA1c of \7% (non-achievers) continued on BOT throughout the 24-week treatment period.

Study End Points
The primary end point was the proportion of patients who achieved an HbA1c \7.0% during BOT and discontinued basal insulin during the 24-week treatment period. Secondary end points were changes of FPG and HbA1c from baseline in achievers and non-achievers during the 24-week study period. C-peptide index (CPI), a measure of insulin secretion capacity [18], was calculated at week 12 using the following formula: [100 9 fasting C-peptide immunoreactivity (CPR) (ng/mL)]/[FPG (mg/ dL)]. In addition, 20/[fasting CPR (mmol/ L) 9 FPG (mmol/L)], a potential index of insulin resistance, was also calculated at week 12 [18]. Lower value of this index indicates being more insulin resistant. HbA1c levels were determined using high-performance liquid chromatography with an automated AH-8280 analyzer (ARKRAY, Kyoto, Japan) at every clinical visit.

Safety Assessment
Hypoglycemic episodes were counted by documentation of any hypoglycemic episodes and any symptoms derived from hypoglycemia based on patients' reports.

Statistical Analysis
All statistical analyses were performed using the StatView software package version 5.0 (Abacus Concept, Berkeley, CA). Changes in FPG and HbA1c at 4, 8, 12, and 24 weeks versus baseline were evaluated using ANOVA followed by Bonferroni's test. Unpaired t test was used to compare the parameters between achievers and non-achievers. A p value of \0.05 was considered statistically significant. Data are presented as mean (±standard deviation [SD]).

Ethics Statement
All procedures followed were in accordance with the ethical standards of the responsible

RESULTS
A total of 22 patients were enrolled in the study and 19 of the participants completed the study protocol. Patient baseline characteristics are summarized in Table 1.
Both FPG and HbA1c in achievers significantly dropped at 4, 8, 12 and 24 weeks from baseline, while those in non-achievers significantly decreased at 12 and 24 weeks from baseline, but failed to reach at target glycemic control (Fig. 1). There were statistically significant differences in FPG at 4, 8, 12 and 24 weeks and in HbA1c at 8, 12 and 24 weeks between achievers and non-achievers.
The achievers experienced a significant reduction in body weight and BMI at 12 and 24 weeks versus baseline, while the nonachievers did not ( Table 2). The insulin requirement for achievers (3.8 ± 0.8 U/day) was significantly lower than that for nonachievers (7.3 ± 3.3 U/day) during BOT.
Concomitant metformin dosage was significantly lower in achievers (500 ± 0 mg/ day; n = 2) than in non-achievers (1,050 ± 450 mg/day; n = 5). There was no significant difference in CPI between achievers and non-achievers; however, non-achievers showed a significant insulin resistance index (value of 20/[fasting CPR 9 FPG]) compared to achievers.

Safety
Two patients in the achiever group and one patient in the non-achiever group experienced hypoglycemia; there were no cases of severe hypoglycemia.
No patients had to discontinue the present protocol because of other side effects.

DISCUSSION
The current study demonstrated that initiating BOT with sitagliptin successfully improved glycemic control and allowed patients to switch from BOT to sitagliptin monotherapy or combination therapy, maintaining adequate glycemic control during a 24-week period in untreated patients with type 2 diabetes. BOT is often prescribed for outpatients because once daily injection is more acceptable than multiple insulin injections. The benefit of BOT in clinical practice has been described previously [3][4][5]. BOT has traditionally comprised an SU plus a long-acting insulin analog [5]. However, one of the biggest problems associated with conventional BOT is postprandial hyperglycemia while FPG is within normal range. DPP-4 inhibitors, as monotherapy or combination therapy, have several advantages over SUs, since these agents enhance insulin secretion in a glucose-dependent manner and suppress glucagon secretion [9,10].
In the current study, 12 patients (63.2%) achieved HbA1c \7% using initial BOT, and subsequently discontinued basal insulin. These achievers showed a significant decrease in HbA1c at 4, 8, 12 and 24 weeks versus baseline, and versus non-achievers at 8, 12 and 24 weeks. The basal insulin dose was relatively low and the duration of BOT was short to achieve target glycemic control. In contrast, the remaining seven patients (36.8%) failed to achieve a target HbA1c \7% during the 24-week treatment period, although in common with the achievers they adhered to their instructed insulin injection. It is reported that insulin therapy is usually required in Japanese type 2 diabetic patients with a CPI (insulin secretion capacity) lower than 0.8 [18]. CPI was measured at 12 weeks because In the Add-on Lantus Ò to Oral Hypoglycemic Agents (ALOHA) study in insulin-naïve 3,515 Japanese patients starting insulin glargine (mean dose 8.5 U/day) plus OHAs, mainly SUs, 15.5% of participants achieved HbA1c \7.0% at 24 weeks, whereas 84.5% of participants did not. In such a study, a shorter duration of diabetes (\1 year) and lower HbA1c (\8.5%) at baseline were significantly associated with a higher rate of achieving target HbA1c (\7.0%) [20]. Previous BOT trials [14][15][16]  Third, the titration of basal insulin and adherence to diet and exercise may have been insufficient for the non-achievers. On this basis, a large prospective study is needed to validate the findings of the current study.

CONCLUSION
The current study showed that initial introduction of BOT with sitagliptin was effective for achievement of glycemic control and subsequent switching from BOT to DPP-IV inhibitor-based therapy in recent onset and untreated patients with type 2 diabetes.

ACKNOWLEDGMENTS
No funding or sponsorship was received for this study or publication of this article. Dr. Yoshioka is the guarantor for this article and takes responsibility for the integrity of the work as a whole.
Conflict of interest. Keiji Yoshioka declares no conflict of interest.