2017, 64 (12), 1165-1172

Original

Efficacy and safety of subgroup analysis stratified by baseline HbA1c in a Japanese phase 3 study of 0.75 mg compared with glargine in patients with type 2 diabetes

Shizuka Kaneko1), Tomonori Oura2), Akiko Matsui2), Tomotaka Shingaki2) and Masakazu Takeuchi2)

1) Takatsuki Red Cross Hospital, Takatsuki, Japan 2) Eli Lilly Japan K.K., Kobe, Japan

Abstract. The efficacy and safety of once-weekly dulaglutide 0.75 mg (dulaglutide) compared with once-daily (glargine) in Japanese patients with type 2 diabetes were evaluated according to subgroups stratified by baseline glycated hemoglobin (HbA1c) (≤8.5% or >8.5%). This exploratory analysis of a randomized, open-label, phase 3 study included 361 patients. In both HbA1c subgroups (patients with baseline HbA1c ≤8.5% or >8.5%), a statistically significantly greater reduction in HbA1c was observed in dulaglutide-treated patients compared with glargine-treated patients after 26 weeks of treatment (HbA1c ≤8.5%: dulaglutide, -1.27%; glargine, -0.72%; HbA1c >8.5%: dulaglutide, -2.04%; glargine, -1.47%; p < 0.001 for both). Mean body weight was decreased from baseline in both subgroups of the dulaglutide group and increased in both subgroups of the glargine group; there were statistically significant differences between the treatment groups in both subgroups (p < 0.05 for both). In both subgroups, similar reductions in fasting blood glucose were observed for dulaglutide- and glargine-treated patients, and a greater reduction in postprandial blood glucose was observed for dulaglutide-treated patients compared with glargine-treated patients. Although dulaglutide increased gastrointestinal adverse events compared with glargine in both subgroups, all gastrointestinal events of diarrhea, nausea, constipation, and vomiting in dulaglutide-treated patients were mild in intensity and well tolerated. In both subgroups, there was a lower incidence of hypoglycemia with dulaglutide than with glargine. Dulaglutide demonstrated significantly greater HbA1c reduction compared with glargine, with an acceptable safety profile, regardless of baseline HbA1c.

Key words: Dulaglutide, GLP-1 receptor agonist, HbA1c subgroup analysis, Type 2 diabetes

DULAGLUTIDE, a long-acting injectable - Subgroup analyses using pooled data from the like peptide-1 (GLP-1) receptor agonist, is a recom- 3 Japanese phase 3 studies of dulaglutide 0.75 mg binant GLP-1 immunoglobulin G4 (IgG4) Fc fusion (dulaglutide) in patients with T2D stratified by -sev protein consisting of 2 identical chains, and it mimics eral patient characteristics, including baseline HbA1c, some of the effects of endogenous GLP-1 [1]. It has were previously reported [12]. However, because been approved and launched in the United States, the these analyses did not include comparator treatments, European Union [2, 3], and Japan [4]. In phase 3 stud- further studies are needed to assess the benefits and ies in Japanese and non-Japanese patients with type risks (efficacy and safety based on baseline HbA1c 2 diabetes (T2D), once-weekly dulaglutide 0.75 mg levels) of dulaglutide compared with basal insulin and/or 1.5 mg showed superiority to insulin glargine (such as glargine) as a treatment option for patients. (glargine) [5-7], [8], and twice-daily exena- In this study, to compare efficacy and safety between tide [9] and noninferiority to once-daily in dulaglutide and glargine based on HbA1c levels, we glycated hemoglobin (HbA1c) changes [10, 11]. conducted further exploratory subgroup analyses of

Submitted May 1, 2017; Accepted Aug. 7, 2017 as EJ17-0189 glucagon-like peptide-1; HbA1c, glycated hemoglobin; IgG4, Released online in J-STAGE as advance publication Sep. 14, 2017 immunoglobulin G4; LS mean, least-squares mean; OHA, oral Correspondence to: Masakazu Takeuchi, PhD, Eli Lilly Japan K.K., hypoglycemic agent; MMRM, mixed-effects model for repeated 7-1-5, Isogami-dori, Chuo-ku, Kobe 651-0086, Hyogo, Japan. measurements; SD, standard deviation; SE, standard error; Email: [email protected] SMBG, self-monitored blood glucose; SU, ; T2D, Abbreviations: BG, ; BMI, body mass index; GLP-1, type 2 diabetes. ©The Japan Endocrine Society 1166 Kaneko et al. the randomized, glargine-controlled study in Japanese statistics of measurements and changes from baseline patients with T2D [5]. were reported for baseline and the 26-week endpoint. P values were calculated from t-tests. Incidences Materials and Methods (%) of patients experiencing adverse events or hypo- glycemia were summarized by treatment and base- Study design and patient population line HbA1c subgroup. P values for incidence of treat- The study was a 26-week, randomized, open-label, ment-emergent adverse events were calculated from noninferiority phase 3 study that compared the efficacy Fisher’s exact test. P values for incidence of hypogly- and safety of once-weekly dulaglutide 0.75 mg with once- cemia were computed by chi-square test if at least 80% daily glargine in Japanese patients with T2D inadequately of cells had an expected value ≥5; otherwise Fisher’s controlled with (SUs) and/or exact test was used. Some demographic characteris- (BGs) [5]. Japanese men and women with T2D, aged tics at baseline were also summarized descriptively by ≥20 years, with HbA1c at screening ≥7.0 and ≤10.0%, treatment and baseline HbA1c subgroup. who were taking stable doses of SUs (2.5-5 mg of gliben- The subgroup analyses of changes in HbA1c and clamide, 60-80 mg of , or 2-3 mg of ) body weight and of incidences of adverse events, and and/or BGs (750-1,500 mg of or 100-150 mg total and nocturnal hypoglycemia were prespecified in of buformin) were randomized. Randomization was the study analysis plan, whereas the analyses of demo- stratified by concomitant oral hypoglycemic agent (OHA) graphic characteristics, insulin dose, SMBG profiles, regimen (SU only, BG only, or SU and BG), body mass and documented symptomatic, asymptomatic, and index (BMI) group at baseline (<25 and ≥25 kg/m2), and probable symptomatic hypoglycemia were all post hoc. screening HbA1c (≤8.5 and >8.5%). The study protocol was approved at each site by an Results institutional review board, and the study was performed in accordance with the principles of the Declaration Patient characteristics of Helsinki and Good Clinical Practice. All patients Demographics for all 361 patients stratified by treat- provided written informed consent before participa- ment and baseline HbA1c subgroup are presented in tion. The study was registered at ClinicalTrials.gov Table 1. Overall, 275/361 (76%) of patients had baseline (NCT01584232). HbA1c ≤8.5%, and 86/361 (24%) had baseline HbA1c >8.5%. Baseline patient characteristics were similar Analysis methods between the treatment groups in each subgroup. For both To evaluate the effects of baseline HbA1c, patients the dulaglutide and glargine treatment groups at baseline, were classified into 2 subgroups based on baseline patients with higher baseline HbA1c (>8.5%) had higher HbA1c (≤8.5% or >8.5%). Subgroup analyses to mean fasting serum glucose levels and greater mean evaluate changes in HbA1c and body weight by base- body weights (186 mg/dL for both; 72.5 and 72.0 kg, line HbA1c subgroup were conducted using a mixed- respectively) than patients with lower baseline HbA1c effects model for repeated measurements (MMRM) (≤8.5%) (151 and 146 mg/dL; 70.4 and 70.8 kg, respec- similar to the primary efficacy analysis [5] in the study tively). There were no meaningful differences in other that included treatment, OHA regimen (SU only, BG factors between the 2 subgroups for either treatment. only, or SU and BG), baseline BMI group (<25 or At endpoint (26 weeks), the mean glargine dose was ≥25 kg/m2), visit, treatment by visit, baseline HbA1c 11.2 and 16.8 IU/day in patients with baseline HbA1c group, treatment-by-baseline HbA1c, visit-by-baseline ≤8.5% and >8.5%, respectively. HbA1c, and treatment-by-visit-by-baseline HbA1c interaction as fixed effects; baseline weight as a covari- Efficacy ate (for weight); and patient as a random effect. Based In both subgroups, dulaglutide-treated patients had a on this MMRM, p values for changes in HbA1c and statistically significantly greater reduction from baseline body weight were calculated from pairwise compar- in HbA1c (LS mean) than glargine-treated patients after isons of least-squares (LS) means at week 26 from 26 weeks (HbA1c ≤8.5%: dulaglutide, -1.27%; glargine, restricted maximum likelihood. For the 8-point self- -0.72%; HbA1c >8.5%: dulaglutide, -2.04%; glargine, monitored blood glucose (SMBG) profiles, summary -1.47%; p < 0.001 for both subgroups) (Fig. 1A). There Dulaglutide analysis by HbA1c in Japan 1167

Table 1 Demographic and baseline characteristics by treatment and baseline HbA1c subgroup HbA1c Subgroup ≤8.5% >8.5% Dulaglutide 0.75 mg Insulin Glargine Dulaglutide 0.75 mg Insulin Glargine Treatment (n = 137) (n = 138) (n = 44) (n = 42) Gender, n (%) Male 92 (67) 98 (71) 33 (75) 35 (83) Female 45 (33) 40 (29) 11 (25) 7 (17) Age, years 57.6 ± 10.4 56.7 ± 11.1 57.2 ± 10.8 54.2 ± 11.9 Diabetes duration, years 8.9 ± 6.9 8.7 ± 6.4 9.1 ± 6.2 9.0 ± 4.8 Weight, kg 70.4 ± 13.4 70.8 ± 13.6 72.5 ± 14.8 72.0 ± 14.5 BMI, kg/m2 25.9 ± 3.4 26.0 ± 3.9 26.5 ± 3.9 25.5 ± 3.8 HbA1c, % 7.7 ± 0.5 7.6 ± 0.5 9.2 ± 0.5 9.2 ± 0.5 Fasting serum glucose, mg/dLa 150.9 ± 33.1 145.9 ± 29.9 185.5 ± 33.8 186.1 ± 37.8 Baseline OHA therapy, n (%) SU only 22 (16) 24 (17) 12 (27) 9 (21) BG only 54 (39) 52 (38) 10 (23) 14 (33) SU and BG 61 (45) 62 (45) 22 (50) 19 (45) Data are mean ± SD, unless indicated. Dulaglutide administered once weekly. Insulin glargine administered once daily. BG, biguanide; BMI, body mass index; HbA1c, glycated hemoglobin; n, number of patients; OHA, oral hypoglycemic agent; SD, standard deviation; SU, sulfonylurea. a Fasting serum glucose was measured at the central laboratory.

Fig. 1 (A) LS mean (SE) changes from baseline to Week 26 in HbA1c (%) by treatment and baseline HbA1c subgroup. (B) LS mean (SE) changes from baseline to Week 26 in body weight (kg) by treatment and baseline HbA1c subgroup *p < 0.05, **p < 0.001 for dulaglutide vs. insulin glargine within subgroup. HbA1c, glycated hemoglobin; LS, least-squares; SE, standard error. 1168 Kaneko et al. was no significant treatment-by-baseline HbA1c inter- ≤8.5%; p < 0.001 for HbA1c >8.5%). Dulaglutide- action effect on the change from baseline in HbA1c treated patients with baseline HbA1c ≤8.5% had sta- (p = 0.503). In both the dulaglutide and glargine treatment tistically significantly higher incidences of diarrhea, groups, patients with baseline HbA1c >8.5% experienced nausea, and lipase-level increase than glargine-treated statistically greater reductions in HbA1c than patients with patients (p < 0.05 for all). Although 1 patient discon- baseline HbA1c ≤8.5% (p < 0.001, respectively) . tinued dulaglutide treatment because of an adverse In both subgroups, LS mean body weight was event of vomiting, all observed gastrointestinal adverse decreased from baseline in dulaglutide-treated patients events (diarrhea, nausea, constipation, and vomiting) and increased from baseline in glargine-treated patients in dulaglutide-treated patients were reported as mild in after 26 weeks (HbA1c ≤8.5%: dulaglutide, -0.57 kg; intensity. The incidences of total, asymptomatic, and glargine, 0.80 kg; HbA1c >8.5%: dulaglutide, -0.20 nocturnal hypoglycemia were statistically significantly kg; glargine, 1.38 kg). For both subgroups, the dif- lower with dulaglutide compared with glargine in both ferences in change in body weight between the treat- subgroups (p < 0.05 for all). The incidence of proba- ment groups were statistically significant (p < 0.05) ble symptomatic hypoglycemia was statistically signif- (Fig. 1B). There was no significant treatment-by-base- icantly lower with dulaglutide compared with glargine line HbA1c interaction effect on the change from base- in patients with baseline HbA1c >8.5% (p < 0.05). line in body weight (p = 0.595). There were no sta- There were no meaningful differences in the incidences tistically significant differences between the subgroups of frequent adverse events or hypoglycemia between in changes in body weight for either treatment group the subgroups for either treatment group. (dulaglutide: p = 0.344; glargine: p = 0.148). Mean 8-point SMBG profiles by treatment groups Discussion at baseline and week 26 (last observation carried for- ward) and the changes from baseline are shown in Fig. This analysis was an exploratory evaluation of the 2 and Fig. 3 for patients with baseline HbA1c ≤8.5% efficacy and safety of once-weekly dulaglutide 0.75 and HbA1c >8.5%, respectively. In patients with base- mg compared with once-daily glargine by subgroups of line HbA1c ≤8.5%, dulaglutide significantly reduced baseline HbA1c (≤8.5% or >8.5%) in Japanese patients SMBG values from baseline after 26 weeks compared with T2D treated for up to 26 weeks in a randomized, with glargine for all time points (p < 0.05 for all), except controlled study [5]. for before breakfast and before breakfast the follow- In this subgroup analysis, in both the dulaglu- ing day (second before breakfast) (Fig. 2). In patients tide and glargine groups, greater HbA1c reduc- with baseline HbA1c >8.5%, dulaglutide significantly tions were observed in patients with higher baseline reduced SMBG values from baseline after 26 weeks HbA1c (>8.5%) compared with patients with lower compared with glargine for the after lunch, before din- baseline HbA1c (≤8.5%). This is because there is a ner, and after dinner time points (p < 0.05 for all) (Fig. greater potential for improvement in glycemic con- 3). Furthermore, patients with baseline HbA1c >8.5% trol in patients with higher baseline HbA1c. Similar in both the dulaglutide and glargine treatment groups relationships between baseline HbA1c levels and experienced greater reductions from baseline at all 8 improvements in glycemic control have also been seen points of their SMBG profiles compared with patients in previous reports of meta-analyses of various glu- with baseline HbA1c ≤8.5% (Fig. 2C and Fig. 3C). cose-lowering therapies [13], meta-analyses of GLP-1 receptor agonists other than dulaglutide [14, 15], and Safety global phase 3 studies of dulaglutide [16]. Table 2 shows the incidences of frequent adverse Because it has been reported that the relative con- events (those occurring in >5% of dulaglutide- or tribution of fasting hyperglycemia to glycemic control glargine-treated patients) and hypoglycemia (defined increases gradually with worsening of T2D [17], it was by blood glucose ≤70 mg/dL and/or symptoms/signs anticipated that glargine, which is considered to have a attributable to hypoglycemia) through week 26 by robust effect on fasting hyperglycemia, would have an treatment and HbA1c subgroup. In both subgroups, advantage for HbA1c reductions in patients with higher gastrointestinal disorders occurred more frequently baseline HbA1c. However, the treatment differences with dulaglutide than glargine (p = 0.002 for HbA1c (dulaglutide − glargine) in HbA1c reduction at week Dulaglutide analysis by HbA1c in Japan 1169

Fig. 2 Mean 8-point SMBG profiles (mg/dL) in patients with Fig. 3 Mean 8-point SMBG profiles (mg/dL) in patients with baseline HbA1c ≤8.5% by treatment. (A) At baseline, (B) baseline HbA1c >8.5% by treatment. (A) At baseline, (B) At Week 26 (LOCF) , (C) Changes from baseline At Week 26 (LOCF), (C) Changes from baseline *, **: SMBG significantly lower, or reduction in SMBG *: SMBG significantly lower, or reduction in SMBG significantly greater in dulaglutide group compared significantly greater in dulaglutide group compared with with insulin glargine group (*p < 0.05, **p < 0.001). +, insulin glargine group (*p < 0.05). AB, after breakfast; ++: SMBG significantly lower, or reduction in SMBG AD, after dinner; AL, after lunch; BB, before breakfast; significantly greater in insulin glargine group compared BB#, before breakfast next day; BD, before dinner; with dulaglutide group (+p < 0.05, ++p < 0.001). AB, BL, before lunch; BT, bedtime; LOCF, last observation after breakfast; AD, after dinner; AL, after lunch; BB, carried forward; SD, standard deviation; SE, standard before breakfast; BB#, before breakfast next day; BD, error; SMBG, self-monitored blood glucose. before dinner; BL, before lunch; BT, bedtime; LOCF, last observation carried forward; SD, standard deviation; SE, standard error; SMBG, self-monitored blood glucose. 1170 Kaneko et al.

Table 2 Incidence (percentage of patients) of frequent treatment-emergent adverse events and hypoglycemia through 26 weeks by treatment and baseline HbA1c subgroup HbA1c Subgroup ≤ 8.5% > 8.5% Dulaglutide Insulin Dulaglutide Insulin p Value p Value Treatment 0.75 mg Glargine 0.75 mg Glargine Between Treatmentsa,b Between Treatmentsa,b (n = 137) (n = 138) (n = 44) (n = 42) Patients with ≥1 TEAE 74.5 60.1 0.014 77.3 66.7 0.339 TEAEs occurring in ≥5% of patients in either treatment group overall Nasopharyngitis 24.8 26.8 0.783 34.1 21.4 0.233 Gastrointestinal disorders 29.9 14.5 0.002 47.7 11.9 <0.001 Diarrhea 11.7 2.2 0.002 13.6 2.4 0.110 Nausea 8.8 0.7 0.001 11.4 2.4 0.203 Constipation 6.6 3.6 0.288 15.9 2.4 0.058 Vomiting 2.9 0.0 0.060 11.4 4.8 0.434 Lipase increased 5.8 0.0 0.003 2.3 2.4 >0.999 Hypoglycemiac Total 27.0 44.9 0.002 22.7 57.1 0.001 Documented symptomaticd 8.0 14.5 0.090 6.8 16.7 0.191 Asymptomatice 19.7 37.0 0.002 15.9 35.7 0.035 Probable symptomaticf 5.8 10.9 0.132 6.8 26.2 0.015 Nocturnal 8.8 23.9 <0.001 9.1 35.7 0.003 Data are percentages of patients. Medical Dictionary for Regulatory Activities version 16.1. Dulaglutide administered once weekly. Insulin glargine administered once daily. HbA1c, glycated hemoglobin; n, number of patients; TEAE, treatment-emergent adverse event. a P values for TEAEs were calculated from Fisher’s exact test. b P values for hypoglycemia were computed by chi-square test if at least 80% of cells had an expected value ≥5; otherwise Fisher’s exact test was used. c Hypoglycemia was defined as a blood glucose concentration of ≤70 mg/dL and/or symptoms/signs attributable to hypoglycemia. d Documented symptomatic hypoglycemia was defined as a blood glucose concentration of ≤70 mg/dL and symptoms/signs attributable to hypoglycemia. e Asymptomatic hypoglycemia was defined as a blood glucose concentration of ≤70 mg/dL without typical symptoms/signs attributable to hypoglycemia. f Probable symptomatic hypoglycemia was defined as symptoms/signs attributable to hypoglycemia without any record of a blood glucose concentration of ≤70 mg/dL.

26 were nearly the same for both HbA1c subgroups Fig. 3, respectively) was higher than the target glucose (-0.54% and -0.57% for HbA1c ≤8.5% and HbA1c levels in this study. Therefore, there remained the pos- >8.5%, respectively). This was supported by the SMBG sibility that this dosing method might not sufficiently results, which showed that, in both HbA1c subgroups, suppress increases of postprandial blood glucose at 1) similar reductions in fasting blood glucose were daytime. However, the mean glargine doses at end- observed for dulaglutide- and glargine-treated patients, point (11.2 and 16.8 IU/day in patients with baseline and 2) a greater reduction in postprandial blood glucose HbA1c ≤8.5% and >8.5%, respectively) in this study was observed for dulaglutide-treated patients compared were similar to the average dose in Japanese patients with glargine-treated patients. In addition, it is thought (10–15 IU/day) reported in clinical studies and post- that long-acting GLP-1 receptor agonists might have marketing surveillance for glargine [18-20]. Also, both stronger effects on both postprandial and fasting blood the mean fasting blood glucose and HbA1c at endpoint glucose than short-acting GLP-1 receptor agonists [9]. as well as the incidence of hypoglycemia in this study In this study, the investigator adjusted glargine dos- were similar to the mean fasting blood glucose and ing based on the dosing algorithm, which was modified HbA1c (121 mg/dL and 7.1%, respectively) reported in from the ATLAS study [5], with a fasting serum glu- treat-to-target glargine studies and the incidence (54%) cose target of ≤110 mg/dL. Consistent with the overall reported in a review article in a treat-to-target study of results of the original study [5], the mean fasting blood insulin glargine [21, 22]. glucose at week 26 in the glargine-treated patients with Treatment differences (dulaglutide − glargine) in baseline HbA1c ≤8.5% and HbA1c >8.5% (Fig. 2 and changes at week 26 in body weight were also Dulaglutide analysis by HbA1c in Japan 1171 similar for both HbA1c subgroups (-1.38 kg and -1.58 Finally, only patients with HbA1c ≥7.0 and ≤10.0% kg for HbA1c ≤8.5% and HbA1c >8.5%, respectively). at screening participated in this clinical study; there- However, patients with lower baseline HbA1c tended fore, the conclusions drawn may not be applicable for to have numerically greater weight loss (dulaglutide) patients with HbA1c >10.0%. or less weight gain (glargine) than patients with higher In conclusion, in this subgroup analysis of a ran- baseline HbA1c. The mean glargine dose at endpoint domized study of once-weekly dulaglutide 0.75 mg in was higher in patients with higher baseline HbA1c than Japanese patients with T2D, reductions in both HbA1c in patients with lower baseline HbA1c (16.8 and 11.2 and body weight observed with dulaglutide were pref- IU/day for HbA1c >8.5% and HbA1c ≤8.5%, respec- erable to the changes with glargine regardless of base- tively). Similarly, for dulaglutide-treated patients, line HbA1c (≤8.5% or >8.5%). Although dulaglu- greater insulin secretion might be required in patients tide increased gastrointestinal symptoms compared with higher baseline HbA1c compared with patients with glargine in both subgroups, it was well tolerated, with lower baseline HbA1c to incorporate excess blood with lower rates of hypoglycemia. Dulaglutide can glucose into peripheral tissues. The glucose-dependent be a first injection treatment option for patients with insulinotropic effect of incretin-based therapies can also T2D inadequately controlled with OHAs in Japanese explain greater insulin secretion in patients with higher patients with T2D. baseline HbA1c. Results from these subgroup analyses showed that Declaration of Interest in both HbA1c subgroups, dulaglutide-treated patients experienced gastrointestinal adverse events more fre- S.K. has received honoraria for lectures from Novo quently than glargine-treated patients; however, all Nordisk Pharma Ltd.. T.O., A.M., T.S., and M.T. are observed gastrointestinal adverse events (diarrhea, employees of Eli Lilly Japan K.K, and M.T. has the nausea, constipation, and vomiting) in dulaglutide- company stock option. treated patients were reported as mild in intensity and well tolerated. The incidences of total, asymptomatic, Funding Source and nocturnal hypoglycemia were statistically signifi- cantly lower with dulaglutide compared with glargine This study was funded by Eli Lilly K.K. (Kobe, in both subgroups. The incidences of hypoglycemia Japan). tended to be lower with dulaglutide than with glargine in all subcategories in both subgroups. Contrary to Author Contributions expectations, in the glargine group, incidences of hypo- glycemia were higher in patients with higher baseline S.K. was a trial investigator and participated in data HbA1c than in patients with lower baseline HbA1c; collection. T.O., A.M., T.S., and M.T. prepared the first this may have been due to larger circadian variation draft of the manuscript. T.O. was responsible for sta- observed in patients with higher baseline HbA1c [23]. tistical considerations. M.T. was responsible for trial The subgroup analyses reported here had some lim- design and medical oversight during the trial. All itations. First, some of these analyses were post hoc, authors participated in reviewing and interpreting the and all were exploratory. Second, this study included a data and providing comments and revisions to the man- relatively small number of patients with HbA1c >8.5% uscript. All authors approved the final version of the in both the dulaglutide and glargine treatment groups. manuscript and take full responsibility for the content.

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