SGLT2 Inhibitor Versus Sulfonylurea on Type 2 Diabetes With NAFLD

NCT ID: NCT02649465

Last Updated: 2021-07-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-11-11
• Study Completion Date: 2021-06-30

Brief Summary

The clinicopathological analyses revealed that reduction in HbA1c and use of insulin independently contribute to the reduction in liver fibrosis scores during the histological course of NAFLD development. These findings led us to hypothesize that glycemic control and insulin ameliorate or protect against the histological progression of liver fibrosis in patients with NAFLD.

In the present study, we investigated the efficacy of SGLT2 inhibitor tofogliflozin and sulfonylurea glimepiride, which lower glucose levels similarly with reduction and elevation in circulating insulin levels, respectively, in NAFLD patients with type 2 diabetes for 48 weeks by examining liver histology, as well as hepatic enzymes, metabolic markers, and hepatic gene expression profiles.

Detailed Description

Nonalcoholic fatty liver disease (NAFLD), ranging from simple fatty liver to nonalcoholic steatohepatitis (NASH), is a liver phenotype of metabolic disorders, such as diabetes, obesity, and metabolic syndrome. NAFLD and type 2 diabetes share epidemiological and pathophysiological features. Specifically, hyperglycemia is closely associated with liver fibrosis, which is associated with liver cirrhosis, hepatocellular carcinoma, and prognosis in patients with NASH.

To date, some anti-diabetic agents have been tested in patients with NAFLD. The guidelines in the Asian Pacific, European, and American association recommended the administration of PPAR gamma agonist (pioglitazone) and glucagon-like peptide receptor agonists (GLP1RA) for the treatment of diabetes with NAFLD/NASH. However, there are concerns about adverse effects such as weight gain, edema, fractures, and carcinogenesis in pioglitazone or gastrointestinal adverse effects and medication burden as an injection in GLP1 RA. In addition, because all of these anti-diabetic agents significantly reduced glycemic levels compared with placebo, liver histological improvement may be theoretically attributable to glucose reduction itself.

Both sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas are chosen as the second-line therapy when glycemic control cannot be achieved with metformin or as the first-line therapy when metformin is contraindicated or not tolerated. In animal models of NAFLD/NASH, SGLT2 inhibitors protect against steatosis, inflammation, and fibrosis. Previous clinical trials have demonstrated that SGLT2 inhibitors exert protective effects on liver enzymes and liver steatosis in patients with NAFLD/NASH. However, these studies lack a control group or histological examination, which precludes meaningful conclusions since the natural course of the disease or tight glycemic control may ameliorate liver histology in some patients with NAFLD. Sulfonylureas are still reliable and potent antidiabetic agents in insulinopenic patients with type 2 diabetes and therefore are used as the second-line therapy, especially when the cost is a significant issue. Besides, sulfonylureas reduce glucose and elevate weight, which may render positive and negative effects, respectively, on liver pathology in NAFLD/NASH. In the phase 3 trial, canagliflozin was non-inferior to glimepiride for reduction of HbA1c at 52 weeks. However, the differences between SGLT2 inhibitors and sulfonylureas on NAFLD patients with type 2 diabetes under similar glucose reduction remain uncertain.

Conditions

Non-alcoholic Fatty Liver Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

SGLT2 inhibitor

N=20 SGLT2 inhibitor dosage (Tofogliflozin): a dose of 20mg once daily for 48 weeks.

Group Type: ACTIVE_COMPARATOR

Tofogliflozin

Intervention Type: DRUG

The group receiving Tofogliflozin (at a dose of 20mg once daily) for 48 weeks

Sulfonylurea

N=20 Sulfonylurea (Glimepiride): an initial dose of 0.5 mg once daily for 48 weeks.

Group Type: ACTIVE_COMPARATOR

Glimepiride

Intervention Type: DRUG

Sulfonylurea dosage (Glimepiride): dosing from 0.5 mg for initial 4 weeks. Then, if there is no adverse effect or no improvement of glucose metabolism, glimepiride is escalated to 6 mg once daily.

Interventions

Tofogliflozin

The group receiving Tofogliflozin (at a dose of 20mg once daily) for 48 weeks

Intervention Type: DRUG

Glimepiride

Sulfonylurea dosage (Glimepiride): dosing from 0.5 mg for initial 4 weeks. Then, if there is no adverse effect or no improvement of glucose metabolism, glimepiride is escalated to 6 mg once daily.

Intervention Type: DRUG

Other Intervention Names

DEBERZA

Eligibility Criteria

Exclusion Criteria

1. Hepatic virus infections (hepatitis B and C, cytomegalovirus, and Epstein-Barr virus), autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, hemochromatosis, alpha 1-antitrypsin deficiency, Wilson's disease, history of parenteral nutrition.

2. Use of agents known to induce steatosis (e.g., valproate, amiodarone, or vitamin E)

3. Hepatic injury caused by substance abuse.

4. Current consumption of more than 20 g of alcohol daily.

5. Hepatic decompensation, such as hepatic encephalopathy, ascites, variceal bleeding

6. Elevated serum bilirubin level of more than two-fold the upper normal limit.

7. Tofogliflozin or glimepiride hypersensitivity or contraindications.

8. History of type 1 diabetes.

9. History of ketoacidosis.

10. History of symptoms of severe hypoglycemia.

11. Treatment with SGLT2 inhibitor including tofogliflozin within 4 weeks of screening.

12. Treatment with glinide and sulfonylurea use within 4 weeks of screening.

13. Concomitant corticosteroid therapy uses within 4 weeks of screening.

14. Poorly controlled unstable diabetes (ketoacidosis or an increase in HbA1c of >3% in the 12 weeks before screening).

15. Poorly controlled hypertension or systolic blood pressure of >160 mmHg or diastolic blood pressure of >100 mmHg.

16. Artificial dialysis or moderate renal dysfunction.

17. Poorly controlled dyslipidemia.

18. Presence of a severe health problem, not being suitable for the study.

19. Pregnant or breastfeeding.

20. Inability to participate in the study (including psychiatric and psychosocial problems), as assessed by the investigators.

• Minimum Eligible Age: 20 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Kowa Company, Ltd.

INDUSTRY

Sponsor Role: collaborator

Kanazawa University

OTHER

Sponsor Role: lead

Responsible Party

Toshinari Takamura, MD, PhD

Department of Disease Control and Homeostasis

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Toshinari Takamura, MD,PhD

Role: STUDY_CHAIR

Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences,

Locations

Kanazawa University Graduate School of Medical Sciences

Kanazawa, Ishikawa-ken, Japan

Countries

Japan

References

Takeshita Y, Honda M, Harada K, Kita Y, Takata N, Tsujiguchi H, Tanaka T, Goto H, Nakano Y, Iida N, Arai K, Yamashita T, Mizukoshi E, Nakamura H, Kaneko S, Takamura T. Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial. Diabetes Care. 2022 Sep 1;45(9):2064-2075. doi: 10.2337/dc21-2049.

Reference Type: DERIVED

PMID: 35894933 (View on PubMed)

Takeshita Y, Kanamori T, Tanaka T, Kaikoi Y, Kita Y, Takata N, Iida N, Arai K, Yamashita T, Harada K, Gabata T, Nakamura H, Kaneko S, Takamura T. Study Protocol for Pleiotropic Effects and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Versus Sulfonylurea in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Diabetes Ther. 2020 Feb;11(2):549-560. doi: 10.1007/s13300-020-00762-9. Epub 2020 Jan 20.

Reference Type: DERIVED

PMID: 31956961 (View on PubMed)

Other Identifiers

CRB4180005

Identifier Type: -

Identifier Source: org_study_id