Cardiovascular Diabetology

Nagao et al. Cardiovascular Diabetology(2024) 23:56
https://doi.org/10.1186/s12933-024-02149-7

Open Access

RESEARCH

Ipragliflozin and sitagliptin differentially affectlipid and apolipoprotein profiles in type 2
diabetes: the SUCRE study
Mototsugu Nagao1, Jun Sasaki2^, Kyoko Tanimura-Inagaki1, Ichiro Sakuma3, Hitoshi Sugihara1, Shinichi Oikawa1,4* andon behalf of the SUCRE Study Investigators
Abstract
Background SGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there
are few randomized controlled trials comparing the effects on the lipid metabolism between the two types ofantidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin andsitagliptin on serum lipid and apolipoprotein profiles and other clinical parameters.
Methods This is a multicenter, open-label, randomized, controlled trial. Patients with type 2 diabetes (20–74 years
old) with HbA1c levels of 7.0-10.5% and serum triglyceride levels of 120–399 mg/dL (1.35–4.50 mmol/L) on dietand/or oral hypoglycemic agents were enrolled. Subjects were randomized to treatment with ipragliflozin (50 mg/
day, n = 77) or sitagliptin (50 mg/day, n = 83). Laboratory measurements were performed at 0, 1, 3, and 6 months oftreatment.
Results Ipragliflozin and sitagliptin reduced fasting plasma glucose, glycoalbumin, and HbA1c almost equally.
Ipragliflozin increased HDL-C and decreased apo E. Sitagliptin decreased TG, apo B48, CII, and CIII, but increased LDL-C.
The between-treatment differences were significant for HDL-C (P = 0.02) and apo B48 (P = 0.006), and nearly significant
for apo A1 (P = 0.06). In addition, ipragliflozin reduced body weight, blood pressure, serum liver enzymes, uric acid,and leptin, and increased serum ketones compared with sitagliptin.
Conclusions While ipragliflozin and sitagliptin showed similar effects on glycemic parameters, the effects on serum
lipid and apolipoprotein profiles were different. Ipragliflozin may have an anti-atherogenic effect through modulationof HDL-C and apo E compared to sitagliptin through TG and apo B48, CII, and CIII in patients with type 2 diabetes.

2^Deceased 1 March 2019.
*Correspondence:
Shinichi Oikawa
shinichi@nms.ac.jp
1
Department of Endocrinology, Metabolism and Nephrology, Graduate
School of Medicine, Nippon Medical School, Sendagi 1-1-5, Bunkyo-ku,
Tokyo 113-8603, Japan

Graduate School of Pharmaceutical Medicine, International University of
Health and Welfare, Nagahama 1-3-1, Chuo-ku, Fukuoka 810-0072, Japan
3
Caress Sapporo Hokko Memorial Clinic, Kita 27 Higashi 8 1-15, Higashiku, Sapporo 065-0027, Japan
4
Diabetes and Lifestyle-Related Disease Center, Fukujuji Hospital, AntiTuberculosis Association (JATA), Matsuyama 3-1-24, Kiyose,Tokyo 204-8522, Japan© The Author(s) 2024. 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) andthe source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in thisarticle are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not includedin the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you willneed 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.

Nagao et al. Cardiovascular Diabetology(2024) 23:56

Background
Diabetes is a major risk factor for the development of
atherosclerosis and is associated with a 2- to 4-foldincreased risk of cardiovascular disease [1]. Hyperglycemia, especially postprandial hyperglycemia, has beenshown to cause atherosclerosis [2]. Adequate glycemic
control is therefore important for the prevention of cardiovascular disease. Both sodium-glucose cotransporter
2 (SGLT2) and dipeptidyl peptidase-4 (DPP4) inhibitors are promising drugs for this purpose [3]. SGLT2
inhibitors promote urinary glucose excretion by inhibiting renal tubular SGLT2 and improve hyperglycemia in
an insulin-independent manner [4]. On the other hand,
DPP4 inhibitors maintain blood incretin levels by inhibiting the incretin-degrading activity of DPP4, promoteinsulin secretory secretion in response to blood glucose levels, and improve glucose metabolism [5]. SGLT2
inhibitors are expected to improve hyperglycemia even in
the presence of insulin deficiency, while DPP4 inhibitors
are effective in those with some preservation of insulin
secretion [3].
Both SGLT2 and DPP4 inhibitors exhibit diverse
advantages beyond their glucose-lowering properties.
DPP4 inhibitors have a neutral influence on body weight,
minimal risk of hypoglycemia [6], and safety in terms ofmajor cardiovascular outcomes [7], excluding heart failure with saxagliptin [8] and possibly alogliptin [9]. Conversely, SGLT2 inhibitors provide significant benefits,
including body weight reduction [10], decreased risk ofatherosclerotic cardiovascular disease and heart failure[11, 12], beneficial effects on kidney function [13], anda reduction in all-cause mortality [14]. Furthermore,both agents have been shown to affect lipid metabolism. For example, SGLT2 inhibitors have been reported
to increase low-density lipoprotein cholesterol (LDLC) and high-density lipoprotein cholesterol (HDL-C)[15, 16] and DPP4 inhibitors to decrease triglycerides(TG) and remnants [17, 18]. Since dysregulation of lipid
metabolism plays a key role in the development of atherosclerosis associated with diabetes [19], it is of great
importance to elucidate the pleiotropic effects of thesedrugs on lipid and apolipoprotein profiles. This understanding is crucial in formulating an optimal treatment
strategy for diabetes, particularly in conjunction withatherosclerosis. However, there are few randomized controlled trials comparing the effects of SGLT2 inhibitorsand DPP4 inhibitors on lipid and apolipoprotein profiles.
Here, we conducted a multicenter, randomized trial tocompare the effects of a SGLT2 inhibitor (ipragliflozin)
and a DPP4 inhibitor (sitagliptin) in patients with type 2
diabetes. The SUCRE study was designed to analyze theeffects of ipragliflozin and sitagliptin primarily on lipid
metabolism, and secondarily on glucose metabolism andother clinical parameters related to atherosclerosis, toPage 2 of 12

clarify the anti-atherogenic benefits of the two drugs. The
primary outcome measures were serum lipids and apolipoproteins. Secondary outcome measures included glucose metabolism parameters, body weight, systolic anddiastolic blood pressure, and renal function parameters.

Methods
Study design

The present study was designed as a multicenter, openlabel, randomized controlled trial. This study was registered in the University Hospital Medical Information
Network (UMIN) as the Sodium-GlUcose Co-transporteR 2 inhibitor, Ipragliflozin, Suglat®, Effect on Lipidand Glucose Metabolism (SUCRE) Study (UMIN ID:
000018084). Recruitment and follow-up of participants took place from June 2015 to September 2019 at
14 hospitals and clinics across Japan. The study adhered
to the principles of the Declaration of Helsinki and wasapproved by the ethics committees at Fukujuji Hospital,
Japan Anti-Tuberculosis Association and, where appropriate, at each of the participating hospitals and clinics.
Written informed consent was obtained from all patients.
Eligible patients were outpatients with type 2 diabetes aged 20–74 years with inadequate glycemic control(HbA1c of 7.0-10.5%) and serum TG of 120–399 mg/dL(1.35–4.50 mmol/L). Patients treated with lifestyle modification and/or antidiabetic agents, excluding insulins,
GLP-1 receptor agonists, SGLT2 inhibitors, and DPP4
inhibitors, were included in the study. Glycemic control
requires HbA1c variability to be stable within 1% in theabsolute value over the past 2 months. Patients were ineligible if they received continuous treatment with lipidlowering agents (statins, ezetimibe, fibrates, nicotinicacid, probucol, anion exchange resins, or eicosatetraenoic acid); if they had type 1 diabetes, proliferative retinopathy, dysuria, urinary and genital infections, chronic
renal impairment (serum creatinine (Cr) > 1.5 mg/dL),severe liver dysfunction (Child-Pugh class C), severe
infection, trauma, or possible pregnancy; if they have a
medical history of ketosis, diabetic coma, cardiovascular disease (cerebral infarction, myocardial infarction,
unstable angina, angioplasty, or heart disease, NYHA
class III-IV) in the past 6 months; treated with diuretics, steroids or immunosuppressive therapy for the past 6months; or if they were allergic to SGLT2 or DPP4 inhibitors. Patients were also ineligible if the study physicians
deemed it inappropriate for them to participate.
Eligible patients were enrolled and randomized (1:1) tothe ipragliflozin group or the sitagliptin group. Randomization was performed using a computer-generated randomization list generated by an independent statistician
using the permuted block method with a block size of 10
and equal allocation to the two treatments. Both patientsand study physicians were informed of their treatment

Nagao et al. Cardiovascular Diabetology(2024) 23:56

assignment. Patients received 50 mg of ipragliflozin
or 50 mg of sitagliptin once daily for at least 6 months
in addition to their previous treatment. The doses were
determined according to the usual doses of both drugs
in Japan. The glycemic target was HbA1c < 7.0%. Study
physicians were asked not to change the antidiabetic regimen during the first 3 months. Thereafter, dose escalation of sitagliptin or ipragliflozin up to 100 mg/day wasallowed to achieve the glycemic target. The addition, dose
titration, or discontinuation of oral antidiabetic medications other than SGLT2 inhibitors, DPP4 inhibitors, and
GLP-1 receptor agonists was also allowed as needed. No
medications for dyslipidemia were prescribed during thestudy period.
Measurements

Venous blood and urine samples were collected underfasting conditions at 0, 1, 3, and 6 months of treatment,
and the samples were transported to the central laboratory (SRL Inc., Tokyo, Japan), where venous blood wascentrifuged to separate serum or plasma for biochemical measurements. Blood pressure and body weight were
measured at the same time of blood sampling. Peripheral
blood cell counts were measured at 0, 1, 3, and 6 months.
The primary outcome measures were serum lipids
and apolipoproteins. Lipid-related parameters included
serum total cholesterol (TC), HDL-C, LDL-C, and TG
and apolipoprotein (apo) AI, AII, B, B48, CII, CIII, and E.
Secondary outcome measures included glucose metabolism parameters [FPG, insulin, HbA1c, and glycoalbumin(GA)], body weight, systolic and diastolic blood pressure,renal function parameters such as estimated glomerular filtration rate (eGFR) and urine albumin-to-Cr ratio(UACR). Serum Cr and cystatin C (CysC) concentrations were used to calculate Cr-based eGFR and cystatin
CysC-based eGFR, respectively [20, 21]. Other laboratory
measurements included blood cell counts, serum liver
enzymes, uric acid, electrolytes, compliments, leptin,
non-cholesterol sterols, selected fatty acids, and ketones.
All the laboratory measurements were performed ata central laboratory (SRL, Tokyo, Japan) using the standard methods. Details of the methods and resources
are provided in Table S1. Briefly, plasma glucose wasmeasured by the hexokinase UV method; serum insulin concentration and HbA1c by chemiluminescence
enzyme immunoassays for each; and GA by the visible
absorption spectrometry enzymatic method. Serum TC
and TG were measured by enzymatic methods for each;
HDL-C by direct assay. LDL-C was calculated using theFriedewald formula. Apo AI, AII, B, CII, CIII, and E were
measured by turbidimetric immunoassays by using corresponding individual kits. Apo B48 was measured bychemiluminescent enzyme-linked immunosorbent assay
using apo B48 CLEA (Fujirebio Inc., Tokyo, Japan).

Page 3 of 12

Statistical analysis

We did not statistically determine a required sample size
because the present study was exploratory with respect
to serum apolipoproteins. There was no information
on potential differences in changes in apolipoproteins
between ipragliflozin and sitagliptin treatment at thetime of protocol development. The target number ofpatients to be enrolled was set at 200 (100 for each group)
based on a previous study that reported statistically significant changes in some of the serum apolipoproteins
with sitagliptin treatment [22].
The full analysis set for the assessment of outcome
variables included randomized patients who had a baseline measurement and at least one follow-up measurement and who adhere to the study protocol. We did notuse measurements of FPG, insulin, and TG if the blood
sample was reported to have been collected in postprandial condition or if plasma insulin was ≥ 25 µU/mL (175pmol/L). LDL-C was not calculated if TG was ≥ 400 mg/
dL. Therefore, the number of patients varied at different
time points during the follow-up varied (Table S2).
The distribution of each continuous variable was tested
for normality using the skewness-kurtosis test. Baseline characteristics of patients were presented as mean
with standard deviation (SD) for normally distributed
variables, median with interquartile range (IQR, 25thand 75th percentiles) for continuous variables with a
non-normal distribution, and proportions for categorical variables. Comparisons between groups at baseline
were made using the unpaired t-test for variables witha normal distribution, the Wilcoxon rank-sum test forcontinuous variables with a non-normal distribution,
and Fisher’s exact test for categorical variables. A mixedmodel repeated-measures analysis was used to assess the
between-treatment difference in the change during treatment from baseline in an outcome parameter (dependent
variable). Adjustment was made for sex, age, and baseline
measurement of a parameter of interest. Fixed effects
were treatment, month of visit, variables used for adjustment, and treatment by month interaction, and the random effect was patient. Month of visit was treated as acategorical variable, and an unstructured variance-covariance matrix was used. The robust method was used toestimate the standard errors to allow for potential departure from the model assumption. Changes from baseline
were used as such in the mixed model analysis, except
for the urine albumin-to-creatinine ratio, which had an
extremely skewed distribution and was transformed tonatural logarithm. Marginal means and 95% confidence
intervals were estimated. The analysis of adverse events
was performed on all the patients who started treatment,
and the comparison was based on the actual treatment
received. The occurrence of adverse events was compared using Fisher’s test. P values < 0.05 (two-tailed) wereNagao et al. Cardiovascular Diabetology(2024) 23:56

Page 4 of 12

Fig. 1 Flowchart of subject enrollment. A total of 175 patients were enrolled and randomized to ipragliflozin or sitagliptin. Of the 175 participants, 15
were excluded from the efficacy analysis due to protocol violations, no baseline measurements, withdrawal of informed consent, and no follow-up measurements. I.C., informed consent

Table 1 Baseline characteristics of study participants
Parameter

Male
Current smoking
Current drinking
Comorbidity
Diabetic retinopathy
Diabetic nephropathy
Dyslipidemia
Hypertension
Hyperuricemia
Liver disease
Coronary artery disease
Arteriosclerosis obliterans
Past medical history
Malignant neoplasm
Myocardial infarction
StrokeHeart failure

Ipragliflozin(n = 77)n%
44 57.1
20 26.035 45.5

Sitagliptin P*(n = 83)
n
44
21
44

%
53.0
25.3
53.0

0.64
1.00
0.35

1
13
56
62
13
7
2
4

1.3
16.9
72.7
80.5
16.9
9.1
2.6
5.2

2
15
60
50
13
8
3
3

2.4
18.1
72.3
60.2
15.7
9.6
3.6
3.6

1.00
1.00
1.00
0.006
1.00
1.00
1.00
0.71

4
1
1
0

5.2
1.3
1.3
0.0

1
0
0
0

1.2
0.0
0.0
0.0

0.20
0.48
0.48
-

*, P < 0.05 indicates the statistical significance based on the Fisher’s exact test forthe between-group difference

considered statistically significant. Statistical analysis was
performed using Stata version 13 software (StataCorp
LLC, College Station, TX, USA).

Results
A total of 175 patients were enrolled and randomized
to ipragliflozin or sitagliptin. Of the participants, a totalof 15 patients were excluded due to protocol violations(n = 8), no baseline measurements (n = 2), withdrawal
of informed consent (n = 3), and no follow-up measurements (n = 2). Finally, 160 patients (n = 77 and n = 83 in
the ipragliflozin and sitagliptin groups, respectively) wereremained in the analysis (Fig. 1).
Baseline characteristics and measurements

There were 44 (57.1%) and 44 (53.0%) men in the ipragliflozin and sitagliptin groups, respectively. There wereno significant differences in the frequency of alcohol
consumption, smoking, comorbidities other than hypertension, and medical history (Table 1). Antidiabetic medications were used by 52 (67.5%) and 56 (67.5%) patientsin the ipragliflozin and sitagliptin groups, respectively(P = 1.00). The number and class of the medications did
not differ between the two groups. For example, the number of participants using pioglitazone was 4 (5.2%) and 3(3.6%) cases in the ipragliflozin and sitagliptin groups,
respectively (P = 0.71). Except for systolic blood pressure, there were no significant differences in the clinicaland laboratory measurements among the participantsNagao et al. Cardiovascular Diabetology(2024) 23:56(Table 2). Among the other laboratory measurements,
serum complement C3 were higher in the ipragliflozingroup (Table S3).
Glucose metabolism parameters

Changes in glucose metabolism parameters from baseline are shown in Fig. 2; Table 3. FPG, HbA1c, and GA
were significantly decreased by the treatments to almost
the same extent in both groups (Fig. 2A and C, and 2D).
Serum insulin decreased at 1 and 3 months in the ipragliflozin group (Fig. 2B).
Serum lipids and apolipoproteins

Changes in serum lipids and apolipoproteins from baseline are shown in Figs. 3 and 4; Table 3. Although TC did
not change in either group (Fig. 3A), LDL-C increased
consistently in the sitagliptin group; TG decreasedtransiently in both groups (Fig. 3C and D); and HDL-C
increased fairly consistently in the ipragliflozin group

Page 5 of 12(Fig. 3B). A significant between-treatment difference wasobserved only for HDL-C (Table 3).
Apo AI increased gradually and apo AII decreasedtransiently in the ipragliflozin group (Fig. 4A and B).
Although apo B did not change in either group, apo B48
decreased consistently in the sitagliptin group (Fig. 4C
and D). Apo CII decreased consistently and apo CIII
decreased almost consistently in the sitagliptin group(Fig. 4E and F). Apo E decreased transiently in the ipragliflozin group (Fig. 4G). Consequently, overall reductions in apo E were observed in the ipragliflozin group,
and in apo B48, CII, and CIII in the sitagliptin group(Table 3). A significant between-treatment difference wasobserved for apo B48 and a near-significant difference for
apo A1 (Fig. 4D; Table 3).
Body weight, blood pressure, and renal function

Changes from baseline in the secondary outcome measures other than glucose metabolism parameters areshown in Table 4. Body weight and blood pressure

Table 2 Clinical and laboratory measurements at baseline
Parameter
Age (year)
Height (cm)Body weight (kg)†Systolic BP (mmHg)
Diastolic BP (mmHg)
FPG (mmol/L)
Insulin (pmol/L)
HbA1c (%)
GA (%)
LipidsTC (mg/dL)†
LDL-C (mg/dL)†
HDL-C (mg/dL)
TG (mg/dL)
Apolipoproteins
AI (mg/dL)†
AII (mg/dL)
B (mg/dL)
B48 (µg/L)
CII (mg/dL)
CIII (mg/dL)
E (mg/dL)
Cr (mg/dL)
CysC (mg/L)
Cr-based eGFR (mL/min/1.73 m2)†
CysC-based eGFR†
UACR (mg/g Cr)

P*

n
77
77
77
77
77
62
62
77
77

Ipragliflozin
Mean/median
SD/IQR
62
53–67
162.7
8.3
69.0
61.8–74.5
138
132–140
78
76–81
8.5
7.2–9.8
62
39–88
7.5
7.1–7.9
19.5
17.6–21.0

n
83
83
83
83
83
70
69
82
82

Sitagliptin
Mean/median
63
161.7
65.3
132
76
8.6
58
7.4
19.6

SD/IQR
54–69
8.4
59.0–72.8
128–138
74–81
7.5–10.0
34–1107.0–8.0
17.3–22.1

0.19
0.45
0.07
0.002
0.14
0.34
0.72
0.58
0.61

77
58
77
62

223.9
137.6
46
161

39.8
33.1
40–54
121–250

82
68
82
70

221.3
131.4
48
184

38.5
33.4
41–61
109–239

0.68
0.29
0.15
0.65

77
77
77
77
77
77
77
77
77
77
77
77

141.6
29.3
114
6.2
5.7
11.9
5.0
0.69
0.89
82.4
81.8
22.9

23.1
27.1–31.9
99–139
3.1–9.7
4.2–7.6
8.9–15.2
4.1–6.1
0.57–0.78
0.78–1.04
17.4
17.1
10.2–71.5

82
82
82
82
82
82
82
82
81
82
81
80

146.0
30.0
111
5.6
5.1
11.5
5.0
0.69
0.89
81.3
81.8
13.6

27.7
26.6–33.3
94–130
4.2–10.9
3.5–6.9
8.8–14.3
4.0–5.6
0.55–0.83
0.79–1.01
18.2
18.8
7.3–54.2

0.28
0.97
0.54
0.58
0.13
0.61
0.57
0.95
0.80
0.72
0.93
0.12

*, P < 0.05 indicates the statistical significance based on unpaired t-test or Wilcoxon rank-sum test for the between-group difference†, Mean and standard deviation (SD) are presented; otherwise, median and interquartile range (IQR) are presented
BP, blood pressure; Cr, creatinine; CysC, cystatin C; FPG, fasting plasma glucose; GA, glycoalbumin; eGFR: estimated glomerular flitration rate, HDL-C, high-density
lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; UACR, urine albumin-to-creatinine ratio

Nagao et al. Cardiovascular Diabetology(2024) 23:56

Page 6 of 12

Fig. 2 Treatment effects of ipragliflozin and sitagliptin on glucose metabolism parameters. Changes from baseline in fasting plasma glucose (FPG,
mmol/L) (A), serum insulin (pmol/L) (B), HbA1c (%) (C), and glycoalbumin (GA, %) (D) in the ipragliflozin and sitagliptin groups are shown as closed circles
with blue lines and closed squares with red lines, respectively. Data are expressed as mean ± 95% confidence interval of the mean. *, P < 0.05; ***, P < 0.001
vs. baseline in each group in the mixed-effects model analysis. §, P < 0.05 for interaction during the overall study period, vs. the sitagliptin group in themixed-effects model analysis

decreased significantly in the ipragliflozin group but notin the sitagliptin group, resulting in overall significant
between-treatment differences. In the ipragliflozin group,
the reduction in body weight was greater in the latermonths of follow-up (P < 10− 3 for interaction). Regarding
renal function parameters, eGFR decreased consistently
in both groups during the treatment period, although thedecrease in Cr-based eGFR was less pronounced in theipragliflozin group. The overall reduction in UACR was
significant in the ipragliflozin group, but there was no
between-treatment difference.
Other laboratory measurements

Overall changes in other laboratory measurements during the treatment period are summarized in Table S4.
Between-treatment differences were observed in blood
cell counts except for white blood cells and platelets,
serum liver function parameters (AST, ALT, GGT, andLDH), uric acid, leptin, and ketones. Most of the differences were induced by ipragliflozin treatment, such asincreases in blood cell counts and ketones, and decreases
in liver function parameters, uric acid, and leptin.
Adverse events

The analysis of adverse events included 171 patients
who received actual treatment with each drug; 80 and 91
patients with ipragliflozin and sitagliptin, respectively.
Reported adverse events are summarized in Table S5. The
number of patients reporting at least one adverse event
was 20 (25.0%) in the ipragliflozin group and 7 (7.7%)in the sitagliptin group. Skin lesions and elevated blood
ketones were reported only in the ipragliflozin group.
Two patients in the ipragliflozin group discontinued
treatment due to the occurrence of rash or cholelithiasis/cholecystitis.

Discussion
In this multicenter, open-label, randomized, controlled
trial, we found that although both ipragliflozin and sitagliptin reduced glucose metabolism parameters to a

Nagao et al. Cardiovascular Diabetology(2024) 23:56

Page 7 of 12

Table 3 Overall changes from baseline in glucose metabolism parameters and serum lipids and apolipoproteinsParameter
Glucose metabolism
FPG (mmol/L)
Insulin (pmol/L)
HbA1c (%)
GA (%)
LipidsTC (mg/dL)
LDL-C (mg/dL)
HDL-C (mg/dL)
TG (mg/dL)
Apolipoproteins
AI (mg/dL)
AII (mg/dL)
B (mg/dL)
B48 (µg/dL)
CII (mg/dL)
CIII (mg/dL)
E (mg/dL)P†

Adjusted overall change (95% CI)*
Ipragliflozin
Sitagliptin

Difference

Interaction−1.28 (− 1.56; −1.00)−8.51 (− 14.7; −2.34)−0.33 (− 0.45; −0.22)−1.97 (− 2.35; −1.58)−1.24 (− 1.51; −0.96)−3.83 (− 9.39; 1.74)−0.44 (− 0.55; −0.33)−2.07 (− 2.44; −1.69)

0.83
0.27
0.19
0.72

0.04
0.75
0.14
0.29

1.7 (− 3.6; 6.9)
1.2 (− 3.1; 5.6)
2.3 (0.9; 3.6)
−12.7 (− 30.3; 4.9)

−1.8 (− 6.8; 3.3)
6.6 (1.6; 11.6)
0.0 (− 1.2; 1.3)
−23.1 (− 40.7; −5.4)

0.36
0.12
0.02
0.42

0.84
0.40
0.59
0.92

2.26 (− 0.89; 5.40)−0.51 (− 1.17; 0.16)−0.69 (− 3.90; 2.52)
0.45 (− 0.60; 1.49)−0.21 (− 0.51; 0.09)−0.07 (− 0.85; 0.72)−0.30 (− 0.56; −0.05)−1.68 (− 4.23; 0.87)−0.18 (− 0.74; 0.39)−1.96 (− 4.74; 0.81)−1.39 (− 2.16; −0.61)−0.40 (− 0.64; −0.17)−0.86 (− 1.38; −0.34)−0.09 (− 0.30; 0.11)

0.06
0.46
0.55
0.006
0.31
0.10
0.21

0.86
0.26
0.59
0.11
0.71
0.51
0.91

Follow-up measurements were done at 1, 3, and 6 months*, Based on a mixed-model repeated-measures analysis adjusting for sex, age, and baseline value of a parameter of interest†, P < 0.05 indicates the statistical significance for the between-treatment difference and treatment-month interaction
CI, confidence interval; FPG, fasting plasma glucose; GA, glycoalbumin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC,
total cholesterol; TG, triglycerides

similar extent, the effects on serum lipid and apolipoprotein profiles were completely different. Ipragliflozin
increased HDL-C and decreased apo E, whereas sitagliptin decreased TG, apo B48, CII, and CIII but
increased LDL-C. Ipragliflozin was more likely to
improve cardiovascular disease risk factors, i.e., HDL-C,
body weight, blood pressure, and uric acid, comparedwith sitagliptin.
To date, three randomized controlled trials havecompared ipragliflozin and sitagliptin head-to-head inpatients with type 2 diabetes [23–25]. Contrary to thepresent finding, these studies reported greater reductions
in FPG with ipragliflozin than with sitagliptin at 12 [23],
24 [24], and 52 weeks [25] of treatment, whereas reductions in HbA1c did not show a measurable difference
between the two treatments [23–25]. These findings may
indicate that sitagliptin primarily act on the improvement of postprandial blood glucose levels compared toipragliflozin. However, under the conditions of the present study, both ipragliflozin and sitagliptin reduced FPG
and HbA1c to a similar extent. Furthermore, GA, whichreflects postprandial blood glucose levels more accurately
than HbA1c, was similarly decreased by both drugs. We
do not have a direct explanation for the present findingsthat differ from previous observations, but the discrepancy in FPG may be due to differences in study design
regarding the use of other antidiabetic drugs. The present study allowed adjustment of existing antidiabetic

drugs after the first 3 months of treatment, whereas theprevious studies did not allow such adjustment. However, the reductions in FPG did not differ between the
two treatments even at 1 month and 3 months when
adjustment for antidiabetic drugs was not allowed. The
previous studies [23, 24] and the present study showedthat ipragliflozin reduced body weight more, accompanied by increased levels of ketone bodies, as comparedwith sitagliptin. This could be due to increased fat oxidation as a result of accelerated urinary glucose excretioncaused by the SGLT2 inhibitory effect of ipragliflozin.
In addition, it has been suggested that body weight loss
with ipragliflozin can be partly explained by a reduction
in extracellular water [26], as SGLT2 inhibitors have an
osmotic diuretic effect with urinary excretion of sodium
accompanied by glucose [27]. This consideration may besupported by the reductions in blood pressure and serum
uric acid, and increases in red blood cell count and hematocrit in the ipragliflozin group in the present study.
The present study showed that ipragliflozin and sitagliptin had different effects on lipid and apolipoprotein
profiles despite similar hypoglycemic effects. Ipragliflozin
increased HDL-C without affecting TC and LDL-C,
whereas sitagliptin decreased TG but increased LDL-C
without affecting TC and HDL-C. In a meta-analysis
by Li, et al. [16]. , SGLT2 inhibitors increased TC, LDLC, and HDL-C and decreased TG. However, the effectsof SGLT2 inhibitors on TC and TG were not consistentNagao et al. Cardiovascular Diabetology(2024) 23:56

Page 8 of 12

Fig. 3 Treatment effects of ipragliflozin and sitagliptin on serum lipids. Changes from baseline in serum total cholesterol (TC, mg/dL) (A), high-density lipoprotein cholesterol (HDL-C, mg/dL) (B), low-density lipoprotein cholesterol (LDL-C, mg/dL) (C), and triglycerides (TG, mg/dL) (D) in the ipragliflozin andsitagliptin groups are shown as closed circles with blue lines and closed squares with red lines, respectively. Data are expressed as mean ± 95% confidence
interval of the mean. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. baseline in each group; †, P < 0.05 for difference at the follow up visit; ‡, P < 0.05 for difference
during the overall study period, vs. the sitagliptin group in the mixed-effects model analysis

across studies. On the other hand, an increase in HDL-C
with SGLT2 inhibitors was consistently found in metaanalyses [28, 29]. Several possible mechanisms havebeen proposed for the HDL-C increase with SGLT2
inhibitors; (1) increased lipolysis of triglycerides, (2)decreased CETP activity, and (3) de novo production of
nascent HDL [30, 31]. According to the finding that apo
A1 was gradually increased by ipragliflozin in the present study, the HDL increase by SGLT2 inhibitors is more
likely explained by de novo synthesis of apo AI and subsequent production of nascent HDL. Notably, although
there was no difference between treatments, apo E wassignificantly reduced in the ipragliflozin group. The liver
is a major source of apo E [32], and elevated plasma apo E
levels have been reported in patients with non-alcoholic
fatty liver disease (NAFLD) regardless of apo E genotype [33]. Since ipragliflozin has been shown to improve
hepatic steatosis [34], and serum liver enzymes werereduced in the present study, circulating apo E may havebeen reduced as hepatic steatosis was improved. On theother hand, sitagliptin reduced TG and apo B48 without

affecting HDL-C and apo AI. These results suggest thatthe effect of sitagliptin on triglyceride metabolism can be
explained by an inhibition of lipoprotein production fromthe small intestine, as manifested by decreases in apo B48
and CII, and not by a lipolytic activity associated with anincrease in HDL-C. These findings are consistent withprevious reports that sitagliptin suppressed postprandial
triglyceride elevation [17] and reduced fasting apo B48 inaddition to CII [22]. In addition, a single-arm, observational study of sitagliptin treatment in drug naïve patientswith type 2 diabetes suggested that sitagliptin might
improve atherogenic lipids in a glycemic efficacy dependent manner [35]. However, the present study would not
be able to address such a hypothesis based on patientswith a baseline HbA1c of 10.2%, which was much higher
than the baseline HbA1c of 7.4% in the sitagliptin group.
SGLT2 inhibitors slow the decline in eGFR in patientswith type 2 diabetes, even with a transient reductionin eGFR early in treatment [36]. DDP-4 inhibitors havebeen reported to be associated with a continuous decline
in eGFR [37]. The present study showed that both

Nagao et al. Cardiovascular Diabetology(2024) 23:56

Page 9 of 12

Fig. 4 Treatment effects of ipragliflozin and sitagliptin on serum apolipoproteins. Changes from baseline in serum apolipoprotein (Apo) AI (mg/dL) (A),AII (mg/dL) (B), B (mg/dL) (C), B48 (µg/dL) (D), CII (mg/dL) (E), CIII (mg/dL) (F), and E (mg/dL) (G) in the ipragliflozin and sitagliptin groups are shown as
closed circles with blue lines and closed squares with red lines, respectively. Data are expressed as mean ± 95% confidence interval of the mean. *, P < 0.05;**, P < 0.01, ***, P < 0.001 vs. baseline in each group; ††, P < 0.01 for difference at the follow up visit; ‡‡, P < 0.01 for difference during the overall study
period, vs. the sitagliptin group in the mixed-effects model analysis

ipragliflozin and sitagliptin decreased eGFR, particularly
CysC-based eGFR, to a similar extent up to 6 months oftreatment. In contrast to eGFR reduction, both SGLT2
and DDP-4 inhibitors are protective against worseningof albuminuria and may even reduce UACR [36–38]. In
the present study, we could show a statistically significant
UACR reduction with ipragliflozin treatment, but notwith sitagliptin treatment, although the between-treatment difference was not appreciable. The findings arecompatible with the recent observation in the network
meta-analysis on SGLT2 inhibitors and DDP-4 inhibitors[39].
The present study has several limitations. First, it wasan open-label study. Second, the number of cases wasNagao et al. Cardiovascular Diabetology(2024) 23:56

Page 10 of 12

Table 4 Changes from baseline in secondary outcome measures other than glucose metabolism parameters
Parameter
Body weight (kg)Systolic BP (mmHg)

Diastolic BP (mmHg)

Cr-based eGFR (mL/min/1.73 m2)

CysC-based eGFR (mL/min/1.73 m2)

UACR (mg/g Cr)‡

Month
1
3
6
Overall136Overall136Overall136Overall136Overall136Overall

Adjusted mean change (95% CI)*
Ipragliflozin
Sitagliptin−0.7 (− 1.0; −0.5)−0.2 (− 0.5; 0.0)
−1.2 (− 1.7; −0.8)−0.1 (− 0.4; 0.2)
−1.8 (− 2.3; −1.4)−0.3 (− 0.7; −0.0)−1.4 (− 1.7; −1.0)−0.2 (− 0.5; 0.0)
−3.9 (− 5.3; −2.6)−1.7 (− 3.4; −0.0)−4.1 (− 6.0; −2.3)
0.8 (− 1.0; 2.7)
−3.8 (− 5.5; −2.1)
0.7 (− 1.3; 2.7)
−3.9 (− 5.2; −2.7)−0.1 (− 1.5; 1.4)
−3.2 (− 4.7; −1.8)−2.1 (− 3.4; −0.8)−3.0 (− 4.7; −1.4)−0.4 (− 1.9; 1.1)
−3.4 (− 4.6; −2.2)−0.7 (− 2.3; 0.8)
−3.2 (− 4.4; −2.0)−1.1 (− 2.1; −0.1)−1.8 (− 4.6; 1.0)
−2.6 (− 4.4; −0.7)−1.0 (− 3.2; 1.2)
−3.8 (− 5.6; −2.1)−2.4 (− 5.2; 0.5)
−5.1 (− 7.0; −3.3)−1.7 (− 3.8; 0.4)
−3.9 (− 5.3; −2.5)−3.3 (− 5.5; −1.1)−1.3 (− 2.8; 0.3)
−2.2 (− 4.4; −0.1)−2.4 (− 4.0; −0.8)−3.4 (− 5.8; −1.0)−2.9 (− 4.7; −1.1)−3.0 (− 4.8; −1.2)−2.2 (− 3.5; −0.9)−0.12 (− 0.33; 0.08)−0.15 (− 0.38; 0.08)−0.16 (− 0.41; 0.09)−0.17 (− 0.44; 0.10)−0.25 (− 0.48; −0.02)−0.13 (− 0.38; 0.12)−0.18 (− 0.34; −0.01)−0.15 (− 0.34; 0.04)

P†
Difference
0.009< 10− 4< 10− 6
< 10− 50.04
< 10− 30.001
< 10− 4
0.25
0.02
0.008
0.009
0.65
0.05
0.11
0.10
0.13
0.91
0.76
0.49
0.87
0.95
0.52
0.84

Interaction< 10− 3

0.08

0.28

0.45

0.28

0.76

*, Based on a mixed mixed-model repeated-measures analysis adjusting for sex, age, and baseline value of a parameter of interest†, P < 0.05 indicates the statistical significance for the between-treatment difference and treatment-month interaction‡, In the natural log-scaleCI, confidence interval; BP, blood pressure; Cr, creatinine; CysC, cystatin C; eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio

insufficient to detect between-treatment differences inchanges in apolipoproteins when within-treatment differences were detected. Because more adverse events wereobserved in the ipragliflozin group, the smaller number of cases in this group may have influenced the study
results. Third, dietary control was not strictly prescribed
during the follow-up period. Fourth, the study protocol
allowed for the addition, dose titration, or discontinuation of oral antidiabetic drugs other than SGLT2 inhibitors, DPP4 inhibitors, and GLP-1 receptor agonists after
3 months of treatment. In fact, changes in drug regimens
were only made within the insulin sensitizer category. For
example, metformin was started in four cases in the ipragliflozin group and pioglitazone in one case in the sitagliptin group. In addition, metformin and/or pioglitazone
were discontinued in two cases in the sitagliptin group.
However, this may have allowed us to evaluate the effectsof ipragliflozin and sitagliptin on lipid and apolipoprotein profiles independent of glycemic levels. Fifth, we did
not have detailed information on antihypertensive drugs
while the prevalence of hypertension was higher in theipragliflozin group. In fact, the participants using antihypertensive drugs were more frequent in the ipragliflozingroup (n = 54, 70.1%) than in the sitagliptin group (n = 43,
51.8%) (P = 0.02). Some antihypertensive drugs have aneutral or beneficial effect on the lipid profile, whileothers have an adverse effect. Different use of antihypertensive drugs may influence the lipid profile. Finally,
although the intent-to-treat (ITT) analysis is a principle in the randomized trial, the present study excluded
patients with no follow-up measurements and those who
did not follow to the protocol, necessarily causing the socalled attrition bias. The present study was exploratory,
and the observed findings should be validated in the ITT
analysis in larger randomized trials in the future. Further investigations, including animal or ex vivo studies,
are also needed to fully understand the pharmacologicaleffects of these drugs on lipid metabolism.

Conclusions
In summary, although ipragliflozin and sitagliptin
showed similar effects on glycemic parameters in thepresent study, the effects of these drugs on lipid and apolipoprotein profiles were different. Both drugs have favorable effects on the profiles, i.e., increased HDL-C anddecreased apo E with ipragliflozin and decreased TG, apo

Nagao et al. Cardiovascular Diabetology(2024) 23:56

B48, CII, and CIII with sitagliptin. Ipragliflozin is more
likely than sitagliptin to contribute to plaque reduction
by improving cardiovascular disease risk factors, including HDL-C, body weight, blood pressure, and uric acid.
These findings in the present study suggest a strong needfor further large clinical trials to validate the protective
effects of ipragliflozin on cardiovascular outcomes.
Abbreviations
SGLT2	Sodium-glucose cotransporter 2
DPP4	Dipeptidyl peptidase-4
SUCRE	Sodium-GlUose Co-transporteR 2 inhibitor, Ipragliflozin, Suglat®,
Effect on Lipid and Glucose Metabolism
UMIN	University hospital Medical Information Network
LDL-C	Low-density lipoprotein cholesterol
HDL-C	High-density lipoprotein cholesteroTG	Triglycerides
HbA1c	Glycohemoglobin
Cr	Creatinine
NYHA	New York Heart Association
GLP-1	Glucagon-like peptide-1
Apo	Apolipoprotein
FPG	Fasting plasma glucose
GA	Glycoalbumin
eGFR	Estimated glomerular filtration rate
UACR	Urine albumin-to-Cr ratio
CysC	Cystatin C
SD	Standard deviation
IQR	Interquartile range
LDH	Lactate dehydrogenase
AST	Aspartate aminotransferase
ALT	Alanine aminotransferase
GGT	Gamma-glutamyl transferase
NAFLD	Non-alcoholic fatty liver disease
ITT	Intent-to-treat

Supplementary Information

The online version contains supplementary material available at https://doi.
org/10.1186/s12933-024-02149-7.
Supplementary Material 1
Acknowledgements
The authors thank Dot World Co., Ltd. (Tokyo) for data management and Dr.
Suminori Kono (MedStat Corporation, Fukuoka) for assistance with statisticalanalysis and preparation of the manuscript. We thank all of the membersof SUCRE study group; Dr. Sano R (Sano Clinic, Yamagata), Osonoi T (NakaKinen Clinic, Ibaraki), Dr. Takahashi S (Ageo Central General Hospital, Saitama),
Dr. Shuto H (Minamikoshigaya-Kennshinkai Clinic, Saitama), Dr. Moritani H(Moritani Clinic, Tokyo), Dr. Nakajima Y (Nakajima Clinic, Tokyo), Dr. Kimura K(Hachijyo Hospital, Tokyo), Dr. Suzuki J (University of Fukui Faculty of Medical
Science, Fukui), Dr. Yamashita S (Rinku General Medical Center, Osaka), Dr.
Ikeda Y (Obase Hospital, Fukuoka), Dr. Otonari T (Otonari Clinic, Fukuoka),
Dr. Sawayama Y (Fukuoka Red Cross Hospital, Fukuoka), Dr. Hashiguchi Y(Tenpozan Naika Clinic, Kagoshima), Dr. Biro S (Tsukasa Health Care Hospital,
Kagoshima), Dr. Yamakawa K (Chubu Tokushukai Hospital, Okinawa), Dr. HigaM (Tomishiro Central Hospital, Okinawa), and Dr. Yamada M (Yamada Clini,
Okinawa). We also thank Dr. Tada N (Jikei University School of Medicine, Tokyo)
and Dr. Kawakami M (Nerimahikarigaoka Hospital, Tokyo) for monitoring thesafety of the participants during the study.
Author contributions
MN: data analysis, interpretation, and drafting and editing of the manuscript;
JS: creation of the study design; KTI: data analysis and interpretation; SI: Patient
recruitment and follow-up; HS: data interpretation; SO: study design, data
analysis and interpretation, and critical revision of the manuscript.

Page 11 of 12

Funding
This trial was funded by Astellas Pharma Inc. The company had no role in the
study design, selection of patients, data collation and analysis, interpretationof the results, or preparation of the manuscript.
Data availability
Some or all datasets generated and/or analyzed during the current study are
not publicly available but are available from the corresponding author on
reasonable request.

Declarations
Ethics approval and consent to participate
The study adhered to the principles of the Declaration of Helsinki andwas approved by the ethics committees at Fukujuji Hospital, Japan AntiTuberculosis Association and, where appropriate, at each of the participating
hospitals and clinics. Written informed consent was obtained from all patients.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 21 November 2023 / Accepted: 30 January 2024

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