Introduction
Concurrent treatment with two or more hypoglycemic agents with differing mechanisms
of action may be useful in type 2 diabetes mellitus patients showing inadequate glycemic
control under treatment with one drug alone. This study was designed to determine
whether concurrent administration of a dipeptidyl peptidase-4 (DPP-4) inhibitor might
yield further improvement of the glycemic control in Japanese type 2 diabetes mellitus
patients receiving a selective inhibitor of sodium glucose co-transporter-2 (SGLT2
inhibitor). SGLT2 is a transporter protein expressed in the proximal renal tubules
that mediates the reabsorption of approximately 90% of all the glucose filtered through
the glomeruli [1]
[2]. SGLT2 inhibitors have been shown to exert their hypoglycemic effect by causing
selective inhibition of SGLT2 in the kidneys, thereby facilitating urinary excretion
of excessive circulating glucose [3]. In addition to their hypoglycemic effect, SGLT2 inhibitors have also been reported
to reduce the body weight, lower the blood pressure, and improve lipid metabolism
and uric acid metabolism [4]. In a previously reported trial, treatment with a SGLT2 inhibitor, as compared to
placebo, significantly suppressed the occurrence of cardiovascular death and heart
failure in high-risk patients with cardiovascular disorders, presumably on account
of the multifaceted effects of this drug class [5]. DPP-4 inhibitors facilitate insulin secretion via increasing the secretion of active
glucagon-like peptide-1 (GLP-1), an incretin [6]
[7]. Therefore, the mechanism of the hypoglycemic action of SGLT2 inhibitors differs
from that of the DPP-4 inhibitors. The present study was conducted to determine whether
concurrent administration of a DPP-4 inhibitor, whose mechanism of action differs
from that of the SGLT1 inhibitors, might yield further improvement of the glycemic
control in Japanese type 2 diabetes mellitus patients showing relatively good glycemic
control under SGLT2 inhibitor monotherapy.
Materials and Methods
Subjects
This is a retrospective non-randomized study. Each potential subject gave informed
consent for participation in this study after receiving an explanation about the objective
of the study from his/her attending physician. This clinical trial was officially
registered as an open-label study (ID: UMIN000021584).
Among the patients enrolled in this study, there were patients who were taking sulfonyl
ureas and/or biguanides (hypoglycemic agents), lipid-lowering agents, and/or antihypertensive
drugs before the start of the study. These patients continued to take those drugs
at the same doses during the study period. Patients with an estimated glomerular filtration
rate (eGFR) of less than 45 were excluded from the study. The primary endpoint of
this study was the change in the level of HbA1c.
The study population consisted of 214 ambulatory Japanese patients with type 2 diabetes
mellitus. The subjects were allocated to two groups, i. e., a group that received
treatment with a SGLT2 inhibitor alone, or SGLT2 monotherapy (n=18; 12 men and 6 women;
age: 54±12 years), and a group that received combined SGLT2 inhibitor+DPP-4 inhibitor
therapy (n=196, 145 men and 51 women; age: 55±11 years).
Therapeutic regimens and administration
The following five SGLT2 inhibitor preparations were used in this study: luseogliflozin,
dapagliflozin, tofogliflozin, empagliflozin, and canagliflozin. Five DPP-4 inhibitor
preparations were also used, including sitagliptin, vildagliptin, alogliptin, anagliptin,
and linagliptin. The SGLT2 inhibitors and DPP-4 inhibitors were administered once
daily, before or after breakfast, for 6 months. The dose levels used of the drugs
are shown in [Table 1]. Each subject of the SGLT2 inhibitor monotherapy group received a SGLT2 inhibitor
preparation. Each subject of the combined SGLT2 inhibitor+DPP-4 inhibitor group received
a SGLT2 inhibitor preparation plus a DPP-4 inhibitor preparation.
Table 1 Dose levels of drugs.
|
Name of drug
|
Dose level
|
|
SGLT2 inhibitor
|
Luseogliflozin
|
2.5 mg/day
|
|
Dapagliflozin
|
5 mg/day
|
|
Tofogliflozin
|
20 mg/day
|
|
Empagliflozin
|
10 mg/day
|
|
Canagliflozin
|
100 mg/day
|
|
DPP-4 inhibitor
|
Sitagliptin
|
100 mg/day
|
|
Vildagliptin
|
100 mg/day
|
|
Alogliptin
|
25 mg/day
|
|
Anagliptin
|
200 mg/day
|
|
Linagliptin
|
5 mg/day
|
Measurements of the body weight, body-mass index (BMI), hemoglobin A1c (HbA1c), serum
lipids and other biochemical parameters
The body weight of the subjects was determined before the initiation of the study
medication(s) (baseline) and after 6 months of treatment with the study medication(s).
At the baseline and after 6 months of treatment with the study medication(s), random
blood samples were obtained and the separated sera were stored frozen at −80°C until
the assays for the blood biochemical parameters. The Handa Medical Association Health
Center (Aichi, Japan) was entrusted with measurement of the blood HbA1c and serum
lipid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase
(γ-GTP) and uric acid levels; the latter five parameters were analyzed in an autoanalyzer
(JCA-BM8000 series, JAOL, Tokyo, Japan). The blood HbA1c level was determined by automated
high-performance liquid chromatography (HPLC) (HLC-723GX, Tosoh Corporation, Tokyo,
Japan).
Statistical analysis
All the data are expressed as the mean±SD. The comparison of pre- vs. post-treatment
data was conducted using the two-way ANOVA and Student's t-test. Statistical significance
was set at p<0.05. Power analysis was performed using G Power (Faul, Erdfelder, Lang
& Buchner).
Results
SGLT2 inhibitor monotherapy
The results are presented in [Table 2]. The data concerning the SGLT2 inhibitors in this study represent the integrated
data of patients treated with one of the 5 types of SGLT2 inhibitors. The blood HbA1c
value tended to decrease following SGLT2 inhibitor treatment for 6 months, although
the degree of decrease did not reach statistical significance. The body weight and
BMI also decreased. The serum lipid profile tended to show improvement, although the
improvement did not reach statistical significance. In addition to the above effects,
the serum levels of AST, ALT, γ-GTP, and uric acid also decreased following the treatment.
Table 2 Responses to combined SGLT2 inhibitor+DPP4 inhibitor therapy.
|
SGLT2 inhibitor monotherapy
|
Combined SGLT2 inhibitor+ DPP4 inhibitor therapy
|
|
n
|
n=18 (male: 12; female: 6)
|
n=196 (male: 145; female: 51)
|
|
Age (yrs.)
|
54±12
|
55±11
|
|
Duration of illness (yrs.)
|
13±8
|
12±7
|
|
Baseline
|
6 mo after
|
Baseline
|
6 mo after
|
|
Body weight (kg)
|
87.0±26.7
|
85.4±26.1*
|
77.6±16.8
|
75.5±16.6**
|
|
BMI (kg/m2)
|
30.2±6.2
|
29.7±6.3*
|
28.1±5.3
|
27.2±4.6**
|
|
HbA1c (%)
|
7.4±1.0
|
7.3±0.9
|
7.1±0.9
|
6.9±0.8**
|
|
AST (U/L)
|
33±18
|
25±8*
|
26±17
|
23±11**
|
|
ALT (U/L)
|
36±20
|
27±13*
|
32±26
|
25±16**
|
|
γ-GTP (U/L)
|
37±24
|
29±16*
|
42±46
|
36±32**
|
|
Uric acid (mg/dL)
|
|
Male
|
5.5±1.3
|
5.1±1.4**
|
5.5±1.2
|
5.0±1.1**
|
|
Female
|
4.6±0.9
|
3.9±1.3**
|
4.8±1.3
|
3.9±1.1**
|
|
T-cho (mg/dL)
|
175±31
|
173±30
|
176±29
|
180±32**
|
|
HDL-cho (mg/dL)
|
57±16
|
58±18
|
58±14
|
61±15**
|
|
LDL-cho (mg/dL)
|
97±31
|
94±26
|
97±23
|
100±27*
|
|
Triglyceride (mg/dL)
|
153±78
|
133±92
|
148±86
|
142±95
|
Data are expressed as mean±SD. ** : P<0.01, *: P<0.05. AST: aspartate aminotransferase,
ALT: alanine aminotransferase, γ-GTP: γ-glutamyltransferase, T-cho: total cholesterol,
HDL-cho: HDL cholesterol, LDL-cho: LDL cholesterol.
Combined SGLT2 inhibitor+DPP-4 inhibitor therapy
The results are presented in [Table 2]. The blood HbA1c value decreased in response to combined SGLT2 inhibitor+DPP-4 inhibitor
therapy. The body weight and BMI also decreased. As for the serum lipid profile, the
serum HDL-cholesterol (HDL-C) increased, whilst the serum LDL and total cholesterol
also increased. The serum levels of AST, ALT, γ-GTP and uric acid decreased.
Comparison between SGLT2 inhibitor monotherapy and combined SGLT2 inhibitor+DPP-4
inhibitor therapy for individual DPP-4 inhibitors
Patients receiving treatment with a SGLT2 inhibitor received concurrent administration
of one of 5 different DPP-4 inhibitors, and the effects of the concurrent SGLT2+DPP-4
inhibitor therapy were assessed by the type of DPP-4 inhibitor used; the results are
summarized in [Table 3]. There was a significant decrease of the blood HbA1c value in the patients receiving
concurrent administration of sitagliptin (one of the DPP-4 inhibitors used) with the
SGLT2 inhibitor, whereas the blood HbA1c value only tended to decrease, the change
not reaching statistical significance, in the patients receiving any of the other
4 DPP-4 inhibitors in combination with the SGLT2 inhibitor. In regard to the effect
on the body weight and BMI, both these physical parameters decreased significantly,
irrespective of the DPP-4 inhibitor preparation used in combination with the SGLT2
inhibitor. The serum AST, ALT and γ-GTP levels (indicators of hepatic function) also
improved significantly in the patients who received sitagliptin in combination with
the SGLT2 inhibitor. In the patients who received vildagliptin concurrently with the
SGLT2 inhibitor also, the serum AST and ALT levels decreased, whereas the serum γ-GTP
level showed no decrease. No decrease of the serum AST, ALT or γ-GTP was observed
in the patients who received alogliptin or anagliptin in combination with the SGLT2
inhibitor. In the patients who received linagliptin with the SGLT2 inhibitor, the
serum ALT and γ-GTP levels decreased, whereas the serum AST level remained unchanged.
Table 3 By-drug comparison of the responses to combined therapy of SGLT2 inhibitors and DPP-4
inhibitors.
|
SGLT2 inhibitor monotherapy
|
Combined therapy of SGLT2 inhibitors and DPP4 inhibitors
|
|
Luseogliflozin, dapagliflozin, tofogliflozin, empagliflozin, or canagliflozin
|
Sitagliptin
|
Vildagliptin
|
|
n
|
n=18 (male: 12, female: 6)
|
n=79 (male: 64, female: 15)
|
n=31 (male: 26, female: 5)
|
|
Age (yrs.)
|
54±12
|
54±10
|
54±12
|
|
Duration of illness (yrs.)
|
13±8
|
12±6
|
12±7
|
|
Baseline
|
6 mo after
|
d/1-β
|
Baseline
|
6 mo after
|
d/1-β
|
Baseline
|
6 mo after
|
d/1-β
|
|
Body weight (kg)
|
87.0±26.7
|
85.4±26.1*
|
0.06/0.06
|
76.8±15.8
|
74.5±15.6**
|
0.15/0.26
|
78.8±16.5
|
76.3±16.1**
|
0.15/0.13
|
|
BMI (kg/m2)
|
30.2±6.2
|
29.7±6.3*
|
0.08/0.06
|
28.1±5.9
|
26.8±4.3*
|
0.25/0.59
|
27.6±4.3
|
26.7±4.2**
|
0.21/0.20
|
|
HbA1c (%)
|
7.4±1.0
|
7.3±0.9
|
0.11/0.07
|
7.1±0.9
|
6.8±0.7**
|
0.37/0.90
|
7.0±1.3
|
6.8±1.0
|
0.17/0.15
|
|
AST (U/L)
|
33±18
|
25±8*
|
0.57/0.63
|
28±21
|
24±13**
|
0.23/0.52
|
27±16
|
21±7*
|
0.49/0.75
|
|
ALT (U/L)
|
36±20
|
27±13*
|
0.53/0.56
|
35±31
|
26±20**
|
0.35/0.87
|
33±25
|
25±13**
|
0.40/0.58
|
|
γ-GTP (U/L)
|
37±24
|
29±16*
|
0.39/0.35
|
48±46
|
39±32**
|
0.23/0.52
|
45±68
|
39±45
|
0.10/0.08
|
|
Uric acid (mg/dL)
|
|
Male
|
5.5±1.3
|
5.1±1.4*
|
0.30/0.16
|
5.4±1.3
|
4.9±1.2**
|
0.40/0.88
|
5.5±1.0
|
4.8±1.0**
|
0.70/0.93
|
|
Female
|
4.6±0.9
|
3.9±1.3*
|
0.63/0.24
|
4.6±1.0
|
3.6±0.7**
|
1.16/0.99
|
4.8±0.8
|
3.6±0.7**
|
1.60/0.76
|
|
T-cho (mg/dL)
|
175±31
|
173±30
|
0.07/0.06
|
178±29
|
179±32
|
0.03/0.06
|
168±24
|
174±34
|
0.20/0.19
|
|
HDL-cho (mg/dL)
|
57±16
|
58±18
|
0.06/0.06
|
59±16
|
61±16**
|
0.13/0.21
|
57±14
|
59±13*
|
0.15/0.13
|
|
LDL-cho (mg/dL)
|
97±31
|
94±26
|
0.11/0.07
|
99±22
|
99±24
|
0.00/0.05
|
90±21
|
96±28
|
0.24/0.25
|
|
Triglyceride (mg/dL)
|
153±78
|
133±92
|
0.24/0.16
|
147±90
|
143±111
|
0.04/0.06
|
153±107
|
143±96
|
0.10/0.08
|
|
Combined therapy of SGLT2 inhibitors and DPP4 inhibitors
|
|
Alogliptin
|
Anagliptin
|
Linagliptin
|
|
n
|
n=45 (male: 29, female: 16)
|
n=13 (male: 8, female: 5)
|
n=28 (male: 18, female: 10)
|
|
Age (yrs.)
|
55±11
|
54±8
|
57±15
|
|
Duration of illness (yrs.)
|
11±5
|
10±8
|
12±9
|
|
Baseline
|
6 mo after
|
d/1-β
|
Baseline
|
6 mo after
|
d/1-β
|
Baseline
|
6 mo after
|
d/1-β
|
|
Body weight (kg)
|
75.4±17.0
|
73.8±17.1**
|
0.09/0.09
|
83.0±20.3
|
81.6±20.1**
|
0.07/0.06
|
79.2±18.1
|
77.0±17.5**
|
0.12/0.09
|
|
BMI (kg/m2)
|
27.5±5.0
|
26.9±5.1**
|
0.12/0.12
|
29.7±6.1
|
29.1±6.0**
|
0.10/0.06
|
28.9±4.6
|
28.2±4.6**
|
0.15/0.12
|
|
HbA1c (%)
|
6.8±0.8
|
6.7±0.5
|
0.15/0.17
|
7.5±1.2
|
7.4±1.0
|
0.09/0.06
|
7.5±0.8
|
7.3±0.8
|
0.25/0.25
|
|
AST (U/L)
|
24±13
|
22±9
|
0.18/0.22
|
21±12
|
20±9
|
0.09/0.06
|
26±12
|
23±9
|
0.28/0.30
|
|
ALT (U/L)
|
28±19
|
24±13
|
0.25/0.37
|
30±30
|
25±16
|
0.21/0.11
|
29±20
|
24±13*
|
0.30/0.33
|
|
γ-GTP (U/L)
|
33±33
|
31±26
|
0.07/0.07
|
43±45
|
35±34
|
0.20/0.10
|
36±33
|
29±20*
|
0.26/0.26
|
|
Uric acid (mg/dL)
|
|
Male
|
5.3±1.1
|
4.8±0.8**
|
0.52/0.77
|
6.6±1.4
|
5.6±1.2*
|
0.77/0.47
|
5.9±1.2
|
5.6±1.3
|
0.24/0.16
|
|
Female
|
4.8±1.4
|
3.9±1.2**
|
0.69/0.73
|
4.6±1.2
|
4.2±0.7
|
0.41/0.11
|
5.3±2.0
|
4.5±1.5*
|
0.45/0.25
|
|
T-cho (mg/dL)
|
177±28
|
183±30
|
0.21/0.28
|
168±34
|
178±37
|
0.28/0.15
|
181±32
|
187±33
|
0.19/0.16
|
|
HDL-cho (mg/dL)
|
61±13
|
64±14**
|
0.22/0.30
|
56±12
|
63±16**
|
0.50/0.38
|
55±12
|
57±13
|
0.16/0.13
|
|
LDL-cho (mg/dL)
|
98±22
|
101±25
|
0.13/0.14
|
94±30
|
101±39
|
0.20/0.10
|
101±27
|
107±29
|
0.21/0.19
|
|
Triglyceride (mg/dL)
|
132±66
|
132±64
|
0.00/0.05
|
137±84
|
122±50
|
0.22/0.11
|
173±75
|
164±103
|
0.10/0.08
|
Data are expressed as mean±SD. ** : P<0.01,*: P<0.05. AST: aspartate aminotransferase,
ALT: alanine aminotransferase, γ-GTP: γ-glutamyltransferase, T-cho: total cholesterol,
HDL-cho: HDL cholesterol, LDL-cho: LDL cholesterol.d: effect size, 1-β: power
As for the serum uric acid level, the serum uric acid level was decreased in both
male and female patients in the SGLT2 inhibitor monotherapy group. On the other hand,
the uric acid was decreased both male and female patients in the combined SGLT2 inhibitor+sitagliptin,
vildagliptin or alogliptin therapy. However, combined SGLT2 inhibitor+anagliptin decreased
the uric acid level in male patients, and combined SGLT2 inhibitor+linagliptin decreased
the uric acid level in female patients.
With regard to the impact on the serum lipid profile, elevation of the serum HDL-C
was observed in the patients receiving concurrent administration of sitagliptin with
a SGLT2 inhibitor. Concomitant use of vildagliptin, alogliptin, or anagliptin with
the SGLT2 inhibitor also caused elevation of the serum HDL-C, while no such elevation
was seen in the patients receiving linagliptin, as the DPP-4 inhibitor, with the SGLT2
inhibitor. Concurrent administration of a DPP-4 inhibitor, regardless of the preparation
used, with a SGLT2 inhibitor had no effect on the serum total cholesterol, LDL-cholesterol
(LDL-C) or triglyceride level.
Discussion
Concurrent use of two or more hypoglycemic agents with differing mechanisms of action
may be useful in type 2 diabetes mellitus patients showing inadequate glycemic control
under treatment with a single drug. It is considered that drugs whose blood-sugar-lowering
mechanism does not involve the pancreatic beta cells may be more effective for concurrent
administration, especially in view of the lower risk of hypoglycemia.
It has been reported that SGLT2 inhibitors exert their hypoglycemic effect by facilitating
urinary excretion of excessive circulating glucose [3]. This class of drugs cause selective inhibition of SGLT2 [1]
[2], a transporter protein that mediates reabsorption of about 90% of the glucose filtered
through the glomeruli. In addition to exerting a hypoglycemic effect, SGLT2 inhibitors
have also been reported to reduce the body weight, lower the blood pressure, and improve
lipid metabolism and uric acid metabolism [4]. In one placebo-controlled study conducted in high-risk patients with cardiovascular
disorders, treatment with a SGLT2 inhibitor, as compared to placebo, significantly
suppressed the incidence of cardiovascular death and heart failure, presumably on
account of the versatile effects of this class of drugs [5].
DPP-4 inhibitors have been shown to facilitate insulin secretion via non-pancreatic
beta cell-mediated increase of active GLP-1, an incretin, and it has been suggested
that inhibition of DPP-4 may also afford extra-pancreatic effects in addition to the
effect on the blood glucose level [8]
[9].
In general, many treatment options exist for patients with poor glycemic control with
markedly elevated blood HbA1c values, because those patients are scarcely at risk
of developing hypoglycemic episodes. On the other hand, in patients with relatively
good glycemic control, it is important to select a treatment agent that would not
entail the risk of development of hypoglycemia. How to safely reduce the blood glucose
level to an HbA1c of 6.9% level without increasing the risk of development of diabetic
complications is an important issue in such patients. In view of this, we conducted
a trial of combined SGLT2 inhibitor+DPP-4 inhibitor treatment, both classes of drugs
being generally thought as being unlikely to cause hypoglycemic attacks, in patients
with type 2 diabetes mellitus showing relatively good glycemic control, using various
combinations of SGLT2 inhibitors and DPP4 inhibitors, to explore which drug combinations
might be more effective. Five different SGLT2 inhibitor preparations were used in
this study, in which the therapeutic response data from patients receiving SGLT2 inhibitor
therapy alone were integrated into SGLT2 inhibitor monotherapy group data for analysis,
without distinction among the preparations prescribed. On the other hand, 5 different
DPP-4 inhibitor preparations were also used, and these were dealt with individually
for comparison with the SGLT2 inhibitor monotherapy group.
First, comparison of the therapeutic responses between the integrated SGLT2 inhibitor
monotherapy group and combined SGLT2 inhibitor+DPP-4 inhibitor therapy group is presented
in [Table 2]. As can be seen, no significant decrease of the blood HbA1c value was observed in
the SGLT2 inhibitor monotherapy group, while significant reduction of this parameter
was noted in the combined therapy group, indicating the favorable effect of concurrent
administration of a DPP-4 inhibitor with a SGLT2 inhibitor. The serum HDL-C level
increased in the combined drug therapy group, again indicating a favorable effect
of the combined therapy. The body weight, BMI and serum uric acid level are widely
recognized to decrease in response to treatment with a SGLT2 inhibitor alone, and
our present study yielded consistent results. These effects were maintained even after
the addition of a DPP-4 inhibitor. The percent decreases of the 3 parameters were
comparable between the two groups, and were not enhanced by combined administration
of a DPP-4 inhibitor with the SGLT2 inhibitor.
Kusunoki et al. have reported that treatment with a SGLT2 inhibitor is associated
with improvement of the hepatic function parameters, namely, serum AST, ALT and γ-GTP
[10]. Consistent with this report, in the present study, treatment with the SGLT2 inhibitor
alone was associated with a lowering of the serum levels of AST, ALT and γ-GTP. Furthermore,
this effect was maintained even after the addition of a DPP-4 inhibitor to the SGTL2
inhibitor therapy. The percent decreases in these 3 parameters were comparable between
the two groups and were not enhanced by the addition of the DPP-4 inhibitor to the
treatment regimen.
In this study, we examined the correlations between the percent changes of the HbA1c
values and percent changes of the serum AST, ALT and γ-GTP, and obtained the following
results: the correlation coefficients (r values) between the percent changes of the
HbA1c levels and percent changes of the serum AST, serum ALT and serum γ-GTP levels
were 0.60 (P<0.05), 0.55 (P<0.05) and 0.53 (P<0.05), respectively, in the SGLT2 inhibitor
monotherapy group. In the combined SGLT2 inhibitor plus DPP4 inhibitor group, the
corresponding values of the correlation coefficient (r) were 0.31 (P<0.01), 0.33 (P<0.05)
and 0.47 (P<0.01), respectively. These results indicate that the improved glycemic
control was also associated with improvement in the markers of liver dysfunction.
As for effects on the serum lipid profile, treatment with a SGTL2 inhibitor alone
had no influence on the serum lipid profile. In the combined SGLT2 inhibitor+DPP-4
inhibitor therapy group, on the other hand, elevation of the serum HDL-C was observed,
indicating the favorable effect of addition of the DPP-4 inhibitor. However, the serum
total cholesterol and LDL-C also increased.
Secondly, the therapeutic responses to combined SGLT2 inhibitor+DPP-4 inhibitor therapy
were assessed for the 5 individual DPP-4 preparations used, and the results are summarized
in [Table 3]. Of the five DPP-4 inhibitors used, only sitagliptin led to significant decrease
of the HbA1c, one of the most important indicators of blood glucose control, when
administered in combination with a SGLT2 inhibitor in the combined SGLT2+DPP-4 inhibitor
therapy group. On the other hand, only a tendency towards decrease of the HbA1c was
observed for the remaining 4 DPP-4 inhibitors administered in combination with a SGLT2
inhibitor.
Elevation of the serum HDL-C without elevation of the serum LDL-C or total cholesterol
was observed when sitagliptin was used in the combined treatment group. This combination
treatment also resulted in lowering of the body weight, BMI, and serum levels of AST,
ALT, γ-GTP and uric acid, the percent decrease of each of these being essentially
the same as that in the SGLT2 inhibitor monotherapy group. There was no consistent
trend of the effects for any of the other four DPP-4 inhibitors administered in combination
with a SGLT2 inhibitor.
It was first pointed out by Merovci et al. that SGLT2 inhibitor therapy with concomitant
use of an insulin-secretion-facilitating DPP-4 inhibitor would be effective in the
treatment of diabetes mellitus, since SGLT2 inhibitors promote glucagon secretion
to increase endogenous glucose production [11].
There are reports suggesting the greater HbA1c-lowering potency of combined SGLT2
inhibitor+DPP-4 inhibitor therapy as compared to monotherapy with either a SGLT2 inhibitor
or a DPP-4 inhibitor [12]
[13]. The baseline blood HbA1c values of the subjects in these studies were, however,
8-9%, indicating poor glycemic control.
Regarding the uric acid, it is generally recognized that gender-related differences
exist in the serum uric acid levels. In view of this, we analyzed the serum uric acid
data in the present series separately for male patients and female patients. Specifically,
the baseline serum uric acid level was significantly higher in the male than in the
female patients in both the SGLT2 inhibitor monotherapy and combined SGLT2 inhibitor
plus DPP4 inhibitor groups (P<0.05). In the SGLT2 inhibitor monotherapy group, the
serum uric acid level decreased in both male and female patients. In the combined
SGLT2 inhibitor plus DPP4 inhibitor (sitagliptin, vidagliptin or alogliptin) group,
and the serum uric acid levels significantly decreased in both male and female patients.
On the other hand, combined SGLT2 inhibitor+anagliptin significantly decreased the
uric acid level in male patients, and combined SGLT2 inhibitor+linagliptin significantly
decreased the uric acid level in female patients.
The present study results confirm that the serum uric acid levels decreased in response
to both the study treatments in male and/or female patients. In regard to the mechanism
underlying such reduction of the uric acid level, it has been considered that the
high urinary glucose level resulting from SGLT2 inhibition suppresses the reabsorption
of uric acid into the blood via GLUT9 isoform 2 (SLC2A9) in the proximal tubule, promoting
excretion of uric acid into the urine [14].
The mean HbA1c values in the subjects included in this study were in the range of
6.8–7.5%, suggesting that the patients showed relatively good control of the blood
glucose levels.
Our present findings suggest that combined SGLT2 inhibitor+DPP-4 inhibitor therapy
has a rather modest additive or synergistic effect in patients with relatively good
glycemic control with blood HbA1c values of around 7%. In terms of the effects on
the glucose parameter, i. e., HbA1c values, concurrent administration of sitagliptin,
as compared to the other 4 DPP-4 inhibitors, with a SGLT2 inhibitor yielded the best
results. However, since the number of study subjects was different in the groups,
therefor we performed power analysis. The result of the power analysis indicated that
effect size (d) and power (1-β) in the SGLT2 inhibitor plus sitagliptin were greater
than other combined SGLT2 inhibitor+DPP4 inhibitor. The analysis showed that the combined
SGLT2 inhibitor plus sitagliptin regimen was superior in efficacy to any of the other
four treatment regimens examined in this study.
This was a retrospective study. Therefore, no particular criteria were set for the
grouping. There was no significant inter-group difference in the pre-treatment baseline
body weight or HbA1c level. The limitations of this study were: (1) its non-randomized,
and (2) its small sample size. We plan to conduct a larger-scale study in the near
future.
