Rationale and Design of the STOP-OB Study for Evaluating the Effects of Tofogliflozin and Glimepiride on Fat Deposition in Type 2 Diabetes Patients Treated with Metformin/DPP-4 Inhibitor Dual Therapy

Hisamitsu Ishihara; Motonobu Anai; Hiroaki Seino; Toru Kitazawa; Hiroshi Ohashi; Masumi Ai; Masahiro Inoue; Midori Fujishiro; Takeshi Inazawa; Hisamoto Kuroda; Masayo Yamada

doi:10.1007/s13300-018-0491-4

Rationale and Design of the STOP-OB Study for Evaluating the Effects of Tofogliflozin and Glimepiride on Fat Deposition in Type 2 Diabetes Patients Treated with Metformin/DPP-4 Inhibitor Dual Therapy

Diabetes Ther. 2018 Oct;9(5):2117-2125. doi: 10.1007/s13300-018-0491-4. Epub 2018 Aug 25.

Authors

Hisamitsu Ishihara^{1

2}, Motonobu Anai^{3

4}, Hiroaki Seino⁵, Toru Kitazawa⁶, Hiroshi Ohashi⁷, Masumi Ai^{8

9}, Masahiro Inoue¹⁰, Midori Fujishiro^{11

12}, Takeshi Inazawa¹³, Hisamoto Kuroda¹⁴, Masayo Yamada¹⁵

Affiliations

¹ Division of Diabetes and Metabolism, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan. ishihara.hisamitsu@nihon-u.ac.jp.
² Department of Internal Medicine, Nihon University Hospital, 1-6 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8309, Japan. ishihara.hisamitsu@nihon-u.ac.jp.
³ Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
⁴ Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 2-2-6 Nihonbashi Magui-cho, Chuo-ku, Tokyo, 103-0002, Japan.
⁵ Seino Internal Medicine Clinic, 6-192-2 Kaisei, Koriyama, Fukushima, 963-8851, Japan.
⁶ Division of Diabetes, Endocrinology and Metabolism, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan.
⁷ Oyama East Clinic, 1-32-1 Ekihigashi-tori, Oyama, Tochigi, 323-0022, Japan.
⁸ Tanaka Clinic, 12-40 Hon-cho, Wako, Saitama, 351-0114, Japan.
⁹ Department of Insured Medical Care Management, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
¹⁰ Sasazuka Inoue Clinic, 1-15-4 Sasazuka, Shibuya-ku, Tokyo, 151-0073, Japan.
¹¹ Division of Diabetes and Metabolism, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
¹² Department of Internal Medicine, Nihon University Hospital, 1-6 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8309, Japan.
¹³ Department of Endocrinology and Metabolism, Kashiwa City Hospital, 1-3 Fuse, Kashiwa, Chiba, 277-0825, Japan.
¹⁴ Green Clinic, 3-9-15 Midori-machi, Mibu, Tochigi, 321-0204, Japan.
¹⁵ Yokohama Sakae Kyosai Hospital, 132 Katsura-cho, Sakae-ku, Yokohama, Kanagawa, 247-8581, Japan.

Abstract

Background: The global pandemic of type 2 diabetes mellitus (T2DM) is an enormous clinical and socioeconomic burden. Biguanides and DPP-4 inhibitors (DPP-4i) are the most commonly used therapies in Japanese T2DM patients. When glycemic control is not adequate despite combination of these drugs, there is no consensus on the next step drug. Systematic reviews and meta-analyses of previous trials have indicated that glycemic control with triple combination therapies yields similar results. Thus, beneficial effects on cardiovascular risk factors may be important. The present study was designed to evaluate body fat percentage and several insulin resistance parameters after addition of tofogliflozin or glimepiride to the regimens of patients being treated with metformin and a DPP-4 inhibitor but failing to attain adequate blood glucose control.

Methods: Sodium glucose cotransporter-2 inhibitor, tofogliflozin versus glimepiride, comparative trial in patients with type 2 diabetes on body composition is an ongoing, multicenter, prospective, randomized, open-label, parallel-group trial. T2DM patients treated with metformin/DPP-4 inhibitor dual therapy have been recruited and randomly assigned to 20 mg/day tofogliflozin (n = 32) or 0.5 mg/day glimepiride (n = 32) groups, with either of these drugs being added to pre-existing regimens for 24 weeks.

Planned outcomes: The primary endpoint is the change in body fat percentage from baseline to 24 weeks. The secondary outcomes are changes in body composition other than fat percentage, body weight, parameters related to glycemic control and β-cell function, parameters related to lipids and arteriosclerosis, parameters related to liver function, parameters related to diabetic nephropathy, and uric acid levels. Safety parameters will also be analyzed. This is the first trial comparing the effects and safety of adding an SGLT2i and a sulfonylurea as the third-line oral agent to metformin/DPP-4i dual therapy. The results will provide valuable information for choosing third-line oral agents.

Trial registration: UMIN000026161.

Funding: Kowa Co. Ltd. and Kowa Pharmaceutical Co. Ltd., Tokyo, Japan.

Keywords: Fat deposition; SGLT2 inhibitor; Sulfonylurea; Third-line oral drug; Type 2 diabetes mellitus.