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Additional effect of luseogliflozin on semaglutide for non-alcoholic steatohepatitis patients with type 2 diabetes (Alight Study)

Additional effect of luseogliflozin on semaglutide for non-alcoholic steatohepatitis patients with type 2 diabetes (Alight Study)

60

Age (years): Intervention group 56.0 (12.3), Control group 57.1 (10.2) Sex (Men/Women): Intervention group 9/15 (37.5/62.5), Control group 19/17 (52.8/47.2) BMI (kg/m2): Intervention group 30.5 (5.0), Control group 30.4 (4.8) HbA1c (%): Intervention group 7.7 (1.3), Control group 7.6 (1.2) ALT (U/L): Intervention group 81.5 (42.8), Control group 72.1 (30.7)

70 patients provided informed consent, and 60 were enrolled (24 in the Intervention group and 36 in the Control group). Two participants in the Intervention group discontinued the study due to withdrawal of consent.

No serious adverse events or deaths were reported. Adverse events occurred in 16 of 24 participants (66.7%) in the intervention group and 19 of 36 (52.8%) in the control group. The most common adverse events were gastrointestinal symptoms, such as nausea (20.8% in the intervention group and 33.3% in the control group).

Primary endpoints - Proportion of participants with resolution of NASH without worsening of fibrosis: 34.9 in the intervention group vs 19.4 in the control group (p=0.214) - Proportion of participants with >=1-point improvement in NAFLD activity score (NAS) from baseline without worsening of fibrosis: 75.5 vs 55.6 (p=0.063) - Proportion of participants with >=1-stage improvement in fibrosis from baseline without worsening of NASH: 26.9 vs 13.9 (p=0.139) Secondary endpoints - Proportion of participants with fibrosis progression status (improvement/no change/worsening): 27.3/54.5/18.2 in the intervention group vs 16.6/55.6/27.8 in the control group (p=0.219/0.919/0.259) - Change in liver stiffness measured by FibroScan from baseline: -30.9 (20.4) in the intervention group vs -10.0 (29.2) in the control group (p=0.01) - Change in hepatic fat content measured by FibroScan from baseline: -9.1 (13.4) vs -8.7 (16.3) (p=0.691) - Change in body weight/BMI/body composition (fat mass) from baseline: -8.5 (4.3)/-8.5 (4.3)/-17.0 (7.6) in the intervention group vs -4.9 (4.7)/-4.9 (4.7)/-10.5 (9.1) in the control group (p=0.002/0.002/0.004) - Change in HbA1c from baseline: -1.6 (1.1) vs -1.0 (0.8) (p=0.003) - Change in AST/ALT/GGT from baseline: -27.9 (15.7)/-42.5 (24.0)/-54.7 (70.8) in the intervention group vs -17.9 (21.7)/-24.4 (24.4)/-32.1 (34.6) in the control group (p=0.007/0.005/0.075)

Add-on luseogliflozin to semaglutide did not demonstrate statistically significant differences in the primary histologic endpoints in the full analysis set (FAS); however, in the per-protocol set (PPS), a potential benefit in NAS was suggested. In addition, significant improvements compared with the control group were observed in body weight, HbA1c, liver enzymes, and liver stiffness and hepatic fat content as assessed by FibroScan.

Aug. 31, 2026

No

No plan to share individual participant data

https://jrct.mhlw.go.jp/latest-detail/jRCTs061210009

Hiasa Yoichi

Ehime University Hospital

454, Shitsukawa, Toon, Ehime

hiasa@m.ehime-u.ac.jp

Miyake Teruki

Ehime University Hospital

454, Shitsukawa, Toon, Ehime

+81-89-960-5308

miyake.teruki.mg@ehime-u.ac.jp

Complete

June. 03, 2021

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

NASH with type 2 diabetes
1. Patients aged 20 to 75 years at the time of consent
2. Patients with type 2 diabetes who were diagnosed with NASH with stage 1 or more and NAS 4 or more according to the classification of the NASH Clinical Research Network (NASH CRN) by liver biopsy within 6 months (180 days) before pre-examination or consent acquisition
3. Patients with HbA1c 6.5% or more (HbA1c 6% or more for those undergoing drug treatment) and 10.5% or less in the preliminary examination
4. Patients who provided written consent to participate in this study

1. Patients who received SGLT2 inhibitors or GLP-1 receptor agonists within 3 months (90 days) prior to the start of the drug administration study or after liver biopsy
2. Patients who used other SGLT2 inhibitors or GLP-1 receptor agonists during the study period
3. Patients with a history of serious adverse reactions to SGLT2 inhibitors or GLP-1 receptor agonists in the past
4. Patients with uncompensated liver cirrhosis (Child-Pugh B or C)
5. Patients with serious renal disease (serum Cr > 2.0 mg/dL or CKD stage 4 or higher)
6. Patients with malignant tumor
7. Patients with a history of severe hypoglycemia
8. Patients with a history of ketoacidosis
9. Patients with a history of cerebral infarction with paralysis
10. Patients with urinary tract/genital infections or repeated urinary tract/genital infections
11. Patients with the following complications: hepatitis due to other causes such as viral hepatitis, autoimmune hepatitis, primary cholestatic cholangitis, psychiatric disorders, seizures, and paroxysmal diseases
12. Patients who were hospitalized for acute coronary syndrome, unstable angina, acute myocardial infarction, acute cerebral infarction, or transient ischemic attack within 3 months (90 days) prior to obtaining consent
13. Pregnant or lactating women, women who may become pregnant, or women who wish to become pregnant
14. Patients who had started or changed the dose of pioglitazone or vitamin E within 6 months (180 days) prior to starting the study drug, or within 3 months (90 days) prior to liver biopsy until starting the study drug
15. Patients who regularly use oral steroids or injectable steroids
16. Patients who are participating or intend to participate in other clinical studies using the study drug while participating in this study
17. If, in the opinion of the Principal Investigator, or others, participation in the research is not in the best interest of the research subject (e.g., to the detriment of the welfare of the research subject), or if it is judged to interfere with, limit, or confuse the specific evaluation of the clinical research protocol
18. A person under the direction of the Principal Investigator or the medical institution conducting the research, an employee of the Principal Investigator or of the medical institution directly involved in this or other clinical research, or family members of such employees or the Principal Investigator

Both

Nonalcoholic steatohepatitis

Intervention group
After obtaining a written consent and completing baseline examination, Ozempic (0.25 mg) will be injected subcutaneously once a week. After 2 weeks of Ozempic treatment, one Lusefi (2.5 mg) tablet will be added once daily by orally before or after breakfast. After 4 weeks of the initial Ozempic treatment, the dose of the Ozempic (0.25 mg) will be increased to 0.5 mg. Ozempic injection will be remained once a week. Medication will be continued until 52 weeks.

Control group
After obtaining a written consent and completing baseline examination, Ozempic (0.25 mg) will be injected subcutaneously once a week. After 4 weeks of Ozempic treatment, the dose of the Ozempic (0.25 mg) will be increased to 0.5 mg. Ozempic injection will be remained once a week. Medication will be continued until 52 weeks.

Nonalcoholic steatohepatitis, Nonalcoholic Fatty Liver Disease, NAFLD, NASH

luseogliflozin, semaglutide

D065626

C549343, C000591245

1. Resolution of NASH (defined by the NASH Clinical Research Network as no more than mild residual inflammatory cells [score of 0 or 1] and no hepatocyte ballooning [score of 0]) without worsening of liver fibrosis (with worsening defined as an increase of one stage or more on the Kleiner fibrosis classification scale) after 52 weeks, in line with regulatory perspectives
2. Improvement of at least one point in NAFLD activity score and no worsening of NASH without worsening of liver fibrosis
3. Improvement of at least one fibrosis stage and no worsening of NASH (with worsening defined as an increase of 1 point or more in either the lobular inflammation score or the hepatocyte ballooning score according to the NASH Clinical Research Network criteria)

1. Proportion of cases with progression of liver fibrosis (improvement/instability/worsening)
2. Change from baseline in liver stiffness according to FibroScan
3. Change from baseline in steatosis according to FibroScan
4. Change from baseline in weight, BMI, and body composition
5. Change from baseline in HbA1c
6. Change from baseline in liver enzymes (AST, ALT, GGT)

+81-89-960-5172

May. 07, 2021

none