Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall-a sub-analysis of the UTOPIA trial

doi:10.1186/s12933-022-01451-6

Randomized Controlled Trial

. 2022 Feb 5;21(1):19.

doi: 10.1186/s12933-022-01451-6.

Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall-a sub-analysis of the UTOPIA trial

Naoto Katakami¹, Tomoya Mita², Norikazu Maeda³, Yasunori Sato⁴, Hirotaka Watada³, Iichiro Shimomura⁵; UTOPIA Study Investigators

Affiliations

¹ Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. katakami@endmet.med.osaka-u.ac.jp.
² Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan.
³ Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁴ Department of Preventive Medicine and Public Health, Keio University School of Medicine, 45 Shinanomachi Shinjuku-ku, Tokyo, 160-8582, Japan.
⁵ Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

PMID: 35123483
PMCID: PMC8817596
DOI: 10.1186/s12933-022-01451-6

Randomized Controlled Trial

Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall-a sub-analysis of the UTOPIA trial

Naoto Katakami et al. Cardiovasc Diabetol. 2022.

. 2022 Feb 5;21(1):19.

doi: 10.1186/s12933-022-01451-6.

Authors

Naoto Katakami¹, Tomoya Mita², Norikazu Maeda³, Yasunori Sato⁴, Hirotaka Watada³, Iichiro Shimomura⁵; UTOPIA Study Investigators

Affiliations

¹ Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan. katakami@endmet.med.osaka-u.ac.jp.
² Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan.
³ Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁴ Department of Preventive Medicine and Public Health, Keio University School of Medicine, 45 Shinanomachi Shinjuku-ku, Tokyo, 160-8582, Japan.
⁵ Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

PMID: 35123483
PMCID: PMC8817596
DOI: 10.1186/s12933-022-01451-6

Abstract

Background: Since sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD).

Methods: The present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as "mean GSM-CCA value."

Results: In a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] - 1.24[- 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] - 2.33[- 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] - 0.29 [- 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline.

Conclusions: The tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups. Clinical trial registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).

Keywords: Atherosclerosis; Carotid artery; Diabetes; SGLT2 inhibitor; Tissue characteristics; Tofogliflozin.

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Conflict of interest statement

Naoto Katakami is a staff member of the endowed chair established by funds from Kowa Co., Ltd., and has received research funds from MSD, and lecture fees from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim, Daiichi Sankyo Inc., Eli Lilly, Kowa Pharmaceutical Co., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Co., Novartis Pharmaceuticals, Novo Nordisk Pharma, Ono Pharmaceutical Co., Taisho Toyama Pharmaceutical Co., Takeda Pharmaceutical Co., and Sanofi-Aventis, and Shionogi & Co.

Tomoya Mita has received lecture fees from Astellas Pharma Inc., Daiichi Sankyo Inc., Eli Lilly, Kowa Pharmaceutical Co., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Co., Novo Nordisk Pharma, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited and Sanofi-Aventis, scholarship donations from MSD K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co. Ltd., Sanofi-Aventis K.K., Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Terumo Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Pfizer Japan Inc., Benefit One Health Care Inc., Mochida Pharmaceutical Co., Ltd., and Nitto Boseki Co., Ltd. as well as funds of endowed chair from MSD K.K., Takeda Pharmaceutical Company Limited.

Norikazu Maeda is a staff member of the endowed chair established by funds from Kowa Co., Ltd., and has received research funds from Kowa Co., Ltd., Teijin Pharma Co., Ltd., and Mitsubishi Tanabe Pharma Co., Ltd., and lecture fees from Astellas Pharma Inc., AstraZeneca K.K., Boehringer Ingelheim, Eli Lilly Japan K.K., Kowa Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd, Novartis Pharmaceuticals, Novo Nordisk Pharma, Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd.

Yasunori Sato has received lecture fees from Mochida Pharmaceutical Co., Ltd.

Hirotaka Watada has received lecture fees from Sumitomo Dainippon Pharma Co., Ltd., Bayer Yakuhin, Ltd. Sanofi-Aventis K.K., MSD K.K., Astellas Pharma Inc., Takeda Pharmaceutical Company Ltd, Mitsubishi Tanabe Pharma Co., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K., Novo Nordisk Pharma Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Kowa Co., Ltd., Novartis Pharmaceuticals Corp., Daiichi Sankyo Company, Ltd, Kyowa Hakko Kirin Co. Ltd., Ono Pharmaceutical Co., Ltd., and Kissei Pharmaceutical Co., Ltd. and research support from Novartis Pharmaceuticals Corp., Otsuka Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., MSD K.K., Astellas Pharma Inc., Bayer Yakuhin, Ltd. Teijin Pharma Ltd., Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co. Ltd., Kowa Pharmaceutical Co. Ltd., Sanofi-Aventis K.K., Sanwa Kagaku Kenkyusho Co., Ltd., Daiichi Sankyo Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Ltd., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd. Yakult and Kissei Pharmaceutical Co. Ltd.

Iichiro Shimomura has received lecture fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Ono Pharmaceutical Co., Kyowa Kirin Co., Ltd., Kowa Company, Ltd., Sanofi K.K., Sanwa Kagaku Kenkyusho Co., Daiichi Sankyo Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Novartis Pharma K.K., Novo Nordisk Pharma, Mochida Pharmaceutical Co., Taisho Pharmaceutical Co. Ltd., Nippon Chemiphar Co., Ltd., Covidien Japan Inc., Amgen Astellas Biopharma K.K., KOBAYASHI Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma Co., Rohto Pharmaceutical Co., Ltd.; and research funds from Astellas Pharma Inc., MSD K.K, Ono Pharmaceutical Co., Kaken Pharmaceutical Co., Kyowa Kirin Co., Ltd., Sanofi K.K., Shionogi & Co., Daiichi Sankyo Co., Dainippon Sumitomo Pharma Co., Takeda Pharma K.K., Mitsubishi Tanabe Pharma Co., Teijin Pharma, Novartis Pharma K.K., Novo Nordisk Pharma, Eli Lilly Japan K.K, Kowa Company, Ltd.; and consulting fees from AstraZeneca K.K., MSD K.K., Taisho Pharmaceutical Co. Ltd., Novo Nordisk Pharma, Lotte Co., Ltd.

Figures

**Fig. 1**
Measurement of GSM values. A The right and left mean-IMT-CCA areas (intima-media complex of the segment 2 cm proximal to the dilation of the carotid bulb) were delineated using a freehand tool (shown as a red frame), and the GSM values of the selected area were read from the entire delineated area (“right GSM-CCA” and “left GSM-CCA”). B Similarly, if atherosclerotic plaque lesions or thickened (focal IMT ≥ 1.0 mm) lesions were detected, the GSM values of all these lesions were measured using the same method: the lesions were delineated with a freehand tool (shown as a red frame), and the GSM value of each plaque was read from the entire delineated area (“GSM-plaque”)

See this image and copyright information in PMC

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References

1. Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148. doi: 10.1186/s12933-014-0148-1. - DOI - PMC - PubMed
1. Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, et al. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE/mice fed a western diet. Diabetologia. 2017;60:364–376. doi: 10.1007/s00125-016-4158-2. - DOI - PubMed
1. Nasiri-Ansari Ν, Dimitriadis GK, Agrogiannis G, Perrea D, Kostakis ID, Kaltsas G, et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc Diabetol. 2018;17:106. doi: 10.1186/s12933-018-0749-1. - DOI - PMC - PubMed
1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(2117–28):26378978. - PubMed
1. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925. - DOI - PubMed

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[1] Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148. doi: 10.1186/s12933-014-0148-1. - DOI - PMC - PubMed

[2] Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148. doi: 10.1186/s12933-014-0148-1. - DOI - PMC - PubMed

[3] Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, et al. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE/mice fed a western diet. Diabetologia. 2017;60:364–376. doi: 10.1007/s00125-016-4158-2. - DOI - PubMed

[4] Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, et al. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE/mice fed a western diet. Diabetologia. 2017;60:364–376. doi: 10.1007/s00125-016-4158-2. - DOI - PubMed

[5] Nasiri-Ansari Ν, Dimitriadis GK, Agrogiannis G, Perrea D, Kostakis ID, Kaltsas G, et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc Diabetol. 2018;17:106. doi: 10.1186/s12933-018-0749-1. - DOI - PMC - PubMed

[6] Nasiri-Ansari Ν, Dimitriadis GK, Agrogiannis G, Perrea D, Kostakis ID, Kaltsas G, et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc Diabetol. 2018;17:106. doi: 10.1186/s12933-018-0749-1. - DOI - PMC - PubMed

[7] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(2117–28):26378978. - PubMed

[8] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(2117–28):26378978. - PubMed

[9] Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925. - DOI - PubMed

[10] Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925. - DOI - PubMed

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Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall-a sub-analysis of the UTOPIA trial

Affiliations

Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall-a sub-analysis of the UTOPIA trial

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Abstract

Conflict of interest statement

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Conflict of interest statement

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