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Comparison of kidney and hepatic outcomes among sodium-glucose cotransporter-2 inhibitors: a retrospective study using multiple propensity scores

Journal of Pharmaceutical Health Care and Sciences volume 10, Article number: 57 (2024) Cite this article

Abstract

Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been reported to have effects beyond lowering blood glucose levels, with certain SGLT2i expanding their indications to chronic kidney disease and chronic heart failure. We focused on the hepatoprotective and renoprotective effects of six SGLT2i and assessed whether the effects were unique to each drug or common class effects, in addition to whether the renal and hepatoprotective effects vary based on renal and hepatic status.

Methods

Patients with diabetes (ipragliflozin: 837, empagliflozin: 850, canagliflozin: 922, dapagliflozin: 590, tofogliflozin: 288, and luseogliflozin: 193) who initiated SGLT2i treatment and were monitored for one year were included. The propensity score (PS) was calculated using patient backgrounds (age, sex, height, weight, body mass index [BMI], disease duration, concomitant diabetes medications, underlying conditions, glycated hemoglobin [HbA1c], estimated glomerular filtration rate [eGFR], aspartate aminotransferase [AST], alanine aminotransferase [ALT], high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglyceride [TG] levels) as covariates. Additionally, the inverse probability of treatment weighting (IPTW) approach was used to compare liver and renal function test values.

Results

Pre- and 12-month post-treatment comparisons demonstrated a significant reduction in hepatic function (AST and ALT) and an increase in renal function (eCcr and eGFR) for all SGLT2i. Comparison of differences between pre- and 12-month post-treatment using the IPTW approach demonstrated no significant differences in AST, ALT, and eGFR levels between SGLT2i. At 12 months post-treatment, 67 patients were classified as having a more severe CKD than those at pre-treatment, representing only 1.8% of all patients (67/3,680). Similarly, 107 patients with AST and 147 patients with ALT were classified as having progressed to a more severe grade than at pre-treatment, representing only 2.9 and 4.0%, respectively.

Conclusions

Renoprotective and hepatoprotective effects are class effects of SGLT2i, and their effects are thought to be independent of kidney or liver status.

Background

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are drugs that lower blood glucose levels without insulin action by inhibiting glucose reabsorption in the proximal tubule, thereby facilitating urinary glucose excretion [1]. In Japan, six SGLT2i (ipragliflozin [IGZ], empagliflozin [EGZ], canagliflozin [CGZ], dapagliflozin [DGZ], tofogliflozin [TGZ], and luseogliflozin [LGZ]) have been approved for the treatment of diabetes. Initially, SGLT2i were anticipated to lower blood glucose levels; reduce body weight, blood pressure, and uric acid levels; and enhance lipids, insulin secretory reserve, and insulin resistance [2,3,4,5,6]. Additionally, renoprotective [7,8,9,10,11] and hepatoprotective effects [12, 13] have recently attracted attention. DGZ is indicated for chronic kidney disease (CKD), and CGZ for CKD complicated by type 2 diabetes in Japan. Despite studies indicating the hepatoprotective effects of SGLT2i in patients with type 2 diabetes [12, 13], their use in liver diseases has not yet been explored. Currently, our understanding of whether all six SGLT2i exhibit renoprotective and hepatoprotective effects, and variations in the effects among the six drugs, in addition to whether the renal and hepatoprotective effects differ based on renal and hepatic status, is limited.

In this study, patients who initiated treatment with SGLT2i were monitored for one year to assess alterations in renal and liver function tests. The inverse probability of treatment weighting (IPTW) approach [14] was used for drug comparisons, in which the propensity score (PS) was calculated using the patient background, and the inverse of the PS was used as the weight.

Methods

Target patients

Patients with diabetes at JA Hokkaido Koseiren hospitals (Asahikawa Koseiren, Sapporo Koseiren, Obihiro Koseiren, Abashiri Koseiren, Engaru Koseiren, and Kutchan Koseiren) for whom treatment with SGLT2i was initiated from April 2014 to March 2020 and who were monitored for 12 months were eligible for the study. As a control, patients who were not taking SGLT2i, for whom treatment with dipeptidyl peptidase-4 inhibitor (DPP-4i) was initiated, and who were monitored for 12 months were also studied. DPP4i is the most prescribed drug for diabetes in Japan. Patients for whom treatment with drugs that exhibit renoprotective and hepatoprotective effects was initiated were excluded. The drugs excluded for their renoprotective effects were the three drugs reported to be effective for diabetic nephropathy, namely angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists [15,16,17,18,19,20,21,22,23]. Additionally, the drugs excluded for their hepatoprotective effects were nine drugs identified through a keyword search in Japanese package inserts for “improvement in liver function” and “improvement in hyperammonemia” (including ursodeoxycholic acid, methylmethionine sulphonium chloride, polyene phosphatidylcholine, taurine, tiopronin, diisopropylamine dichloroacetate, monoammonium glycyrrhizinate/glycine/aminoacetic acid/dl-methionine, lactulose, and rifaximin).

Survey variables

Patient background

We assessed patient background, such as age, sex, height, weight, body mass index (BMI), diabetes duration, concomitant use of hypoglycemic drugs (DPP-4i, sulfonylurea [SU], α-glucosidase inhibitor [α-GI], glinide [GL], biguanide [BG], and thiazolidinediones [TZ]), underlying diseases (liver disease, renal disease, heart disease, cerebrovascular disease, hypertension, and dyslipidemia) and laboratory values (glycated hemoglobin [HbA1c], estimated glomerular filtration rate [eGFR], aspartate aminotransferase [AST], alanine aminotransferase [ALT], high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides [TG]). In all cases, the data were obtained before the initiation of SGLT2i or DPP4i treatment.

Alterations in laboratory values associated with renal and hepatic function

We assessed renal function (eGFR) and hepatic function (AST and ALT) laboratory values pre- and 6 and 12 months post-SGLT2i treatment initiation. Additionally, alterations in laboratory values (ΔeGFR, ΔAST, and ΔALT) were calculated using the following formula as an assessment index of renoprotective and hepatoprotective effects. Calculation formula: (test values after 12 months of SGLT2i treatment)−(test values before SGLT2i treatment).

Statistical analysis

Statistical analyses were conducted using JMP® Pro 17 (SAS Institute Inc., Cary, NC, USA). The Mann–Whitney U-test was used to assess two related groups, whereas the Kruskal–Wallis test was used to assess multiple groups. The IPTW approach was used to compare ΔeGFR, ΔAST, and ΔALT values to adjust for factors that may affect renoprotective and hepatoprotective effects. To calculate the PS required for the IPTW approach, 25 patient background variables were used as covariates. Using this approach, we intended to perform adjustment among SGLT2i and did not use DPP4i patient background variables. P values < 0.05 were considered statistically significant.

Ethical considerations

This study was approved by the ethics committees at each hospital (Asahikawa Kosei [approval number: 2020056], Sapporo Kosei [approval number: 554], Obihiro Kosei [approval number: 2020–089], Abashiri Kosei [approval number: 202012], Engaru Kosei [approval number: 2020–13], and Kutchan Kosei [approval number: R2-3]). In this study, we used only existing data, without acquiring written or oral consent from the patients. Therefore, we disclosed data regarding the study on the web or posted them in the hospital (or both), and guaranteed the opportunity for all patients to decline participation.

Results

Patient background

There were 3,680 cases (IGZ: 837, EGZ: 850, CGZ: 922, DGZ: 590, TGZ: 288, and LGZ: 193) (Table 1). There were 7,172 control DPP4i cases. To assess covariate balance in the SGLT2i cases, a standardized difference score (Std diff) was calculated. |Std diff|< 0.1 was considered a minor difference [24]. |Std diff| was > 0.1 for age, weight, BMI, diabetes duration, concomitant medications (α-GI), heart disease, cerebrovascular disease, hypertension, dyslipidemia, HbA1c, and HDL-C (Table 2). This indicates an uneven distribution of SGLT2i patient backgrounds.

Table 1 Patient background
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Table 2 Standardized difference scores pre- and post-adjustment in SGLT2i
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Renal function laboratory values

There was a significant reduction in eGFR levels before treatment across all SGLT2i compared to 12 months post-treatment (Fig. 1). For all SGLT2i, there was a temporary reduction in eGFR levels at six months. There was a significant reduction in the DPP4i control.

Fig. 1
figure 1

Alteration in eGFR levels pre-, 6, and 12 months post-SGLT2i or DPP4i treatment. Data are presented as the mean ± SD. The Mann–Whitney U-test was used to compare eGFR values pre- and 12 months post-SGLT2i or DPP4i treatment

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Pre-treatment eGFR levels with SGLT2i were classified based on CKD severity as follows: G1 (eGFR ≥ 90: 583), G2 (90 > eGFR ≥ 30: 1,384), G3 (60 > eGFR ≥ 30: 1,272), and G4 (30 > eGFR: 441; Fig. 2). At 12 months post-treatment, 67 patients (G1: 37 and G2: 30) were classified as having a more severe CKD than those at pre-treatment, representing only 1.8% of all patients (67/3,680). The eGFR levels in 92.6% of the patients were either increased, unaltered, or reduced within the classification criteria.

Fig. 2
figure 2

Classification of eGFR levels using reference values. eGFR pre- and 12 months post-SGLT2i treatment was classified as G1 (eGFR ≥ 90), G2 (90 > eGFR ≥ 30), G3 (60 > eGFR ≥ 30), and G4 (30 > eGFR) according to the severity classification of CKD

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Hepatic function laboratory values

There was a significant reduction in AST and ALT levels before treatment across all SGLT2i compared to 12 months post-treatment (Fig. 3). There were no significant alterations in AST and ALT in the DPP4i control.

Fig. 3
figure 3

Alteration in AST and ALT levels pre-, 6, and 12 months post-SGLT2i or DPP4i treatment. Data are presented as the mean ± SD. The Mann–Whitney U-test was used to compare eGFR values pre- and 12 months post-SGLT2i or DPP4i treatment

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Pre-treatment AST and ALT levels with SGLT2i were classified based on common terminology criteria for adverse events (CTCAE) ver5.0 as follows: below upper limit of normal (ULN; AST: ≤ 38, ALT: male ≤ 44, female ≤ 23), Grade 1 (ULN—ULN*3; 38 < AST ≤ 114, male: 44 < ALT ≤ 132, female: 23 < ALT ≤ 69), Grade 2 (ULN*3—ULN*5; 114 < AST ≤ 190, male: 132 < ALT ≤ 220, female: 69 < ALT ≤ 115), Grade 3 (ULN*5—ULN*20; 190 < AST ≤ 760, male: 220 < ALT ≤ 880, female: 115 < ALT ≤ 460; Fig. 4). The respective numbers of cases of AST and ALT were 2,778 and 2,317 for below ULN; 886 and 1,273 for Grade 1; 11 and 8 for Grade 3, and 5 and 6 for Grade 3.

Fig. 4
figure 4

Classification of AST and ALT levels using reference values. AST or ALT pre- and 12 months post-SGLT2i treatment were classified as below ULN (AST: ≤ 38 IU/L, ALT: male ≤ 44, female ≤ 23), Grade 1 (38 < AST ≤ 114, male: 44 < ALT ≤ 132, female: 23 < ALT ≤ 69), Grade 2 (114 < AST ≤ 190, male: 132 < ALT ≤ 220, female: 69 < ALT ≤ 115), and Grade 3 (190 < AST ≤ 760, male: 220 < ALT ≤ 880, female: 115 < ALT ≤ 460) according to the severity classification of CTCAE ver5.0

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In the below ULN AST group, 96.5% (2,682/2,778) of patients remained normal after 12 months, whereas 56.4% (509/902) of patients in the high AST group (38 <) returned to normal after 12 months. In the below ULN ALT group, 94.5% (2,190/2,317) of patients remained normal after 12 months, whereas 44.5% (607/1,363) of patients in the high ALT group (male: 44; female: 23) returned to normal after 12 months.

Alterations in renal and hepatic function laboratory values

PS was calculated using 25 patient background variables as covariates (Table 1). Patient background was adjusted using the IPTW approach, with 1/PS used as a weight in the statistical analysis. Weight, BMI, concomitant medications (α-GI), diseases (heart disease, cerebrovascular disease, hypertension, and dyslipidemia), and HbA1c and HDL-C levels with |Std diff|≥ 0.1 could be adjusted to < 0.1. The |Std diff| adjusted for diabetes duration was 0.118, which was approximately 0.1. However, the |Std diff| for age was 0.217, even after adjustment, indicating a persistent distributional imbalance. No significant difference was observed in ΔeGFR, ΔAST, or ΔALT levels when comparing SGLT2i with homogenized patient backgrounds (Fig. 5, 6).

Fig. 5
figure 5

Box plots of ΔeGFR in pre- and post-SGLT2i treatment. The two ends of the whiskers represent the minimum and maximum values in the range of the first quartile + 1.5*interquartile range (IQR) to third quartile + 1.5*IQR. Data beyond the ends of the whiskers are plotted individually. Inbox bars represent the median for ΔeGFR of each group. ΔeGFR: (eGFR post 12 months of SGLT2i treatment)−(eGFR pre-SGLT2i treatment). IPTW was performed and tested using the Kruskal–Wallis test

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Fig. 6
figure 6

Box plots of ΔAST or ΔALT in pre- and post-SGLT2i treatment. The two ends of the whiskers represent the minimum and maximum values in the range of the first quartile + 1.5*interquartile range (IQR) to the third quartile + 1.5*IQR. Data beyond the ends of the whiskers are plotted individually. Inbox bars represent the median for ΔAST or ΔALT of each group. ΔAST: (AST post 12 months of SGLT2i treatment)−(AST pre-SGLT2i treatment). ΔALT: (ALT post 12 months of SGLT2i treatment)−(ALT pre-SGLT2i treatment). IPTW was performed and tested using the Kruskal–Wallis test

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Discussion

This study revealed that SGLT2i treatment maintained eGFR, AST, and ALT levels pre- and one year post-SGLT2i treatment. This indicates that all six SGLT2i exhibit renoprotective and hepatoprotective effects. Additionally, the IPTW approach was used to compare the alterations in eGFR, AST, and ALT levels pre- and one year post-treatment, and no significant differences were observed. These results indicate that renoprotective and hepatoprotective effects are common to SGLT2i. Furthermore, our data suggest that eGFR, AST, and ALT are enhanced regardless of liver or kidney status.

A comparison of SGLT2i using the receipt database with a focus on renal function indicated that the renoprotective effect of SGLT2i was a class effect [25]. This aligns with the results of this study, in which 25 variables of pre-treatment patient data were used to homogenize patient backgrounds through the IPTW approach. Sub-analyses of the dapagliflozin and prevention of adverse outcomes (DAPA)-CKD Trial (for DGZ) [26, 27] and the CREDENCE Trial (for CGZ) [8, 28] indicated renoprotective effects in patients with severely impaired renal function (eGFR < 30 mL/min/1.73 m2). In this study, renoprotective effects were observed at all CKD severity levels (G1 to G4), which we consider a novelty. Additionally, ΔeGFR was compared between SGLT2i for each CKD severity category, and no significant differences were observed (Additional file 1).

Additionally, an initial dip [29] (transient reduction in renal function post-administration, followed by an increase) was observed in all SGLT2i. The initial dip was observed in the early phase of treatment. In this study, the data at 6 months demonstrated a slight reduction in eGFR levels compared to that of the pre-treatment data. The CREDENCE Trial [8] reported a reduction in eGFR levels of 3.72 mL/min/1.73 m2 after three weeks of CGZ treatment. Compared with this report, the difference between the pre-treatment and 6-month follow-up was small, indicating that eGFR was in the process of recovery. This indicates that the renoprotective effects of SGLT2i should be assessed in the medium term (6–12 months).

Depending on the state of proteinuria and blood sugar control, diabetes causes a gradual decline in renal function [30]. It has also been reported that GFR declines at a rate of 0.36 mL/min/1.73 m2/year after the age of 40, even without renal disease [31]. Cases treated with DPP4i exhibited a significant decrease in eGFR. However, whether this was due to the progression of diabetes, aging, or other factors cannot be determined based on the data collected in this study. On the other hand, cases treated with SGLT2i exhibited a slight increase or maintenance of eGFR. While improvements in values are worth evaluating, we believe that maintaining stable kidney function without deterioration is crucial in diabetes treatment because diabetes causes a gradual decline in renal function.

Hepatoprotective effects were assessed based on alterations in the AST and ALT levels. AST and ALT levels decreased by 6.5 and 6.2 IU/L, respectively, after one year compared to the pre-treatment levels. Approximately 56.4% of patients with high pre-treatment AST levels and 44.5% of patients with high pre-treatment ALT levels achieved normal values. The pre-treatment AST and ALT grade classifications worsened after 12 months in only 108 and 147 cases, respectively. These results indicate that SGLT2i enhances and maintains liver function. Additionally, SGLT2i (six drugs) were divided into grades of AST and ALT levels to compare ΔAST and ΔALT, and no significant differences were observed between the drugs (Additional files 2 and 3). Fatty liver increases insulin resistance, which is associated with the development and severity of diabetes [32], and increased insulin resistance promotes further fat accumulation in the liver. SGLT2i improves hyperinsulinemia [33] and insulin resistance [34], which is thought to be involved in correcting fatty liver and improving and maintaining liver function. On the other hand, sitagliptin, classified as DPP-4i, has been reported to not improve fatty liver [35]. Blood insulin levels and insulin resistance could not be evaluated in this study. A positive correlation between insulin resistance and the TG/HDL ratio has been reported [36, 37]. An AST/ALT ratio ≤ 1 is an indicator of fatty liver due to overnutrition, in which ALT is predominantly elevated. Results with missing data but a significant decrease in the TG/HDL-Cho ratio and a positive correlation between ΔALT and the ΔTG/HDL-Cho ratio have been confirmed (Additional file 4 and 5). We thus infer that the improvement of hepatic function and insulin resistance is involved, although this is an indirect assessment. We believe that maintaining stable liver function without deterioration is crucial in diabetes treatment because reduced liver function (fatty liver) increases insulin resistance, which is associated diabetes progression. A Japanese study group of non-alcoholic fatty liver disease (NAFLD) [38] studied 1,365 cases of NAFLD and reported that the presence of diabetes was a risk factor for advanced fibrosis in non-alcoholic steatohepatitis (NASH). Additionally, according to the NASH study group of Japan’s Ministry of Health, Labour, and Welfare, the risk of death from hepatocellular carcinoma is the highest among malignant tumors in patients with diabetes [39]. Monitoring liver function is crucial for AST and ALT levels, liver fibrosis markers, and FibroScan results.

However, this study has limitations. Summarize the aforementioned as well. First, we could not evaluate blood insulin levels and insulin resistance. Second, we could not identify NASH or NAFLD and assess factors beyond AST, ALT levels. Third, diabetes has various complications, resulting in diverse patient backgrounds, but we used the IPTW approach to homogenize patient backgrounds to the maximum. In this study, we used 25 items for weighing, resulting in an average |Std diff| of 0.065, < 0.1. However, we failed to reduce the |Std diff| to < 0.1 for weight, BMI, duration of disease, and age. Despite this limitation, we believe that the IPTW approach is valuable for analyzing intricate clinical data. Finally, our data indicated that alterations in kidney- and liver-related laboratory values did not differ between SGLT2 inhibitors, but it was not possible to determine whether the mechanism of action was the same.

Conclusions

Renoprotective and hepatoprotective effects are class effects of SGLT2i that are thought to be independent of kidney or liver status. This study lasted only one year. Because diabetes is a chronic disease, it is essential to assess the long-term persistence of its protective effects.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article and its additional files.

Abbreviations

SGLT2i:

Sodium-glucose cotransporter-2 inhibitors

PS:

Propensity score

HbA1c:

Glycated hemoglobin

eCcr:

Estimated creatinine clearance

eGFR:

Estimated glomerular filtration rate

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

HDL-C:

High-density lipoprotein-cholesterol

LDL-C:

Low-density lipoprotein-cholesterol

TG:

Triglyceride

IGZ:

Ipragliflozin

EGZ:

Empagliflozin

CGZ:

Canagliflozin

DGZ:

Dapagliflozin

TGZ:

Tofogliflozin

LGZ:

Luseogliflozin

CKD:

Chronic kidney disease

IPTW:

Inverse probability of treatment weighting

BMI:

Body mass index

DPP-4i:

Dipeptidyl peptidase-4 inhibitor

SU:

Sulfonylurea

GL:

Glinide

α-GI:

α-Glucosidase Inhibitor

BG:

Biguanide

TZ:

Thiazolidinediones

Std diff:

Standardized difference score

CTCAE:

Common terminology criteria for adverse events

ULN:

Upper limit of normal

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

IQR:

Interquartile range

IPTW:

Inverse probability of treatment weighting

DAPA:

Dapagliflozin and prevention of adverse outcomes

References

  1. Rajasekeran H, Lytvyn Y, Cherney DZI. Sodium–glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89:524–6.

    Article  PubMed  CAS  Google Scholar 

  2. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58:429–42.

    Article  PubMed  Google Scholar 

  3. Bonds DE, Miller ME, Bergenstal RM, Buse JB, Byington RP, Cutler JA, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ. 2010;340: b4909.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Bailey CJ, Iqbal N, T’Joen C, List JF. Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab. 2012;14:951–9.

    Article  PubMed  CAS  Google Scholar 

  6. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–33.

    Article  PubMed  CAS  Google Scholar 

  7. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.

    Article  PubMed  CAS  Google Scholar 

  8. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.

    Article  PubMed  CAS  Google Scholar 

  9. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    Article  PubMed  CAS  Google Scholar 

  10. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.

    Article  PubMed  CAS  Google Scholar 

  11. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    Article  PubMed  CAS  Google Scholar 

  12. Seino Y, Sasaki T, Fukatsu A, Ubukata M, Sakai S, Samukawa Y. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin. 2014;30:1245–55.

    Article  PubMed  CAS  Google Scholar 

  13. Seko Y, Sumida Y, Sasaki K, Itoh Y, Iijima H, Hashimoto T, et al. Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials. J Gastroenterol. 2018;53:140–51.

    Article  PubMed  CAS  Google Scholar 

  14. Austin PC. The performance of different propensity score methods for estimating marginal hazard ratios. Stat Med. 2012;32:2837–49.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–62.

    Article  PubMed  CAS  Google Scholar 

  16. Katayama S, Kikkawa R, Isogai S, Sasaki N, Matsuura N, Tajima N, et al. Effect of captopril or imidapril on the progression of diabetic nephropathy in Japanese with type 1 diabetes mellitus: a randomized controlled study (JAPAN-IDDM). Diabetes Res Clin Pract. 2002;55:113–21.

    Article  PubMed  CAS  Google Scholar 

  17. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    Article  PubMed  CAS  Google Scholar 

  18. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.

    Article  PubMed  CAS  Google Scholar 

  19. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8.

    Article  PubMed  CAS  Google Scholar 

  20. Chan JC, Wat NM, So WY, Lam KS, Chua CT, Wong KS, et al. Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study. Diabetes Care. 2004;27:874–9.

    Article  PubMed  CAS  Google Scholar 

  21. Sun LJ, Sun YN, Shan JP, Jiang GR. Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy. J Diabetes Investig. 2017;8:609–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, et al. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2006;1:940–51.

    Article  PubMed  CAS  Google Scholar 

  23. Okuda Y, Ito S, Kashihara N, Shikata K, Nangaku M, Wada T, et al. The renoprotective effect of esaxerenone independent of blood pressure lowering: a post hoc mediation analysis of the ESAX-DN trial. Hypertens Res. 2023;46:437–44.

    Article  PubMed  CAS  Google Scholar 

  24. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res. 2011;46:399–424.

    Article  Google Scholar 

  25. Suzuki Y, Kaneko H, Okada A, Matsuoka S, Fujiu K, Michihata N, et al. Kidney outcomes in patients with diabetes mellitus did not differ between individual sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2022;102:1147–53.

    Article  PubMed  CAS  Google Scholar 

  26. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383:1436–46.

    Article  PubMed  CAS  Google Scholar 

  27. Chertow GM, Vart P, Jongs N, Toto RD, Gorriz JL, Hou FF, et al. Effects of dapagliflozin in stage 4 chronic kidney disease. J Am Soc Nephrol. 2021;32:2352–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Bakris G, Oshima M, Mahaffey KW, Agarwal R, Cannon CP, Capuano G, et al. Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m(2): Subgroup Analysis of the Randomized CREDENCE Trial. Clin J Am Soc Nephrol. 2020;15:1705-14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Takahashi K, Nakamura A, Furusawa S, Yokozeki K, Sugawara H, Yanagisawa H, et al. Initial dip predicts renal protective effects after the administration of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes and chronic kidney disease with normoalbuminuria. J Clin Transl Endocrinol. 2020;22: 100244.

    PubMed  PubMed Central  Google Scholar 

  30. Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical Manifestations of Kidney Disease Among US Adults With Diabetes, 1988–2014. JAMA. 2016;316:602–10.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Imai E, Horio M, Yamagata K, Iseki K, Hara S, Ura N, et al. Slower decline of glomerular filtration rate in the Japanese general population: a longitudinal 10-year follow-up study. Hypertens Res. 2008;31:433–41.

    Article  PubMed  Google Scholar 

  32. DeFronzo RA. Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia. 1992;35:389–97.

    Article  PubMed  CAS  Google Scholar 

  33. Komiya C, Tsuchiya K, Shiba K, Miyachi Y, Furuke S, Shimazu N, et al. Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction. PLoS ONE. 2016;11: e0151511.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Honda Y, Imajo K, Kato T, Kessoku T, Ogawa Y, Tomeno W, et al. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice. PLoS ONE. 2016;11: e0146337.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Cui J, Philo L, Nguyen P, Hofflich H, Hernandez C, Bettencourt R, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial. J Hepatol. 2016;65:369–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Murguía-Romero M, Jiménez-Flores JR, Sigrist-Flores SC, Espinoza-Camacho MA, Jiménez-Morales M, Piña E, et al. Plasma triglyceride/HDL-cholesterol ratio, insulin resistance, and cardiometabolic risk in young adults. J Lipid Res. 2013;54:2795–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Cordero A, Andrés E, Ordoñez B, León M, Laclaustra M, Grima A, et al. Usefulness of triglycerides-to-high-density lipoprotein cholesterol ratio for predicting the first coronary event in men. Am J Cardiol. 2009;104:1393–7.

    Article  PubMed  CAS  Google Scholar 

  38. Nakahara T, Hyogo H, Yoneda M, Sumida Y, Eguchi Y, Fujii H, et al. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol. 2014;49:1477–84.

    Article  PubMed  CAS  Google Scholar 

  39. Shima T, Uto H, Ueki K, Kohgo Y, Yasui K, Nakamura N, et al. Hepatocellular carcinoma as a leading cause of cancer-related deaths in Japanese type 2 diabetes mellitus patients. J Gastroenterol. 2019;54:64–77.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to thank Editage (www.editage.jp) for English language editing.

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Authors and Affiliations

  1. Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine, Sapporo, Hokkaido, 006-8590, Japan

    Kazuya Hiura

  2. Hospital Pharmacy, Obihiro Kosei General Hospital, Obihiro, 080-0024, Japan

    Chinami Suzuki, Kiyomi Ishida & Yuki Tanaka

  3. Hospital Pharmacy, Asahikawa Kosei General Hospital, Asahikawa, 078-8211, Japan

    Junichi Kubo, Haruka Goto, Shigo Takatori, Ryu Kobayashi & Akio Shibanami

  4. Hospital Pharmacy, Sapporo Kosei General Hospital, Sapporo, 060-0033, Japan

    Akifumi Mizutani & Yuki Yamashita

  5. Hospital Pharmacy, Abashiri Kosei General Hospital, Abashiri, 093-0076, Japan

    Chiho Kurumazuka

  6. Hospital Pharmacy, Engaru Kosei General Hospital, Engaru, 099-0404, Japan

    Akihiko Takagi

Authors
  1. Kazuya Hiura
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  2. Chinami Suzuki
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Contributions

KH, CS, and AS designed the research. JK, HG, ST, KI, YT, AM, CK, and AT acquired and analyzed data. KH, YY, RK, and AS participated in interpretation of the results. KH drafted the manuscript, and AS revised the manuscript and provided an editorial review. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Kazuya Hiura.

Ethics declarations

Ethics approval and consent to participate

The study protocol was in compliance with the “Ethical Guidelines for Medical Research Involving Human Subjects” and was approved by the ethics committees at each hospital [Asahikawa Kosei Hospital (approval number: 2020056), Sapporo Kosei Hospital (approval number: 554), Obihiro Kosei Hospital (approval number: 2020–089), Abashiri Kosei Hospital (202012), Engaru Kosei Hospital (approval number: 2020–13), Kutchan Kosei Hospital (approval number: R2-3)]. In this study, we used only existing data, without acquiring written or oral consent from the patients. Therefore, we disclosed data regarding the study on the web or posted them in the hospital (or both), and guaranteed the opportunity for all patients to decline participation.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests. Furthermore, the funding body has no competing interests in the interpretation of the present results.

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Hiura, K., Suzuki, C., Kubo, J. et al. Comparison of kidney and hepatic outcomes among sodium-glucose cotransporter-2 inhibitors: a retrospective study using multiple propensity scores. J Pharm Health Care Sci 10, 57 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40780-024-00378-2

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40780-024-00378-2

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Journal of Pharmaceutical Health Care and Sciences

ISSN: 2055-0294

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