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Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB).

ABSTRACT: Metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i) is the most common therapy for Japanese patients with type 2 diabetes. This 24-week, multicentre, open-label, parallel-group trial randomized patients on dual therapy to add-on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31). The primary outcome was change in body fat percentage. The secondary outcomes included changes in HbA1c, fat mass, fat-free mass, liver function variables and uric acid. Tofogliflozin and glimepiride reduced HbA1c to a similar extent. Body fat percentage did not change from baseline in either group. Fat mass was reduced by tofogliflozin but was increased by glimepiride (by -2.0 ± 1.7 kg and +1.6 ± 1.6 kg, P = .002). Fat-free mass was also reduced by tofogliflozin and increased by glimepiride (by -1.3 ± 1.3 kg and +0.9 ± 2.0 kg, P < .001). Alanine aminotransferase and uric acid levels were reduced by tofogliflozin (P = .006 and P < .001, respectively). These data provide novel information useful for selecting the third oral agent for patients whose diabetes is inadequately controlled with metformin plus DPP-4i dual therapy.

SUBMITTER: Kitazawa T

PROVIDER: S-EPMC7496555 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB).

Kitazawa Toru T Seino Hiroaki H Ohashi Hiroshi H Inazawa Takeshi T Inoue Masahiro M Ai Masumi M Fujishiro Midori M Kuroda Hisamoto H Yamada Masayo M Anai Motonobu M Ishihara Hisamitsu H

Diabetes, obesity & metabolism 20200507 9

Metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i) is the most common therapy for Japanese patients with type 2 diabetes. This 24-week, multicentre, open-label, parallel-group trial randomized patients on dual therapy to add-on tofogliflozin (20 mg/day, n = 33) or glimepiride (0.5 mg/day, n = 31). The primary outcome was change in body fat percentage. The secondary outcomes included changes in HbA1c, fat mass, fat-free mass, liver function variables and uric acid. Tofogliflozin and glime ...[more]

PMID: 32314464

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Project description:BackgroundThe global pandemic of type 2 diabetes mellitus (T2DM) is an enormous clinical and socioeconomic burden. Biguanides and DPP-4 inhibitors (DPP-4i) are the most commonly used therapies in Japanese T2DM patients. When glycemic control is not adequate despite combination of these drugs, there is no consensus on the next step drug. Systematic reviews and meta-analyses of previous trials have indicated that glycemic control with triple combination therapies yields similar results. Thus, beneficial effects on cardiovascular risk factors may be important. The present study was designed to evaluate body fat percentage and several insulin resistance parameters after addition of tofogliflozin or glimepiride to the regimens of patients being treated with metformin and a DPP-4 inhibitor but failing to attain adequate blood glucose control.MethodsSodium glucose cotransporter-2 inhibitor, tofogliflozin versus glimepiride, comparative trial in patients with type 2 diabetes on body composition is an ongoing, multicenter, prospective, randomized, open-label, parallel-group trial. T2DM patients treated with metformin/DPP-4 inhibitor dual therapy have been recruited and randomly assigned to 20 mg/day tofogliflozin (n = 32) or 0.5 mg/day glimepiride (n = 32) groups, with either of these drugs being added to pre-existing regimens for 24 weeks.Planned outcomesThe primary endpoint is the change in body fat percentage from baseline to 24 weeks. The secondary outcomes are changes in body composition other than fat percentage, body weight, parameters related to glycemic control and β-cell function, parameters related to lipids and arteriosclerosis, parameters related to liver function, parameters related to diabetic nephropathy, and uric acid levels. Safety parameters will also be analyzed. This is the first trial comparing the effects and safety of adding an SGLT2i and a sulfonylurea as the third-line oral agent to metformin/DPP-4i dual therapy. The results will provide valuable information for choosing third-line oral agents.Trial registrationUMIN000026161.FundingKowa Co. Ltd. and Kowa Pharmaceutical Co. Ltd., Tokyo, Japan.

Project description:ObjectiveNonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown.Research design and methodsWe conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles.ResultsFibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin.ConclusionsTofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.

Dataset Information

Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB).

Publications

Comparison of tofogliflozin versus glimepiride as the third oral agent added to metformin plus a dipeptidyl peptidase-4 inhibitor in Japanese patients with type 2 diabetes: A randomized, 24-week, open-label, controlled trial (STOP-OB).

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