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Comparing the Effects of Ipragliflozin versus Metformin Added to Sitagliptin on Visceral Fat Reduction in Asian Patients with Type 2 Diabetes: A Prospective, Multicenter, Blinded-Endpoint Randomized Controlled Study (PRIME-V Study)

116 Pages Posted: 11 Oct 2018

See all articles by Masaya Koshizaka

Masaya Koshizaka

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Ko Ishikawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Ryoichi Ishibashi

Chiba University - Department of Clinical Cell Biology and Medicine; Kimitsu Central Hospital - Department of Endocrinology and Metabolism

Yoshiro Maezawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Kenichi Sakamoto

Chiba University - Department of Clinical Cell Biology and Medicine; Chiba University - Eastern Chiba Medical Center

Daigaku Uchida

Hotaruno Central Naika

Susumu Nakamura

Odayama Clinic

Masaya Yamaga

Japanese Red Cross Narita Hospital

Hidetaka Yokoh

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Akina Kobayashi

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Shunichiro Onishi

Asahi General Hospital

Kazuki Kobayashi

Chiba University - Department of Clinical Cell Biology and Medicine; Asahi General Hospital

Jun Ogino

Tokyo Womens Medical University - Yachiyo Medical Center

Naotake Hashimoto

Tokyo Womens Medical University - Yachiyo Medical Center

Hirotake Tokuyama

Yukarigaoka Tokuyama Medical Clinic

Fumio Shimada

National Hospital Organization (NHO) - Chiba Medical Center

Emi Ohara

National Hospital Organization (NHO) - Chiba Medical Center

Takahiro Ishikawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Geriatric Medical Center

Mayumi Shoji

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Shintaro Ide

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Kana Ide

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Yusuke Baba

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Akiko Hattori

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Takumi Kitamoto

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Takuro Horikoshi

Chiba University - Diagnostic Radiology and Radiation Oncology

Ryouta Shimofusa

Sannou Hospital

Sho Takahashi

Chiba University - Clinical Research Center

Kengo Nagashim

Chiba University - Department of Global Clinical Research

Yasunori Sato

Chiba University - Department of Global Clinical Research

Minoru Takemoto

International University of Health and Welfare, Narita Campus

L. Kristin Newby

Duke University - Duke Clinical Research Institute

Koutaro Yokote

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

More...

Abstract

Background: Visceral fat accumulation is associated with insulin resistance and various metabolic complications. We aimed to determine the effect of ipragliflozin (sodium-dependent glucose transporter-2 inhibitor) versus metformin with a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) in reducing visceral fat in Asian patients with insufficiently controlled type 2 diabetes.

Methods: A prospective, multicenter, blinded-endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with either ipragliflozin or metformin combined with sitagliptin on visceral fat reduction and glycemic control among Japanese patients with type 2 diabetes, HbA1c 7-10%, and BMI ≥22 kg/m2. Patients who met the eligibility criteria were randomly assigned (1:1) to receive ipragliflozin 50 mg (n=51) or metformin 1000-1500 mg daily (n=52). The primary outcome was rate change in visceral fat area measured by computed tomography at 24 weeks of therapy. Two radiologists, blinded to patients' clinical information and randomized treatment assignment, analyzed the images. Secondary outcomes included effects on blood glucose, fasting insulin level, and lipids. The full analysis set was used for analysis.

Findings: Mean percent reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (-12·06% vs. -3·65%, group difference [95% CI] -8·40%; [-16·4 to -3·38], P=0·040). The ipragliflozin group also showed significant lowering of fasting insulin (-20·73% vs. 0·85%, group difference [95% CI] -21·58%, [2·80 to 34·20], P=0·018), while HbA1c decreased in the metformin group compared with ipragliflozin group.

Interpretation: Ipragliflozin significantly reduced the visceral fat area compared with metformin, as the secondary agent used in combination with DPP-4 inhibitor. Since the fasting insulin level decreased, the reduction in visceral fat associated with ipragliflozin administration might have contributed to the improvement in insulin resistance.

Trial Registration Number: Trial registration: UMIN 000015170.

Funding Statement: To conduct this study, an agreement was signed between Chiba University and Astellas Pharma Inc. (Tokyo, Japan). Astellas Pharma Inc. funded this work.

Declaration of Interests: KY received research grants from Astellas Pharma Inc. and MSD K.K. (Tokyo, Japan), and received a lecture fee from Astellas Pharma Inc. and Sumitomo Dainippon Pharma (Tokyo, Japan). No conflicts of interest are declared for other authors.

Ethics Approval Statement: The study protocol was approved by the Institutional Review Boards (IRBs), Ethics Review Committees, or Ethics Committees of the following institutions: Chiba University Hospital (ID number: G26009), Asahi General Hospital (ID number: 2014091602), National Hospital Organization Chiba Medical Center, Seirei Sakura Citizen Hospital, Chiba Rosai Hospital (ID number: 26-21), Toho University Sakura Medical Center (ID number: 2014-077), Tokyo Women’s Medical University Yachiyo Medical Center (ID number: 150303), Chiba Aoba Municipal Hospital, Kimitsu Chuo Hospital, Funabashi Central Hospital (ID number: H27-1), and Chiba Kaihin Municipal Hospital. In other facilities, approval was provided at Chiba University Hospital (which had the centralized IRB).

Suggested Citation

Koshizaka, Masaya and Ishikawa, Ko and Ishibashi, Ryoichi and Maezawa, Yoshiro and Sakamoto, Kenichi and Uchida, Daigaku and Nakamura, Susumu and Yamaga, Masaya and Yokoh, Hidetaka and Kobayashi, Akina and Onishi, Shunichiro and Kobayashi, Kazuki and Ogino, Jun and Hashimoto, Naotake and Tokuyama, Hirotake and Shimada, Fumio and Ohara, Emi and Ishikawa, Takahiro and Shoji, Mayumi and Ide, Shintaro and Ide, Kana and Baba, Yusuke and Hattori, Akiko and Kitamoto, Takumi and Horikoshi, Takuro and Shimofusa, Ryouta and Takahashi, Sho and Nagashim, Kengo and Sato, Yasunori and Takemoto, Minoru and Newby, L. Kristin and Yokote, Koutaro, Comparing the Effects of Ipragliflozin versus Metformin Added to Sitagliptin on Visceral Fat Reduction in Asian Patients with Type 2 Diabetes: A Prospective, Multicenter, Blinded-Endpoint Randomized Controlled Study (PRIME-V Study) (June 10, 2018). Available at SSRN: https://ssrn.com/abstract=3263665 or http://dx.doi.org/10.2139/ssrn.3263665

Masaya Koshizaka

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Ko Ishikawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Ryoichi Ishibashi

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Kimitsu Central Hospital - Department of Endocrinology and Metabolism

Sakurai 1010
Kisarazu City, Chiba 292-0822
Japan

Yoshiro Maezawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Kenichi Sakamoto

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Chiba University - Eastern Chiba Medical Center

Okasandai 3-6-2
Togane City, Chiba 283-8686
Japan

Daigaku Uchida

Hotaruno Central Naika

3-30-3 Hotaruno
Kisarazu City, Chiba 292-0038
Japan

Susumu Nakamura

Odayama Clinic

Ota 3-2-2
Kisarazu City, Chiba 292-0044
Japan

Masaya Yamaga

Japanese Red Cross Narita Hospital

90-1, Iida-cho
Narita City, Chiba 286-8523
Japan

Hidetaka Yokoh

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Akina Kobayashi

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Shunichiro Onishi

Asahi General Hospital

I-1326
Asahi City, Chiba 289-2511
Japan

Kazuki Kobayashi

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Asahi General Hospital

I-1326
Asahi City, Chiba 289-2511
Japan

Jun Ogino

Tokyo Womens Medical University - Yachiyo Medical Center

477-96, Owadashinden
Yachiyo City, Chiba 276-8524
Japan

Naotake Hashimoto

Tokyo Womens Medical University - Yachiyo Medical Center

477-96, Owadashinden
Yachiyo City, Chiba 276-8524
Japan

Hirotake Tokuyama

Yukarigaoka Tokuyama Medical Clinic

Nishi-Yukarigaoka 7-2-2
Sakura City, Chiba 285-0850
Japan

Fumio Shimada

National Hospital Organization (NHO) - Chiba Medical Center

Tsubakimori 4-1-2
Chuo-ku
Chiba City, Chiba 260-8606
Japan

Emi Ohara

National Hospital Organization (NHO) - Chiba Medical Center

Tsubakimori 4-1-2
Chuo-ku
Chiba City, Chiba 260-8606
Japan

Takahiro Ishikawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Geriatric Medical Center

1-8-1 Inohana, Chuo-ku
Chiba City, Chiba 260-8677
Japan

Mayumi Shoji

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Shintaro Ide

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Kana Ide

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Yusuke Baba

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Akiko Hattori

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Takumi Kitamoto

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Takuro Horikoshi

Chiba University - Diagnostic Radiology and Radiation Oncology

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Ryouta Shimofusa

Sannou Hospital

166-2 Sannou-chou
Inage-ku
Chiba City, Chiba 263-0002
Japan

Sho Takahashi

Chiba University - Clinical Research Center

1-8-1 Inohana, Chuo-ku
Chiba City, 260-8677
Japan

Kengo Nagashim

Chiba University - Department of Global Clinical Research

1-8-1 Inohana, Chuo-ku
Chiba City, Chiba 260-8670
Japan

Yasunori Sato

Chiba University - Department of Global Clinical Research

1-8-1 Inohana, Chuo-ku
Chiba City, Chiba 260-8670
Japan

Minoru Takemoto

International University of Health and Welfare, Narita Campus

4-3 Kozunomori
Narita City, Chiba 286-0048
Japan

L. Kristin Newby

Duke University - Duke Clinical Research Institute

2400 Pratt Street
Durham, NC 27705
United States

Koutaro Yokote (Contact Author)

Chiba University - Division of Diabetes, Metabolism and Endocrinology ( email )

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine ( email )

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

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