The SGLT-2 inhibitor, dapagliflozin, is a relatively new antidiabetic medication (Vivian, 2015). The study aimed to assess the benefit of using dapagliflozin as an add-on therapy to metformin on InRs and liver function; thereby facilitating the clinical decision-making by the healthcare practitioners during therapeutic intervention. In terms of age and gender, the baseline characteristics of the groups under investigation were identical. In addition, BMI values and the duration of diabetes for all patient groups were identical to rule out the influence of these variables on the investigated parameters. Aside from DM and the investigated agents, the selected patients did not have other chronic illnesses and were not using additional chronic medications.
The risk for the development of many liver diseases is usually augmented when DM is present (Hamed et al., 2019). Additionally, some antidiabetics may show a negative impact on the liver. Therefore, selecting an antidiabetic agent with a neutral or positive impact on the liver is of critical importance (Yen et al., 2022). In the current study, the ALT and total bilirubin levels seem to be comparable in all of the studied groups. The only exception was the level of AST, which appeared to be significantly lower in the dapagliflozin users when compared to metformin. This could be explained by the unique characteristics of AST, which is different from other liver function enzymes that are only produced in the liver. AST could be present in many organs, including the liver, kidneys, and heart (De Vos et al., 2019). The statistically significant reduction in AST levels in the dapagliflozin group is likely due to the therapeutic advantage of this drug on renal and cardiac function; suggesting a possible correlation between the AST and the improved renal and cardiac functions in the studied individuals (Zelniker et al., 2019). The results of this study are in accordance with previous clinical studies. In 2021, a meta-analysis explored the effect of SGLT-2 inhibitors on hepatic parameters in 15,800 subjects from 19 randomized controlled trials. Its results revealed a significant reduction in AST after prescribing SGLT-2 inhibitors, while bilirubin levels showed a significant increase (Simental-Mendía et al., 2021). Another meta-analysis, which evaluated eleven studies and gathered the results of 839 patients with NAFLD, suggested a potential efficacy of dapagliflozin in improving liver functions via a significant reduction in AST and ALT levels in the users of dapagliflozin compared to the control (He et al., 2022). These studies and the results of the present one suggest that dapagliflozin could be used safely in type 2 DM patients with liver diseases due to the positive effects of these medications on liver function.
Regarding InRs, previous attempts for the development of a new medication that can effectively manage InRs were delayed due to its mysterious origin and off-target effects (Bailey, 2019). OS, inflammation, hexosamine biosynthetic pathway, ectopic lipid accumulation, and endoplasmic reticulum stress are the predicted mechanisms for the development of InRs (K. A. Hadid et al., 2024; Lee et al., 2022). In the present study, there was a significantly higher level of serum insulin in the dapagliflozin users compared to the other groups. Similarly, the HOMA-IR assessment also revealed significant differences among the studied groups. The highest level was shown in the DM + MET + DAPA group compared to the DM + MET and the control groups. The high levels of serum insulin and HOMA-IR in the DM + MET + DAPA group indicated that the patients in the dapagliflozin group have higher InRs than those in the other groups.
The results of serum insulin and HOMA-IR of the present study are in accordance with Cuatrecasas et al. which documented that the use of dapagliflozin for 6 months as an add-therapy to metformin resulted in a higher serum insulin and a higher HOMA-IR levels compared to metformin only therapy (Cuatrecasas et al., 2024). On the other hand, the results of the present study show disagreement with Zekry et al, who stated a significant decrease in HOMA-IR after 3 months of treatment with dapagliflozin along with a non-significant change in the serum insulin. The decreased HOMA-IR in the Zakry et al study was attributed to the impact of dapagliflozin on blood glucose levels, rather than its effect on insulin levels. Nevertheless, it is important to acknowledge that the omission of detection of diabetes duration could represent the cause of the discrepancy between their study and ours (Zekry et al., 2023). The results of the present study are also in discrepancy with the DEFENCE study by Shigiyama et al, which included two study groups, the metformin group and the dapagliflozin group. InRs, as assessed by HOMA-IR, was decreased significantly in both dapagliflozin and metformin groups in patients with early-stage type 2 DM in comparison to control. Moreover, the improvement in insulin sensitivity was comparable between the two groups. However, the inclusion of only newly diagnosed diabetic patients may be the major difference between the results of our study and the Shigiyama et al study (Shigiyama et al., 2017). Given that type 2 DM is a progressive disease characterized by a decline in β-cell function and worsening InRs (Wysham & Shubrook, 2020), different durations of diabetes may produce varying treatment responses distinct from those observed in the early stage of the disease.
OS, as a suggested mechanism for InRs, promotes the expression of proinflammatory genes, resulting in inflammatory conditions, which could interfere with the insulin signaling pathway and inhibit insulin action at insulin receptors (Hurrle & Hsu, 2017). Furthermore, redox imbalance promotes the development of endoplasmic reticulum stress, which further intensifies InRs (Victor et al., 2021). Therefore, we hypothesized that the evaluation of OS is necessary
The measurement of MDA and TAC levels reflected the level of OS in this study. The findings of this study indicated that dapagliflozin has a very modest antioxidant effect when compared to both the control group and the metformin group. The concentration of MDA in the DM + MET + DAPA group is substantially greater than that in the control group. Although the level of MDA in those treated with metformin alone is higher than the control group, it is lower than that of the DM + MET + DAPA group. However, these differences are not statistically significant. Furthermore, the TAC concentration in patients using dapagliflozin is significantly lower than that of the metformin group.
These results are in accordance with other clinical studies. Nabrdalik-Leśniak et al. reported that the level of urinary TAC in dapagliflozin users was lower than that of the control group imposing higher OS in diabetic patients using dapagliflozin. Additionally, patients using dapagliflozin showed elevated levels of antioxidant enzymes such as superoxide dismutase, which could be a compensatory mechanism for high OS levels (Nabrdalik-Leśniak et al., 2021). On the other hand, Dogan and Uzun reported the potential of dapagliflozin in reducing OS in cardiomyocytes when cells are treated with methotrexate. The concentration of MDA was markedly reduced and the concentration of TAC was notably elevated in the dapagliflozin group as compared to the methotrexate group. However, this study did not investigate the level of OS parameters in the serum; their results were specific to cardiomyocytes. Also, the induced OS was due to the use of methotrexate, which could be different mechanically from the OS induced by DM. Furthermore, they did not include another medication with confirmed antioxidant activity (Dogan, 2024). Another study by Çadırcı et al. stated an enhancement in the TAC of the cultured human blood cells following the usage of dapagliflozin. However, the results of this study were not confirmed clinically (Çadırcı et al., 2019).
InRs and OS are strongly correlated in dapagliflozin users in our study. There was a strong positive correlation between the MDA levels and HOMA-IR in the DM + MET + DAPA group. Conversely, HOMA-IR and TAC levels showed a strong negative correlation in the same group. On the other hand, a slight non-significant positive correlation was observed between HOMA-IR and MDA levels in patients who are treated with metformin alone. Likewise, a slight non-significant negative correlation was reported between HOMA-IR and the TAC in the same group. Such correlations suggest that the OS in the dapagliflozin group may be the underlying mechanism responsible for the high HOMA-IR value and InRs compared to the remaining study groups. The results of the current study can, however, be explained in a variety of ways. One possible explanation is that dapagliflozin induced glucosuria and promoted the hepatic β-oxidation of ingested free fatty acids to ketones. This process also involves the mobilization of free fatty acids from the adipose tissues, which contributes to ketosis (Wallenius et al., 2022). Compared to glucose breakdown, the breakdown of free fatty acids generates a higher level of free radicals (Speijer et al., 2014). In addition to that, HbA1c levels in dapagliflozin users were significantly higher than those in the metformin group indicating poor glycemic control. The presence of hyperglycemia can trigger the activity of up to eight different types of oxidase enzymes via both direct and indirect pathways, that finally generate OS (González et al., 2023). Consequently, dapagliflozin may generate more free radicals compared to metformin, resulting in an elevated level of MDA with a reduced level of TAC.
A strong positive correlation between HOMA-IR and glycemic control, represented by serum insulin and HbA1c, was found in the DM + MET + DAPA group. Increased HOMA-IR causes an increase in InRs increase, with deterioration of glycemic status. So, the utilization of dapagliflozin in diabetic patients beyond the early stages of the disease fails to produce prominent enhancement in glycemic control when compared to metformin monotherapy. Moreover, the efficacy of dapagliflozin in improving insulin sensitivity in the presence of OS appears to be limited. As a result, InRs could explain the unexpectedly high levels of HbA1c along with the high levels of serum insulin compared to other study groups.
Based on the findings related to InRs and the consequent glycemic control, healthcare providers should be aware when considering the use of dapagliflozin in an attempt to improve insulin sensitivity in diabetic patients who are not in the early stage of the disease. Close monitoring and individualized treatment plans are recommended, and further clinical studies are needed to improve these findings and to identify the possible mechanisms beyond the correlations between dapagliflozin, OS, InRs, and glycemic status.
It is essential to acknowledge the limitations of the present study. Firstly, the open-label design of the study raises the possibility of unexpected bias, as both medical professionals and individuals knew what drugs were taken. However, in the present study, proper selection criteria were performed by matching the age, sex, BMI, and duration of diabetes to minimize any variables that could affect the obtained results. The second issue to be acknowledged is the limited number of patients that were included in the study; future trials with a bigger sample size, ideally including people of diverse ethnic backgrounds are recommended. Additionally, the study did not evaluate postprandial InRs, which is a further limitation that needs to be addressed in future research. Nevertheless, the study provided valuable insight into the possible drawback in insulin sensitivity following the addition of dapagliflozin to metformin in patients with type 2 DM.