2017, 64 (10), 995-1005 Original Comparison of tofogliflozin 20 mg and ipragliflozin 50 mg used together with insulin glargine 300 U/mL using continuous glucose monitoring (CGM): A randomized crossover study Soichi Takeishi, Hiroki Tsuboi and Shodo Takekoshi Department of Diabetes, General Inuyama Chuo Hospital, Inuyama 484-8511, Japan Abstract. To investigate whether sodium glucose co-transporter 2 inhibitors (SGLT2i), tofogliflozin or ipragliflozin, achieve optimal glycemic variability, when used together with insulin glargine 300 U/mL (Glargine 300). Thirty patients with type 2 diabetes were randomly allocated to 2 groups. For the first group: After admission, tofogliflozin 20 mg was administered; Fasting plasma glucose (FPG) levels were titrated using an algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using continuous glucose monitoring (CGM); Tofogliflozin was then washed out over 5 days; Subsequently, ipragliflozin 50 mg was administered; FPG levels were titrated using the same algorithm and stabilized at 80 mg/dL level with Glargine 300 for 5 days; Next, glucose levels were continuously monitored for 2 days using CGM. For the second group, ipragliflozin was administered prior to tofogliflozin, and the same regimen was maintained. Glargine 300 and SGLT2i were administered at 8:00 AM. Data collected on the second day of measurement (mean amplitude of glycemic excursion [MAGE], average daily risk range [ADRR]; on all days of measurement) were analyzed. Area over the glucose curve (<70 mg/dL; 0:00 to 6:00, 24-h), M value, standard deviation, MAGE, ADRR, and mean glucose levels (24-h, 8:00 to 24:00) were significantly lower in patients on tofogliflozin than in those on ipragliflozin. Tofogliflozin, which reduces glycemic variability by preventing nocturnal hypoglycemia and decreasing postprandial glucose levels, is an ideal SGLT2i when used together with Glargine 300 during basal insulin therapy. Key words: Tofogliflozin, Insulin glargine 300 U/mL, Continuous glucose monitoring BASAL INSULIN THERAPY, in which the patient’s the Somogyi phenomenon, nocturnal hypoglycemia preferences and view-points are considered, is effec- causes an increase in the difference between pre- and tive and safe, and has been commonly used as a part post-breakfast glucose levels [2], and this leads to an of insulin therapy. Basal insulin therapy can sup- increase in daytime glucose levels. Thus, hypogly- port basal and bolus insulin secretion by combining cemia and increased glycemic variability occur at the once-daily dosage of basal insulin and oral hypoglyce- same time during the Somogyi phenomenon. Large mic agents (OHA). In the ideal basal insulin therapy, clinical studies have shown that hypoglycemia and basal insulin is used to decrease fasting plasma glu- glycemic variability are associated with mortality in cose (FPG) levels, reducing the occurrence of hypo- patients with diabetes mellitus [3-5]. We wanted to pre- glycemia, while an oral hypoglycemic agent is used dict the Somogyi phenomenon, in which hypoglycemia to decrease postprandial glucose levels, reducing the and increased glycemic variability occur concomitantly, occurrence of hypoglycemia. and we have previously reported that major increases A relationship between nocturnal hypoglycemia between pre- and post-breakfast glucose levels may and sudden death has been suggested [1]. As per predict nocturnal hypoglycemia in type 2 diabetes [6]. When the Somogyi phenomenon is suspected, Submitted May 12, 2017; Accepted Jul. 11, 2017 as EJ17-0206 reducing both nocturnal hypoglycemia and increases Released online in J-STAGE as advance publication Aug. 18, 2017 in daytime glucose levels through increases between Correspondence to: Soichi Takeishi, M.D., Department of pre- and post-breakfast glucose levels, establishing an Diabetes, General Inuyama Chuo Hospital, 6, Futagozuka, Goromaru, Inuyama-city, Aichi, 484-8511, Japan. appropriate control of pre-breakfast glucose levels, is E-mail: [email protected] necessary [1, 4, 7]. We believe that long-acting insulin University Medical Information Network (no. UMIN000023972) to reduce nocturnal hypoglycemia, and OHA to reduce ©The Japan Endocrine Society 996 Takeishi et al. daytime (postprandial) glucose levels efficiently is use- the occurrence of nocturnal hypoglycemia when used ful in basal insulin therapy. together with insulin and in decreasing postprandial Sodium glucose co-transporter 2 inhibitors (SGLT2i) glucose levels) administered in the morning, may be an are useful OHAs that decrease glucose levels in a glu- ideal basal insulin therapy using SGLT2i. To investi- cose-level dependent manner with a single agent [8] gate whether tofogliflozin decreases the occurrence of and that leads to many second order effect, such as nocturnal hypoglycemia and postprandial glucose lev- decrease in body weight and blood pressure [9]. It els when used together with insulin, we compared the has been reported that tofogliflozin taken in the morn- effects of tofogliflozin 20 mg + Glargine 300, to that ing decreases postprandial glucose levels of about 70 of ipragliflozin 50 mg + Glargine 300, using continu- mg/dL and FPG of about 35 mg/dL [10]. In contrast, ous glucose monitoring (CGM) in a randomized cross- It has also been reported that ipragliflozin decreases over study. postprandial glucose levels of about 60 mg/dL and FPG of about 45 mg/dL [11]. From those reports, we Materials and Methods can estimate that the effect of tofogliflozin is stron- ger during the daytime and weaker during the night- Study design and patient selection time than that of ipragliflozin even though there are no Nocturnal urinary frequency of the ipragliflozin differences between the overall effects of tofogliflozin group is 1.7 ± 0.7 times, as reported by Yoshida in a or ipragliflozin. Thus, an optimal SGLT2i used in clinical trial investigating urinary frequency of patients basal insulin therapy, tofogliflozin taken in the morn- administered tofogliflozin [14]. Thirty individuals ing may decrease postprandial glucose levels more were required in each control group and treatment than ipragliflozin. In addition, SGLT2i when used group, in order to be able to detect a 30% alteration in together with insulin, increases the risk of hypoglyce- the mean nocturnal urinary frequency, with an α value mia. Therefore, when SGLT2i is used together with of 0.05 and with a statistical power of 80%. We there- insulin, if the effect of the SGLT2i remains at night- fore determined that the total number of participants time, the risk of hypoglycemia is thought to increase, required was 30. because of the combined effect of SGLT2i and insulin. Thirty patients with type 2 diabetes, treated with It has been reported that tofogliflozin has the shortest Glargine 300 during basal insulin therapy for 3 months half-life among all other SGLT2i [12] and that a rate of or longer, were randomly allocated into 2 groups. For urinary tofogliflozin excretion is more than 80 % at the the first group (T/I group): After admission, tofogli- time of 12 h after administration [12]. It has also been flozin 20 mg was administered once daily; FPG lev- reported that a rate of urinary tofogliflozin excretion is els were titrated using an algorithm made refering to a more than 96 % at the time of 24 h after administration clinical trial [FPG levels on the day of dosage adjust- and only about 3 % during 24 h ~ 48 h after adminis- ment, dosage adjustment of Glargine 300 (U/day): FPG tration [12]. Thus, morning administeration of tofo- levels ≥ 180 mg/dL, +4; 140 mg/dL ≤ FPG levels < gliflozin may reduce the risk of hypoglycemia because 180 mg/dL, +3; 110 mg/dL ≤ FPG levels < 140 mg/ the SGLT2i’s effects almost disappear by nighttime and dL, +2; 90 mg/dL ≤ FPG levels < 110 mg/dL, +1; 80 there are almost no overcarrying effect since 24 h after mg/dL ≤ FPG levels < 90 mg/dL, no change; FPG lev- administration. els < 80 mg/dL, -2; adjustment on every second day] Regarding reduction of nocturnal hypoglycemia, it [13] and stabilized at 80 mg/dL level with Glargine was observed that nocturnal and overall occurrence 300 for 5 days; Next, glucose levels were continu- of hypoglycemic events were significantly reduced ously monitored for 2 days using the continuous glu- in patients on insulin glargine 300 U/mL (Glargine cose monitoring (CGM) device; Tofogliflozin was then 300), as opposed to insulin glargine 100 U/mL [13]. washed out over the next 5 days; Subsequently, ipra- Therefore, Glargine 300 is thought to be a useful long- gliflozin 50 mg was administered once daily; FPG lev- acting insulin for reducing nocturnal hypoglycemia. els were titrated using the same algorithm and stabi- Thus, combination therapy using Glargine 300 (con- lized at 80 mg/dL level with Glargine 300 for 5 days; sidered to help in decreasing pre-breakfast glucose lev- Next, glucose levels were continuously monitored for els, reducing the occurrence of nocturnal hypoglyce- 2 days using the CGM device. For the second group mia) and tofogliflozin (considered to help in reducing (I/T group), ipragliflozin was administered prior to Comparison of SGLT2i + Glargine 300 by CGM 997 tofogliflozin, and the same regimen was maintained lunch 35% of total calories, and supper 35% of total (Fig. 1). Patients were allocated to groups using a ran- calories)], irrespective of differences in physique dur- dom number table, and the study design was continu- ing the CGM measurement period. Physical activity ous and prospective. Glargine 300 and SGLT2i were during the reserch period was 1.5 metabolic equiva- administered at 8:00 AM. The Glargine 300 dose was lents, based on the analysis of baseline data. Patients adjusted to be constant no later than start of continu- whose estimated glomerular filtration rate was less ous glucose monitoring. The Glargine 300 dose was than 45 mL/min/1.73m2 or were judged to be unsuit- constant during the CGM measurement period.