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1 Expert Opinion on Pharmacotherapy ISSN: (Print) (Online) Journal homepage: Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week openlabel extension Takashi Kadowaki, Satsuki Muto, Yoshiumi Ouchi, Ryutaro Shimazaki & Yutaka Seino To cite this article: Takashi Kadowaki, Satsuki Muto, Yoshiumi Ouchi, Ryutaro Shimazaki & Yutaka Seino (2017) Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension, Expert Opinion on Pharmacotherapy, 18:18, , DOI: / To link to this article: View supplementary material Accepted author version posted online: 13 Sep Published online: 12 Oct Submit your article to this journal Article views: 1276 View Crossmark data Citing articles: 1 View citing articles Full Terms & Conditions of access and use can be found at

2 EXPERT OPINION ON PHARMACOTHERAPY, 2017 VOL. 18, NO. 18, ORIGINAL RESEARCH Efficacy and safety of saxagliptin in combination with insulin in Japanese patients with type 2 diabetes mellitus: a 16-week double-blind randomized controlled trial with a 36-week open-label extension Takashi Kadowaki a, Satsuki Muto b, Yoshiumi Ouchi b, Ryutaro Shimazaki b and Yutaka Seino c a Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; b R&D Division, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan; c Center for Diabetes, Endocrinology and Metabolism, Kansai Electric Power Hospital, Osaka, Japan ABSTRACT Background: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus. Research design and methods: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint. Results: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference 0.92% [95% confidence interval 1.07%, 0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups. Conclusions: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes. ARTICLE HISTORY Received 16 June 2017 Accepted 12 September 2017 KEYWORDS Dipeptidyl peptidase-4 inhibitors; elderly patients; insulin; Japanese; saxagliptin; type 2 diabetes mellitus 1. Introduction The Japan Diabetes Society (JDS) guidelines propose a target hemoglobin A1c (HbA1c) of <6.0% for normoglycemia and <7.0% to prevent complications in patients with diabetes [1]. The guidelines also suggest a target of <8.0% if intensification of therapy is considered difficult. However, treatment objectives should be tailored to individual patients. For example, the JDS/Japan Geriatrics Society (JGS) Joint Committee on Improving Care for Elderly Patients with Diabetes recommends that the target for glycemic control be determined for each elderly patient according to background characteristics and health status (including age, cognitive function, and physical function), comorbidities, risk for severe hypoglycemia, and life expectancy [2]. The JDS guidelines recommend initial diet and exercise therapy and other lifestyle improvements as treatment for patients with type 2 diabetes mellitus (T2DM), while initial pharmacotherapy may involve an oral antidiabetic drug (OAD), insulin, or a glucagon-like peptide-1 receptor agonist (GLP-1RA). If these treatments prove insufficient, the OAD dose should be increased or another OAD added. Alternatively, the patient may be switched to insulin or to an OAD combined with insulin, or switched to a GLP-1RA alone or in combination with an OAD or insulin. Many Japanese T2DM patients share a common pathological feature of reduced insulin secretion [3], where OAD therapy alone is often insufficient to achieve adequate glycemic control, and therefore, insulin therapy is needed. However, despite the opportunity to titrate the insulin dose and select an insulin type (e.g., long-acting, intermediate-acting, or premixed insulin) that suits the patient s lifestyle and medical needs, insulin therapy alone does not necessarily provide sufficient or durable improvements in glycemic control. Thus, some patients might be candidates for insulin in combination with other drugs. In particular, the risk of hypoglycemia may limit the extent to which the insulin dose can be increased, while weight gain may occur with long-term insulin treatment. Accordingly, many patients in Japan are prescribed insulin therapy in combination with another OAD to achieve the recommended treatment targets. Dipeptidyl peptidase (DPP)-4 inhibitors are widely used OADs [3,4]. The enzyme DPP-4 cleaves incretins, which stimulate insulin secretion and suppress glucagon secretion. CONTACT Satsuki Muto satsuki.muto@kyowa-kirin.co.jp R&D Division, Kyowa Hakko Kirin Co., Ltd., Otemachi Financial City Grand Cube, Otemachi, Chiyoda-ku, Tokyo , Japan Clinical trial registration number: JapicCTI ( Prior publications Results of this trial have been submitted as abstracts to the 60th Annual Meeting of The Japan Diabetes Society (18 May 2017). Supplemental data for this article can be accessed here Informa UK Limited, trading as Taylor & Francis Group

3 1904 T. KADOWAKI ET AL. Inhibition of DPP-4 with DPP-4 inhibitors promotes the action of incretins, which in turn attenuates hyperglycemia [5]. In addition, DPP-4 inhibitors can be used safely even in elderly patients with T2DM [6 8], and are often used in combination with insulin in Japanese diabetic patients. Several clinical studies have examined the efficacy of DPP-4 [9 16] inhibitors as an add-on to insulin therapy. However, thus far, no studies have compared the safety and efficacy of combination therapy with DPP-4 inhibitors and insulin between Japanese elderly and non-elderly diabetic patients in a double-blind, placebocontrolled fashion that includes the meal tolerance test and self-monitoring of blood glucose. Saxagliptin is a DPP-4 inhibitor approved in Japan for the treatment of T2DM, based in part on results from four studies of Japanese patients that examined the efficacy and safety of saxagliptin as monotherapy or add-on therapy to other OADs [17 20]. Until now, however, no studies have examined the efficacy or safety of saxagliptin in combination with insulin in Japan. We designed this study to test the hypothesis that saxagliptin and insulin combination therapy in Japanese T2DM patients would result in a significant decrease in HbA1c compared with insulin monotherapy, and that this level of adequate glycemic control would be maintained in the long term. We performed a 52-week clinical trial including a 16-week, double-blind period with patients on insulin monotherapy randomized to either 5-mg saxagliptin or placebo. This was followed by a 36-week extension when all patients received open-label saxagliptin with insulin. We further assessed the efficacy and safety of saxagliptin added to insulin monotherapy in elderly and non-elderly T2DM patient groups. 2. Methods 2.1. Ethics This postmarketing clinical trial was performed in accordance with the Declaration of Helsinki, the Japanese Pharmaceutical Affairs Law, Good Clinical Practice and Good Post-marketing Study Practice. This trial was registered on (registration number: JapicCTI ) Patients All patients gave written informed consent to participate. Patients were eligible for this trial if they met the following inclusion criteria: age 20 years; diagnosis of T2DM; stable dietary and exercise therapy; fasting C-peptide 0.5 ng/ml at screening or at 2 weeks before starting the allocated treatment (Week 2); administration of a stable dose of insulin (daily dose of 8 units to 40 units) for 12 weeks before starting the allocated treatment, with a difference in the total daily insulin dose of 20% during the run-in period (patients could use long-acting, intermediate-acting, or premixed insulin [ 50% of insulin as short-acting or rapid-acting insulin as one component] formulations with up to three injections per day); fasting plasma glucose (FPG) at screening and at Week 2 of 220 mg/dl; and HbA1c of 7.5% to <10.0% at Week 2, and a difference in HbA1c between screening and Week 2 of 1.0%. Patients taking insulin monotherapy for 14 weeks at Week 6 wereeligible, providing their HbA1c at screening was 7.5% to <10.0%. Patients taking one OAD for 8 weeks at Week 12, who had HbA1c 7.0% to 9.0% at Week 12 and who could tolerate a washout of the OAD, entered a 12- week washout period prior to randomization. Only patients who recorded 80% of the daily insulin doses in the entire run-in period using diaries were eligible for randomization. The major exclusion criteria were similar to those of other clinical trials of saxagliptin in Japan and included patients with: severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus; other conditions requiring glycemic control with insulin injection (severe infections, serious injuries, or perioperative patients); elevated liver enzymes at Week 2 (aspartate aminotransferase or alanine aminotransferase 2.5 times the upper limit of normal); kidney dysfunction (serum creatinine >1.4 mg/dl for men and >1.2 mg/dl for women, or creatinine clearance <50 ml/min at Week 2); difficulty with completing a 52-week trial (e.g., patients with progressive renal disease); low hemoglobin at Week 2 (<11.0 g/dl for men and <10.0 g/dl for women), or history of hemoglobinopathies; hypoglycemic symptoms at least twice a week 12 weeks before starting the allocated treatment; poorly controlled hypertension (mean systolic pressure of >160 mmhg or mean diastolic pressure of >100 mmhg calculated as the mean of values at screening and at Week 2); New York Heart Association stage III or IV heart failure; medical history of acute coronary syndrome, percutaneous coronary intervention or coronary artery bypass graft, cerebral stroke or transient ischemic attack, arteriosclerosis obliterans of the lower extremity accompanied by pain at rest, ischemic ulcer, or necrosis (classified as grade III or IV according to the Fontaine classification) 6 months before screening; and patients who used any other antihyperglycemic medication during the run-in period Trial design This trial was performed at 62 centers in Japan. The trial design is illustrated in Figure 1 and comprised a run-in period, a 16-week double-blind randomized period, and a 36-week open-label extension period. All patients were on insulin monotherapy for 12 weeks before randomization. The following measures were taken to ensure that patients were not exposed to abnormally high blood glucose concentrations. Patients with HbA1c 10.0% at Week 2 or FPG >220 mg/dl at Weeks 6 or 2 were ineligible for the study, while those who showed abnormally high blood glucose concentrations after washout were discontinued from the study at that time-point. Before randomization, the daily dose of insulin could be increased or decreased by 20% compared with the prescribed insulin at Week 12. After starting the study treatment, criteria for up-titration of insulin dose (rescue dose) were available. Patients with HbA1c 10.4% or FPG 270 mg/dl at two consecutive blood samples were discontinued from the study. Patients were randomized to receive either saxagliptin or placebo on Day 1 using a dynamic allocation method in

4 EXPERT OPINION ON PHARMACOTHERAPY 1905 Figure 1. Study design. OAD: oral antidiabetic drug which patients were stratified according to the following factors: insulin type (long-acting, intermediate-acting, or premixed insulin) as the first factor and HbA1c (<8.5% or 8.5%) at Week 2 as the second factor. The randomization allocation sequence, enrollment, and assigning of patients to their interventions were all performed by Bell Medical Solutions (Tokyo, Japan). Patients could be withdrawn from the trial at any time for the usual reasons in clinical trials (e.g., patient request, investigator decision, inclusion/exclusion criteria contravened, inability to undergo required assessments, adverse events, and pregnancy). In addition, patients were to be discontinued for the following reasons: HbA1c 10.4% or FPG 270 mg/dl, as measured by the central laboratory in two consecutive blood samples, or altered renal function (serum creatinine > 1.4 mg/dl for men or >1.2 mg/dl for women, or creatinine clearance <50 ml/min) Treatments Patients received either placebo or 5-mg saxagliptin once daily during the double-blind period (both drugs were identical in appearance and packaging), and all patients received 5-mg saxagliptin during the open-label extension period (placebo saxagliptin and saxagliptin saxagliptin). Insulin was to be continued throughout the double-blind periodatthesamestabledose,providedthecriteriaforuptitration (rescue dose) or down-titration were not met. During the open-label extension period, the insulin dose could be varied at the physician s discretion by reference to the criteria for up-titration or down-titration. No changes in insulin product were allowed at any stage of the trial unless they reached the criteria for up-titration as follows. Down-titration of the prescribed insulin dose by 1 4 units per day was permitted according to the investigator s decision if the patient was deemed to be at increased risk of hypoglycemia. Although the number of down-titrations was not limited, the maximum cumulative reduction in insulin dose was 4 units (relative to the dose used in the run-in period). Down-titration was permitted in the following circumstances: the patient experienced hypoglycemic symptoms with self-monitored blood glucose (SMBG) <70 mg/dl in the absence of acute changes in daily life or physical activity, or two or more consecutive SMBG measurements of <80 mg/dl with a high risk of hypoglycemia as determined by the physician. Up-titration of the insulin dose was permitted if the centrally measured FPG was >240 mg/dl at Week 23 or 200 mg/dl at Week 24 in the absence of acute changes in daily life or physical activity. Patients who did not meet the criteria for up-titration or down-titration but required an increase or decrease in the insulin dose during the double-blind period based on the investigator s decision were handled as protocol deviations but were not withdrawn from the study. Patients were prohibited from using drugs likely to interfere with glucose levels (e.g., other OADs, GLP-1RAs, and steroids [except for local/nasal administration]), strong CYP3A4/5 inhibitors (except for external administration), erythropoiesis-stimulating drugs, other investigational drugs, and red blood cell transfusion.

5 1906 T. KADOWAKI ET AL Assessments and endpoints All clinical and laboratory results were analyzed centrally by LSI Medience Corporation (Tokyo, Japan), except for SMBG, which was measured by patients at home. HbA1c and FPG were measured at each visit. 1,5-anhydroglucitrol, fasting C-peptide, and fasting glucagon were measured at baseline, and at Weeks 16, 32, and 52 (or at discontinuation). Patients were instructed to perform 7-point SMBG measurements (taken before and 2 h after each main meal, and at bedtime) at baseline and Weeks 16 and 52. Meal tolerance tests were performed at baseline and Week 16, in which patients consumed a standard meal comprising 8.8 g (19.8%) of fat, 15.2 g (15.2%) of protein, and 65.0 g (65.0%) of carbohydrate (total 400 kcal). Plasma glucose, C-peptide, and glucagon levels were measured before the meal, and at 30 min, 1 h, and 2 h after the meal. C-peptide and glucagon in either fasting state or during the meal tolerance test were measured by chemiluminescent immunoassay and radioimmunoassay, respectively. The primary efficacy endpoint was the change in HbA1c from baseline to Week 16. Secondary efficacy endpoints included the changes in 2-h postprandial plasma glucose (PPG) and area under the plasma glucose concentration-time curve from 0 to 2 h(auc 0 120min ) in the meal tolerance test, and the change in FPG from baseline to Week 16. Exploratory efficacy endpoints included the changes in HbA1c at each time-point and the proportion of patients with HbA1c <7.0% at each time-point during the double-blind and open-label extension periods. Safety-related variables were recorded throughout the trial, and included treatment-emergent adverse events (TEAEs), clinical laboratory tests, and vital signs. Investigators assessed the AEs in terms of severity, duration, and whether they were drug-related. Hypoglycemia was confirmed by investigators based on hypoglycemic symptoms recorded in patient diaries. Low blood glucose without hypoglycemic symptoms (SMBG value <50 mg/dl) was classified as blood glucose decreased. Twelve-lead electrocardiography was performed at baseline, Week 16, and Week 52 (or at discontinuation) Sample size The difference in the change from baseline in HbA1c at Week 16 between the saxagliptin + insulin group and the placebo + insulin group was assumed to be 0.4% with an SD of 1.0% based on the saxagliptin trials that were conducted outside Japan [21 25]. The sample size of 100 patients per group provided 90% power to detect the difference between saxagliptin and placebo using a t test at a two-sided significance level of 5%. Considering unevaluable patients (5%), the planned sample size was 105 patients per group Statistical analyses The primary efficacy endpoint (change from baseline in HbA1c at Week 16) was analyzed using the analysis of covariance (ANCOVA) model with terms for treatment group, prior treatment with OADs, and type of insulin as fixed effects and baseline HbA1c as a covariate. Based on the ANCOVA model, the adjusted change in HbA1c from baseline and its 95% confidence intervals were calculated for each group. To demonstrate the superiority of saxagliptin, a t test based on the adjusted change from baseline was conducted at a twosided significance level of 5%. The 95% confidence interval of the difference in the adjusted change from baseline between saxagliptin and placebo was also calculated. The changes in FPG and meal tolerance test-related variables were compared between the two groups in the same way as HbA1c. The last observation carried forward (LOCF) method was used to handle missing data at Week 16 for HbA1c and FPG. Values of HbA1c and FPG observed after the insulin dose increased were handled as missing values. The M value was calculated using SMBG values [26]. Safety endpoints were analyzed descriptively in terms of the mean ± SD or number (percent) of patients. Data analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA). There were no changes to the preplanned statistical analysis after enrollment began. We also performed post hoc analyses for further interpretation of the data obtained in this study after conducting the prespecified analyses. We calculated the C-peptide index (CPI; C-peptide divided by postprandial glucose in meal tolerance test and multiplied by 100) and insulin secretion rate (ISR) [27] to evaluate beta-cell function. Subgroup analyses of the efficacy (except for change from baseline in HbA1c at Week 16, prespecified in the statistical analysis plan) and safety endpoints by age (e.g., <65 vs. 65 years) and by insulin type (premixed/intermediate-acting vs. long-acting) were performed. Regarding the exploratory and post hoc analyses, summary statistics were used to evaluate the profiles over time, and no formal statistical tests were conducted. 3. Results 3.1. Patients This trial was performed between November 2013 and December Of 478 patients who provided informed consent, 240 were randomized (119 to saxagliptin and 121 to placebo). The remaining 238 patients were not randomized, mainly due to not meeting HbA1c, FPG, C-peptide, or kidney dysfunction criteria (Figure 2). One patient allocated to placebo discontinued before the first dose. A total of 107 and 109 patients in the saxagliptin and placebo groups, respectively, completed the double-blind period while 98 and 93, respectively, completed the open-label extension period (Figure 2). The main reasons for discontinuing the trial included altered kidney function and inability to conduct observation or assessment in the double-blind period, and altered kidney function and TEAEs in the open-label extension period (Figure 2). Seven patients whose data were not sufficiently reliable were excluded from all analysis sets. The numbers of patients included in the full and safety analysis sets in each treatment period are presented in Figure 2. The baseline characteristics of patients are shown in Table 1 and Supplemental Table 1 with no marked differences between the groups. Two-thirds of patients were using premixed insulin and the remainder was using long-acting insulin; only one patient used intermediateacting insulin.

6 EXPERT OPINION ON PHARMACOTHERAPY 1907 Figure 2. Patient disposition. Regarding the reasons why some patients were not randomized, these were collected cumulatively. Note that some patients had more than one reason for not being randomized. For this reason, the total number of patients does not add up to 238. *A hundred patients were not randomized because they did not meet HbA1c inclusion criteria at Weeks 12, 6, or 2. Serum creatinine >1.4 mg/dl (males) or >1.2 mg/dl (females) or creatinine clearance <50 ml/min. Centrally measured. Reasons for non-inclusion in the analysis sets following first dose of study drug (in the double-blind period) or open-label saxagliptin (in the open-label extension period) are as follows: Saxagliptin. FAS-DB: Four patients without any evaluable HbA1c data obtained after starting the allocated treatment, two patients whose data were not sufficiently reliable. SAF-DB: Two patients whose data were not sufficiently reliable. FAS-LT: Four patients without any evaluable HbA1c data obtained after starting the allocated treatment, two patients whose data were not sufficiently reliable. SAF-LT: Two patients whose data were not sufficiently reliable. Placebo. FAS-DB: Five patients whose data were not sufficiently reliable. SAF-DB: Five patients whose data were not sufficiently reliable. FAS-LT: Three patients without any evaluable HbA1c data obtained after starting open-label saxagliptin, five patients whose data were not sufficiently reliable. SAF-LT: Five patients whose data were not sufficiently reliable. FAS-DB, full analysis set during the double-blind period; FAS-LT, full analysis set during the long-term period; SAF-DB, safety analysis set during the double-blind period; SAF-LT, safety analysis set during the long-term period Insulin doses The mean total daily insulin doses (95% confidence interval) (in units) at baseline, Week 16, and Week 52 for patients in the full analysis set (double-blind period) were (21.24, 24.59) (n = 113), (20.96, 24.37) (n = 106), and (21.15, 24.97) (n = 96), respectively, in the saxagliptin saxagliptin group. The corresponding values in the placebo saxagliptin group were (22.09, 25.36) (n = 115), (21.71, 25.10) (n = 106), and (22.13, 26.08) (n = 90). During the doubleblind period, the insulin dose of one patient in the saxagliptin group (0.9%) was increased because of high HbA1c levels based on their own judgment, while one in the placebo group (0.9%) required dose increases and decreases applicable to a sliding-scale regimen during hospitalization because of an AE. No patients met the criteria for up-titration in either group. Six patients in the saxagliptin group (5.3%) and one in the placebo group (0.9%) met the criteria for down-titration. However, for one patient in the saxagliptin group (0.9%) and one in the placebo group (0.9%), the treating physicians decided to decrease the dose because these patients were considered at an increased risk of hypoglycemia Efficacy of saxagliptin HbA1c Figure 3a shows the adjusted changes in HbA1c from baseline in both groups. HbA1c increased by 0.51% in the placebo group and decreased by 0.40% in the saxagliptin group between baseline and Week 16 (LOCF), corresponding to a difference of 0.92% (95% confidence interval 1.07%, 0.76%; p < 0.001). As illustrated in Figure 3b, HbA1c was continuously lower in the saxagliptin group than in the placebo group during the double-blind period. In patients who used saxagliptin in both treatment periods, the reduction in

7 1908 T. KADOWAKI ET AL. Table 1. Demographic and other baseline characteristics in the full analysis set from the double-blind treatment period. All patients Saxagliptin Placebo Characteristic N = 228 N = 113 N = 115 Sex Female 89 (39.0%) 44 (38.9%) 45 (39.1%) Male 139 (61.0%) 69 (61.1%) 70 (60.9%) Age (years) Mean ± SD 63.4 ± ± ± 10.1 < (51.8%) 61 (54.0%) 57 (49.6%) (48.2%) 52 (46.0%) 58 (50.4%) Height (cm) Mean ± SD ± ± ± 9.65 Weight (kg) Mean ± SD ± ± ± BMI (kg/m 2 ) Mean ± SD ± ± ± 4.35 Type of insulin Long 69 (30.3%) 34 (30.1%) 35 (30.4%) Intermediate 1 (0.4%) 1 (0.9%) 0 Premixed 158 (69.3%) 78 (69.0%) 80 (69.6%) Duration of diabetes (years) Mean ± SD ± ± ± 9.71 HbA1c (%) Mean ± SD 8.31 ± ± ± 0.61 FPG (mg/dl) Mean ± SD ± ± ± 37.0 Creatinine clearance (ml/min) Mean ± SD ± ± ± OAD washout period Yes 104 (45.6%) 52 (46.0%) 52 (45.2%) Daily insulin dose (IU) Mean ± SD ± ± ± 8.85 Complications Any 227 (99.6%) 113 (100.0%) 114 (99.1%) Diabetic neuropathy 79 (34.6%) 39 (34.5%) 40 (34.8%) Diabetic retinopathy 109 (47.8%) 57 (50.4%) 52 (45.2%) Diabetic nephropathy 94 (41.2%) 46 (40.7%) 48 (41.7%) Other 226 (99.1%) 113 (100.0%) 113 (98.3%) Data set: Full analysis set during the double-blind period. SD: standard deviation; BMI: body mass index; HbA1c: hemoglobin A1c; FPG: fasting plasma glucose; OAD: oral antidiabetic drug. HbA1c at Week 16 was maintained through to Week 52 (Figure 3b). Switching from placebo to saxagliptin at Week 16 was associated with a reduction in HbA1c that was maintained through to the end of the open-label extension period (Figure 3b). This reduction was similar to that in patients who received saxagliptin in both periods. Results of the subgroup analysis of the changes in HbA1c at the end of the double-blind period are shown in Table 2. As indicated in this table, saxagliptin was associated with reductions in HbA1c in all subgroups of patients relative to placebo. Changes in HbA1c in patients taking saxagliptin in the doubleblind period were largely maintained through the end of the open-label extension period; furthermore, patients administered placebo in the double-blind period and saxagliptin in the open-label extension period also had reductions in HbA1c by Week 52 (Supplemental Table 2). Overall, 22/105 patients (21.0%) in the saxagliptin group and 1/104 (1.0%) patients in the placebo group achieved HbA1c <7.0% at Week 16. For the long-term period, 16/96 patients (16.7%) in the saxagliptin saxagliptin group (Weeks 0 52) and 14/89 (15.7%) in the placebo saxagliptin group (Weeks of treatment only) had achieved HbA1c < 7.0% at Week 52. The proportion of patients with therapeutic glycemic response by age (7.0% in those aged <65 or 65 years, 7.5% in those aged 65 and <75 years, and 8.0% in those aged 75 years) are shown in Supplemental Table Meal tolerance test Figure 4 and Supplemental Table 4 show the changes in meal tolerance test-related variables at baseline and Week 16. As indicated, 2-h PPG and AUC 0 120min for plasma glucose decreased in the saxagliptin group, but not in the placebo group. There was no difference between the two groups in the change in C-peptide from baseline. The reduction in concentrations and AUC 0 120min for glucagon was numerically greater in the saxagliptin group than in the placebo group. The CPI at Week 16 in the saxagliptin group increased relative to baseline, while the CPI did not change in the placebo group. Increases in ISR at each plasma glucose concentration from baseline to Week 16 in the saxagliptin group were numerically greater than in the placebo group. A similar trend was observed in the subgroup analysis by age ( 65 years, <65 years) and by insulin type (premixed/intermediate-acting, long-acting) (Supplemental Tables 5 and 6, and Supplemental Figures 1 and 2) FPG and SMBG Consistent with the changes in HbA1c, we also observed a greater reduction in FPG from baseline to the end of the double-blind period (Figure 3c) in the saxagliptin group. The adjusted change in FPG from baseline to Week 16 (LOCF) was 30.3 mg/dl (95% confidence interval 9.2, 51.5) in the placebo group and 11.2 mg/dl (95% confidence interval 9.5, 31.8) in the saxagliptin group, corresponding to a difference of 19.2 mg/dl (95% confidence interval 27.2, 11.1). FPG was also continuously lower in the saxagliptin group during the double-blind period and the reduction in FPG was maintained through to Week 52 (Figure 3c). SMBG was measured at baseline, Week 16, and Week 52, and the results are shown in Figure 5. SMBG values at each time of day decreased in the saxagliptin group but not in the placebo group in the double-blind period (Figure 5a, b). The reductions in SMBG observed in the saxagliptin group were maintained through Week 52 (Figure 5c). A similar trend was observed in the subgroup analysis by age. In Supplemental Figure 3, we show the SMBG values from baseline to Week 16 and through Week 52 in patients aged <65 years (Supplemental Figure 3a c) and those aged 65 years (Supplemental Figure 3d f).

8 EXPERT OPINION ON PHARMACOTHERAPY 1909 Figure 3. (a) Adjusted change in HbA1c (%) from baseline to Week 16 (with last observation carried forward). (b) Changes in HbA1c over time in the double-blind period and open-label extension period. (c) Changes in fasting plasma glucose over time in the double-blind period and open-label extension period. HbA1c: hemoglobin A1c; FAS-DB: full analysis set during the double-blind period. The mean M values (95% confidence interval) at baseline and Week 16 in the double-blind period were (39.45, 52.88) (n = 105) and (27.56, 39.93) (n = 99), respectively, in the saxagliptin group. The corresponding values in the placebo group were (39.52, 51.36) (n = 108) and (36.17, 46.59) (n = 99). In the long-term period, the mean M values

9 1910 T. KADOWAKI ET AL. Table 2. Subgroup analysis of the changes in HbA1c (%) from baseline to the end of the double-blind treatment period. Saxagliptin Placebo N = 113 N = 115 Difference versus placebo a (95% CI) Age <65 years Baseline n Mean (95% CI) 8.36 (8.20, 8.53) 8.51 (8.33, 8.68) Change from baseline n Mean (95% CI) 0.65 ( 0.83, 0.48) 0.23 (0.09, 0.38) 0.88 ( 1.11, 0.65) 65 years Baseline n Mean (95% CI) 8.25 (8.04, 8.45) 8.11 (7.98, 8.23) Change from baseline n Mean (95% CI) 0.89 ( 1.06, 0.71) 0.08 ( 0.07, 0.24) 0.97 ( 1.20, 0.73) HbA1c (%) <8.0 Baseline n Mean (95% CI) 7.66 (7.60, 7.71) 7.66 (7.59, 7.72) Change from baseline n Mean (95% CI) 0.55 ( 0.72, 0.39) 0.18 ( 0.03, 0.39) 0.74 ( 0.99, 0.48) 8.0 Baseline n Mean (95% CI) 8.76 (8.63, 8.88) 8.58 (8.47, 8.69) Change from baseline n Mean (95% CI) 0.89 ( 1.07, 0.72) 0.14 (0.01, 0.26) 1.03 ( 1.24, 0.82) Insulin type Long-acting Baseline n Mean (95% CI) 8.49 (8.24, 8.74) 8.45 (8.23, 8.68) Change from baseline n Mean (95% CI) 0.65 ( 0.96, 0.34) 0.25 (0.06, 0.44) 0.90 ( 1.25, 0.55) Intermediate-acting Baseline n 1 0 Mean (95% CI) 8.60 Change from baseline n 1 0 Mean (95% CI) 0.10 N/A Premixed Baseline n Mean (95% CI) 8.23 (8.08, 8.38) 8.24 (8.11, 8.37) Change from baseline n Mean (95% CI) 0.82 ( 0.94, 0.70) 0.10 ( 0.02, 0.23) 0.92 ( 1.10, 0.75) FPG at baseline <140 mg/dl Baseline n Mean (95% CI) 8.10 (7.85, 8.34) 8.22 (7.99, 8.44) Change from baseline n Mean (95% CI) 0.79 ( 1.03, 0.54) 0.14 ( 0.08, 0.36) 0.92 ( 1.24, 0.60) 140 to <210 mg/dl Baseline n Mean (95% CI) 8.33 (8.18, 8.48) 8.30 (8.17, 8.42) Change from baseline n Mean (95% CI) 0.74 ( 0.89, 0.60) 0.17 (0.04, 0.29) 0.91 ( 1.10, 0.72) 210 mg/dl Baseline n 13 9 Mean (95% CI) 8.65 (8.14, 9.17) 8.69 (8.02, 9.36) Change from baseline n 9 6 Mean (95% CI) 0.79 ( 1.56, 0.02) 0.07 ( 0.51, 0.64) 0.86 ( 1.83, 0.12) Fasting C-peptide <1.0 ng/ml Baseline n Mean (95% CI) 8.32 (8.15, 8.49) 8.22 (8.07, 8.36) Change from baseline n Mean (95% CI) 0.75 ( 0.91, 0.59) 0.11 ( 0.04, 0.26) 0.86 ( 1.08, 0.65) 1.0 ng/ml Baseline n Mean (95% CI) 8.30 (8.09, 8.50) 8.40 (8.23, 8.58) Change from baseline n Mean (95% CI) 0.77 ( 0.99, 0.55) 0.20 (0.05, 0.36) 0.97 ( 1.23, 0.72) Daily insulin dose <23.32 units b Baseline n Mean (95% CI) 8.35 (8.17, 8.53) 8.25 (8.10, 8.40) Change from baseline n Mean (95% CI) 0.94 ( 1.10, 0.78) 0.19 (0.03, 0.35) 1.14 ( 1.36, 0.91) units Baseline n Mean (95% CI) 8.27 (8.08, 8.45) 8.37 (8.20, 8.54) Change from baseline n Mean (95% CI) 0.56 ( 0.75, 0.38) 0.11 ( 0.03, 0.25) 0.67 ( 0.90, 0.44) Data set: Full analysis set during the double blind period. HbA1c: hemoglobin A1c; FPG: fasting plasma glucose; CI: confidence interval. Baseline was defined as Week 0 in both groups. a Difference versus placebo: Mean change for saxagliptin Mean change for placebo. b Indicates the average daily insulin dose.

10 EXPERT OPINION ON PHARMACOTHERAPY 1911 Figure 4. Mean values during the meal tolerance test at baseline and at the end of the double-blind period in the full analysis set. (a) Plasma glucose (mg/dl) in the saxagliptin group at baseline and Week 16. (b) Plasma glucose (mg/dl) in the placebo group at baseline and Week 16. (c) Mean change in plasma glucose (mg/dl) from baseline at Week 16. (d) C-peptide (ng/ml) in the saxagliptin group at baseline and Week 16. (e) C-peptide (ng/ml) in the placebo group at baseline and Week 16. (f) Mean change in C-peptide (ng/ml) from baseline at Week 16. (g) Glucagon (pg/ml) in the saxagliptin group at baseline and Week 16. (h) Glucagon (pg/ml) in the placebo group at baseline and Week 16. (i) Mean change in glucagon (pg/ml) from baseline at Week 16. (j) C-peptide Index in the saxagliptin group at baseline and Week 16. (k) C-peptide Index in the placebo group at baseline and Week 16. (l) Insulin secretion rate (pmol/kg/min) at each plasma glucose concentration (mg/ dl) in the saxagliptin group at baseline and Week 16. (m) Insulin secretion rate (pmol/kg/min) at each plasma glucose concentration (mg/dl) in the placebo group at baseline and Week 16. (l) and (m) are regression lines. (95% confidence interval) at baseline, Week 16, and Week 52 were (39.45, 52.88) (n = 105), (27.56, 39.93) (n =99), and (24.99, 33.59) (n = 92), respectively, in the saxagliptin saxagliptin group. A decrease in the M value was also observed in the placebo saxagliptin group: (35.87, 46.56) (n = 95) at Week 16 and (28.42, 37.75) (n = 82) at Week Fasting C-peptide, fasting glucagon, and 1,5- anhydroglucitol In terms of other efficacy variables, saxagliptin was associated with no changes in fasting C-peptide or fasting glucagon, and an increase in 1,5-anhydroglucitol during the double-blind period, and these results were maintained through to Week 52 (Table 3). A similar trend was observed in the subgroup analysis by age ( 65 years, <65 years) (Supplemental Table 7) Safety TEAEs In the double-blind period, TEAEs and drug-related TEAEs occurred in 62.4% and 23.1% of patients in the saxagliptin group

11 1912 T. KADOWAKI ET AL. Figure 4. (continued). versus 53.0% and 21.7% of patients in the placebo group (Table 4). Using data from both treatment periods, the incidences of TEAEs and drug-related TEAEs were 84.6% and 40.2% for the saxagliptin saxagliptin group (Weeks 0 52) and 71.8% and 26.2% for the placebo saxagliptin group (Weeks of treatment only). TEAEs in 5% of patients in either group are summarized in Table 4, the most common being hypoglycemia and nasopharyngitis in both groups and in both treatment periods. Hypoglycemia was also the most common drugrelated TEAE in both the double-blind period and the long-term period Hypoglycemia In the double-blind period, hypoglycemia occurred as a TEAE and as a drug-related TEAE in 20.5% and 15.4% of patients in the saxagliptin group. The corresponding values in the placebo group were 14.8% and 13.0%. Blood glucose decreased was reported as a TEAE and drug-related TEAE in 1.7% and 0.9% patients in the saxagliptin group, respectively, but was not observed in the placebo group. The incidence of hypoglycemia was not markedly increased with saxagliptin relative to placebo in the double-blind period. In the long-term period, the incidence of hypoglycemia and blood glucose decreased was not markedly increased in the saxagliptin saxagliptin group relative to the saxagliptin group in the double-blind period. Additionally, the incidence of hypoglycemia in the placebo saxagliptin group in the open-label extension period was similar to that in the placebo group in the double-blind period (Table 4). The incidences of hypoglycemia and blood glucose decreased by age and by insulin type in both treatment periods are shown in Table 5 and Supplemental Table 8. The severity of hypoglycemia and blood glucose decreased was also assessed. In the double-blind period, one episode of hypoglycemia in the saxagliptin group was

12 EXPERT OPINION ON PHARMACOTHERAPY 1913 Figure 4. (continued). rated as severe and two episodes in the placebo group were rated as moderate. There were no moderate or severe cases of hypoglycemia or blood glucose decreased in the open-label extension period. There were no withdrawals because of hypoglycemia or blood glucose decreased in either treatment period. The patient who developed severe hypoglycemia was a 42- year-old woman treated with twice-daily premixed insulin, which contains 50% of rapid-acting insulin. The episode occurred shortly after the administration of insulin with dinner 14 days after starting the allocated study treatment. At the time of hypoglycemia, the patient presented blurred vision and unconsciousness. She was treated with intravenous glucose infusion and recovered in 1 h and 40 min after the onset of symptoms. From the following day onward, she continued administration of the study drug with a decreased dose of insulin Laboratory variables and vital signs Body weight remained unchanged during the trial (Supplemental Table 9). Among patients treated with saxagliptin in both treatment periods (saxagliptin saxagliptin), the mean (±SD) body weight was ± kg (n = 117) at baseline, ± kg (n = 105) at Week 16, and ± kg (n = 96) at Week 52. The corresponding values in the placebo saxagliptin group were ± kg (n = 115), ± kg (n = 106), and ± kg (n = 89), respectively. There were no clinically relevant changes in laboratory variables, other vital signs, or 12-lead electrocardiogram in either period.

13 1914 T. KADOWAKI ET AL. Figure 4. (continued). 4. Discussion Administration of saxagliptin in combination with insulin was associated with improvements in glycemic control and meal tolerance test parameters during the 16-week, randomized, placebo-controlled double-blind period that were maintained through the end of the 36-week open-label extension period. Switching from placebo to open-label saxagliptin was also associated with improvements in both HbA1c and FPG during the open-label extension period that were similar to those observed in the saxagliptin group in the double-blind period. Furthermore, the glycemic improvement in this study is consistent with the results of studies of saxagliptin monotherapy [19,20] and combination therapy with OADs [20]. Consistent improvements in HbA1c were observed in subgroups of patients divided by baseline characteristics, including age, insulin type, FPG, fasting C-peptide, and daily insulin dose, suggesting that the efficacy of saxagliptin in combination with insulin is largely independent of patient characteristics. In the meal tolerance test, a decrease of postprandial glucose and suppression of glucagon secretion were observed in the saxagliptin group, although the mean changes of postprandial C-peptide from baseline to Week 16 were similar between both groups. However, from baseline to Week 16, the increases of CPI and ISR at each plasma glucose concentration in the saxagliptin group were greater compared with the placebo group. This suggests that saxagliptin may contribute to the improvement of beta-cell function. In the SAVOR-TIMI 53 study, Leibowitz et al.

14 EXPERT OPINION ON PHARMACOTHERAPY 1915 Figure 5. Self-monitored blood glucose values in the double-blind (a, b) and the double-blind period and open-label extension periods (c) according to the treatment received. showed that saxagliptin improved glycaemia and prevented the reduction in HOMA2-beta values, which may result in less decline of beta-cell function in patients treated with saxagliptin than in those treated with placebo. However, their patients were not undergoing insulin treatment [28]. In our study, we assessed beta-cell function in patients who were treated with insulin. Our findings suggest that treatment with insulin for patients with more advanced diabetes may result in improved beta-cell function. The blood glucose-lowering effect and increases of CPI and ISR were observed in the meal tolerance test regardless of age or insulin type. These results suggest that saxagliptin may improve beta-cell function in various clinical settings. In this study, we focused on elderly patients and performed subgroup analyses of the efficacy endpoints. The results of these analyses showed that the efficacy of saxagliptin was similar between elderly patients ( 65 years) and non-elderly patients (<65 years). This combination also proved to be well tolerated in terms of the low rates of TEAEs and drug-related TEAEs. The most common TEAE/drug-related TEAE was hypoglycemia in the double-blind period. During this period, the incidence was not substantially increased in the saxagliptin group compared with the placebo group, suggesting that many episodes of hypoglycemia were related to insulin rather than saxagliptin. Moreover, switching from placebo to saxagliptin at the start of the open-label extension period did not markedly increase the incidence of hypoglycemia. Additionally, only one episode of severe hypoglycemia was reported in the saxagliptin group in the double-blind period and two episodes of moderate hypoglycemia in the placebo group; all of the other episodes were classified as mild. Theseresultssuggestthatsaxagliptindoesnotsubstantially increase the incidence or severity of hypoglycemia in insulin-treated patients. Furthermore, the episodes of hypoglycemia were well tolerated regardless of patient age. The patient who developed severe hypoglycemia was a 42- year-old woman, indicating that the severity of hypoglycemia is not age-related. In the present study, there was very little change in the insulin dose in both study arms. The reason for this is that no patients met the criteria for up-titration in either group in the double-blind period, which was as short as 16 weeks. In the

15 1916 T. KADOWAKI ET AL. Table 3. Clinical efficacy variables during the double-blind and open-label extension periods. Saxagliptin Placebo Variable (unit) Study period N = 113 N = 115 Difference vs. placebo a (95% CI) Double-blind period Fasting C-peptide (ng/ml) n Baseline Mean (SE) 1.00 (0.056) 1.02 (0.056) Week 16 Mean (SE) 0.99 (0.056) 1.04 (0.057) Adjusted change from baseline Mean (95% CI) 0.07 ( 0.18, 0.31) 0.11 ( 0.14, 0.36) 0.04 ( 0.14, 0.06) Fasting glucagon (pg/ml) n Baseline Mean (SE) (2.25) (1.96) Week 16 Mean (SE) (1.91) (1.99) Adjusted change from baseline Mean (95% CI) 16.8 ( 28.3, 5.4) 17.3 ( 29.1, 5.5) 0.5 ( 4.2, 5.1) 1,5-AG (µg/ml) n Baseline Mean (SE) 4.04 (0.259) 3.88 (0.234) Week 16 Mean (SE) 7.06 (0.492) 3.70 (0.253) Adjusted change from Mean (95% CI) 2.01 (0.29, 3.73) 1.17 ( 2.94, 0.60) 3.18 (2.48, 3.88) baseline Saxagliptin saxagliptin Placebo saxagliptin N = 113 N = 100 Double-blind period and open-label extension period Fasting C-peptide (ng/ml) Baseline b n Mean (95% CI) 1.02 (0.92, 1.13) 1.04 (0.92, 1.15) Week 52 n Mean (95% CI) 0.97 (0.86, 1.09) 1.10 (0.96, 1.24) Fasting glucagon (pg/ml) Baseline b n Mean (95% CI) (120.4, 128.8) (111.4, 119.6) Week 52 n Mean (95% CI) (108.8, 118.6) (105.0, 115.4) 1,5-AG (µg/ml) Baseline b n Mean (95% CI) 4.07 (3.58, 4.56) 3.55 (3.12, 3.98) Week 52 n Mean (95% CI) 6.23 (5.41, 7.06) 5.93 (5.08, 6.77) Data set: Full analysis set during the double-blind period and full analysis set during the long-term period. SE: standard error; CI: confidence interval; 1,5-AG: 1,5-anhydroglucitol. a Difference versus placebo: Adjusted change from baseline for saxagliptin Adjusted change from baseline for placebo. b Baseline was defined as the start of saxagliptin: Week 0 in the saxagliptin saxagliptin group; Week 16 in the placebo saxagliptin group. Table 4. TEAEs in 5% of patients in either treatment group, serious TEAEs, and TEAEs of special interest. TEAEs Drug-related TEAEs Saxagliptin Placebo Saxagliptin Placebo n (%) N = 117 N = 115 N = 117 N = 115 Double-blind period Patients with any TEAE 73 (62.4%) 61 (53.0%) 27 (23.1%) 25 (21.7%) Serious TEAE 3 (2.6%) 2 (1.7%) 1 (0.9%) 0 TEAE leading to study drug discontinuation 1 (0.9%) 1 (0.9%) 1 (0.9%) 1 (0.9%) TEAE by preferred term Hypoglycemia 24 (20.5%) 17 (14.8%) 18 (15.4%) 15 (13.0%) Blood glucose decreased a 2 (1.7%) 0 1 (0.9%) 0 Nasopharyngitis 14 (12.0%) 12 (10.4%) 0 0 Saxagliptin saxagliptin Placebo saxagliptin Saxagliptin saxagliptin Placebo saxagliptin N = 117 N = 103 N = 117 N = 103 Double-blind period and open-label extension period b Patients with any TEAE 99 (84.6%) 74 (71.8%) 47 (40.2%) 27 (26.2%) Serious TEAE 9 (7.7%) 10 (9.7%) 1 (0.9%) 1 (1.0%) TEAE leading to study drug discontinuation 2 (1.7%) 1 (1.0%) 2 (1.7%) 1 (1.0%) TEAE by preferred term Nasopharyngitis 39 (33.3%) 23 (22.3%) 0 0 Hypoglycemia 36 (30.8%) 18 (17.5%) 27 (23.1%) 12 (11.7%) Blood glucose decreased a 8 (6.8%) 3 (2.9%) 5 (4.3%) 2 (1.9%) Upper respiratory tract inflammation 7 (6.0%) 3 (2.9%) 0 0 Influenza 7 (6.0%) 2 (1.9%) 0 0 Diabetic retinopathy 6 (5.1%) 3 (2.9%) 2 (1.7%) 0 Bronchitis 6 (5.1%) 3 (2.9%) 0 0 Data set: Safety analysis set during the double-blind period and safety analysis set during the long-term period. TEAE: treatment-emergent adverse event. a Blood glucose decreased was a TEAE of special interest. b Treatment duration: 52 weeks for saxagliptin saxagliptin group (Weeks 0 52) and 36 weeks for placebo saxagliptin group (Weeks 16 52).

16 EXPERT OPINION ON PHARMACOTHERAPY 1917 Table 5. Subgroup analysis of the incidence of hypoglycemia, blood glucose decreased, and serious TEAEs by age. TEAEs Drug-related TEAEs Saxagliptin Placebo Saxagliptin Placebo Age <65 years N =61 N =57 N =61 N =57 Age 65 years N =56 N =58 N =56 N =58 n (%) Double-blind period Patients with any TEAE Age <65 years 40 (65.6%) 27 (47.4%) 16 (26.2%) 9 (15.8%) Age 65 years 33 (58.9%) 34 (58.6%) 11 (19.6%) 16 (27.6%) Serious TEAE Age <65 years 2 (3.3%) 0 1 (1.6%) 0 Age 65 years 1 (1.8%) 2 (3.4%) 0 0 TEAE leading to study drug discontinuation Age <65 years 1 (1.6%) 1 (1.8%) 1 (1.6%) 1 (1.8%) Age 65 years TEAE by preferred term Hypoglycemia Age <65 years 13 (21.3%) 5 (8.8%) 10 (16.4%) 4 (7.0%) Age 65 years 11 (19.6%) 12 (20.7%) 8 (14.3%) 11 (19.0%) Blood glucose decreased Age <65 years 1 (1.6%) Age 65 years 1 (1.8%) 0 1 (1.8%) 0 Saxagliptin saxagliptin Placebo saxagliptin Saxagliptin saxagliptin Placebo saxagliptin Age <65 years N =61 N =48 N =61 N =48 Age 65 years N =56 N =55 N =56 N =55 n (%) Double-blind period and open-label extension period a Patients with any TEAE Age <65 years 52 (85.2%) 32 (66.7%) 26 (42.6%) 8 (16.7%) Age 65 years 47 (83.9%) 42 (76.4%) 21 (37.5%) 19 (34.5%) Serious TEAE Age <65 years 6 (9.8%) 3 (6.3%) 1 (1.6%) 0 Age 65 years 3 (5.4%) 7 (12.7%) 0 1 (1.8%) TEAE leading to study drug discontinuation Age <65 years 1 (1.6%) 0 1 (1.6%) 0 Age 65 years 1 (1.8%) 1 (1.8%) 1 (1.8%) 1 (1.8%) TEAE by preferred term Hypoglycemia Age <65 years 19 (31.1%) 8 (16.7%) 14 (23.0%) 4 (8.3%) Age 65 years 17 (30.4%) 10 (18.2%) 13 (23.2%) 8 (14.5%) Blood glucose decreased Age <65 years 4 (6.6%) 1 (2.1%) 2 (3.3%) 1 (2.1%) Age 65 years 4 (7.1%) 2 (3.6%) 3 (5.4%) 1 (1.8%) Data set: Safety analysis set during double-blind period and safety analysis set during the long-term period. TEAE: treatment-emergent adverse event. a Treatment duration: 52 weeks for saxagliptin saxagliptin group (Weeks 0 52) and 36 weeks for placebo saxagliptin group (Weeks 16 52). open-label period, all subjects used saxagliptin and insulin in combination. Although the dose of insulin was changed in some patients, the mean dose of insulin was stable during the open-label period. Several other studies have examined the efficacy and safety of DPP-4 inhibitors in combination with insulin in Japanese patients [9 16]. There appear to be similar trends between the present study results and the results from combination therapy studies using other DPP-4 inhibitors and insulin. Some aspects of our trial warrant mention. In particular, insulin may be used in combination with other OADs in Japan, especially in patients with poorly controlled diabetes, but our trial evaluated only the combination of insulin and saxagliptin. By contrast, in trials of vildagliptin and anagliptin, patients could continue another OAD and insulin at the time of starting the DPP-4 inhibitor [9,13], and this may have influenced the changes in glycemic control during the trials. In clinical practice, it is feasible that some patients will be prescribed a DPP-4 inhibitor, insulin, and another OAD as intensive therapy. It should be noted that the Japanese diabetes clinical practice guideline recommends not only metformin but also other OADs, insulin, and GLP-1RAs as the first-line agents for initial drug therapy because Japanese diabetes patients have a different pathology and lifestyle compared with diabetes patients in Western countries. Therefore, combination therapy with a DPP-4 inhibitor and insulin without metformin is the usual practice in Japan; no subjects took metformin during the present study. The mean BMI of patients in the present study was relatively low compared with the BMI of T2DM in Western countries. Our findings highlight the efficacy of saxagliptin in patients with low BMI and/or reduced insulin secretion, which are common features shared by East Asian T2DM patients [3].