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J Pharm Health Care Sci
J Pharm Health Care Sci
Journal of Pharmaceutical Health Care and Sciences
2055-0294
BioMed Central London

39285495
378
10.1186/s40780-024-00378-2
Research Article
Comparison of kidney and hepatic outcomes among sodium-glucose cotransporter-2 inhibitors: a retrospective study using multiple propensity scores
http://orcid.org/0009-0008-3133-2784
Hiura Kazuya hiura-k@hus.ac.jp

1
Suzuki Chinami 2
Kubo Junichi 3
Goto Haruka 3
Takatori Shigo 3
Ishida Kiyomi 2
Tanaka Yuki 2
Mizutani Akifumi 4
Yamashita Yuki 4
Kurumazuka Chiho 5
Takagi Akihiko 6
Kobayashi Ryu 3
Shibanami Akio 3
1 https://ror.org/05gqsa340 grid.444700.3 0000 0001 2176 3638 Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, 7-15-4-1 Maeda, Teine, Sapporo, Hokkaido 006-8590 Japan
2 https://ror.org/027fjzp74 grid.416691.d 0000 0004 0471 5871 Hospital Pharmacy, Obihiro Kosei General Hospital, Obihiro, 080-0024 Japan
3 Hospital Pharmacy, Asahikawa Kosei General Hospital, Asahikawa, 078-8211 Japan
4 https://ror.org/029jhw134 grid.415268.c 0000 0004 1772 2819 Hospital Pharmacy, Sapporo Kosei General Hospital, Sapporo, 060-0033 Japan
5 Hospital Pharmacy, Abashiri Kosei General Hospital, Abashiri, 093-0076 Japan
6 Hospital Pharmacy, Engaru Kosei General Hospital, Engaru, 099-0404 Japan
17 9 2024
17 9 2024
2024
10 5730 5 2024
9 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40780-024-00378-2.

Keywords

SGLT2i
Renoprotective
Hepatoprotective
IPTW
issue-copyright-statement© Japanese Society of Pharmaceutical Health Care and Sciences and BioMed Central Ltd. 2024
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pmcBackground

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 [2–6]. Additionally, renoprotective [7–11] 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 [15–23]. 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

	IGZ
(n = 837)	EGZ
(n = 850)	CGZ
(n = 922)	DGZ
(n = 590)	TGZ
(n = 288)	LGZ
(n = 193)	DPP4i
(n = 7,172)	
Age, year	55.2 ± 14.9	60.2 ± 13.9	58.0 ± 15.6	52.2 ± 17.0	46.8 ± 14.6	49.7 ± 17.7	69.5 ± 12.1	
Sex, males/females	579/258	579/271	614/308	410/180	164/124	134/59	4,390/2,782	
Height, cm	162.3 ± 9.8	161.5 ± 10.5	160.8 ± 11.0	162.1 ± 10.1	161.2 ± 10.8	161.7 ± 11.0	159.9 ± 10.0	
Weight, kg	72.4 ± 17.1	70.9 ± 17.3	70.8 ± 18.0	72.9 ± 17.5	76.5 ± 17.4	73.2 ± 17.4	60.3 ± 13.5	
BMI	27.5 ± 6.2	27.2 ± 6.1	27.4 ± 7.1	27.8 ± 6.7	29.6 ± 6.7	28.2 ± 6.7	23.5 ± 4.2	
Diabetes duration, year	0.7 ± 1.3	1.4 ± 2.4	1.1 ± 1.4	1.5 ± 2.6	1.3 ± 1.6	1.5 ± 2.2	1.5 ± 2.4	
DPP4i, + / − 	534/303	465/385	595/327	352/238	173/115	106/87	-	
SU, + / − 	186/651	173/677	212/710	89/501	49/239	29/164	1,943/5,229	
α-GI, + / − 	112/725	81/769	66/856	41/549	10/278	8/185	515/6,657	
GL, + / − 	44/793	34/816	46/876	24/566	12/276	3/190	289/6,883	
BG, + / − 	337/500	344/506	315/607	226/364	99/189	84/109	1,700/5,472	
TZ, + / − 	56/781	67/783	42/880	34/556	10/278	12/181	130/7,042	
Liver disease, + / − 	78/759	119/731	64/858	57/533	20/268	11/182	3,016/4,156	
Renal disease, + / − 	66/771	99/751	70/852	49/541	33/255	11/182	2,719/4,453	
Heart disease, + / − 	174/663	210/640	174/748	106/484	58/230	13/180	2,732/4,440	
Cerebrovascular disease, + / − 	35/802	35/815	36/886	14/576	8/280	0/193	1,043/6,129	
Hypertension, + / − 	183/654	243/607	165/757	124/466	55/233	26/167	2,678/4,494	
Dyslipidemia, + / − 	228/609	281/569	193/729	164/426	51/237	26/167	2,421/4,751	
HbA1c, %	8.3 ± 1.8	8.1 ± 1.7	7.8 ± 1.6	8.2 ± 1.7	8.4 ± 1.9	8.4 ± 2.0	8.0 ± 2.2	
eGFR, mL/min/1.73m2	67.1 ± 29.7	64.4 ± 28.0	64.3 ± 28.7	61.5 ± 28.5	61.3 ± 33.2	56.8 ± 26.5	63.9 ± 27.6	
AST, IU/L	30.4 ± 18.9	31.3 ± 17.1	31.1 ± 25.1	30.9 ± 18.1	30.7 ± 19.3	31.9 ± 16.9	32.7 ± 65.1	
ALT, IU/L	34.8 ± 26.5	33.9 ± 22.2	34.0 ± 24.6	36.2 ± 26.9	36.6 ± 26.6	37.5 ± 24.9	31.1 ± 53.4	
HDL-C, mg/dL	44.8 ± 17.5	48.4 ± 16.6	49.5 ± 16.7	49.0 ± 17.9	49.6 ± 17.7	47.0 ± 16.3	49.4 ± 15.8	
LDL-C, mg/dL	116.4 ± 37.2	115.6 ± 37.4	114.9 ± 36.8	114.3 ± 34.9	120.5 ± 39.8	119 ± 34.9	109.5 ± 34.0	
TG, mg/dL	166.7 ± 189.3	165.7 ± 123.2	158.5 ± 93.7	153.4 ± 81.1	180.5 ± 160.0	169.6 ± 92.6	154.1 ± 141.5	
Data are expressed as the mean ± standard deviation (SD)

IGZ Ipragliflozin, EGZ Empagliflozin, CGZ Canagliflozin, DGZ Dapagliflozin, TGZ Tofogliflozin, LGZ Luseogliflozin, BMI Body mass index, DPP-4i Dipeptidyl peptidase-4 inhibitor, SU Sulfonylurea, GL Glinide, α-GI α-glucosidase inhibitor, BG Biguanide, TZ Thiazolidinediones, HbA1c Glycated hemoglobin, 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

Table 2 Standardized difference scores pre- and post-adjustment in SGLT2i

	|Std diff|	Adjusted |Std diff|	
Age	0.358	0.217	
Sex	0.071	0.094	
Height	0.059	0.040	
Weight	0.137	0.017	
BMI	0.139	0.014	
Diabetes duration	0.152	0.118	
DPP4i	0.083	0.026	
SU	0.092	0.046	
α-GI	0.218	0.041	
GL	0.088	0.025	
BG	0.072	0.050	
TZ	0.062	0.048	
Liver disease	0.096	0.050	
Renal disease	0.080	0.023	
Heart disease	0.116	0.023	
Cerebrovascular disease	0.219	0.078	
Hypertension	0.109	0.059	
Dyslipidemia	0.167	0.027	
HbA1c	0.123	0.009	
eGFR	0.077	0.029	
AST	0.016	0.013	
ALT	0.051	0.013	
HDL-C	0.110	0.018	
LDL-C	0.063	0.053	
TG	0.077	0.014	
Std diff Standardized difference scores, BMI Body mass index, DPP-4i Dipeptidyl peptidase-4 inhibitor, SU Sulfonylurea, GL Glinide, α-GI α-glucosidase inhibitor, BG Biguanide, TZ Thiazolidinediones, HbA1c Glycated hemoglobin, 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

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 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

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 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

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 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

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 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

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 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

Fig. 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

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.

Supplementary Information

Additional file 1.

Additional file 2.

Additional file 3.

Additional file 4.

Additional file 5.

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

Acknowledgements

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

Authors’ 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.

Funding

Not applicable.

Availability of data and materials

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

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.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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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 89 524 526 26880444
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;89:524–6.26880444
2. Inzucchi SE Bergenstal RM Buse JB Diamant M Ferrannini E Nauck M 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 58 429 442 25583541
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;58:429–42.25583541
3. Bonds DE Miller ME Bergenstal RM Buse JB Byington RP Cutler JA The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study BMJ 2010 340 b4909 20061358
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: b4909.20061358
4. Schernthaner G Gross JL Rosenstock J Guarisco M Fu M Yee J 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 2515 23564919
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;36:2508–15.23564919
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 14 951 959 22776824
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;14:951–9.22776824
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 2233 20609968
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;375:2223–33.20609968
7. Neal B Perkovic V Mahaffey KW de Zeeuw D Fulcher G Erondu N Canagliflozin and cardiovascular and renal events in type 2 diabetes N Engl J Med 2017 377 644 657 28605608
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;377:644–57.28605608
8. Perkovic V Jardine MJ Neal B Bompoint S Heerspink HJL Charytan DM Canagliflozin and renal outcomes in type 2 diabetes and nephropathy N Engl J Med 2019 380 2295 2306 30990260
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;380:2295–306.30990260
9. Wanner C Inzucchi SE Lachin JM Fitchett D von Eynatten M Mattheus M Empagliflozin and progression of kidney disease in type 2 diabetes N Engl J Med 2016 375 323 334 27299675
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;375:323–34.27299675
10. Wiviott SD Raz I Bonaca MP Mosenzon O Kato ET Cahn A Dapagliflozin and cardiovascular outcomes in type 2 diabetes N Engl J Med 2019 380 347 357 30415602
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;380:347–57.30415602
11. Zinman B Wanner C Lachin JM Fitchett D Bluhmki E Hantel S Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes N Engl J Med 2015 373 2117 2128 26378978
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;373:2117–28.26378978
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 1255 24708292
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;30:1245–55.24708292
13. Seko Y Sumida Y Sasaki K Itoh Y Iijima H Hashimoto T 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 53 140 151 28669071
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;53:140–51.28669071
14. Austin PC The performance of different propensity score methods for estimating marginal hazard ratios Stat Med 2012 32 2837 2849 23239115
Austin PC. The performance of different propensity score methods for estimating marginal hazard ratios. Stat Med. 2012;32:2837–49.23239115
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 8413456
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;329:1456–62.8413456
16. Katayama S Kikkawa R Isogai S Sasaki N Matsuura N Tajima N 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 55 113 121 11796177
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;55:113–21.11796177
17. Brenner BM Cooper ME de Zeeuw D Keane WF Mitch WE Parving HH Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy N Engl J Med 2001 345 861 869 11565518
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;345:861–9.11565518
18. Lewis EJ Hunsicker LG Clarke WR Berl T Pohl MA Lewis JB Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes N Engl J Med 2001 345 851 860 11565517
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;345:851–60.11565517
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 345 870 878 11565519
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;345:870–8.11565519
20. Chan JC Wat NM So WY Lam KS Chua CT Wong KS Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study Diabetes Care 2004 27 874 879 15047641
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;27:874–9.15047641
21. Sun LJ Sun YN Shan JP Jiang GR Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy J Diabetes Investig 2017 8 609 618 28107779
Sun LJ, Sun YN, Shan JP, Jiang GR. Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy. J Diabetes Investig. 2017;8:609–18.28107779
22. Epstein M Williams GH Weinberger M Lewin A Krause S Mukherjee R Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes Clin J Am Soc Nephrol 2006 1 940 951 17699311
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;1:940–51.17699311
23. Okuda Y Ito S Kashihara N Shikata K Nangaku M Wada T The renoprotective effect of esaxerenone independent of blood pressure lowering: a post hoc mediation analysis of the ESAX-DN trial Hypertens Res 2023 46 437 444 36100672
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;46:437–44.36100672
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
Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res. 2011;46:399–424.
25. Suzuki Y Kaneko H Okada A Matsuoka S Fujiu K Michihata N Kidney outcomes in patients with diabetes mellitus did not differ between individual sodium-glucose cotransporter-2 inhibitors Kidney Int 2022 102 1147 1153 35961884
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;102:1147–53.35961884
26. Heerspink HJL Stefansson BV Correa-Rotter R Chertow GM Greene T Hou FF Dapagliflozin in patients with chronic kidney disease N Engl J Med 2020 383 1436 1446 32970396
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;383:1436–46.32970396
27. Chertow GM Vart P Jongs N Toto RD Gorriz JL Hou FF Effects of dapagliflozin in stage 4 chronic kidney disease J Am Soc Nephrol 2021 32 2352 2361 34272327
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;32:2352–61.34272327
28. Bakris G Oshima M Mahaffey KW Agarwal R Cannon CP Capuano G 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 33214158
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;15:1705-14.33214158
29. Takahashi K Nakamura A Furusawa S Yokozeki K Sugawara H Yanagisawa H 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 33318949
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: 100244.33318949
30. Afkarian M Zelnick LR Hall YN Heagerty PJ Tuttle K Weiss NS Clinical manifestations of kidney disease among US adults with diabetes, 1988–2014 JAMA 2016 316 602 610 27532915
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;316:602–10.27532915
31. Imai E Horio M Yamagata K Iseki K Hara S Ura N Slower decline of glomerular filtration rate in the Japanese general population: a longitudinal 10-year follow-up study Hypertens Res 2008 31 433 441 18497462
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;31:433–41.18497462
32. DeFronzo RA Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview Diabetologia 1992 35 389 397 1516769
DeFronzo RA. Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia. 1992;35:389–97.1516769
33. Komiya C Tsuchiya K Shiba K Miyachi Y Furuke S Shimazu N 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 26977813
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: e0151511.26977813
34. Honda Y Imajo K Kato T Kessoku T Ogawa Y Tomeno W The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice PLoS ONE 2016 11 e0146337 26731267
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: e0146337.26731267
35. Cui J Philo L Nguyen P Hofflich H Hernandez C Bettencourt R Sitagliptin vs. placebo for non-alcoholic fatty liver disease: a randomized controlled trial J Hepatol. 2016 65 369 376 27151177
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;65:369–76.27151177
36. Murguía-Romero M Jiménez-Flores JR Sigrist-Flores SC Espinoza-Camacho MA Jiménez-Morales M Piña E Plasma triglyceride/HDL-cholesterol ratio, insulin resistance, and cardiometabolic risk in young adults J Lipid Res 2013 54 2795 2799 23863983
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;54:2795–9.23863983
37. Cordero A Andrés E Ordoñez B León M Laclaustra M Grima A Usefulness of triglycerides-to-high-density lipoprotein cholesterol ratio for predicting the first coronary event in men Am J Cardiol 2009 104 1393 1397 19892056
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;104:1393–7.19892056
38. Nakahara T Hyogo H Yoneda M Sumida Y Eguchi Y Fujii H 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 1484 24277052
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;49:1477–84.24277052
39. Shima T Uto H Ueki K Kohgo Y Yasui K Nakamura N Hepatocellular carcinoma as a leading cause of cancer-related deaths in Japanese type 2 diabetes mellitus patients J Gastroenterol 2019 54 64 77 30006904
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;54:64–77.30006904
