Endocrine Journal 2015, 62 (5), 399-409
Original
Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes Kumiko Tanaka1), Yoshifumi Saisho1), Toshihide Kawai1), Masami Tanaka1), Shu Meguro1), Junichiro Irie1), Takatoshi Imai2), Toshikatsu Shigihara3), Jiro Morimoto4), Ken Yajima5), Yoshihito Atsumi6), Izumi Takei7) and Hiroshi Itoh1) 1)
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan Department of Internal Medicine, Yokohama Municipal Citizens’ Hospital, Kanagawa, Japan 3) Department of Internal Medicine, Eiju General Hospital, Tokyo, Japan 4) Department of Internal Medicine, Japan Community Health Care Organization Saitama Medical Center, Saitama, Japan 5) Department of Internal Medicine, Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tokyo, Japan 6) Diabetes Center, Eiju General Hospital, Tokyo, Japan 7) Department of Internal Medicine, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan 2)
Abstract. There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 ± 0.80% vs. -0.80 ± 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM. Key words: Liraglutide, Metformin, Type 2 diabetes, Japanese, Randomized controlled trial
The prevalence of obesity and type 2 diabetes (T2DM) continues to increase all over the world [1]. Individuals with T2DM have 2- to 3-fold increased risk of cardiovascular disease [2, 3]. Obesity, especially abdominal obesity, itself is also a risk factor for cardiovascular disease, independent of T2DM [4, 5, 6]. Obesity is also associated with various other medical Submitted Nov.10, 2014 as EJ14-0537; Accepted Feb. 6, 2015 as EJ14-0602 Released online in J-STAGE as advance publication Feb. 26, 2015
Correspondence to: Yoshifumi Saisho, M.D., Ph.D., Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected] ©The Japan Endocrine Society
conditions such as hypertension, dyslipidemia, sleep apnea syndrome and cancer [7]. Thus, simultaneous treatment of obesity and T2DM is an urgent issue for obese patients with T2DM. Metformin is recommended as a first-line oral antihyperglycemic agent for the treatment of T2DM in the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines [8]. Treatment with metformin has been shown to have a neutral or even beneficial effect on body weight, in addition to improvement of glycemic control [8]. However, since only a low dose (up to 750 mg/day) of metformin had been approved in Japan until 2010,
Tanaka et al.
400
the efficacy and safety of a high dose (up to 2250 mg) of metformin remains to be established in Japanese patients with T2DM. On the other hand, a meta-analysis of randomized clinical trials has demonstrated significant weight loss as well as improvement of glycemic control and cardiometabolic risk factors in patients with T2DM treated with glucagon-like peptide-1 receptor agonists (GLP1RA) [9, 10]. It has also been reported that the glucoselowering effect of incretin therapy is more marked in Asians than in Caucasians [11, 12]. Thus, once-daily administration of a GLP-1RA, liraglutide, could be a first-line treatment for individuals with T2DM, especially those who are overweight or obese, in Japan. Therefore, in this study we evaluated the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in Japanese overweight/obese patients with T2DM.
Research Design and Methods Subjects Overweight or obese patients (i.e., BMI ≥ 23.5 kg/m2 for Asians) with T2DM aged 20-75 years whose glycemic control was suboptimal (HbA1c 6.9-9.4%) were enrolled in this study. To compare liraglutide vs. metformin monotherapy, we enrolled only patients treated with lifestyle modification ± an a-glucosidase inhibitor ± low-dose metformin (i.e., 750 mg/day or less) over 3 months, but not those treated with insulin secretagogues such as sulfonylureas and glinides, thiazolidinedione or insulin. The study participants were recruited at six hospitals between September 2010 and September 2013. Exclusion criteria included 1) type 1 diabetes, 2) contraindication to metformin or liraglutide, 3) advanced diabetic retinopathy (i.e., preproliferative or proliferative retinopathy) and 4) pregnancy. The study was approved by the ethical committee of Keio University School of Medicine and registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www. umin.ac.jp/ctr/) as the Keio study for Initial treatment of type 2 Diabetes with Liraglutide versus Metformin (KIND-LM); UMIN000004243. Written informed consent was obtained from all study subjects. Study protocol The study was a 24-week, open-labeled, randomized controlled study. Subjects were randomized to either metformin (1500 mg daily or more) or liraglu-
tide monotherapy. Oral hypoglycemic agents that had been used before randomization were discontinued at week 0. The patients were asked to continue lifestyle modification during the study. Metformin was started at an initial dose of 500-750 mg daily, then the dosage was up-titrated weekly to 1500 mg daily. After week 10, the attending physicians were allowed to increase the dosage up to 2250 mg daily, if tolerated. The initial dose of liraglutide was 0.3 mg once daily by subcutaneous injection, and the dosage was up-titrated by 0.3 mg weekly to 0.9 mg daily, which is the maximum dose approved in Japan. The patients were followed monthly for 24 weeks. The primary endpoint was change in HbA1c at week 24. Estimation of sample size The study was powered to show superiority in the primary endpoint, HbA1c, at week 24 in the liraglutide group. Based on the phase 2 and 3 studies [13, 14], we estimated HbA1c reduction in the liraglutide group and metformin group to be 1.8% and 1.2%, respectively. In order to detect a difference in HbA1c of 0.6% with SD of 1.0% between the two treatment groups, 50 subjects per group would yield a power of 80% with a 5% twosided significance level. Assuming a withdrawal rate of 10%, enrollment of 55 subjects per group was planned. Measurements Body weight and blood pressure were measured at each visit. Waist circumference at the umbilical level was measured at baseline and week 24. Blood and urine samples were obtained after an overnight fast at each visit. Plasma glucose, HbA1c, insulin, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, creatinine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured using routine automated laboratory methods [15, 16]. HbA1c was measured by high-performance liquid chromatography (HPLC) and expressed as the National Glycohemoglobin Standardized Program (NGSP) value [17]. Serum insulin and C-peptide immunoreactivity (CPR) were measured by EIA. Proinsulin and glucagon were measured by radioimmunoassay (RIA) (Millipore Corp., Darmstadt, Germany). Homeostasis model assessment of insulin resistance (HOMA-IR) or beta cell function (HOMA-b) was calculated using the HOMA-2 calculator (https://www.dtu.ox.ac.uk/homacalculator/). CPR index was calculated as: serum CPR
401
Liraglutide compared with metformin
(ng/mL)/plasma glucose (mg/dL) x 100, as previously described [15]. The following variables were assessed at baseline and week 24. Oxidized LDL was measured by ELISA (Sekisui Medical Corp., Tokyo, Japan) and pentosidine was measured by ELISA (Fushimi Pharmaceutical Co., Ltd., Kagawa, Japan). Urinary excretion rate of 8-hydroxydeoxyguanosine (8-OHdG) was measured by high performance liquid chromatography (HPLC) (in-house prepared solution), and urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2a) was measured by enzyme immunoassay (EIA) (Cayman Chemical Co., Ann Arbor, MI, USA). High-molecularweight adiponectin was measured by chemiluminescent enzyme immunoassay (CLEIA) (Fuji Rebio Corp., Tokyo, Japan). Leptin was measured by RIA (Millipore Corp.). C-reactive protein (CRP) was measured by nephelometry (Siemens Healthcare Diagnostics Corp., Tokyo, Japan). Daily glycemic profile Subjects were asked to conduct 7-point self-monitoring of blood glucose (SMBG) using a Onetouch® UltraVue (LifeScan Inc., Milpitas, CA, USA) at weeks 0 and 24 to assess the daily glycemic profile. Sevenpoint SMBG was conducted seven times a day; before and 1 h after each meal and at bedtime, for two consecutive days, and the mean of the two days was used for analysis, as previously described [16]. We chose 1 h after meals to assess postprandial glucose level because it has been reported that the postmeal glucose peak in patients with T2DM occurred mostly within 1 h after a meal, and this incremental glucose peak was related to carotid intima-media thickness [18]. Meal Tolerance Test The standard mixed meal tolerance test (MTT) was performed at baseline and week 24. On the day of MTT, the patients were asked to attend hospital after an overnight fast and instructed to ingest the meal within 15 min. The meal consisted of crackers, pudding and bisque soup (460 kcal; 56.5 g carbohydrate, 18 g fat, 18 g protein, Janefu E460F18, Kewpie Corp., Tokyo, Japan). Plasma glucose, insulin, C-peptide and glucagon were measured before and 60 min after meal ingestion. Assessment of hypoglycemia, gastrointestinal symptoms and treatment satisfaction The incidence and severity of hypoglycemia were
assessed using a questionnaire completed by the patients at each visit. Hypoglycemia was defined as having hypoglycemic symptoms and/or blood glucose less than 70 mg/dL. Severe hypoglycemia was defined as hypoglycemia needing the assistance of a third party to recover. To evaluate changes in gastrointestinal symptoms, patients were asked to fill in the Gastrointestinal Symptom Rating Scale (GSRS) score [17], a validated survey of gastrointestinal symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation) at each visit. The patients were also asked to complete the Diabetes Treatment Satisfaction Questionnaire (DTSQ) [19] and the Diabetes Medication Satisfaction Questionnaire (DiabMedSat) [20] to assess treatment satisfaction at weeks 0 and 24. Statistical analysis All normally distributed data are presented as mean ± SD in the text and tables and as mean ± standard error (SE) in the figures, while non-normal data are presented as median and interquartile range (IQR). Statistical analyses were performed using SPSS version 22 (IBM, Chicago, IL, USA). Mann-Whitney’s U test or Fisher’s exact test was used to compare differences between the groups. Wilcoxon signed-rank test was used to analyze the difference in each parameter from baseline. To analyze sensitivity, the longitudinal profile was also analyzed by mixed model repeated measures (MMRM). A p value
Original
Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes Kumiko Tanaka1), Yoshifumi Saisho1), Toshihide Kawai1), Masami Tanaka1), Shu Meguro1), Junichiro Irie1), Takatoshi Imai2), Toshikatsu Shigihara3), Jiro Morimoto4), Ken Yajima5), Yoshihito Atsumi6), Izumi Takei7) and Hiroshi Itoh1) 1)
Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan Department of Internal Medicine, Yokohama Municipal Citizens’ Hospital, Kanagawa, Japan 3) Department of Internal Medicine, Eiju General Hospital, Tokyo, Japan 4) Department of Internal Medicine, Japan Community Health Care Organization Saitama Medical Center, Saitama, Japan 5) Department of Internal Medicine, Federation of National Public Service Personnel Mutual Aid Associations, Tachikawa Hospital, Tokyo, Japan 6) Diabetes Center, Eiju General Hospital, Tokyo, Japan 7) Department of Internal Medicine, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan 2)
Abstract. There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 ± 0.80% vs. -0.80 ± 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM. Key words: Liraglutide, Metformin, Type 2 diabetes, Japanese, Randomized controlled trial
The prevalence of obesity and type 2 diabetes (T2DM) continues to increase all over the world [1]. Individuals with T2DM have 2- to 3-fold increased risk of cardiovascular disease [2, 3]. Obesity, especially abdominal obesity, itself is also a risk factor for cardiovascular disease, independent of T2DM [4, 5, 6]. Obesity is also associated with various other medical Submitted Nov.10, 2014 as EJ14-0537; Accepted Feb. 6, 2015 as EJ14-0602 Released online in J-STAGE as advance publication Feb. 26, 2015
Correspondence to: Yoshifumi Saisho, M.D., Ph.D., Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected] ©The Japan Endocrine Society
conditions such as hypertension, dyslipidemia, sleep apnea syndrome and cancer [7]. Thus, simultaneous treatment of obesity and T2DM is an urgent issue for obese patients with T2DM. Metformin is recommended as a first-line oral antihyperglycemic agent for the treatment of T2DM in the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines [8]. Treatment with metformin has been shown to have a neutral or even beneficial effect on body weight, in addition to improvement of glycemic control [8]. However, since only a low dose (up to 750 mg/day) of metformin had been approved in Japan until 2010,
Tanaka et al.
400
the efficacy and safety of a high dose (up to 2250 mg) of metformin remains to be established in Japanese patients with T2DM. On the other hand, a meta-analysis of randomized clinical trials has demonstrated significant weight loss as well as improvement of glycemic control and cardiometabolic risk factors in patients with T2DM treated with glucagon-like peptide-1 receptor agonists (GLP1RA) [9, 10]. It has also been reported that the glucoselowering effect of incretin therapy is more marked in Asians than in Caucasians [11, 12]. Thus, once-daily administration of a GLP-1RA, liraglutide, could be a first-line treatment for individuals with T2DM, especially those who are overweight or obese, in Japan. Therefore, in this study we evaluated the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in Japanese overweight/obese patients with T2DM.
Research Design and Methods Subjects Overweight or obese patients (i.e., BMI ≥ 23.5 kg/m2 for Asians) with T2DM aged 20-75 years whose glycemic control was suboptimal (HbA1c 6.9-9.4%) were enrolled in this study. To compare liraglutide vs. metformin monotherapy, we enrolled only patients treated with lifestyle modification ± an a-glucosidase inhibitor ± low-dose metformin (i.e., 750 mg/day or less) over 3 months, but not those treated with insulin secretagogues such as sulfonylureas and glinides, thiazolidinedione or insulin. The study participants were recruited at six hospitals between September 2010 and September 2013. Exclusion criteria included 1) type 1 diabetes, 2) contraindication to metformin or liraglutide, 3) advanced diabetic retinopathy (i.e., preproliferative or proliferative retinopathy) and 4) pregnancy. The study was approved by the ethical committee of Keio University School of Medicine and registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www. umin.ac.jp/ctr/) as the Keio study for Initial treatment of type 2 Diabetes with Liraglutide versus Metformin (KIND-LM); UMIN000004243. Written informed consent was obtained from all study subjects. Study protocol The study was a 24-week, open-labeled, randomized controlled study. Subjects were randomized to either metformin (1500 mg daily or more) or liraglu-
tide monotherapy. Oral hypoglycemic agents that had been used before randomization were discontinued at week 0. The patients were asked to continue lifestyle modification during the study. Metformin was started at an initial dose of 500-750 mg daily, then the dosage was up-titrated weekly to 1500 mg daily. After week 10, the attending physicians were allowed to increase the dosage up to 2250 mg daily, if tolerated. The initial dose of liraglutide was 0.3 mg once daily by subcutaneous injection, and the dosage was up-titrated by 0.3 mg weekly to 0.9 mg daily, which is the maximum dose approved in Japan. The patients were followed monthly for 24 weeks. The primary endpoint was change in HbA1c at week 24. Estimation of sample size The study was powered to show superiority in the primary endpoint, HbA1c, at week 24 in the liraglutide group. Based on the phase 2 and 3 studies [13, 14], we estimated HbA1c reduction in the liraglutide group and metformin group to be 1.8% and 1.2%, respectively. In order to detect a difference in HbA1c of 0.6% with SD of 1.0% between the two treatment groups, 50 subjects per group would yield a power of 80% with a 5% twosided significance level. Assuming a withdrawal rate of 10%, enrollment of 55 subjects per group was planned. Measurements Body weight and blood pressure were measured at each visit. Waist circumference at the umbilical level was measured at baseline and week 24. Blood and urine samples were obtained after an overnight fast at each visit. Plasma glucose, HbA1c, insulin, triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, creatinine, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured using routine automated laboratory methods [15, 16]. HbA1c was measured by high-performance liquid chromatography (HPLC) and expressed as the National Glycohemoglobin Standardized Program (NGSP) value [17]. Serum insulin and C-peptide immunoreactivity (CPR) were measured by EIA. Proinsulin and glucagon were measured by radioimmunoassay (RIA) (Millipore Corp., Darmstadt, Germany). Homeostasis model assessment of insulin resistance (HOMA-IR) or beta cell function (HOMA-b) was calculated using the HOMA-2 calculator (https://www.dtu.ox.ac.uk/homacalculator/). CPR index was calculated as: serum CPR
401
Liraglutide compared with metformin
(ng/mL)/plasma glucose (mg/dL) x 100, as previously described [15]. The following variables were assessed at baseline and week 24. Oxidized LDL was measured by ELISA (Sekisui Medical Corp., Tokyo, Japan) and pentosidine was measured by ELISA (Fushimi Pharmaceutical Co., Ltd., Kagawa, Japan). Urinary excretion rate of 8-hydroxydeoxyguanosine (8-OHdG) was measured by high performance liquid chromatography (HPLC) (in-house prepared solution), and urinary excretion rate of 8-iso-prostaglandin F2alpha (8-iso-PGF2a) was measured by enzyme immunoassay (EIA) (Cayman Chemical Co., Ann Arbor, MI, USA). High-molecularweight adiponectin was measured by chemiluminescent enzyme immunoassay (CLEIA) (Fuji Rebio Corp., Tokyo, Japan). Leptin was measured by RIA (Millipore Corp.). C-reactive protein (CRP) was measured by nephelometry (Siemens Healthcare Diagnostics Corp., Tokyo, Japan). Daily glycemic profile Subjects were asked to conduct 7-point self-monitoring of blood glucose (SMBG) using a Onetouch® UltraVue (LifeScan Inc., Milpitas, CA, USA) at weeks 0 and 24 to assess the daily glycemic profile. Sevenpoint SMBG was conducted seven times a day; before and 1 h after each meal and at bedtime, for two consecutive days, and the mean of the two days was used for analysis, as previously described [16]. We chose 1 h after meals to assess postprandial glucose level because it has been reported that the postmeal glucose peak in patients with T2DM occurred mostly within 1 h after a meal, and this incremental glucose peak was related to carotid intima-media thickness [18]. Meal Tolerance Test The standard mixed meal tolerance test (MTT) was performed at baseline and week 24. On the day of MTT, the patients were asked to attend hospital after an overnight fast and instructed to ingest the meal within 15 min. The meal consisted of crackers, pudding and bisque soup (460 kcal; 56.5 g carbohydrate, 18 g fat, 18 g protein, Janefu E460F18, Kewpie Corp., Tokyo, Japan). Plasma glucose, insulin, C-peptide and glucagon were measured before and 60 min after meal ingestion. Assessment of hypoglycemia, gastrointestinal symptoms and treatment satisfaction The incidence and severity of hypoglycemia were
assessed using a questionnaire completed by the patients at each visit. Hypoglycemia was defined as having hypoglycemic symptoms and/or blood glucose less than 70 mg/dL. Severe hypoglycemia was defined as hypoglycemia needing the assistance of a third party to recover. To evaluate changes in gastrointestinal symptoms, patients were asked to fill in the Gastrointestinal Symptom Rating Scale (GSRS) score [17], a validated survey of gastrointestinal symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation) at each visit. The patients were also asked to complete the Diabetes Treatment Satisfaction Questionnaire (DTSQ) [19] and the Diabetes Medication Satisfaction Questionnaire (DiabMedSat) [20] to assess treatment satisfaction at weeks 0 and 24. Statistical analysis All normally distributed data are presented as mean ± SD in the text and tables and as mean ± standard error (SE) in the figures, while non-normal data are presented as median and interquartile range (IQR). Statistical analyses were performed using SPSS version 22 (IBM, Chicago, IL, USA). Mann-Whitney’s U test or Fisher’s exact test was used to compare differences between the groups. Wilcoxon signed-rank test was used to analyze the difference in each parameter from baseline. To analyze sensitivity, the longitudinal profile was also analyzed by mixed model repeated measures (MMRM). A p value
