SGLT2 inhibitors are widely used to treat obese patients with type 2 diabetes mellitus, owing to the weight reduction effect of SGLT2. Of late, body weight management in type 1 diabetes mellitus has become an important health issue. Insulin therapy is essential for patients with type 1 diabetes mellitus; however, a gain in body weight is a major side effect, which is of concern. SGLT2 inhibitors excrete blood glucose into the urine, thereby promoting energy loss and body weight reduction. Furthermore, they stimulate the absorption of phosphate and lead to calcinuria . In this study, body weight reduced rapidly after the administration of the SGLT2 inhibitor, and this reduction was sustained for a long time. This drug has diuretic effects; therefore, a body composition analysis showed a loss of total body water after 12 weeks of treatment. Interestingly, there were no remarkable changes in total body water between 12 and 52 weeks. This result further indicates that long-term changes in body weight are not caused by water loss. The ratio of extracellular water to total body water showed a few differences; hence, there was no measurement error of BIA regarding the change of water distribution. Body composition analysis also revealed that SGLT2 inhibitors decreased fat mass, muscle mass, and bone mineral content. When compared to baseline, the reduction ratio indicates that total fat mass is the dominant factor, which is affected by the use of SGLT2 inhibitors, indicating that this drug has the therapeutic potential to manage obese patients with type 1 diabetes mellitus.
Despite previously established advantages, there are potential risks to muscle and bone. Reportedly, SGLT2 inhibitors reduced muscle mass in type 2 diabetes mellitus [7, 14]. In our study involving patients with type 1 diabetes, the muscle volume decreased after treatment. The reduction ratio was smaller than the total mass, but this result suggests a potential risk for sarcopenia. The mechanism of fat mass reduction is believed to be the activation of gluconeogenesis. As a result, lipolysis and proteolysis can occur . In addition, our study showed that age tended to be negatively correlated with the change in skeletal muscle mass, and patients with a lower BMI showed lower skeletal muscle mass index. Older adults have reduced protein synthesis and smaller satellite cells in muscles compared to younger adults . Therefore, these drugs should be used cautiously in lean patients who lack sufficient muscle mass, such as older adults.
In a previous study, the bone resorption marker tartrate resistant acid phosphatase 5b decreased after 24 weeks of SGLT2 inhibitor treatment . Our findings also showed that bone mineral content calculated from BIA decreased after treatment. Although this change was similar to that of the total fat mass, the reduction in the bone mineral content recovered slightly at 52 weeks. Our regression analysis revealed that the reduction in bone mineral content was correlated with total body water loss. This suggests that bone mineral content may be affected by the excretion of calcium in urine. The effect of SGLT2 inhibitors on bone remains unclear, even with large clinical trials. Therefore, studies conducted for longer terms are required.
In this study, administration of SGLT2 inhibitors also aided in reducing the basal insulin dose. Although we reduced the insulin dose by 10–20% after the administration of the SGLT2 inhibitor, the reduction in basal insulin levels was sustained for long durations and affected changes in body weight. However, the change in the dose of basal insulin level, the bolus insulin dose, did not differ at 52 weeks of SGLT2 inhibitor treatment. A previous meta-analysis showed that SGLT2 inhibitors reduced the doses of both basal and bolus insulin . In our study, the insulin dose adjustments were entrusted to the patients, and the amount of food intake affected bolus insulin. Moreover, previous studies frequently used higher dose of SGLT2 inhibitors; however, our study used a lower dose of SGLT2 inhibitors. A previous study showed that a lower dose of SGLT2 inhibitors reduced basal insulin but not bolus insulin , which is consistent with our findings.
SGLT2 inhibitors adjust plasma glucose levels by inhibiting glucose reabsorption in the renal proximal tubule. Since insulin therapy does not have this advantage, a combination therapy can be useful to manage glucose variability in patients with type 1 diabetes mellitus. Our study showed that SGLT2 inhibitors decreased not only the mean plasma glucose but also SD and MAGE, which are indices of glucose variation, which leads to increased TIR. Previous research has shown that reductions of TIR are strongly associated with the risk of microvascular diabetic complications . Therefore, the use of SGLT2 inhibitors in patients with type 1 diabetes mellitus would be beneficial not only for decreasing plasma glucose but also for preventing diabetic complications by reducing glucose variability. Although many antidiabetic agents potentially increase hypoglycemia, the dose of SGLT2 inhibitors did not increase TBR after 52 weeks of treatment in our study. One of the causes could be a decrease in insulin dose, especially basal insulin, at 52 weeks of SGLT2 inhibitor administration. In addition, SGLT2 inhibitors increase endogenous glucose production , reducing the possibility of hypoglycemia.
This study has some limitations. First, this study had a small number of participants, raising concerns regarding selection bias. Second, dual-energy x-ray absorptiometry, which is a standard method to evaluate bone density, was not used in this study. Although the BIA is a preferable method because it is noninvasive and economically feasible, it is limited by the variabilities in chemical composition, such as water, proteins, glycogen, and minerals . Nonetheless, BIA has improved recently in terms of accuracy  and evaluation in bone  and is frequently used to analyze body composition. Third, this study used the FGM to evaluate glycemic variability. This device shows a glycemic trend when worn by patients and can be useful for self-management . The FGM was supplied to the patients prior to SGLT2 inhibitor administration; however, its management by the patient may affect glucose variabilities. Finally, the study duration was limited to 52 weeks, which may not be sufficient to evaluate the long-term effects of SGLT2 inhibitors on bone. In addition, the occurrence of fractures was not assessed in this study. Therefore, further studies are needed to fully evaluate the effects of SGLT2 inhibitors on bone metabolism.