This multicentre, randomised, open-label, parallel-group comparison study evaluated the short-term and long-term efficacies of dapagliflozin in type 2 diabetes patients on BOT. We obtained two main results. First, we observed dissimilar changes in the 24-h glucose variables in the add-on and no add-on groups on BOT. The addition of dapagliflozin had positive results on mean blood glucose, maximum blood glucose, standard deviation, and time in ranges in CGM. Second, the levels of urinary -OHdG, which is 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 preferable 24-h glucose profile and the long-term efficacy on oxidative stress in type 2 diabetes patients on BOT.
Twenty-four-hour Glucose Variables And Dapagliflozin
SGLT2 inhibitors plus insulin therapy showed a reduction in HbA1c, daily insulin dose, and body weight and an improvement in insulin resistance, ꞵ-cell function, and cardiovascular benefits.[7] 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.[11] Inagaki et al. reported the efficacy and safety of canagliflozin in combination with insulin therapy in Japanese type 2 diabetes patients.[12] HbA1c and body weight after the 16th week 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 hypoglycaemia was higher in the canagliflozin group.[12] In our study, the incidence of hypoglycaemia 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 al.[12] and the incidence of hypoglycaemia associated with SGLT add-on observed in our study. The difference in insulin preparations (BOT, basal-bolus insulin therapy, or R/NPH mix insulin[12] vs. BOT in our study) could be one of the reasons. Our study is the first to assess TIR as a measure of glycaemic control beyond A1C 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 positive profiles of SGLT2 inhibitors in TIR in type 1[13] and type 2 diabetes patients.[14] However, no previous study has assessed TIR in the combination therapy with SGLT2 inhibitors and insulin.
In the present study, TIR in the no add-on group remained unchanged, whereas it was significantly increased in the dapagliflozin add-on group (Fig. 4). The increase in TIR was obtained by decreasing TAR without increasing TBR, which can be regarded as an effective and safe result.[9]
Long-term Diabetes-related Variables And Dapagliflozin
In this study, HbA1c and body weight significantly improved at 12 weeks after dapagliflozin administration, although there was no significant difference in FPG or blood pressure levels. Long-term complications were prevented as evidenced by the significant improvements in HbA1c and/or TIR.[9] Beck et al. reported that progression of diabetic retinopathy and microalbuminuria was associated with changes in TIR[15]: 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 type 2 diabetes patients with advanced retinopathy, and the prevalence of DR decreased with increasing TIR.[16]
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.[17] In this study, the dapagliflozin add-on group showed a significant decrease in the urinary 8-OHdG level at 12 weeks. Previous studies have reported that the administration of SGLT2 inhibitors decreased the 8-OHdG levels (canagliflozin[18], ipragliflozin[19], and empagliflozin[20]). As a mechanism of ROS enhancement in diabetes, various metabolic abnormalities mediated by hyperglycaemia, namely, advanced glycation end product production, polyol metabolic abnormality, and enhanced mitochondrial superoxide production, have been reported.[17, 21, 22] A decrease in NO production[23, 24] or an improvement in glycaemic control[25–28] has been reported to improve vascular endothelial function in patients with type 2 diabetes. In fact, improvement in endothelial dysfunction was reported after use of SGLT2 inhibitors.[29, 30] One of the possible mechanisms of dapagliflozin's secondary prevention of coronary artery disease is through suppression of oxidative stress.[31] Although the mechanism by which urinary 8-OHdG was decreased by SGLT2 inhibitors remains unclear, their multiple beneficial effects such as weight loss,[32] reduction in blood pressure levels,[33, 34] improvement in lipid profile,[35] and decrease in uric acid[34, 36] might be related to the decrease in 8-OHdG.
Limitations: The strengths of our study are as follows: this was the first randomised controlled trial to directly compare the effects of no add-on or add-on of an SGLT2 inhibitor on glucose fluctuation in type 2 diabetes patients on BOT; there were no significant biases in the pre-treatment for type 2 diabetes mellitus in both study arms. We could assess the relationship between glucose fluctuations and other metabolic parameters. However, our small sample size may limit our ability to draw a conclusion. Other major limitations of this study were lack of double blinding, short study duration, and lack of dietary uniformity because of the ambulatory care setting. To resolve these potential issues, our findings need to be validated in a larger scale, long-term, dietary-controlled double-blind trial.