Endocrine Journal 2015, 62 (7), 593-603
Original
Fifty-two-week long-term clinical study of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise Yutaka Seino1), Kohei Kaku 2), Nobuya Inagaki 3), Masakazu Haneda4), Takashi Sasaki 5), Atsushi Fukatsu6), Michito Ubukata7), Soichi Sakai 7) and Yoshishige Samukawa7) 1)
Kansai Electric Power Hospital, Osaka 553-0003, Japan Kawasaki Medical School, Department of Internal Medicine, Kurashiki 701-0192, Japan 3) Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto 606-8501, Japan 4) Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa 0788510, Japan 5) Division of Diabetes and Endocrinology, The Jikei University Graduate School of Medical Research, Tokyo 105-8461, Japan* 6) Yachiyo Hospital, Anjo 446-8510, Japan 7) Taisho Pharmaceutical Co., Ltd., Tokyo 170-8633, Japan 2)
Abstract. Luseogliflozin, a selective sodium glucose cotransporter 2 inhibitor, was demonstrated in a previous 24-week study of type 2 diabetic patients to be efficacious and well tolerated. This study mainly aimed to evaluate the long-term safety of luseogliflozin monotherapy in Japanese type 2 diabetic patients based on the Japanese guidelines. Additionally, long-term efficacy was also evaluated. Patients on diet and exercise therapy alone with an HbA1c of 6.9-10.5% received luseogliflozin 2.5 mg once daily for 52 weeks. For patients with insufficient glycemic control, this dose was able to be increased to 5 mg at Week 24. Adverse events (AEs), clinical laboratory tests, vital signs and 12-lead electrocardiograms were used to assess safety. Efficacy endpoints consisted of changes in HbA1c, fasting plasma glucose (FPG), and body weight from baseline. Of 299 patients who received luseogliflozin, 279 completed the study. Most AEs were mild in severity with incidences of AEs and adverse drug reactions at 75.3% and 16.7%, respectively. Although hypoglycemia was observed in 7 patients (2.3%), no major hypoglycemic episodes occurred. The incidences of AEs of special interest, including pollakiuria, volume depletion and urinary tract/genital infections, were at acceptable levels. Luseogliflozin significantly lowered HbA1c (-0.50%, P< 0.001), FPG (-16.3 mg/dL, P< 0.001) and body weight (-2.68 kg, P< 0.001) at Week 52 compared to baseline. Up-titration to 5 mg further improved glycemic control. In this long-term study of Japanese type 2 diabetic patients, luseogliflozin monotherapy was well tolerated for 52 weeks and provided a sustained glycemic lowering effect and reduced body weight. Key words: Long-term, Luseogliflozin, Monotherapy, Sodium glucose cotransporter 2 inhibitor, Type 2 diabetes mellitus
In 2014, it was estimated that there were over 387 million patients with diabetes globally, with 7.2 million Submitted Feb. 13, 2015; Accepted Apr. 5, 2015 as EJ15-0097 Released online in J-STAGE as advance publication May 12, 2015
Correspondence to: Soichi Sakai, Taisho Pharmaceutical Co., Ltd., 3-24-1, Takada, Toshima-ku, Tokyo 170-8633, Japan. E-mail: [email protected] Previous presentation: Parts of this study were reported as an abstract and poster (abstract P-1472) at the International Diabetes Federation 2013 World Diabetes Congress, Melbourne, Australia, December 2-6, 2013 *The present address is as follows; Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa 277-8567, Japan. ©The Japan Endocrine Society
patients in Japan alone [1]. Type 2 diabetes mellitus, which accounts for more than 90% of all diabetic diseases, is a complex and progressive metabolic disorder that is associated with complications such as obesity, hypertension, and hyperlipidemia [2]. Several oral antidiabetic drugs, such asbiguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, α-glucosidase inhibitors and glinides, are currently available in Japan. However, it is not uncommon for these agents to be associated with inadequate glycemic control, reduced efficacy after continuous long-term use, or adverse effects that restrict continued treatment such as hypoglycemia or
Seino et al.
594
weight gain [3-5]. Therefore, an antidiabetic agent that lowers plasma glucose levels but does not elicit serious adverse effects and undesirable influence on body weight or other factors associated with metabolic syndrome is needed. Sodium glucose cotransporter 2 (SGLT2) inhibitors are expected to function as a new class of hypoglycemic agents. Such drugs increase urinary glucose excretion (UGE) by inhibiting SGLT2 located in the renal proximal tubules, thereby reducing plasma glucose levels in an insulin-independent manner. In a previous dose-finding 12-week study [6], monotherapy with luseogliflozin, a selective SGLT2 inhibitor, provided clinically meaningful glycemic control at doses of 2.5 mg or more (for some parameters such as body weight, maximum effect was seen at a dose of 5 mg) and had good tolerability up to a dose of 10 mg. In addition, efficacy and safety of the drug given as monotherapy for up to 24 weeks compared to placebo was confirmed [7]. Given that the treatments for type 2 diabetes mellitus are often required over a long period of time, investigations into the safety and efficacy of long-term treatment with any antidiabetic agent is of great importance. Therefore, to evaluate the long-term safety of luseogliflozin monotherapy based on the Japanese guidelines for the clinical evaluation of oral antidiabetic drugs and long-term treatment [8, 9], luseogliflozin 2.5 mg was administered for 52 weeks to Japanese patients with type 2 diabetes mellitus whose glycemic control was insufficient with diet/exercise therapy alone. In addition, safety and efficacy of luseogliflozin up-titration to 5 mg was also evaluated in cases where glycemic control with 2.5 mg was insufficient.
Materials and Methods This study was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice (GCP),
Fig. 1 Study design
and the International Conference on Harmonisation (ICH) guidelines. The study protocol was reviewed and approved by the institutional review boards (IRBs) of all participating medical institutions and written informed consent was obtained from all subjects enrolled in this study. The equivalent National Glycohemoglobin Standardization Program (NGSP) value (%) for HbA1c was calculated using the Japan Diabetes Society (JDS)-assigned value [10]. This study was registered beforehand at the Japan Pharmaceutical Information Center (JapicCTI-111509). The list of study sites and principle investigators are included in the supporting information (Table S1). Study design Aimed at investigating the safety and efficacy of luseogliflozin monotherapy, this long-term administration study was designed based on the Japanese guidelines for the clinical evaluation of oral antidiabetic drugs and long-term treatment [8, 9]. This was a multicenter, open-label, uncontrolled clinical study that consisted of a 4-week observation period and 52-week treatment period. Japanese patients with type 2 diabetes mellitus with inadequate plasma glucose control from diet and exercise therapies alone were enrolled in the study. Luseogliflozin 2.5 mg was orally administered to all subjects before breakfast once daily, with an allowable dose increase to 5 mg at Week 24 in subjects whose HbA1c was ≥7.4% at both Weeks 16 and 20. The study was carried out at 50 medical institutions between May 2011 and October 2012. The study design is shown in Fig. 1. Patients Of the type 2 diabetic patients who had received regular diet therapy for more than 8 weeks before the observation period, those aged ≥20 years and whose HbA1c was 6.9-10.5% with changes within 1.0% dur-
595
Long-term luseogliflozin monotherapy
ing the 4-week observation period were selected as study subjects. Major exclusion criteria consisted of presence of diabetes other than type 2, endocrine disorders other than diabetes that may affect plasma glucose, implementation of diabetic treatment within 8 weeks prior to initiation of the observation period, history of nephrectomy or renal transplantation, renal disorder requiring active treatment, estimated glomerular filtration rate (eGFR) of 170/100 mmHg, change in antihypertensive agent during the observation period, diabetic microangiopathy, and severe heart disease. Use of an insulin product and an antidiabetic drug was prohibited. Use of a hypolipidemic agent, antihypertensive agent or diuretic agent was permitted as long as the dose was kept constant throughout the study period. Clinical evaluation Major safety endpoints consisted of the nature and frequency of adverse events (AEs), including changes in laboratory values, vital signs and 12-lead electrocardiogram (ECG) findings. During the study period, subjects visited medical institutions at Weeks 0, 2 and 4 and every 4 weeks thereafter until Week 52 to undergo medical examinations, laboratory tests (hematology, blood chemistry and urinalysis), physical examinations (blood pressure, pulse rate and body temperature) and 12-lead ECG examination. AEs, including hypoglycemia, were judged by the participant investigators based on symptoms, laboratory tests, physical examinations and 12-lead ECG results. When an AE was observed, its description, severity, seriousness, causal relationship to the study drug and other pertinent information were recorded. All laboratory tests and 12-lead ECG examinations were analyzed at a central laboratory. Major efficacy endpoints consisted of the changes from baseline (Week 0) in HbA1c, fasting plasma glucose (FPG) and body weight at Week 52 of treatment. Statistical analyses Safety and efficacy assessments were performed on all subjects who received the study drug at least once and underwent examination/observation for the postadministration assessment. Adverse events observed were coded using
MedDRA Ver. 15.0, and their frequencies during the 52-week treatment period were tabulated. Basic statistics of laboratory values, vital signs and 12-lead ECG findings at each evaluation point through Week 52 were calculated. Basic statistics of each efficacy endpoint were calculated at each evaluation point through Week 52 (missing or unacceptable data were not complemented). Changes from baseline (Week 0) in each efficacy endpoint at Week 52 were evaluated using a one-sample t-test. Significance level was set at 5% (two-sided) and confidence coefficient was set at 95% (two-sided). Proportions of subjects that achieved HbA1c treatment goals (
Original
Fifty-two-week long-term clinical study of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise Yutaka Seino1), Kohei Kaku 2), Nobuya Inagaki 3), Masakazu Haneda4), Takashi Sasaki 5), Atsushi Fukatsu6), Michito Ubukata7), Soichi Sakai 7) and Yoshishige Samukawa7) 1)
Kansai Electric Power Hospital, Osaka 553-0003, Japan Kawasaki Medical School, Department of Internal Medicine, Kurashiki 701-0192, Japan 3) Kyoto University Graduate School of Medicine, Department of Diabetes, Endocrinology and Nutrition, Kyoto 606-8501, Japan 4) Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa 0788510, Japan 5) Division of Diabetes and Endocrinology, The Jikei University Graduate School of Medical Research, Tokyo 105-8461, Japan* 6) Yachiyo Hospital, Anjo 446-8510, Japan 7) Taisho Pharmaceutical Co., Ltd., Tokyo 170-8633, Japan 2)
Abstract. Luseogliflozin, a selective sodium glucose cotransporter 2 inhibitor, was demonstrated in a previous 24-week study of type 2 diabetic patients to be efficacious and well tolerated. This study mainly aimed to evaluate the long-term safety of luseogliflozin monotherapy in Japanese type 2 diabetic patients based on the Japanese guidelines. Additionally, long-term efficacy was also evaluated. Patients on diet and exercise therapy alone with an HbA1c of 6.9-10.5% received luseogliflozin 2.5 mg once daily for 52 weeks. For patients with insufficient glycemic control, this dose was able to be increased to 5 mg at Week 24. Adverse events (AEs), clinical laboratory tests, vital signs and 12-lead electrocardiograms were used to assess safety. Efficacy endpoints consisted of changes in HbA1c, fasting plasma glucose (FPG), and body weight from baseline. Of 299 patients who received luseogliflozin, 279 completed the study. Most AEs were mild in severity with incidences of AEs and adverse drug reactions at 75.3% and 16.7%, respectively. Although hypoglycemia was observed in 7 patients (2.3%), no major hypoglycemic episodes occurred. The incidences of AEs of special interest, including pollakiuria, volume depletion and urinary tract/genital infections, were at acceptable levels. Luseogliflozin significantly lowered HbA1c (-0.50%, P< 0.001), FPG (-16.3 mg/dL, P< 0.001) and body weight (-2.68 kg, P< 0.001) at Week 52 compared to baseline. Up-titration to 5 mg further improved glycemic control. In this long-term study of Japanese type 2 diabetic patients, luseogliflozin monotherapy was well tolerated for 52 weeks and provided a sustained glycemic lowering effect and reduced body weight. Key words: Long-term, Luseogliflozin, Monotherapy, Sodium glucose cotransporter 2 inhibitor, Type 2 diabetes mellitus
In 2014, it was estimated that there were over 387 million patients with diabetes globally, with 7.2 million Submitted Feb. 13, 2015; Accepted Apr. 5, 2015 as EJ15-0097 Released online in J-STAGE as advance publication May 12, 2015
Correspondence to: Soichi Sakai, Taisho Pharmaceutical Co., Ltd., 3-24-1, Takada, Toshima-ku, Tokyo 170-8633, Japan. E-mail: [email protected] Previous presentation: Parts of this study were reported as an abstract and poster (abstract P-1472) at the International Diabetes Federation 2013 World Diabetes Congress, Melbourne, Australia, December 2-6, 2013 *The present address is as follows; Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa 277-8567, Japan. ©The Japan Endocrine Society
patients in Japan alone [1]. Type 2 diabetes mellitus, which accounts for more than 90% of all diabetic diseases, is a complex and progressive metabolic disorder that is associated with complications such as obesity, hypertension, and hyperlipidemia [2]. Several oral antidiabetic drugs, such asbiguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, α-glucosidase inhibitors and glinides, are currently available in Japan. However, it is not uncommon for these agents to be associated with inadequate glycemic control, reduced efficacy after continuous long-term use, or adverse effects that restrict continued treatment such as hypoglycemia or
Seino et al.
594
weight gain [3-5]. Therefore, an antidiabetic agent that lowers plasma glucose levels but does not elicit serious adverse effects and undesirable influence on body weight or other factors associated with metabolic syndrome is needed. Sodium glucose cotransporter 2 (SGLT2) inhibitors are expected to function as a new class of hypoglycemic agents. Such drugs increase urinary glucose excretion (UGE) by inhibiting SGLT2 located in the renal proximal tubules, thereby reducing plasma glucose levels in an insulin-independent manner. In a previous dose-finding 12-week study [6], monotherapy with luseogliflozin, a selective SGLT2 inhibitor, provided clinically meaningful glycemic control at doses of 2.5 mg or more (for some parameters such as body weight, maximum effect was seen at a dose of 5 mg) and had good tolerability up to a dose of 10 mg. In addition, efficacy and safety of the drug given as monotherapy for up to 24 weeks compared to placebo was confirmed [7]. Given that the treatments for type 2 diabetes mellitus are often required over a long period of time, investigations into the safety and efficacy of long-term treatment with any antidiabetic agent is of great importance. Therefore, to evaluate the long-term safety of luseogliflozin monotherapy based on the Japanese guidelines for the clinical evaluation of oral antidiabetic drugs and long-term treatment [8, 9], luseogliflozin 2.5 mg was administered for 52 weeks to Japanese patients with type 2 diabetes mellitus whose glycemic control was insufficient with diet/exercise therapy alone. In addition, safety and efficacy of luseogliflozin up-titration to 5 mg was also evaluated in cases where glycemic control with 2.5 mg was insufficient.
Materials and Methods This study was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice (GCP),
Fig. 1 Study design
and the International Conference on Harmonisation (ICH) guidelines. The study protocol was reviewed and approved by the institutional review boards (IRBs) of all participating medical institutions and written informed consent was obtained from all subjects enrolled in this study. The equivalent National Glycohemoglobin Standardization Program (NGSP) value (%) for HbA1c was calculated using the Japan Diabetes Society (JDS)-assigned value [10]. This study was registered beforehand at the Japan Pharmaceutical Information Center (JapicCTI-111509). The list of study sites and principle investigators are included in the supporting information (Table S1). Study design Aimed at investigating the safety and efficacy of luseogliflozin monotherapy, this long-term administration study was designed based on the Japanese guidelines for the clinical evaluation of oral antidiabetic drugs and long-term treatment [8, 9]. This was a multicenter, open-label, uncontrolled clinical study that consisted of a 4-week observation period and 52-week treatment period. Japanese patients with type 2 diabetes mellitus with inadequate plasma glucose control from diet and exercise therapies alone were enrolled in the study. Luseogliflozin 2.5 mg was orally administered to all subjects before breakfast once daily, with an allowable dose increase to 5 mg at Week 24 in subjects whose HbA1c was ≥7.4% at both Weeks 16 and 20. The study was carried out at 50 medical institutions between May 2011 and October 2012. The study design is shown in Fig. 1. Patients Of the type 2 diabetic patients who had received regular diet therapy for more than 8 weeks before the observation period, those aged ≥20 years and whose HbA1c was 6.9-10.5% with changes within 1.0% dur-
595
Long-term luseogliflozin monotherapy
ing the 4-week observation period were selected as study subjects. Major exclusion criteria consisted of presence of diabetes other than type 2, endocrine disorders other than diabetes that may affect plasma glucose, implementation of diabetic treatment within 8 weeks prior to initiation of the observation period, history of nephrectomy or renal transplantation, renal disorder requiring active treatment, estimated glomerular filtration rate (eGFR) of 170/100 mmHg, change in antihypertensive agent during the observation period, diabetic microangiopathy, and severe heart disease. Use of an insulin product and an antidiabetic drug was prohibited. Use of a hypolipidemic agent, antihypertensive agent or diuretic agent was permitted as long as the dose was kept constant throughout the study period. Clinical evaluation Major safety endpoints consisted of the nature and frequency of adverse events (AEs), including changes in laboratory values, vital signs and 12-lead electrocardiogram (ECG) findings. During the study period, subjects visited medical institutions at Weeks 0, 2 and 4 and every 4 weeks thereafter until Week 52 to undergo medical examinations, laboratory tests (hematology, blood chemistry and urinalysis), physical examinations (blood pressure, pulse rate and body temperature) and 12-lead ECG examination. AEs, including hypoglycemia, were judged by the participant investigators based on symptoms, laboratory tests, physical examinations and 12-lead ECG results. When an AE was observed, its description, severity, seriousness, causal relationship to the study drug and other pertinent information were recorded. All laboratory tests and 12-lead ECG examinations were analyzed at a central laboratory. Major efficacy endpoints consisted of the changes from baseline (Week 0) in HbA1c, fasting plasma glucose (FPG) and body weight at Week 52 of treatment. Statistical analyses Safety and efficacy assessments were performed on all subjects who received the study drug at least once and underwent examination/observation for the postadministration assessment. Adverse events observed were coded using
MedDRA Ver. 15.0, and their frequencies during the 52-week treatment period were tabulated. Basic statistics of laboratory values, vital signs and 12-lead ECG findings at each evaluation point through Week 52 were calculated. Basic statistics of each efficacy endpoint were calculated at each evaluation point through Week 52 (missing or unacceptable data were not complemented). Changes from baseline (Week 0) in each efficacy endpoint at Week 52 were evaluated using a one-sample t-test. Significance level was set at 5% (two-sided) and confidence coefficient was set at 95% (two-sided). Proportions of subjects that achieved HbA1c treatment goals (
