Discussion
In this study, we investigated the effects of SGLT2 inhibitors on renal and patient outcomes in patients with type 2 DM and normal or low BMI. We found that patients with type 2 DM and normal or low BMI who received SGLT2 inhibitors showed an improvement in renal function compared with the control group. In addition, SGLT2 inhibitor use was associated with a lower risk of composite renal outcomes and all-cause mortality.
In our study, the control group showed an initial increase in BMI, whereas the SGLT2 inhibitor group maintained their BMI. Meta-analysis has demonstrated that SGLT2 inhibitors reduce the body weight of patients with obesity.14 29 30 Researchers are concerned that SGLT2 inhibitors may worsen the outcomes of patients with normal or low BMI—as hypothesized in the obesity paradox.19 Our study showed that SGLT2 inhibitors did not cause significant weight loss in patients with normal or low BMI. These results are consistent with those of a recent Japanese postmarketing surveillance study, which showed that the weight loss effect of SGLT2 inhibitors was attenuated in patients with lower BMI.31 Moreover, we found that patients who did not receive SGLT2 inhibitors gained weight during the first 2 years of follow-up—suggesting that SGLT2 inhibitors may prevent weight gain in patients with type 2 DM who have normal or low BMI.
Recent post hoc analyses of the Canagliflozin Cardiovascular Assessment Study (CANVAS), Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), and Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) clinical trials found that SGLT2 inhibitor use offered renal and cardiovascular benefits regardless of BMI.24–26 The CANVAS trial enrolled patients with type 2 diabetes and a history of or high risk for CVD32; the EMPA-REG OUTCOME trial enrolled patients with type 2 diabetes and CVD;4 and the DAPA-CKD trial enrolled patients with eGFR 25–75 mL/min/1.73 m2 or uACR 200–5,000 mg/gCr with or without type 2 diabetes.7 These trials demonstrated that SGLT2 inhibitors improve renal and cardiovascular outcomes in high-risk populations. Our study indicates that SGLT2 inhibitor use was associated with improved renal function and decreased all-cause mortality, even in patients with well-maintained renal function, no or low-grade albuminuria, and less CVD. Hyperfiltration in early diabetes is well known to occur regardless of obesity status.33 34 Therefore, SGLT2 inhibitors may alleviate the injury caused by hyperfiltration in patients with diabetes and normal or low BMI. Furthermore, inflammation plays an important role in the development and progression of diabetic kidney disease and related complications.35 36 Given that SGLT2 inhibitors have anti-inflammatory properties,37 they may provide significant benefits even for patients with diabetes and normal or low BMI.
The effect of SGLT2 inhibitors was not affected by RAS inhibitor use, consistent with previous studies. Previous clinical trials have shown no differences in the efficacy of SGLT2 inhibitors regardless of RAS inhibitor use.4 32 38 In patients with CKD or overt proteinuria, SGLT2 inhibitors have shown the renal and mortality benefits of SGLT2 inhibitors in addition to the effects of RAS inhibitors.6–8 39 Post hoc analyses of BMI in previous clinical trials did not address differences in outcomes based on RAS inhibitor use.24–26 Similarly, the impact of SGLT2 inhibitor use was not affected by proteinuria or GFR. On the other hand, the use of SGLT2 inhibitors tended to be associated with a lower HR of mortality in the group with HbA1c≥7.5%, although it is not clear whether this is an effect of additional glycemic control with SGLT2 inhibitors or an effect of SGLT2 inhibitors independent of glycemic control. This result suggests that SGLT2 inhibitors can be considered first when additional glycemic control is needed in patients with low or normal BMI.
We defined normal or low BMI as a value below 23 kg/m2. Overweight is defined as a BMI of 25 kg/m2 or higher in Caucasian populations. However, based on studies showing increased morbidity and mortality at BMIs above a lower cut-off level than 25 kg/m2 in Asia-Pacific populations,27 40 the WHO defines a BMI of≥23 kg/m2 as overweight for this demographic. In a post hoc analysis of participants in the EMPA-REG OUTCOME trial that focused on the Asian population, those with BMI<24 kg/m2 had pronounced benefits of SGLT2 inhibitor use.25 Additionally, the subgroup analysis of the Asian population in the DAPA-CKD trial demonstrated pronounced benefits of SGLT2 inhibitor use in those with BMI<23 kg/m2.26 The findings of the present study corroborate those of the aforementioned clinical trials, showing that SGLT2 inhibitor use offers renal and mortality benefits in a relatively low-risk population of East Asians with a normal or low BMI of<23 kg/m2.
This study had some limitations. First, this was a single-center, retrospective observational study. Due to the retrospective nature of our study, inconsistencies or incompleteness in data collection may exist, and the presence of unmeasured confounders cannot be ruled out. Consequently, fully eliminating confounding factors is challenging even after propensity score matching. In particular, studies on drug use are prone to selection bias or indication bias unless conducted as randomized controlled trials. In our center, SGLT2 inhibitors were likely to be prescribed to patients with normal or low BMI because of poor glycemic control despite conventional oral hypoglycemic or insulin therapy, rather than because of proteinuria. Propensity score matching revealed differences in HbA1c only; however, the residual confounding factors, especially regarding the decision to use SGLT2 inhibitors, cannot be disregarded. Second, the small number of events makes the reliability of the results questionable, reflecting the low-risk nature of our study population. In addition, the relatively small sample size and limited follow-up period may have contributed to the low event rate, potentially weakening the reliability of the findings and making it more difficult to reveal true differences in effects. However, despite questions about the reliability of the effect size, our study shows that even low-risk patients with normal or low BMI may benefit from the use of SGLT2 inhibitors. Third, this study included a South Korean population, so the results cannot be generalized to other ethnic groups. Fourth, our study included a heterogeneous population, with some individuals with CVD or reduced renal function. Nevertheless, the study predominantly included a low-risk population with relatively good kidney function and no or low-grade proteinuria. Therefore, we believe that our study may offer insights regarding the indication of SGLT2 inhibitors in low-risk individuals with normal or low BMI in clinical settings.
In conclusion, SGLT2 inhibitor use was associated with a lower risk of eGFR decline and composite renal outcome in patients with Type 2 DM and normal or low BMI. Furthermore, SGLT2 inhibitor use was associated with a lower risk of mortality. These results suggest that SGLT2 inhibitors are not harmful in low-risk patients with type 2 DM and normal or low BMI and may provide renal and mortality benefits.
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