Warning: fopen(/home/virtual/enm-kes/journal/upload/ip_log/ip_log_2025-04.txt): failed to open stream: Permission denied in /home/virtual/lib/view_data.php on line 100 Warning: fwrite() expects parameter 1 to be resource, boolean given in /home/virtual/lib/view_data.php on line 101 Discrepancies in Dapagliflozin Response in Terms of Glycemic Control and Body Weight Reduction
Skip Navigation
Skip to contents

Endocrinol Metab : Endocrinology and Metabolism

clarivate
OPEN ACCESS
SEARCH
Search
Advanced Search
mobile menu button

Articles

Page Path
HOME > Endocrinol Metab > Ahead-of print > Article
Original Article
Discrepancies in Dapagliflozin Response in Terms of Glycemic Control and Body Weight Reduction
Ji Eun Jun1orcid, Kyoung-Ah Kim2, Nan-Hee Kim3, Kwan-Woo Lee4, In-Kyung Jeong1orcid, on Behalf of the BEYOND Investigators

DOI: https://doi.org/10.3803/EnM.2024.2142
Published online: March 19, 2025

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea

2Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea

3Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea

4Department of Endocrinology and Metabolism, Ajou University Hospital, Ajou University School of Medicine, Suwon, Korea

Corresponding author: In-Kyung Jeong Division of Endocrinology and Metabolism, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, 892 Dongnam-ro, Gangdong-gu, Seoul 05278, Korea Tel: +82-2-440-6126, Fax: +82-2-440-6296, E-mail: jik1016@naver.com
• Received: August 18, 2024   • Revised: November 3, 2024   • Accepted: November 15, 2024

Copyright © 2025 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 526 Views
  • 28 Download
Full Article

Download PDF Download PDF

  • Background
    Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduces hyperglycemia and obesity by inhibiting renal glucose reabsorption. This post hoc study evaluated clinical factors influencing patient response to dapagliflozin.
  • Methods
    The analysis focused on patients treated with dapagliflozin (10 mg/day for 52 weeks) within the randomized, double-blind, parallel-group BEYOND trial. Adequate glycemic control (GC) was defined as a reduction in glycated hemoglobin (HbA1c) of ≥ 1.0% or the achievement of an HbA1c level <7.0% at week 52. Significant weight loss (WL) referred to a reduction in body weight of ≥3.0% at week 52. Participants were classified into four groups based on their GC and WL responses: GC+/WL+, GC+/WL−, GC−/WL+, and GC−/WL−.
  • Results
    Among dapagliflozin recipients (n=56), at 52 weeks, HbA1c had decreased by 1.0%±0.8% from baseline, while body weight had declined by 2.4±3.1 kg. Overall, 69.6% of participants achieved GC+, and 57.1% achieved WL+. Male sex and shorter diabetes duration were significantly associated with achieving GC+. Conversely, higher estimated glomerular filtration rate was significantly linked to WL+. The only factor significantly associated with both GC+ and WL+ was shorter diabetes duration (odds ratio, 0.81; 95% confidence interval, 0.68 to 0.97; P=0.023). The GC+ and WL+ groups exhibited favorable responses beginning soon after dapagliflozin therapy was initiated. Furthermore, HbA1c decline was more strongly associated with reduction in visceral fat than with WL.
  • Conclusion
    A short duration of diabetes and early response to treatment appear to represent key factors in maximizing the benefits of dapagliflozin for blood glucose and weight management.
  • Keywords: Sodium-glucose transporter 2 inhibitors; Dapagliflozin; Diabetes mellitus, type 2; Effectiveness
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve glycemic control (GC) by selectively inhibiting glucose reabsorption in the renal proximal convoluted tubule, causing increased glucosuria [1]. This process results in the elimination of approximately 60 to 100 g of glucose per day through the urine, contributing to an average weight loss (WL) of 2 to 3 kg in patients with diabetes [2]. However, real-world evidence suggests substantial variation in the extent of GC and WL observed among individuals after SGLT2i therapy [3]. Additionally, some patients experience an increased desire for sweet foods after starting SGLT2i treatment, which can lead to weight gain or elevated blood glucose levels due to higher caloric intake [4,5].
Regarding glycemic outcomes of SGLT2i therapy, a reduction in glycated hemoglobin (HbA1c) is significantly associated with preserved renal function [6,7] and a higher baseline HbA1c level [8,9]. However, the factors influencing WL in patients taking SGLT2i are less consistent; those with a higher body mass index (BMI) tend to experience greater WL [10], with the caveat that some studies have not found a significant association [11,12]. Greater WL with SGLT2i treatment has been observed in individuals with longer durations of diabetes [13], although the reasons behind this observation were not addressed in that report. In one study, a higher HbA1c level was linked to less WL [14], while another study reported no correlation between HbA1c level and the extent of WL [15]. Notably, the weight-lowering effect of SGLT2i seems to be maintained in patients with impaired renal function, which contrasts with the potential reduction in glucose-lowering efficacy [16].
Previous research has explored the efficacy of dapagliflozin in reducing glucose levels and facilitating WL. While some patients may achieve both glycemic and weight management goals with SGLT2i, others may meet only one of these targets. Consequently, this post hoc analysis of the Effects of Dapagliflozin Compared with Glimepiride on Body Composition in Patients with Type 2 Diabetes Inadequately Controlled with Metformin (BEYOND) trial seeks to confirm the heterogeneity of treatment responses and to identify factors contributing to these differences. To this end, we concurrently investigated the effects of dapagliflozin on hyperglycemia and body weight. Moreover, this study examines changes in body composition, extending beyond weight alone as the traditional measure of obesity.
Study design and participants
The BEYOND trial was a 52-week, multicenter, randomized, parallel-group, open-label, phase IV study conducted in Korea from January 2016 to January 2018. It assessed the effects of dapagliflozin on body composition in patients with type 2 diabetes in comparison to glimepiride [17]. Eligible participants were those between 19 and 75 years old, with HbA1c levels inadequately controlled (7.0% to <10.0%) despite being on a stable regimen of metformin monotherapy (≥1,000 mg/day) for at least 8 weeks prior to randomization. The inclusion and exclusion criteria of the BEYOND trial are detailed in Supplemental Fig. S1 [17]. A total of 124 patients were randomly assigned in a 1:1 ratio to receive either dapagliflozin (10 mg once daily) or glimepiride (1–2 mg/day), alongside metformin. Of these, 56 patients in the dapagliflozin group who completed the 52-week follow-up (constituting the full analysis set) were included in this post hoc analysis (Supplemental Fig. S2) [17].
Physical examinations, laboratory tests, and body composition assessments—including dual-energy X-ray absorptiometry (DXA) and abdominal computed tomography (CT) scans—were performed at baseline and at week 52 (Supplemental Fig. S1). Whole-body DXA operates on the principle that the differential attenuation of two distinct X-ray energies by body tissues supports a three-component model that quantifies total fat mass and lean mass. CT scans were utilized to measure the areas of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (Supplemental Table S1) [17]. The level of the L3 vertebra, which most clearly displayed both transverse processes, was selected for VAT and SAT evaluation [18].
The BEYOND trial was conducted in accordance with the Declaration of Helsinki (NCT02564926; clinicaltrials.gov) and received approval from the Institutional Review Board of Kyung Hee University Hospital at Gangdong (No. 2019-08-020-001). Due to the anonymization of study information, the requirement for informed consent was waived.
Study outcomes
Adequate glucose control was defined as either a reduction in HbA1c (calculated as HbA1c at week 52 minus baseline HbA1c) of at least 1.0% or the achievement of an HbA1c level of <7.0% at week 52 [19]. Significant WL was determined by a change in body weight, calculated as [(weight at week 52–baseline weight) divided by baseline weight], of ≥−3.0% [20]. Patients were subsequently divided into four groups (Supplemental Fig. S3): group 1, those who achieved both adequate GC and significant WL (GC+/WL+); group 2, those with adequate GC without significant WL (GC+/WL−); group 3, those with significant WL but inadequate GC (GC−/WL+); and group 4, those with neither adequate GC nor significant WL (GC−/WL−).
Statistical analysis
Data that follow a normal distribution are presented as mean±standard deviation, whereas data not following a normal distribution are presented as median (interquartile range). For continuous variables, either analysis of variance or Kruskal-Wallis tests were utilized, and for categorical variables, chi-square tests were employed. To assess changes in clinical values within individuals from baseline to follow-up, we used the paired t test or—for non-normally distributed data—the Wilcoxon signed-rank test.
Logistic regression analysis was performed to identify factors associated with the efficacy of dapagliflozin therapy. In the multivariate model, we included variables that had P values less than 0.1 in the univariate analyses and a variance inflation factor below 5.0. Backward stepwise selection was employed to determine significant covariates. To assess the predictive capabilities of the models for GC, WL, or both, the area under the receiver operating characteristic curve (AUC) was utilized. Pearson correlation analysis was applied to explore the relationship between changes in HbA1c levels and body composition parameters. A two-tailed P value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA).
Characteristics of the study population
The total study population (n=56) had a mean age of 54.4 years, with 64.3% male and a mean BMI of 27.0 kg/m2 (Table 1). The mean duration of diabetes was 6.0 years, and the initial HbA1c level was 8.0% (Table 1). Among all participants, between baseline and week 52, the HbA1c level decreased by an average of 1.0%±0.8%, while body weight declined by 2.4±3.1 kg (Supplemental Table S2).
Among the participants, 69.6% (n=39) achieved GC+, and 57.1% (n=32) experienced WL+. When categorized based on glycemic and weight control over a 52-week period (Supplemental Fig. S4), certain baseline characteristics differed significantly across the four groups. The GC+/WL+ group included 42.8% (n=24) of participants, while the GC+/WL− group comprised 26.8% (n=15). The GC−/WL+ classification encompassed 14.3% (n=8), while GC−/WL− applied to 16.1% (n=9).
Significant baseline differences were observed among the groups regarding diabetes duration, lean mass, diastolic blood pressure, fasting plasma glucose (FPG) levels, high-density lipoprotein cholesterol (HDL-C) levels, and estimated glomerular filtration rate (eGFR). Group 1 exhibited the shortest duration of diabetes, differing significantly from group 4 (4.6±4.2 years vs. 9.3±5.3 years, P=0.009). Group 2 also had a shorter duration of diabetes than group 4 (4.8±4.8 years vs. 9.3±5.3 years, P=0.022), along with higher FPG levels (178.3±41.7 mg/dL vs. 147.0±30.1 mg/dL, P=0.031) and lower HDL-C levels (43.1±8.5 mg/dL vs. 53.1±8.2 mg/dL, P=0.032). Regardless of WL, participants in groups 1 and 2, who demonstrated adequate glucose control, had a significantly shorter duration of diabetes than those in groups 3 and 4, who did not achieve such control. No significant baseline differences were observed between groups 3 and 4.
Changes in glycemic status and body composition over 52 weeks
Supplemental Table S1, Fig. 1, Supplemental Fig. S2 present the final values at week 52, along with the changes in glycemic status and body composition from baseline. The final HbA1c level decreased significantly, with groups 1 and 2 (both GC+) experiencing a greater reduction from baseline compared to group 4. Individuals classified as early responders, defined by a substantial HbA1c reduction by week 12, demonstrated a consistent decrease in HbA1c over the 52-week period (Supplemental Fig. S5A). Furthermore, significant reductions in FPG levels were observed in groups 1 and 2.
No significant differences in final body weight were observed among the groups. In groups 1 and 3 (both WL+), body weight gradually decreased over the 52 weeks, while it remained stable in the other two groups (Supplemental Fig. S5B). Individuals classified as early responders, who had lost weight at both week 4 and week 12, exhibited consistent weight reduction throughout the 52-week period (Supplemental Fig. S5B). Only group 2 displayed a significantly greater final lean mass compared to group 4. Groups 1 and 3 experienced reductions in weight, BMI, fat proportion, and fat mass when compared to group 4. However, a significant reduction in waist circumference was observed exclusively in group 3. Both groups 1 and 2 (GC+) demonstrated reductions in VAT area, regardless of body weight reduction, while groups 3 and 4 (GC−) did not (Supplemental Table S2).
Clinical determinants associated with glycemic response of dapagliflozin
In the univariate logistic analysis, factors including male sex, duration of diabetes, diastolic blood pressure, and HDL-C levels were associated with adequate GC (Table 2). Upon further examination in the multivariate logistic analysis, only male sex (odds ratio [OR], 4.17; 95% confidence interval [CI], 1.45 to 33.33; P=0.016) and a shorter duration of diabetes (OR, 0.77; 95% CI, 0.64 to 0.92; P=0.003) remained significant. Male sex also exhibited a positive correlation with reductions in HbA1c levels (r=0.32, P=0.017).
The model that incorporated diabetes duration had an AUC of 0.78 (95% CI, 0.65 to 0.90; P=0.001) (Supplemental Fig. S6). A diabetes duration cut-off of 6.9 years yielded a sensitivity of 70.6% and a specificity of 74.4% for predicting the achievement of an adequate GC. When participants were stratified by this duration, those with a longer history of diabetes had 6.96 times higher odds of achieving adequate GC (95% CI, 1.96 to 24.71; P=0.030; data not shown).
Clinical determinants of weight response to dapagliflozin
In both univariate (OR, 1.07; 95% CI, 1.01 to 1.12; P=0.013) and multivariate (OR, 1.07; 95% CI, 1.02 to 1.13; P=0.014) logistic regression models, eGFR was the only factor significantly associated with achieving significant WL (Table 3).
The AUC of eGFR was 0.72 (95% CI, 0.58 to 0.85; P=0.006) (Supplemental Fig. S7). A cut-off point of 96.2 mL/min/1.73 m2 yielded a sensitivity of 62.5% and a specificity of 66.7% for predicting the achievement of WL of at least 3%. When participants were stratified by an eGFR cut-off of 96.2 mL/min/1.73 m2, the OR for achieving adequate WL was 3.33 (95% CI, 1.10 to 10.12; P=0.034; data not shown).
Clinical determinants of dual response in glycemic control and weight reduction
A shorter duration of diabetes was the only significant factor associated with achieving both GC and WL (OR, 0.81; 95% CI, 0.68 to 0.97; P=0.023) (Supplemental Table S3). The AUC of the model that included diabetes duration was 0.76 (95% CI, 0.57 to 0.94; P=0.024) (Supplemental Fig. S8). A threshold of 5.4 years yielded a sensitivity of 77.8% and a specificity of 70.8% for predicting responders. Participants with a diabetes duration of less than 5.4 years were 8.5 times more likely to be responders (95% CI, 1.40 to 51.48; P=0.020; data not shown).
Association between changes in HbA1c levels and body composition parameters
Changes in HbA1c level (%) displayed a significant positive correlation with changes in VAT alone (Table 4, Supplemental Fig. S9A). No significant correlations were observed for other body composition parameters, including weight (Table 4, Supplemental Fig. S9B).
This post hoc study revealed heterogeneous effects of dapagliflozin on HbA1c and body weight responses in patients with type 2 diabetes. Male sex and a shorter duration of diabetes were independently associated with achieving adequate GC in response to dapagliflozin therapy. Additionally, a higher eGFR was significantly associated with more pronounced WL under dapagliflozin treatment. Moreover, a diabetes duration of less than 5.5 years continued to be a significant predictor for achieving both GC and WL. Furthermore, of the various changes in body composition, only reduced VAT was positively correlated with decreased HbA1c.
Recent studies have explored the efficacy of SGLT2i regarding the identification of individuals who respond well to treatment. A longitudinal prospective study conducted in Korea pinpointed those who responded to dapagliflozin regarding GC. The study suggested a link between higher baseline HbA1c levels, shorter duration of diabetes, and the use of dapagliflozin as an additional therapy with a relative reduction in HbA1c of more than 10% from baseline [21]. The extent of HbA1c reduction is strongly correlated with baseline HbA1c levels and tends to increase with higher initial HbA1c levels [22]. However, in our study, baseline HbA1c levels did not appear to significantly correlate with HbA1c reduction, which is inconsistent with the results of the previous study. The difference between these studies in how GC is defined may have contributed to this discrepancy. Importantly, the previous study may have included some patients with very high HbA1c levels due to the lack of specific criteria for baseline HbA1c levels and the inclusion of patients on insulin or triple therapy.
In this study, male sex was independently associated with a reduction in HbA1c levels. Preclinical animal experiments indicate that male mice may experience a more pronounced decrease in HbA1c when treated with SGLT2i, possibly due to increased SGLT2 expression in the kidneys compared to females [23]. Additionally, women typically have a lower plasma volume and a higher percentage of body fat than men, factors that contribute to a larger volume of distribution for lipophilic drugs such as SGLT2i [24]. Nevertheless, large clinical trials have not demonstrated significant sex-based differences in glycemic response to SGLT2i therapy [25,26], although limited data suggest a potential benefit for men [21,27].
Another key consideration for dapagliflozin treatment is WL. The factors contributing to WL following SGLT2i use did not consistently align with those influencing GC. One retrospective cohort study identified potential contributors to WL as age over 70 years, a BMI greater than 25 kg/m2, and the concurrent use of sulfonylureas [28]. However, the study’s participants were older and had a higher prevalence of comorbidities and various medications. In patients over 70 years old, WL might be attributed to sarcopenia, especially in the absence of information on body composition [29]. Moreover, the study did not investigate significant factors affecting WL that we identified, such as eGFR or the duration of diabetes. A pooled analysis of four tofogliflozin studies suggested that baseline body weight, uric acid level, male sex, and age could influence the degree of WL [27], although none of these factors were associated with WL in our study.
SGLT2i-mediated urinary glucose excretion (UGE) is dependent on renal function and decreases with renal impairment [30]. Consequently, a higher eGFR may contribute to superior glycemic response [27,31] and promote WL by creating a calorie deficit [32] due to the increased UGE resulting from SGLT2 inhibition. However, in our study, eGFR was only associated with WL, not with GC. Subgroup analyses revealed that patients with an eGFR ≥120 mL/min/1.73 m2 experienced a more pronounced reduction in HbA1c levels after dapagliflozin treatment [21]. However, the significance of eGFR disappeared after adjusting for various covariates. While the glucose-lowering effect of SGLT2i therapy is lessened in patients with an eGFR <60 mL/min/1.73 m2 [31], the average eGFR in our study was 96.3 mL/min/1.73 m2. This high average eGFR limited our ability to observe a significant difference among our participants, who had relatively well-preserved kidney function. Currently, no definitive evidence indicates that a high eGFR directly influences WL. However, some evidence suggests that greater WL following the initiation of SGLT2i treatment may be associated with a slower decline in eGFR [33]. Further research is required to clarify the relationship between eGFR and WL.
Our analysis stands out from previous investigations by considering the impact of dapagliflozin on both hyperglycemia and obesity. Consistent with other research [6,21], we found that a shorter duration of diabetes was a key prognostic factor for achieving GC and WL with dapagliflozin treatment. Since SGLT2i function independently of insulin secretion, they can be utilized at any stage of type 2 diabetes, from a recent diagnosis to long-standing disease. However, research indicates that the duration of diabetes is inversely related to the improvement in insulin sensitivity following SGLT2i administration [34]. This implies that patients in the earlier stages of diabetes, who may have better-preserved insulin sensitivity, could derive greater benefits from the glycemic and weight-lowering effects of SGLT2i [35]. Achieving target HbA1c levels early has been linked to sustained GC in those newly diagnosed with type 2 diabetes [36]. Similarly, our study indicated that patients who responded well to dapagliflozin treatment, as evidenced by reductions in HbA1c or WL at week 12, maintained these improvements over the course of 52 weeks. Therefore, if dapagliflozin does not elicit an adequate response shortly after initiation, it may be prudent to consider lifestyle modifications or the introduction of other antidiabetic medications.
Another clinical implication is the absence of an association between weight reduction and HbA1c reduction, which aligns with the results of prior studies [27,28]. Although both GC+/WL+ and GC+/WL− groups exhibited similar reductions in HbA1c, the latter did not achieve substantial WL despite having higher baseline HbA1c levels and body weight. This highlights the importance of consistent patient education regarding healthy diet and exercise, especially for individuals with both hyperglycemia and obesity. In certain patients, dapagliflozin may effectively regulate blood glucose levels while being insufficient for weight management, and vice versa.
The strength of our research lies in its analysis of body composition changes, extending beyond assessments of body weight or BMI and utilizing abdominal CT and DXA. To our knowledge, this study is the first to suggest that a decrease in VAT, rather than overall WL, is significantly associated with GC in patients receiving SGLT2i treatment. Notably, a reduction in VAT over a period of 52 weeks was significantly linked to a decrease in HbA1c levels. Supporting this finding, a meta-analysis has shown that SGLT2i reduce VAT, SAT, and ectopic liver fat more effectively than other antidiabetic drugs or placebo [26]. This effect is likely due to the caloric deficit induced by glycosuria, which prompts a metabolic shift from glucose to lipids substrates, leading to increased lipolysis and oxidation of free fatty acids [37,38]. Excess visceral fat is known to be associated with a reduced sensitivity of glucose uptake to insulin stimulation [39], and the visceral fat is positively correlated not only with the extent of fasting hyperglycemia but also with HbA1c levels [40]. In contrast, the surgical removal of visceral fat has been shown to improve metabolic parameters without detectable changes in body weight, fat mass, or lean body mass [41].
This post hoc analysis utilized reliable data from a previous randomized controlled trial to identify independent factors associated with treatment responses to dapagliflozin. However, several limitations should be acknowledged. First, factors such as food intake and energy expenditure, which can influence glycemia and weight, were not examined. Notably, WL resulting from chronic dapagliflozin treatment may be mitigated by compensatory hyperphagia [42]. Second, UGE and plasma volume measurements were not taken concurrently. Third, we lacked data on insulin resistance or sensitivity prior to and following dapagliflozin treatment, although the triglyceride/HDL-C ratio was used as a surrogate marker [43]. Additionally, the small sample size of the study may lack the statistical power necessary to detect differences between groups. Lastly, we did not consider the potential effects of other medications, such as those affecting the renin-angiotensin-aldosterone system, on renal hyperfiltration.
In conclusion, patients with type 2 diabetes exhibit varying responses to dapagliflozin treatment regarding GC and WL. Male sex and a shorter duration of diabetes were associated with the achievement of adequate GC, while higher eGFR was linked to greater WL. Shorter duration of diabetes emerged as a key factor in attaining both GC and WL. Patients who showed early responses to dapagliflozin treatment, evidenced by reductions in HbA1c or WL, were more likely to sustain these improvements over time. Our findings suggest that a reduction in visceral fat, which is specifically targeted by SGLT2i treatment, may have a more pronounced effect on HbA1c reduction than overall WL. Therefore, our results could assist in identifying patients with type 2 diabetes who are more likely to benefit from dapagliflozin therapy in a clinical context. However, these findings require further validation in a larger population.

Supplemental Table S1.

Detailed Procedure of Dual-Energy X-Ray Absorptiometry and Computed Tomography Assessment
enm-2024-2142-Supplemental-Table-S1.pdf

Supplemental Table S2.

Changes in Parameters of Glycemic Status and Body Composition among Four Different Groups Based on Responder or Non-Responder
enm-2024-2142-Supplemental-Table-S2.pdf

Supplemental Table S3.

Baseline Parameters Affecting Both Glucose-Lowering and the Weight-Reducing Effect of Dapagliflozin
enm-2024-2142-Supplemental-Table-S3.pdf

Supplemental Fig. S1.

Summary of study protocols. Adapted from Park et al. [17]. BEYOND, Effects of Dapagliflozin Compared with Glimepiride on Body Composition in Patients with Type 2 Diabetes Inadequately Controlled with Metformin; HbA1c, glycated hemoglobin; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; CBC, complete blood count; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; FBG, fasting blood glucose; AE, adverse event; SAE, severe adverse event. aBody composition was assessed using dual-energy X-ray absorptiometry and computed tomography scans.
enm-2024-2142-Supplemental-Fig-S1.pdf

Supplemental Fig. S2.

Flowchart of patient dispositions in the study population. Adapted from Park et al. [17]. aMetal insertion; bGenital pruritus, transient ischaemic attack, urinary tract infection; cAcute pyelonephritis, upper abdominal pain.
enm-2024-2142-Supplemental-Fig-S2.pdf

Supplemental Fig. S3.

Classification of patients following the initiation of dapagliflozin treatment based on change in body weight (BW) and glycemic response. GC, glycemic control; WL, weight loss; HbA1c, glycated hemoglobin.
enm-2024-2142-Supplemental-Fig-S3.pdf

Supplemental Fig. S4.

Scatter plot illustrating the correlation between the percentage change in glycated hemoglobin (HbA1c) level and the change in body weight (kg) following the initiation of dapagliflozin treatment. GC, glycemic control; WL, weight loss.
enm-2024-2142-Supplemental-Fig-S4.pdf

Supplemental Fig. S5.

Trends in glycated hemoglobin (HbA1c) level (%) and body weight (kg) from baseline to week 52 following the initiation of dapagliflozin treatment. (A) HbA1c level (%). (B) Body weight (kg). GC, glycemic control; WL, weight loss.
enm-2024-2142-Supplemental-Fig-S5.pdf

Supplemental Fig. S6.

Receiver operating characteristic curve of the duration of diabetes in predicting the achievement of glycemic control. AUC, area under the receiver operating characteristic curve; CI, confidence interval.
enm-2024-2142-Supplemental-Fig-S6.pdf

Supplemental Fig. S7.

Receiver operating characteristic curve of estimated glomerular filtration rate for predicting adequate weight loss. AUC, area under the receiver operating characteristic curve; CI, confidence interval.
enm-2024-2142-Supplemental-Fig-S7.pdf

Supplemental Fig. S8.

Receiver operating characteristic curve of the duration of diabetes in predicting concurrent glycemic control and weight loss. AUC, area under the receiver operating characteristic curve; CI, confidence interval.
enm-2024-2142-Supplemental-Fig-S8.pdf

Supplemental Fig. S9.

Scatter plot depicting the correlation between changes in glycated hemoglobin (HbA1c) level and body composition. (A) HbA1c change and visceral adipose tissue (VAT) change. (B) HbA1c change and weight change.
enm-2024-2142-Supplemental-Fig-S9.pdf

CONFLICTS OF INTEREST

This work was financially supported by AstraZeneca Korea. The company funder had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the article for publication.

ACKNOWLEDGMENTS

The authors thank the study participants, trial staff, and investigators who participated in the BEYOND trial.

AUTHOR CONTRIBUTIONS

Conception or design: I.K.J. Acquisition, analysis, or interpretation of data: J.E.J., K.A.K., N.H.K., K.W.L. Drafting the work or revising: J.E.J. Final approval of the manuscript: J.E.J., K.A.K., N.H.K., K.W.L., I.K.J.

Fig. 1.
Scatter plot illustrating the correlation between absolute percentage change in glycated hemoglobin (HbA1c) level and percentage change in body weight (BW). Blue dots indicate patients who achieved both adequate glycemic control (GC) and significant weight loss (WL). Green dots denote patients who achieved adequate GC without significant WL. Red dots represent patients who have achieved adequate WL without GC. Black dots indicate patients who did not achieved adequate GC or WL.
enm-2024-2142f1.jpg
Table 1.
Baseline Characteristics of Four Groups Based on Responsiveness Regarding Glycemic Control and Weight Loss
Characteristic Total Group 1
 Group 2
 Group 3
 Group 4
 P value for ANOVA
Glycemic control (+) Glycemic control (+) Glycemic control (−) Glycemic control (−)
Weight loss (+) Weight loss (−) Weight loss (+) Weight loss (−)
Number 56 (100.0) 24 (42.8) 15 (26.8) 8 (14.3) 9 (16.1)
Age, yr 54.8±9.0 51.9±9.7 55.5±7.5 57.6±8.3 56.4±9.9 0.324
Female sex 36 (64.3) 16 (66.7) 13 (86.7) 3 (37.5) 4 (44.4) 0.850
DM duration, yr 6.0±4.8 4.6±4.2b 4.8±4.8a 8.9±3.1 9.3±5.3 0.013
 <1.0 10 (17.9) 5 (20.8) 4 (26.7) 0 1 (11.1) 0.398
 <5.0 29 (51.8) 16 (66.7) 9 (60.0) 2 (25.0) 2 (22.2) 0.046
 <7.0 34 (60.7) 19 (79.2) 19 (66.7) 2 (25.0) 3 (33.3) 0.013
 <10.0 43 (76.8) 20 (83.3) 14 (86.7) 5 (62.5) 5 (55.6) 0.204
Body composition
 Weight, kg 73.0±11.6 72.4±12.7 78.4±10.8 67.1±11.1 71.2±6.8 0.126
 BMI, kg/m2 27.0±3.2 26.6±3.2 27.6±2.9 26.9±4.5 27.0±2.6 0.845
 WC, cm 91.5±8.1 89.2±8.1 94.9±8.4 92.1±9.6 91.4±4.3 0.200
 Fat % 33.1±7.3 33.3±6.1 31.2±7.1 34.1±9.6 34.9±8.6 0.637
 Fat mass, kg 23.6±6.7 23.4±5.4 24.2±7.0 22.3±9.6 24.2±7.4 0.918
 Lean mass, kg 46.3±8.4 45.4±9.4 51.3±6.8 41.2±6.0 44.6±6.1 0.026
 VAT, cm2 139.1±47.2 125.1±34.9 165.8±50.1 141.9±62.2 131.2±45.3 0.074
 SAT, cm2 170.0±74.6 172.8±74.4 161.5±60.4 158.9±99.9 186.0±79.8 0.856
Systolic BP, mm Hg 126.3±13.4 127.5±11.8 129.7±15.8 116.6±13.7 125.8±19.6 0.146
Diastolic BP, mm Hg 79.5±8.2 79.9±6.7 83.1±9.2 73.0±7.1 78.4±8.3 0.036
HbA1c, % 8.0±0.7 7.9±0.6 8.3±0.8 8.0±0.7 7.8±0.5 0.139
FPG, mg/dL 157.8±35.1 154.0±32.8 178.3±41.7a 143.3±16.9 147.0±30.1 0.049
TG, mg/dL 141.2±65.1 147.4±74.4 141.9±64.4 119.5±46.4 142.8±59.3 0.784
HDL-C, mg/dL 48.8±11.4 48.6±12.2 43.1±8.5b 56.0±12.6 53.1±8.2 0.035
LDL-C, mg/dL 80.5±28.2 85.7±29.8 75.9±26.0 70.0±32.8 83.3±23.1 0.499
TG/HDL-C 3.2±1.9 3.5±2.4 3.3±1.5 2.3±1.1 2.9±1.7 0.493
AST, U/L 29.5±15.4 28.4±14.7 32.7±21.3 27.6±9.2 28.7±11.0 0.835
ALT, U/L 36.0±21.8 37.7±21.6 38.7±27.8 25.3±13.0 36.3±17.3 0.520
eGFR, mL/min/1.73 m2 96.3±12.9 101.0±11.4 88.5±14.2 98.2±8.0 95.2±13.2 0.026
Adiponectin, μg/mL 3,544.1 (2,537.5–4,616.6) 3,544.1 (2,243.8–4,375.6) 4,051.0 (2,530.8–4,637.5) 4,127.0 (3,056.3–8,254.4) 2,677.5 (2,081.9–8,470.4) 0.595
hs-CRP, mg/dL 0.83 (0.43–1.75) 0.77 (0.42–1.68) 0.88 (0.37–1.72) 2.02 (0.53–3.45) 0.70 (0.40–1.51) 0.403

Values are expressed as number (%), mean ± standard deviation, or median (interquartile range).

ANOVA, analysis of variance; DM, diabetes; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue, BP, blood pressure; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein.

P value for comparing other groups with group 4:

a P<0.05;

b P<0.01.

Table 2.
Baseline Parameters Affecting the Glucose-Lowering Effect of Dapagliflozin
Variable HbA1c reduction ≥1% or final HbA1c <7%
Crude
 Multivariatea
OR (95% CI) P value OR (95% CI) P value
Age, yr 0.95 (0.89–1.02) 0.164
Male sex 4.17 (1.23–14.29) 0.021 5.88 (1.45–33.33) 0.016
DM duration, yr 0.81 (0.70–0.93) 0.003 0.77 (0.64–0.92) 0.003
Weight, kg 1.05 (0.99–1.11) 0.112
BMI, kg/m2 1.01 (0.84–1.20) 0.951
WC, cm 1.00 (0.93–1.07) 0.887
Fat % 0.96 (0.89–1.04) 0.338
Fat mass, kg 1.01 (0.93–1.10) 0.860
Lean mass, kg 1.08 (0.99–1.16) 0.060
VAT, cm2 1.00 (0.99–1.01) 0.756
SAT, cm2 1.00 (0.99–1.01) 0.827
Systolic BP, mm Hg 1.04 (0.99–1.09) 0.082
Diastolic BP, mm Hg 1.09 (1.01–1.19) 0.034 1.11 (0.99–1.24) 0.050
HbA1c, % 1.66 (0.66–4.18) 0.282
FPG, mg/dL 1.02 (0.99–1.04) 0.086
TG, mg/dL 1.00 (0.99–1.01) 0.476
HDL-C, mg/dL 0.93 (0.88–0.99) 0.023
LDL-C, mg/dL 1.01 (0.99–1.03) 0.545
TG/HDL 1.33 (0.90–1.98) 0.159
AST, U/L 1.01 (0.97–1.05) 0.674
ALT, U/L 1.02 (0.99–1.05) 0.276
eGFR, mL/min/1.73 m2 0.99 (0.95–1.04) 0.904
Log adiponectin, μg/mL 0.23 (0.02–2.30) 0.209
Log hs-CRP, mg/dL 0.85 (0.25–2.85) 0.787

HbA1c, glycated hemoglobin; OR, odds ratio; CI, confidence interval; DM, diabetes mellitus; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; BP, blood pressure; FPG, fasting plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein.

a Determined by backward stepwise entry method.

Table 3.
Baseline Parameters Affecting the Weight-Reducing Effect of Dapagliflozin
Variable Weight reduction ≥3%
Crude
 Multivariatea
OR (95% CI) P value OR (95% CI) P value
Age, yr 0.97 (0.91–1.03) 0.300
Male sex 1.66 (0.54–5.13) 0.378
DM duration, yr 0.96 (0.86–1.08) 0.517
Weight, kg 0.96 (0.92–1.01) 0.137
BMI, kg/m2 0.94 (0.79–1.11) 0.445
WC, cm 0.94 (0.88–1.01) 0.097
Fat % 1.02 (0.95–1.10) 0.633
Fat mass, kg 0.98 (0.90–1.06) 0.537
Lean mass, kg 0.94 (0.87–1.00) 0.055 0.94 (0.87–1.01) 0.060
VAT, cm2 0.99 (0.98–1.00) 0.082
SAT, cm2 1.00 (0.99–1.01) 0.928
Systolic BP, mm Hg 0.98 (0.94–1.02) 0.347
Diastolic BP, mm Hg 0.95 (0.89–1.02) 0.149
HbA1c, % 0.62 (0.27–1.40) 0.249
FPG, mg/dL 0.99 (0.97–1.00) 0.115
TG, mg/dL 1.00 (0.99–1.01) 0.916
HDL-C, mg/dL 1.03 (0.98–1.08) 0.256
LDL-C, mg/dL 1.00 (0.99–1.02) 0.683
TG/HDL 0.99 (0.76–1.32) 0.996
AST, U/L 0.99 (0.95–1.02) 0.478
ALT, U/L 0.99 (0.97–1.02) 0.581
eGFR, mL/min/1.73 m2 1.07 (1.01–1.12) 0.013 1.07 (1.02–1.13) 0.014
Log adiponectin, μg/mL 0.93 (0.11–7.80) 0.950
Log hs-CRP, mg/dL 1.32 (0.41–4.25) 0.637

OR, odds ratio; CI, confidence interval; DM, diabetes mellitus; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; BP, blood pressure; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein.

a Determined by backward stepwise entry method.

Table 4.
Correlations between the Change in HbA1c and the Change in Body Composition Parameters
Change in body composition parameters HbA1c change, %
Pearson coefficient P value
Δ Weight, % −0.133 0.328
Δ BMI, % −0.133 0.328
Δ WC, % −0.095 0.487
Δ Body fat mass, % −0.087 0.524
Δ Body fat proportions, % −0.065 0.633
Δ Lean body mass, % 0.003 0.981
Δ VAT, % 0.371 0.006
Δ SAT, % 0.131 0.346

HbA1c, glycated hemoglobin; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue area; SAT, subcutaneous adipose tissue area.

  • 1. Ni L, Yuan C, Chen G, Zhang C, Wu X. SGLT2i: beyond the glucose-lowering effect. Cardiovasc Diabetol 2020;19:98.ArticlePubMedPMCPDF
  • 2. Pereira MJ, Eriksson JW. Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs 2019;79:219–30.ArticlePubMedPMCPDF
  • 3. Kim H, Lee SH, Lee H, Yim HW, Cho JH, Yoon KH, et al. Blood glucose levels and bodyweight change after dapagliflozin administration. J Diabetes Investig 2021;12:1594–602.ArticlePubMedPMCPDF
  • 4. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care 2015;38:1730–5.ArticlePubMedPMCPDF
  • 5. Horie I, Abiru N, Hongo R, Nakamura T, Ito A, Haraguchi A, et al. Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment. Diabetes Res Clin Pract 2018;135:178–84.ArticlePubMed
  • 6. Lee JY, Cho Y, Lee M, Kim YJ, Lee YH, Lee BW, et al. Predictors of the therapeutic efficacy and consideration of the best combination therapy of sodium-glucose co-transporter 2 inhibitors. Diabetes Metab J 2019;43:158–73.PubMedPMC
  • 7. Scheerer MF, Rist R, Proske O, Meng A, Kostev K. Changes in HbA1c, body weight, and systolic blood pressure in type 2 diabetes patients initiating dapagliflozin therapy: a primary care database study. Diabetes Metab Syndr Obes 2016;9:337–45.ArticlePubMedPMCPDF
  • 8. DeFronzo RA, Ferrannini E, Schernthaner G, Hantel S, Elsasser U, Lee C, et al. Slope of change in HbA1c from baseline with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes. Endocrinol Diabetes Metab 2018;1:e00016.ArticlePubMedPMCPDF
  • 9. Del Parigi A, Tang W, Liu D, Lee C, Pratley R. Machine learning to identify predictors of glycemic control in type 2 diabetes: an analysis of target HbA1c reduction using empagliflozin/linagliptin data. Pharmaceut Med 2019;33:209–17.ArticlePubMedPDF
  • 10. Cho YK, Kim YJ, Jung CH. Effect of sodium-glucose cotransporter 2 inhibitors on weight reduction in overweight and obese populations without diabetes: a systematic review and a meta-analysis. J Obes Metab Syndr 2021;30:336–44.ArticlePubMedPMC
  • 11. Cai X, Yang W, Gao X, Chen Y, Zhou L, Zhang S, et al. The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: a meta-analysis. Obesity (Silver Spring) 2018;26:70–80.ArticlePubMedPDF
  • 12. Gerlanc NM, Cai J, Tkacz J, Bolge SC, Brady BL. The association of weight loss with patient experience and outcomes in a population of patients with type 2 diabetes mellitus prescribed canagliflozin. Diabetes Metab Syndr Obes 2017;10:89–99.ArticlePubMedPMCPDF
  • 13. Brown RE, Gupta N, Aronson R. Effect of dapagliflozin on glycemic control, weight, and blood pressure in patients with type 2 diabetes attending a specialist endocrinology practice in Canada: a retrospective cohort analysis. Diabetes Technol Ther 2017;19:685–91.ArticlePubMed
  • 14. Iemitsu K, Iizuka T, Takihata M, Takai M, Nakajima S, Minami N, et al. Factors influencing changes in hemoglobin A1c and body weight during treatment of type 2 diabetes with ipragliflozin: interim analysis of the ASSIGN-K study. J Clin Med Res 2016;8:373–8.ArticlePubMedPMC
  • 15. Zhang L, Feng Y, List J, Kasichayanula S, Pfister M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes Metab 2010;12:510–6.ArticlePubMed
  • 16. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 2014;85:962–71.ArticlePubMed
  • 17. Park HK, Kim KA, Min KW, Sohn TS, Jeong IK, Ahn CW, et al. Effects of dapagliflozin compared with glimepiride on body composition in Asian patients with type 2 diabetes inadequately controlled with metformin: the BEYOND study. Diabetes Obes Metab 2023;25:2743–55.PubMed
  • 18. Kwon MR, Ko ES, Park MS, Jeong WK, Hwang NY, Kim JH, et al. Impact of skeletal muscle loss and visceral obesity measured using serial CT on the prognosis of operable breast cancers in Asian patients. Korean J Radiol 2022;23:159–71.ArticlePubMedPMCPDF
  • 19. Hong AR, Koo BK, Kim SW, Yi KH, Moon MK. Efficacy and safety of sodium-glucose cotransporter-2 inhibitors in Korean patients with type 2 diabetes mellitus in real-world clinical practice. Diabetes Metab J 2019;43:590–606.ArticlePubMedPMCPDF
  • 20. Muramoto A, Matsushita M, Kato A, Yamamoto N, Koike G, Nakamura M, et al. Three percent weight reduction is the minimum requirement to improve health hazards in obese and overweight people in Japan. Obes Res Clin Pract 2014;8:e466–75.ArticlePubMed
  • 21. Han E, Kim A, Lee SJ, Kim JY, Kim JH, Lee WJ, et al. Characteristics of dapagliflozin responders: a longitudinal, prospective, nationwide dapagliflozin surveillance study in Korea. Diabetes Ther 2018;9:1689–701.ArticlePubMedPMCPDF
  • 22. Taylor SI, Yazdi ZS, Beitelshees AL. Pharmacological treatment of hyperglycemia in type 2 diabetes. J Clin Invest 2021;131:e142243.ArticlePubMedPMC
  • 23. Kharazmi F, Dastgerdi HH, Saberi S, Maleki M, Soltani N, Nematbakhsh M. Glucose transporters in kidney; the role of gender and diabetes mellitus. J Nephropharmacol 2022;11:e3.ArticlePDF
  • 24. Singh AK, Singh R. Gender difference in cardiovascular outcomes with SGLT-2 inhibitors and GLP-1 receptor agonist in type 2 diabetes: a systematic review and meta-analysis of cardio-vascular outcome trials. Diabetes Metab Syndr 2020;14:181–7.ArticlePubMed
  • 25. Young KG, McInnes EH, Massey RJ, Kahkoska AR, Pilla SJ, Raghavan S, et al. Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review. Commun Med (Lond) 2023;3:131.PubMedPMC
  • 26. Wang X, Vaduganathan M, Claggett BL, Hegde SM, Pabon M, Kulac IJ, et al. Sex differences in characteristics, outcomes, and treatment response with dapagliflozin across the range of ejection fraction in patients with heart failure: insights from DAPA-HF and DELIVER. Circulation 2023;147:624–34.ArticlePubMed
  • 27. Abe T, Matsubayashi Y, Yoshida A, Suganami H, Nojima T, Osawa T, et al. Predictors of the response of HbA1c and body weight after SGLT2 inhibition. Diabetes Metab 2018;44:172–4.ArticlePubMed
  • 28. Danpanichkul P, Manosroi W, Nilsirisuk T, Tosukhowong T. Predictors of weight reduction effectiveness of SGLT2 inhibitors in diabetes mellitus type 2 patients. Front Endocrinol (Lausanne) 2024;14:1251798.ArticlePubMedPMC
  • 29. Bales CW, Ritchie CS. Sarcopenia, weight loss, and nutritional frailty in the elderly. Annu Rev Nutr 2002;22:309–23.PubMed
  • 30. Hu S, Lin C, Cai X, Zhu X, Lv F, Nie L, et al. The urinary glucose excretion by sodium-glucose cotransporter 2 inhibitor in patients with different levels of renal function: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2022;12:814074.ArticlePubMedPMC
  • 31. Cherney DZ, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, et al. Pooled analysis of phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 2018;93:231–44.ArticlePubMed
  • 32. Pratama KG, Tandarto K, Hengky A. Weight loss effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with obesity without diabetes: a systematic review. Acta Endocrinol (Buchar) 2022;18:216–24.ArticlePubMedPMC
  • 33. Jimba T, Kaneko H, Azegami T, Suzuki Y, Okada A, Ko T, et al. Body weight change associated kidney outcomes of sodium-glucose cotransporter new users. Diabetes Obes Metab 2024;26:4535–43.PubMed
  • 34. Goto Y, Otsuka Y, Ashida K, Nagayama A, Hasuzawa N, Iwata S, et al. Improvement of skeletal muscle insulin sensitivity by 1 week of SGLT2 inhibitor use. Endocr Connect 2020;9:599–606.ArticlePubMedPMC
  • 35. Clamp LD, Hume DJ, Lambert EV, Kroff J. Enhanced insulin sensitivity in successful, long-term weight loss maintainers compared with matched controls with no weight loss history. Nutr Diabetes 2017;7:e282.ArticlePubMedPMCPDF
  • 36. Kim KJ, Choi J, Bae JH, Kim KJ, Yoo HJ, Seo JA, et al. Time to reach target glycosylated hemoglobin is associated with long-term durable glycemic control and risk of diabetic complications in patients with newly diagnosed type 2 diabetes mellitus: a 6-year observational study. Diabetes Metab J 2021;45:368–78.PubMed
  • 37. Sheu WH, Chan SP, Matawaran BJ, Deerochanawong C, Mithal A, Chan J, et al. Use of SGLT-2 inhibitors in patients with type 2 diabetes mellitus and abdominal obesity: an Asian perspective and expert recommendations. Diabetes Metab J 2020;44:11–32.ArticlePubMedPMCPDF
  • 38. Obata A, Kubota N, Kubota T, Iwamoto M, Sato H, Sakurai Y, et al. Tofogliflozin improves insulin resistance in skeletal muscle and accelerates lipolysis in adipose tissue in male mice. Endocrinology 2016;157:1029–42.ArticlePubMedPDF
  • 39. Brochu M, Starling RD, Tchernof A, Matthews DE, Garcia-Rubi E, Poehlman ET. Visceral adipose tissue is an independent correlate of glucose disposal in older obese postmenopausal women. J Clin Endocrinol Metab 2000;85:2378–84.ArticlePubMed
  • 40. Gastaldelli A, Miyazaki Y, Pettiti M, Matsuda M, Mahankali S, Santini E, et al. Metabolic effects of visceral fat accumulation in type 2 diabetes. J Clin Endocrinol Metab 2002;87:5098–103.ArticlePubMed
  • 41. Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, et al. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes 2002;51:2951–8.PubMed
  • 42. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881–7.ArticlePubMedPDF
  • 43. Yang Y, Wang B, Yuan H, Li X. Triglycerides to high-density lipoprotein cholesterol ratio is the best surrogate marker for insulin resistance in nonobese middle-aged and elderly population: a cross-sectional study. Int J Endocrinol 2021;2021:6676569.ArticlePubMedPMC

Figure & Data

References

    Citations

    Citations to this article as recorded by  

      Figure
      • 0
      Discrepancies in Dapagliflozin Response in Terms of Glycemic Control and Body Weight Reduction
      Image
      Fig. 1. Scatter plot illustrating the correlation between absolute percentage change in glycated hemoglobin (HbA1c) level and percentage change in body weight (BW). Blue dots indicate patients who achieved both adequate glycemic control (GC) and significant weight loss (WL). Green dots denote patients who achieved adequate GC without significant WL. Red dots represent patients who have achieved adequate WL without GC. Black dots indicate patients who did not achieved adequate GC or WL.

      Fig. 1.

      Discrepancies in Dapagliflozin Response in Terms of Glycemic Control and Body Weight Reduction
      Characteristic Total Group 1
      		 Group 2
      		 Group 3
      		 Group 4
      		 P value for ANOVA
      Glycemic control (+) Glycemic control (+) Glycemic control (−) Glycemic control (−)
      Weight loss (+) Weight loss (−) Weight loss (+) Weight loss (−)
      Number 56 (100.0) 24 (42.8) 15 (26.8) 8 (14.3) 9 (16.1)
      Age, yr 54.8±9.0 51.9±9.7 55.5±7.5 57.6±8.3 56.4±9.9 0.324
      Female sex 36 (64.3) 16 (66.7) 13 (86.7) 3 (37.5) 4 (44.4) 0.850
      DM duration, yr 6.0±4.8 4.6±4.2b 4.8±4.8a 8.9±3.1 9.3±5.3 0.013
       <1.0 10 (17.9) 5 (20.8) 4 (26.7) 0 1 (11.1) 0.398
       <5.0 29 (51.8) 16 (66.7) 9 (60.0) 2 (25.0) 2 (22.2) 0.046
       <7.0 34 (60.7) 19 (79.2) 19 (66.7) 2 (25.0) 3 (33.3) 0.013
       <10.0 43 (76.8) 20 (83.3) 14 (86.7) 5 (62.5) 5 (55.6) 0.204
      Body composition
       Weight, kg 73.0±11.6 72.4±12.7 78.4±10.8 67.1±11.1 71.2±6.8 0.126
       BMI, kg/m2 27.0±3.2 26.6±3.2 27.6±2.9 26.9±4.5 27.0±2.6 0.845
       WC, cm 91.5±8.1 89.2±8.1 94.9±8.4 92.1±9.6 91.4±4.3 0.200
       Fat % 33.1±7.3 33.3±6.1 31.2±7.1 34.1±9.6 34.9±8.6 0.637
       Fat mass, kg 23.6±6.7 23.4±5.4 24.2±7.0 22.3±9.6 24.2±7.4 0.918
       Lean mass, kg 46.3±8.4 45.4±9.4 51.3±6.8 41.2±6.0 44.6±6.1 0.026
       VAT, cm2 139.1±47.2 125.1±34.9 165.8±50.1 141.9±62.2 131.2±45.3 0.074
       SAT, cm2 170.0±74.6 172.8±74.4 161.5±60.4 158.9±99.9 186.0±79.8 0.856
      Systolic BP, mm Hg 126.3±13.4 127.5±11.8 129.7±15.8 116.6±13.7 125.8±19.6 0.146
      Diastolic BP, mm Hg 79.5±8.2 79.9±6.7 83.1±9.2 73.0±7.1 78.4±8.3 0.036
      HbA1c, % 8.0±0.7 7.9±0.6 8.3±0.8 8.0±0.7 7.8±0.5 0.139
      FPG, mg/dL 157.8±35.1 154.0±32.8 178.3±41.7a 143.3±16.9 147.0±30.1 0.049
      TG, mg/dL 141.2±65.1 147.4±74.4 141.9±64.4 119.5±46.4 142.8±59.3 0.784
      HDL-C, mg/dL 48.8±11.4 48.6±12.2 43.1±8.5b 56.0±12.6 53.1±8.2 0.035
      LDL-C, mg/dL 80.5±28.2 85.7±29.8 75.9±26.0 70.0±32.8 83.3±23.1 0.499
      TG/HDL-C 3.2±1.9 3.5±2.4 3.3±1.5 2.3±1.1 2.9±1.7 0.493
      AST, U/L 29.5±15.4 28.4±14.7 32.7±21.3 27.6±9.2 28.7±11.0 0.835
      ALT, U/L 36.0±21.8 37.7±21.6 38.7±27.8 25.3±13.0 36.3±17.3 0.520
      eGFR, mL/min/1.73 m2 96.3±12.9 101.0±11.4 88.5±14.2 98.2±8.0 95.2±13.2 0.026
      Adiponectin, μg/mL 3,544.1 (2,537.5–4,616.6) 3,544.1 (2,243.8–4,375.6) 4,051.0 (2,530.8–4,637.5) 4,127.0 (3,056.3–8,254.4) 2,677.5 (2,081.9–8,470.4) 0.595
      hs-CRP, mg/dL 0.83 (0.43–1.75) 0.77 (0.42–1.68) 0.88 (0.37–1.72) 2.02 (0.53–3.45) 0.70 (0.40–1.51) 0.403
      Variable HbA1c reduction ≥1% or final HbA1c <7%
      Crude
      		 Multivariatea
      OR (95% CI) P value OR (95% CI) P value
      Age, yr 0.95 (0.89–1.02) 0.164
      Male sex 4.17 (1.23–14.29) 0.021 5.88 (1.45–33.33) 0.016
      DM duration, yr 0.81 (0.70–0.93) 0.003 0.77 (0.64–0.92) 0.003
      Weight, kg 1.05 (0.99–1.11) 0.112
      BMI, kg/m2 1.01 (0.84–1.20) 0.951
      WC, cm 1.00 (0.93–1.07) 0.887
      Fat % 0.96 (0.89–1.04) 0.338
      Fat mass, kg 1.01 (0.93–1.10) 0.860
      Lean mass, kg 1.08 (0.99–1.16) 0.060
      VAT, cm2 1.00 (0.99–1.01) 0.756
      SAT, cm2 1.00 (0.99–1.01) 0.827
      Systolic BP, mm Hg 1.04 (0.99–1.09) 0.082
      Diastolic BP, mm Hg 1.09 (1.01–1.19) 0.034 1.11 (0.99–1.24) 0.050
      HbA1c, % 1.66 (0.66–4.18) 0.282
      FPG, mg/dL 1.02 (0.99–1.04) 0.086
      TG, mg/dL 1.00 (0.99–1.01) 0.476
      HDL-C, mg/dL 0.93 (0.88–0.99) 0.023
      LDL-C, mg/dL 1.01 (0.99–1.03) 0.545
      TG/HDL 1.33 (0.90–1.98) 0.159
      AST, U/L 1.01 (0.97–1.05) 0.674
      ALT, U/L 1.02 (0.99–1.05) 0.276
      eGFR, mL/min/1.73 m2 0.99 (0.95–1.04) 0.904
      Log adiponectin, μg/mL 0.23 (0.02–2.30) 0.209
      Log hs-CRP, mg/dL 0.85 (0.25–2.85) 0.787
      Variable Weight reduction ≥3%
      Crude
      		 Multivariatea
      OR (95% CI) P value OR (95% CI) P value
      Age, yr 0.97 (0.91–1.03) 0.300
      Male sex 1.66 (0.54–5.13) 0.378
      DM duration, yr 0.96 (0.86–1.08) 0.517
      Weight, kg 0.96 (0.92–1.01) 0.137
      BMI, kg/m2 0.94 (0.79–1.11) 0.445
      WC, cm 0.94 (0.88–1.01) 0.097
      Fat % 1.02 (0.95–1.10) 0.633
      Fat mass, kg 0.98 (0.90–1.06) 0.537
      Lean mass, kg 0.94 (0.87–1.00) 0.055 0.94 (0.87–1.01) 0.060
      VAT, cm2 0.99 (0.98–1.00) 0.082
      SAT, cm2 1.00 (0.99–1.01) 0.928
      Systolic BP, mm Hg 0.98 (0.94–1.02) 0.347
      Diastolic BP, mm Hg 0.95 (0.89–1.02) 0.149
      HbA1c, % 0.62 (0.27–1.40) 0.249
      FPG, mg/dL 0.99 (0.97–1.00) 0.115
      TG, mg/dL 1.00 (0.99–1.01) 0.916
      HDL-C, mg/dL 1.03 (0.98–1.08) 0.256
      LDL-C, mg/dL 1.00 (0.99–1.02) 0.683
      TG/HDL 0.99 (0.76–1.32) 0.996
      AST, U/L 0.99 (0.95–1.02) 0.478
      ALT, U/L 0.99 (0.97–1.02) 0.581
      eGFR, mL/min/1.73 m2 1.07 (1.01–1.12) 0.013 1.07 (1.02–1.13) 0.014
      Log adiponectin, μg/mL 0.93 (0.11–7.80) 0.950
      Log hs-CRP, mg/dL 1.32 (0.41–4.25) 0.637
      Change in body composition parameters HbA1c change, %
      Pearson coefficient P value
      Δ Weight, % −0.133 0.328
      Δ BMI, % −0.133 0.328
      Δ WC, % −0.095 0.487
      Δ Body fat mass, % −0.087 0.524
      Δ Body fat proportions, % −0.065 0.633
      Δ Lean body mass, % 0.003 0.981
      Δ VAT, % 0.371 0.006
      Δ SAT, % 0.131 0.346
      Table 1. Baseline Characteristics of Four Groups Based on Responsiveness Regarding Glycemic Control and Weight Loss

      Values are expressed as number (%), mean ± standard deviation, or median (interquartile range).

      ANOVA, analysis of variance; DM, diabetes; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue, BP, blood pressure; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein.

      P value for comparing other groups with group 4:

      P<0.05;

      P<0.01.

      Table 2. Baseline Parameters Affecting the Glucose-Lowering Effect of Dapagliflozin

      HbA1c, glycated hemoglobin; OR, odds ratio; CI, confidence interval; DM, diabetes mellitus; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; BP, blood pressure; FPG, fasting plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein.

      Determined by backward stepwise entry method.

      Table 3. Baseline Parameters Affecting the Weight-Reducing Effect of Dapagliflozin

      OR, odds ratio; CI, confidence interval; DM, diabetes mellitus; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue; BP, blood pressure; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; AST, aspartate aminotransferase; ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; hs-CRP, high-sensitivity C-reactive protein.

      Determined by backward stepwise entry method.

      Table 4. Correlations between the Change in HbA1c and the Change in Body Composition Parameters

      HbA1c, glycated hemoglobin; BMI, body mass index; WC, waist circumference; VAT, visceral adipose tissue area; SAT, subcutaneous adipose tissue area.

      Table 1.

      Table 2.

      Table 3.

      Table 4.

      Endocrinol Metab : Endocrinology and Metabolism
      © Korean Endocrine Society.
      TOP