Discussion
This study evaluated the changes in mean daily blood glucose levels before and after 48–72 hours of add-on or no dapagliflozin (primary end point), diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) in Japanese patients with type 2 diabetes who received BOT. We obtained two main results. First, we observed different changes in the 24-hour glucose variables in the add-on and no add-on groups on BOT. The addition of dapagliflozin had positive effects on mean blood glucose and maximum blood glucose, SD, and time in ranges in CGM. Second, the levels of urinary 8OHdG, an oxidative stress marker, and HbA1c decreased after 12 weeks of treatment with dapagliflozin as the add-on therapy. This study showed for the first time that SGLT2 inhibitors show a short time (48–72 hours) improvement in 24-hour glucose profile in patients with type 2 diabetes on BOT. This study also found that the add-on of dapagliflozin showed long-term efficacy on oxidative stress in such patients.
Twenty-four-hour glucose variables and dapagliflozin
SGLT2 inhibitors plus insulin therapy have been reported to show a reduction in HbA1c, daily insulin dose, and body weight and an improvement in insulin resistance, beta-cell function, and cardiovascular benefits.9 However, the advantages and disadvantages of this therapy when used for optimal glucose control remain unclear. There are reports on the effectiveness of combining SGLT2 inhibitors with various insulin preparations.15 Inagaki et al reported the efficacy and safety of canagliflozin in combination with insulin therapy in Japanese patients with type 2 diabetes.16 HbA1c and body weight after 16 weeks of canagliflozin treatment were lower than those in the placebo group, which were in line with our findings. No significant side effects were noted, but the incidence of hypoglycemia was higher in the canagliflozin group.16 In our study, the incidence of hypoglycemia was not increased in the dapagliflozin group compared with that in the no add-on group. We cannot explain the reason for the discrepancy between the results reported by Inagaki et al16 and the incidence of hypoglycemia associated with the SGLT2 add-on observed in our study. The difference in insulin preparations (BOT, basal-bolus insulin therapy, or R/NPH mix insulin16 vs BOT in our study) could be one of the reasons. Our study is the first to assess TIR as a measure of glycemic control beyond HbA1c in BOT with or without SGLT2 inhibitors. The ATTD consensus panel recommends that the primary goal for effective and safe glucose control is to increase the TIR while reducing the TBR. SGLT2 inhibitors showed favourable profiles of SGLT2 inhibitors in TIR in patients with type 117 and type 2 diabetes.12 Henry et al evaluated TIR in people with type 2 diabetes on insulin therapy either with dapagliflozin or placebo, showing that there was no difference in TIR between the dapagliflozin and placebo groups.12 The discrepancy between their results and ours might be explained by the difference in the protocol. Henry et al recruited people with diabetes on insulin therapy with higher doses (≥30 U/day vs no dose requirement in ours) and with more than one type of insulin (71.2% used short-acting or intermediate-acting insulin alone or in combination with long-acting insulin vs long-acting insulin alone in ours).12 In addition, the timing of measurements of TIR was different: days 21–28 in Henry et al12 vs 48–72 hours in ours after initiation of dapagliflozin. A more uniform population regarding insulin therapy and an earlier period in ours might bring the improved 24-hour glucose profile in the dapagliflozin add-on group. However, this notion should be carefully interpreted in future studies.
In the present study, TIR in the no add-on group remained unchanged, whereas it was significantly increased in the dapagliflozin add-on group (figure 4). The increase in TIR was obtained by decreasing TAR without increasing TBR, which can be regarded as an effective and safe result.11
Reportedly, long-term complications could be amended at least partly by the significant improvements in HbA1c and/or TIR.11 Beck et al reported that progression of diabetic retinopathy and microalbuminuria was associated with changes in TIR18: a 10% decrease in TIR was shown to increase the risk of developing retinopathy by 64%; the risk of developing microalbuminuria increased by 40% for every 10% decrease in TIR. Lu et al also showed that TIR was lower in patients with type 2 diabetes with advanced retinopathy, and the prevalence of diabetic retinopathy decreased with increasing TIR.19 However, evidence about the long-term effects of an improved TIR is still lacking and requires results in future studies.
Long-term diabetes-related variables and dapagliflozin
Long-term diabetes-related variables of SGLT2 inhibitors have been reported in conjunction with insulin therapy. In two meta-analyses evaluating the add-on effects of SGLT2 inhibitors in people treated with either basal insulin alone or basal plus bolus insulin, SGLT2 inhibitors have improved the HbA1c, fasting plasma glucose, and body weight and decreased the dose of insulin without increasing the risk of hypoglycemia.8 9 The studies evaluating the effect of SGLT2 inhibitors in people with basal insulin alone, the same as in this study, are limited. Rosenstock et al20 reported that 5 or 10 mg of empagliflozin added to basal insulin decreased HbA1c at ~0.6%–0.8% and reduced body weight ~1–2 kg with a similar risk of hypoglycemia to placebo for 12–78 weeks. This result is consistent with our results. In the current study, dapagliflozin added to basal insulin reduced HbA1c by −0.5% and body weight by 1.4 kg after 12 weeks.
The reduction in HbA1c and weight loss with SGLT2 inhibitors observed in previous reports8 9 20 and ours can be explained as follows. A sustained decrease in daily glucose concentration through urinary glucose excretion is the primary mechanism of declined HbA1c by SGLT2 inhibitors.7 Two indirect mechanisms are also considered for declined HbA1c. Reducing hyperglycemia by SGLT2 inhibitors could correct two core defects present in type 2 diabetes mellitus: pancreatic β-cell dysfunction and insulin resistance.21 The body weight reduction by SGLT2 inhibitors may influence decreases in HbA1c.7 Based on data from animal studies and clinical trials, the effects of SGLT2 inhibitors on urinary sodium excretion and diuresis appear to be transient.22 The composition of body weight reduction in SGLT2 inhibitors therapy at ~16 weeks is body water 15%–35%, body fat 50%–75%, subcutaneous fat 25%–45%, and visceral fat ~25%.23 Combined above, improvement in insulin sensitivity by reducing visceral fat24 can be linked to decreased HbA1c in people treated with SGLT2 inhibitors.21
Oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and antioxidant defence systems, has been associated with the development of diabetes and its complications.25 In this study, the dapagliflozin add-on group showed a significant decrease in the urinary 8OHdG level at 12 weeks. Previous studies have reported that the administration of SGLT2 inhibitors decreased the 8OHdG levels (canagliflozin,26 ipragliflozin,27 and empagliflozin28). As a mechanism of ROS enhancement in diabetes, various metabolic abnormalities mediated by hyperglycemia, namely, advanced glycation end-product production, polyol metabolic abnormality, and enhanced mitochondrial superoxide production, have been reported.25 29 30 Increased ROS is associated with human vascular endothelial dysfunction.31 Endothelial dysfunction is considered one of the main mechanisms of vascular complications due to chronic hyperglycemia.32 Therefore, a sustained decrease in ROS could be linked at least partly to protection against diabetic vascular complications by antidiabetic drugs.32 In fact, improvement in endothelial dysfunction was reported after the use of SGLT2 inhibitors.33 34 One of the possible mechanisms of dapagliflozin’s secondary prevention of coronary artery disease is considered through suppression of ROS.35 Although the mechanism by which SGLT2 inhibitors decreased urinary 8OHdG remains unclear, their multiple beneficial effects such as weight loss,36 reductions in blood pressure levels,37 38 improvements in lipid profile,39 and decrease in uric acid38 40 might be related to the reduction in 8OHdG.
Limitations
The strengths of our study are as follows: this was the first randomized controlled trial to directly compare the effects of no add-on or add-on of an SGLT2 inhibitor on glucose fluctuation in patients with type 2 diabetes on BOT; there were no significant biases in the pretreatment for type 2 diabetes mellitus in both study arms. We could assess the relationship between glucose fluctuations and other metabolic parameters.
However, there are limitations to our study. First, our small sample size may limit our ability to conclude. Second, this study was lack of double blinding, short study duration, and lack of dietary uniformity because of the ambulatory care setting. Our findings must be validated in a larger, long-term, dietary-controlled double-blind trial to resolve these potential issues. Third, we did not measure glucose oscillation markers such as glycated albumin/HbA1c ratio other than those based on continuous glucose monitoring. This study cannot determine the relationship between the effects of dapagliflozin on short-term glycemic variables and long-term biochemical variables. We have only determined the short-term glycemic variability on days 2 and 5, not the long-term. HbA1c was significantly lower in the dapagliflozin add-on group only, which may suggest that TIR was better than no add-on. Meanwhile, decreasing body weight might include mechanisms other than improving short-term glycemic variability. Henry et al evaluated TIR at days 21–28 on various insulin combinations, either with dapagliflozin or placebo, showing no difference in TIR.12 Taken above, we cannot argue how the short-term effect could affect the long-term variables and further explain the clinical benefits of dapagliflozin observed in the previous large-scale clinical trials. Future large-scale studies to evaluate the long-term effects of dapagliflozin on BOT are needed to clarify this point.
Fourth, fewer CGM data were obtained than recommended, so the CGM data must be interpreted as directional or suggestive.11 We took CGM measures on day 2 (the baseline 48 hours of data) and day 5 (48–72 hours after the dapagliflozin add-on). We wanted to see acute effects in the first 48–72 hours. The reason was that after 1–2 weeks of dapagliflozin use, weight loss and insulin adjustment would be assumed, and the difference between the direct effect of dapagliflozin and the effect of weight loss would not be discernible. However, the method differs from the general CGM guideline,11 limiting our interpretation of CGM measures. Fifth, over 50% of our patients had taken biguanide and DPP-4 inhibitors. Although combinations of SGLT-2 inhibitors and both OADs could differ in glucose-lowering efficacy,41 we could not compare the efficacy of the combination therapy primarily due to the small sample size.