Comparing the effects of ipragliflozin versus metformin on visceral fat reduction and metabolic dysfunction in Japanese patients with type 2 diabetes treated with sitagliptin: A prospective, multicentre, open‐label, blinded‐endpoint, randomized controlled study (PRIME‐V study)

Abstract A prospective, multicentre, open‐label, blinded‐endpoint, randomized controlled study was conducted to evaluate the efficacy of treatment with ipragliflozin (sodium‐dependent glucose transporter‐2 inhibitor) versus metformin for visceral fat reduction and glycaemic control among Japanese patients with type 2 diabetes treated with sitagliptin, HbA1c levels of 7%‐10%, and body mass index (BMI) ≥ 22 kg/m2. Patients were randomly assigned (1:1) to receive ipragliflozin 50 mg or metformin 1000‐1500 mg daily. The primary outcome was change in visceral fat area as measured by computed tomography after 24 weeks of therapy. The secondary outcomes were effects on glucose metabolism and lipid metabolism. Mean percentage reduction in visceral fat area was significantly greater in the ipragliflozin group than in the metformin group (−12.06% vs. −3.65%, P = 0.040). Ipragliflozin also significantly reduced BMI, subcutaneous fat area, waist circumference, fasting insulin, and homeostatic model assessment (HOMA)‐resistance, and increased HDL‐cholesterol levels. Metformin significantly reduced HbA1c and LDL‐cholesterol levels and increased HOMA‐beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase‐4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors.


Funding information
Funding to conduct this study, an agreement was signed between Chiba University and Astellas Pharma Inc. (Tokyo, Japan), who funded this work. The funding source had no role in the design of this study; its execution, analyses, interpretation of the data, and decision to publish; or the preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Peer Review
The peer review history for this article is available at https://publons.com/publon/ 10.1111/dom.13750. homeostatic model assessment (HOMA)-resistance, and increased HDL-cholesterol levels. Metformin significantly reduced HbA1c and LDL-cholesterol levels and increased HOMA-beta. There were no severe adverse events. The use of ipragliflozin or metformin in combination with dipeptidyl peptidase-4 inhibitors, widely used in Japan, may have beneficial effects in ameliorating multiple cardiovascular risk factors. For Japanese patients initially treated with DPP-4is who failed to achieve optimal glycaemic control, metformin is a candidate as the second-line medication. A combination of metformin and DPP-4i reportedly reduces body weight. 5 Sodium-dependent glucose transporter-2 inhibitors (SGLT2is) decrease blood glucose level in a non-insulin-dependent manner, and reportedly reduce body weight. 6 Randomized clinical trials have suggested that SGLT2is may have an effect of reducing cardiovascular events. 7 However, it is still unclear how SGLT2is improve metabolic dysfunction. In previous studies, SGLT2is have been administered as the second-line drug to patients already receiving metformin. The pathophysiology and common treatment regimen for T2D in Japanese patients differs from previous studies; therefore, the present study was designed to address these nuances in the treatment of Japanese patients.
To clarify the second-line antidiabetes drug that is preferable for Japanese patients with T2D after DPP-4i, this study investigated the effect of ipragliflozin, a novel SGLT2i, on visceral fat accumulation, as measured by computed tomography (CT), compared with the effect of metformin as the second drug for patients already receiving sitagliptin.

| METHODS
This was a prospective, multicentre, open-label, blinded-endpoint, randomized controlled study. The design has been described previously. 8 The protocol was approved by the responsible ethics committees and was conducted in full compliance with the Declaration of Helsinki. Eligible participants were diagnosed with T2D, were aged 20-75 years old, had received DPP-4i (sitagliptin 50 mg daily) for ≥12 weeks, and had current HbA1c > 7.0% and < 10.0% and body mass index (BMI) > 22.0 kg/m 2 . 9 The exclusion criteria are described in the Appendix S1 (see the supporting information for this article).
Participants were randomly assigned to the ipragliflozin or metformin group in a 1:1 allocation. Patients in the ipragliflozin group received oral ipragliflozin 50 mg daily. Patients in the metformin group were initially administered 500 mg of metformin daily, and then 1000 mg daily after 2 to 4 weeks. For the patients with an inadequate glucose-lowering effect observed in the metformin group, the dose of metformin was increased to 1500 mg daily at 12 weeks. During the study period, diet, exercise therapy, and other drugs did not change, as orally verified by the physicians.
The primary outcome was any change in the visceral fat area in 24 weeks between the two groups. CT imaging was performed before study drug administration and after 24 weeks. Two radiologists, who were masked to patients' clinical information and treatment assignment, centrally evaluated the CT images. Secondary outcomes included changes in HbA1c, body weight and BMI, waist circumference, fasting plasma glucose and insulin levels, homeostatic model assessment (HOMA)-beta, HOMA-R, total cholesterol, LDL-cholesterol, fasting triglycerides, and HDL-cholesterol, blood pressure, adiponectin, high sensitivity C-reactive protein (hs-CRP), subcutaneous and total fat area. Safety was assessed by recording all adverse events that were observed during the study.
In the primary analysis, the least-square mean difference in any change in the visceral fat area in 24 weeks between the two groups and its 95% confidence intervals (CI) were estimated using ANCOVA adjusted for age, baseline waist circumference, HbA1c, and baseline visceral fat area. All P-values are two-sided. P < 0.05 was considered statistically significant.

| RESULTS
The enrolment process is presented in Figure S1. Participant characteristics were balanced between the groups (Table S1). In the metformin group, five (10.4%) patients continued with 500 mg daily dose while for 24 (49.0%) and 19 (38.8%) patients the daily dose increased to 1000 and 1500 mg, respectively. The average dosage of metformin was 1124 mg.  Table 1).

| Other assessments
Changes in adiponectin, hs-CRP and blood pressure were similar between the two groups ( Figure S3). The data were not normally distributed and had outliers; non-parametric analysis (Wilcoxon rank sum test and group difference confidence interval by Hodges-Lehmann estimator) was performed. Changes from baseline are shown as median.

| Adverse events
Ipragliflozin showed significantly less gastrointestinal disturbances and more thirst and frequent urination compared with metformin.
There were no severe adverse events (Table S3). Waist circumference percentage reductions were smaller than those in the visceral fat area. This could indicate that waist circumference, which was used as a surrogate measure of central adiposity, underestimates visceral fat. The visceral fat reduction in the ipragliflozin group could be partially a result of the water reduction in adipose tissue. However, the slight reduction in blood pressure by ipragliflozin may indicate that a dehydration effect of ipragliflozin was not particularly strong. In the present study, the visceral fat area was measured by use of CT, which has been reported to be highly correlated with total visceral adipose tissue mass with significance. 11 This study showed that ipragliflozin simultaneously reduced visceral fat and fasting insulin in association with elevation of adiponectin levels from the baseline. Fat loss increases adiponectin, 12 which regulates glucose levels and fatty acid breakdown and reverses insulin resistance. 13 In the ipragliflozin group, adiponectin levels increased from baseline, a result which may have been associated with reduced fasting insulin levels and reduced HOMA-R, a marker of insulin resistance in the present study.

| DISCUSSION
The extent to which HbA1c levels were reduced was greater in the metformin versus ipragliflozin group at 24 weeks. In fasting conditions, SGLT2 inhibition switches from carbohydrate to fat oxidation and stimulates ketone body production and hepatic cholesterol synthesis. These metabolic alterations result in lower LDL receptor expression and moderate increases in LDL-cholesterol levels. 19 By contrast, metformin lowered LDL-cholesterol levels, through increased recycling of LDL receptors via reduced arachidonic acid in the liver. 20 The decrease in LDL-cholesterol was observed in parallel with a decrease in total cholesterol. There were no significant differences in changes in blood pressure between the two groups.
This study has a few limitations. First, it was an open-label trial; however, evaluators of the primary outcome were blinded to the clinical information. Second, the study population was small and limited to Japanese patients, which may affect the generalizability of the findings. Finally, the study period was limited to 24 weeks.
In conclusion, both drugs showed beneficial effects in ameliorating multiple cardiovascular risk factors. Ipragliflozin was superior in terms of reduced visceral fat, improved hyperinsulinaemia, and low HDLcholesterol. Metformin showed advantage in terms of improved hyperglycaemia and high LDL-cholesterol. Metformin is used globally as the first-line medication for T2D. To the best of our knowledge, the present study is the first to compare metformin and ipragliflozin as a secondary drug with a DPP-4i. The study results may provide a rationale for alternative treatment strategies for T2D, especially in Japanese patients.

CONFLICT OF INTEREST
K.Y. received research grants from Astellas Pharma Inc. and MSD K.K. (Tokyo, Japan). He also received a lecture fee from Astellas Pharma Inc. and Sumitomo Dainippon Pharma (Tokyo, Japan). No conflicts of interest are declared for the other authors.