Combination of tofogliflozin and pioglitazone for NAFLD: Extension to the ToPiND randomized controlled trial

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Abstract

The incidence of nonalcoholic fatty liver disease (NAFLD) has recently increased and is related to obesity and the associated surge in type 2 diabetes mellitus (T2DM) and metabolic syndromes. This trial follows up on our previous work and forms part of the ToPiND study. We aimed to combine tofogliflozin and pioglitazone treatment for hepatic steatosis in patients with NAFLD and T2DM. In this open‐label, prospective, single‐center, randomized clinical trial, patients with NAFLD with T2DM and a hepatic fat fraction of ≥10% were assessed based on magnetic resonance imaging proton density fat fraction. Eligible patients received either 20 mg tofogliflozin or 15–30 mg pioglitazone orally, once daily for 24 weeks, followed by combination therapy with both medicines for an additional 24 weeks. The effects on diabetes mellitus and hepatic steatosis were examined at baseline and after the completion of monotherapy and combination therapy. Thirty‐two eligible patients received the combination therapy of tofogliflozin and pioglitazone. The combination therapy showed additional improvement in glycated hemoglobin compared with each monotherapy group and showed improvement in steatosis, hepatic stiffness, and alanine aminotransferase levels compared with the tofogliflozin monotherapy group. Pioglitazone monotherapy–mediated increase in body weight decreased following concomitant use of tofogliflozin. The combination therapy resulted in lower triglyceride, higher high‐density lipoprotein cholesterol, higher adiponectin, and higher ketone body levels. Conclusion: In addition to the additive effects of tofogliflozin and pioglitazone in patients with T2DM and NAFLD, combination therapy was suggested to reduce weight gain and induce cardioprotective effect. Further studies with more patients are needed to investigate the combination therapy of various drugs.

Abstract

In the present study, we investigated the effectiveness of combination therapy with tofogliflozin and pioglitazone, compared to that of monotherapy for the treatment of NAFLD in patients with type 2 diabetes.

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Most cited references 49

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Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.

Zobair Younossi, Aaron Koenig, Dinan Abdelatif … (2016)

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of hepatocellular carcinoma (HCC), cirrhosis, overall mortality, and liver-related mortality were determined. NASH required histological diagnosis. All studies were reviewed by three independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication, and study population. We used random-effects models to provide point estimates (95% confidence interval [CI]) of prevalence, incidence, mortality and incidence rate ratios, and metaregression with subgroup analysis to account for heterogeneity. Of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. Global prevalence of NAFLD is 25.24% (95% CI: 22.10-28.65) with highest prevalence in the Middle East and South America and lowest in Africa. Metabolic comorbidities associated with NAFLD included obesity (51.34%; 95% CI: 41.38-61.20), type 2 diabetes (22.51%; 95% CI: 17.92-27.89), hyperlipidemia (69.16%; 95% CI: 49.91-83.46%), hypertension (39.34%; 95% CI: 33.15-45.88), and metabolic syndrome (42.54%; 95% CI: 30.06-56.05). Fibrosis progression proportion, and mean annual rate of progression in NASH were 40.76% (95% CI: 34.69-47.13) and 0.09 (95% CI: 0.06-0.12). HCC incidence among NAFLD patients was 0.44 per 1,000 person-years (range, 0.29-0.66). Liver-specific mortality and overall mortality among NAFLD and NASH were 0.77 per 1,000 (range, 0.33-1.77) and 11.77 per 1,000 person-years (range, 7.10-19.53) and 15.44 per 1,000 (range, 11.72-20.34) and 25.56 per 1,000 person-years (range, 6.29-103.80). Incidence risk ratios for liver-specific and overall mortality for NAFLD were 1.94 (range, 1.28-2.92) and 1.05 (range, 0.70-1.56).

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The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.

Naga Chalasani, Zobair Younossi, Joel E Lavine … (2018)

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Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

Bruce Neal, Vlado Perkovic, Kenneth Mahaffey … (2017)

Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).

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Author and article information

Contributors

Masato Yoneda:

ORCID: https://orcid.org/0000-0001-7815-549X

yoneda@yokohama-cu.ac.jp

Journal

Journal ID (nlm-ta): Hepatol Commun

Journal ID (iso-abbrev): Hepatol Commun

Journal ID (doi): 10.1002/(ISSN)2471-254X

Journal ID (publisher-id): HEP4

Title: Hepatology Communications

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2471-254X

Publication date (Electronic): 16 May 2022

Publication date Collection: September 2022

Volume: 6

Issue: 9 ( doiID: 10.1002/hep4.v6.9 )

Pages: 2273-2285

Affiliations

[ ¹ ] Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine Yokohama Japan

[ ² ] Gastroenterology Division National Hospital Organization Yokohama Medical Center Yokohama Japan

[ ³ ] Department of Gastroenterology Shin‐yurigaoka General Hospital Kawasaki Japan

[ ⁴ ] Department of Data Science Yokohama City University School of Data Science Yokohama Japan

[ ⁵ ] Laboratory of Physiology Yokohama City University Hospital Yokohama Japan

Author notes

[*] [* ] Correspondence

Masato Yoneda, Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3‐9 Fukuura, Kanazawa‐ku, Yokohama 236‐0004, Japan.

Email: yoneda@ 123456yokohama-cu.ac.jp

Author information

Masato Yoneda https://orcid.org/0000-0001-7815-549X

Takashi Kobayashi https://orcid.org/0000-0002-7240-4851

Atsushi Nakajima https://orcid.org/0000-0002-6263-1436

Article

Publisher ID: HEP41993 Other ID: HEP4-22-0058.R2

DOI: 10.1002/hep4.1993

PMC ID: 9426404

PubMed ID: 35578445

SO-VID: b5f6b179-7379-4c0f-a73f-d002d6fe2ce8

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date revision received : 16 April 2022

Date received : 27 January 2022

Date accepted : 26 April 2022

Page count

Figures: 5, Tables: 2, Pages: 13, Words: 6910

Funding

Funded by: Kowa Company , doi 10.13039/100015993;

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cover-date September 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:30.08.2022

Combination of tofogliflozin and pioglitazone for NAFLD: Extension to the ToPiND randomized controlled trial

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Most cited references 49

Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.

The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases.

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

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