The efficacy of ‘Basal supported Oral Therapy ’ with ‘Sitagliptin’ in Japanese type 2 diabetes patients: Yoshihiko Suzuki HDC Atlas Clinic,

Methods Objective to clarify the effectiveness of ‘basal supported oral therapy:(BOT)’ with oral hypoglycemic agents (OHA) and glargine(Gla) after add-on of sitagliptin(Sita) in Japanese type 2 diabetic patients on cross-sectional study. ●18 patients with type 2 diabetes (13 men and 5 women) aged ( y/o, 60.5±13.7 y/o.) were enrolled. The subjects were previously treated with BOT(OHA±Gla) without incretin treatment. ●They added sitagliptin upon BOT(OHA±Gla) therapy. Concomitant oral drugs included sulfonylureas, α-glucosidase inhibitors, metoformin, and pioglitazone. ●The primary analysis assessed whether add-on of sitagliptin was associated with the change of HbA1c and weight-gain.

Results Hemoglobin Aic (HbA1c) improved significantly from 8.4±1.4 % at baseline to 7.2±1.2% after 12 weeks of add-on therapy with sitagliptin (p<0.01), and the insulin dosage was reduced on average from 16.3±6.8 U/day to 14.7±7.1 U/day. Body weight increased slightly but not significantly and severe hypoglycemia was not observed. Conclusion The addition of sitagliptin provided significant improvement in HbA1c and was generally well tolerated. In other clinical trial by using mainly mixed insulin injections twice daily and adding sitagliptin, HbA1c decreased by 0.6% within 4 month. In this study, HbA1c decreased by 1.2% within 3 months. These findings suggest that add-on therapy with sitagliptin on glargine could improve glycemic control strongly compared with multiple insulin injection therapy. Because glargine and sitagliptin are once daily medications, the combination increased QOL of patients.

18 patients with type 2 diabetes (13 men and 5 women) aged ( y/o, 60.5±13.7 y/o.) were enrolled. Type 2 diabetes was diagnosed from clinical criteria according to the Japan Diabetes Society guidelines. They were all patients periodically attending HDC Atlas Clinic. They were all Japanese, prescribed adequate diet/exercise therapy by specialists and nutritionists and received other appropriate treatment depending on their condition. Enrolled patients were all receiving BOT (OHA+Gla+Sita). The present treatment was identical. All of them were previously treated with BOT(OHA+Gla) without incretin treatment. The prescription of sitagliptin was added on the BOT(OHA+Gla) therapy. So, their baseline was the time of add-on sitagliptin medication. Inclusion criteria was type 2 diabetes on BOT(OHA+Gla) therapy for at least 3 months, and hemoglobin A1c (HbA1) ≧ 6.5% (National Glycohemoglobin Standardizaion Program [NGSP] value). Subject

Exclusion criteria were 1) type 1 diabetes, 2) treatment with insulin formulation other than once daily glargine injection, 3) treatment with oral DPP4-inhibitor agents other than sitagliptin, 4) treatment with steroids, 5)severe hypoglycemia or recurrent asymptomatic hypoglycemia, 6)severe infection, 7) patients scheduled for surgery or those with serious trauma, 8) pregnant or nursing women and those who might be pregnant, and 9) other patients whom the investigation judged to be inappropriate for the study, and 10) patients who beforehand started sitagliptin with other antidiabetic oral agents and afterwards added glargine injection were also excluded. Each patient provided informed consent for monthly blood tests. This study was approved by the institutional review board of Hanzoumon Diabetes City Atlas Clinic. This study was conducted in accordance with the principles of the Declaration of Helsinki. All subjects were given an explanation of this clinical study and written informed consent was obtained voluntarily from each subject

Throughout the five months observation period, the dose of oral antidiabetic agents including sitagliptine (50mg or 100mg), dose of glargine, timing of glargine injection was adjusted carefully according to the patient’s life style, and glucose daily excursion curve judged by self monitoring blood glucose (SMBG) test. Dose modifications of OHA were not principally allowed during the treatment phase. However, if there was a tendency and a risk of progressive hyperglycemia in patients on concomitant sulfonylurea (SU) or metformin therapy, dose titration was allowed. Also, to get better glycemic control, dose modification of glarigine was adjusted principally. Insulin was down-titrated if 2 or more self-monitored blood glucose reading were 4.4 mmol/L or less (=<80 mg/dL). Sitagliptin dose was not changed and remained as same of 50mg or 100mg during five months. To prevent the severe hypoglycemia, every necessary adjustment was done individually, according to the patients’ condition. For instance, when the patients were afraid of hypoglycemia during the night, diabetologists gave an advice to start glargine in the morning. When the subjects were afraid of hypoglycemia during the day time, the subjects injected glargine in the morning without using sulfonylurea (SU). If there was a risk of hypoglycemia in patients on concomitant SU therapy, dose reduction of SU therapy was allowed. All of these dose and timing administration were conducted under the direction of expert diabetologists. Treatment

Fasting plasma glucose (FPG) was taken as a sample, but was not analyzed. Because some patients of BOT (OHA+Gla+Sita) were likely to have glycemic state near hypoglycemia at home in the morning, it disturbs the taking of ‘actually fasting-state’ sampling at out-department of our institutes. To prevent the hypoglycemia, the subjects often took some sugars and/or breakfast at home. Therefore, not only FPG but also other lipid parameters were not analyzed due to the contamination. HbA1c and weight were measured in all patients prior to starting combination therapy with sitagliptin (Week 0, baseline), as well as in 1 month, 2nd month, 3rd month, 4th month, and 5th month after the initiation of combination therapy. The incidence of severe hypoglycemia during the treatment period was also evaluated. In all patients, the changes of HbA1c and body weight, BMI in month 1st from 5th versus baseline were evaluated by the one-factor repeated measure ANOVA. For all analyses, p<0.05 was taken to indicate statistical significance. Data in the text and Tables are expressed as the mean ± standard deviation (S.D.), while data in the Figures are shown as the mean ± standard error (S.E.). Statistical analysis

● Patient characteristics The subjects consisted of 13 men and 5 women with a mean age of 63.4±13.3 years and a mean diabetes duration of 13.9±10.9 years. As for complication, three subjects showed background retinopathy and three subjects had preproliferative retinopathy while the others did not show any signs of retinopathy. Six subjects had microalubuminemia, and two subjects had macroalbuminuria, and the urine tests of the other subjects were normal. ●Change of HbA1c HbA1c was 8.4±1.4 % at baseline. After add-on of sitagliptin, HbA1c decreased to 7.9±1.1% at 1st month (p<0.01), 7.4±1.0 % at 2nd month(p<0.01), 7.2±1.0 % at 3rd month(p<0.01), 7.2±1.0 at 4 th month(p<0.01), and 7.2±1.1% at 5 th month(p<0.01). Results Figure. １ Change of HbA1c after the add-on of sitagliptin on BOT(OHA+Gla) therapy. There was significant difference between the 6 conditions. *:p<0.05. **;p<0.01, by the paired t-test (vs. baseline)

●Changes of Body Weight On baseline, body weight was 69.1±17.9 kg. After add-on of sitagliptin, body weight increased to 69.4±18kg at 1st month, 69.8±18.0 kg at 2nd month, 70.1±16.5kg at 3rd month, 70.0±18.8kg at 4 th month, and 70.4±18.8kg at 5 th month. Increase of 1.3kg at 5 th moth from baseline was not statistically significant. Figure 2. Change of body weight after the add-on of sitagliptin ●Changes of BMI Body mass index was 25.7±5.7 kg on baseline. After the switching, weight increased to 25.8±5.7 kg at 1 st month, 26.0±5.8 kg at 2 nd month, 26.0±5.9 kg at 3 rd month, 26.0±6.0 kg at 4 th month, and 26.1±5.9 kg at 5 th month. Changes of body mass index are presented in Fig.3. Body mass index was not significantly higher compared with that in baseline.

Figure 3. Change of body mass index after the add-on of sitagliptin ●Hypoglycemia There were episodes of mild hypoglycemia in eight subjects during these five months. There were no episodes of moderate/severe hypoglycemia. Four patients experienced mild hypoglycemia within one month after add-on sitagliptin therapy. All of them prevented the hypoglycemia by down-titration of insulin dose during the first month period and could prevent mild hypoglycemia by compliance with the instructions for added food (3). No patient discontinued BOT (OHA+Gla+Sita) therapy.

●Change of Therapeutic Medication. The difference between baseline and after 5 th month represents the characteristics of therapeutical change (Table 1).

Discussion When patients of diabetes are supplemented with BOT (OHA + Gla), DPP4 inhibitors could have a complementary effect. Because additional early intrinsic insulin secretion from pancreas by DPP4 inhibitors works on postprandial hyperglycemia, and because the basal insulin works during one day long, the combination of these two medications is conceptually suitable for suppressing the whole day profile of hyperglycemia in type 2 diabetes. The result of this study showed the clear evidence that once daily insulin with glargine and sitagliptin is suitable as the combination therapy of BOT. It confirmed a concept, supporting the previous studies (8,9). Especially, our result supports the report of Katsuno et al. and their stratified analysis. In this study, HbA1c decreased of -1.2% in 3 months. In the clinical phase 3 trial (C- P3-trial) for the approval of sitagliptin by Minister of Health in Japan, patients were mainly the subjects with mixed insulin injection or intermediate type insulin injection twice daily (7). And the result of the C-P3-trial was decline of HbA1c, -0.6% in four months. Compared with these previous studies (6,7,8,9), the decline of HbA1c (-1.2%) in this study was remarkably superior. Interestingly, Taneda et al. reported similar phenomenon that the result of BOT with long-time acting insulin and with sitagliptin was superior to those of intermediate-acting insulin, Mix type insulin and multiple injections (10).

Various explanations are possible. In C-P3-trial, the starting dose of sitagliptin was all 50mg. However, in this study, 58% of the subjects started 100mg of sitagliptin from the beginning, which made the hypoglycemic effect of sitagliptin stronger. In addition, 7 (36%) out of 19 subjects increased the dose of glargine to suppress the hyperglycemia. This up-titration of glargine decreased HbA1c during the early phase of this observation. In addition, the close titration of concomitant drugs might have contributed to the sharp decline of HbA1c after the add-on of sitagliptin. In C-P3-trial, the curve of HbA1c presents the nadir at 3rd – 4 th month after the combination therapy (7). In this study, nadir was at the 3rd – 4 th month of HbA1c curve. The same timing of HbA1c’s nadir in this study seems to be a characteristic of the DPP4 inhibitors, when added on insulin therapy. In this study, the concomitant sitagliptin therapy resulted in the slightly decrease of the insulin dose. Because sitagliptin could improve postprandial glucose, both by glucose-dependent increase of insulin secretion and glucacon suppression, the advantages of combination therapy are not only improvement of glycemic control, but also a reduction of the insulin dose. In addition, reduction of hypoglycemia risk and alleviation of psychological stress can be expected. Although the statistically insignificant, the undesired effect of BOT (OHA+Gla+Sita) therapy was increased body weight. Several explanations are possible. Weight gain is typically observed with insulin therapy because of improved glycemic control (11). Otherwise, relatively high insulin concentration.

caused by glargine, and added sitagliptin might prevent lipolysis, thereby causing weight-gain. Furthermore, the anorectic effect of sitagliptin might have been so weak to prevent the weight-gain. To overcome this problem, several solutions can be considered. According to the GeatGoal Duo study, usage of lixisenatide on BOT(OHA+Gla) might solve this problem of weight-gain (12). Because lixisenatide has stronger anoretic effect than sitagliptin, it could prevent overeating, thereby losing weight, and also reduce HbA1c. In the future, adding of SGLT2 （ sodium-glucose cotransporter 2 ） inhibitor on BOT(OHA+Gla+Sita) therapy might be an another solution, because SGLT2 inhibitor can reduce the weight and improve glycemic control, independently of blood insulin concentration (13, 14). As for AEs, hypoglycemia episode was few. Add-on of sitagliptin can narrow the range of glucose fluctuation (15). It has contributed a lot to the stabilization of glycemic control, thereby preventing the increase of hypoglycemia. The results were consistent with the similar previous studies (5,6,7,8,9,10). In conclusion, it was confirmed that BOT(OHA+Gla+Sita) therapy reduced HbA1c distinctively. An excellent hypoglycemic effect of ‘glargine’ based BOT plus sitagliptin can be expected compared with other insulin formulations plus sitagliptin. Because glargine injection is once daily, it raises QOL. The safety was confirmed by the low incidence of hypoglycemia. Thus, this concomitant therapy is surely effective in patients with poor glycemic control. Since this was a cross-sectional observation study, further large-scale studies are warranted in the future.

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