(Liu - ) Empagliflozin Vs Linagliptin (+insulin)
(Liu - ) Empagliflozin Vs Linagliptin (+insulin)
(Liu - ) Empagliflozin Vs Linagliptin (+insulin)
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Original article
A R T I C L E I N F O A B S T R A C T
Article history: Aims. – Sodium–glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase (DPP)-4 inhibitors
Received 7 June 2020 added to insulin regimens in patients with type 2 diabetes mellitus (T2DM) can improve glycaemic
Received in revised form 5 August 2020 control. This study compared the efficacy and safety of empagliflozin and linagliptin added to premixed
Accepted 8 August 2020
insulin therapy in patients with poorly controlled T2DM.
Available online 19 August 2020
Methods. – In this 24-week, open-label, parallel-design randomized controlled trial, patients with
poorly controlled T2DM despite a premixed insulin regimen were randomized to receive 5 mg of
Keywords:
linagliptin (n = 53) or 25 mg of empagliflozin (n = 53) for 24 weeks.
DPP4 inhibitor
Insulin
Results. – At week 24, changes in glycated haemoglobin (HbA1c) from baseline were 0.06 0.17% and
SGLT2 inhibitor 1.01 0.16% in the linagliptin and empagliflozin groups, respectively, and the mean treatment HbA1c
Type 2 diabetes difference was 0.88% (95% CI: 1.33, 0.43). At week 24, the empagliflozin group showed significant
reductions, compared with the linagliptin group, in fasting plasma glucose (P < 0.001), body weight
(P < 0.001), systolic blood pressure (P = 0.003) and total daily insulin dose (P = 0.042). Hypoglycaemia was
reported to be slightly, and not significantly, higher in the empagliflozin group vs linagliptin group (30.2% vs
22.6%, respectively; P = 0.51). Similar percentages of patients (1.9%) had urinary tract infections in the two
groups.
Conclusion. – In Asian patients with inadequately controlled T2DM while taking premixed insulin, the
addition of empagliflozin for 24 weeks provided better glycaemic control and greater reductions in body
weight and systolic blood pressure than the addition of linagliptin.
Clinical Trial Registration #: NCT03458715.
C 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-
Introduction
Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; BMI, body mass
index; CI, confidence interval; DBP, diastolic blood pressure; DPP-4, dipeptidyl
peptidase 4; eGFR, estimated glomerular filtration rate; FPG, fasting plasma
Type 2 diabetes mellitus (T2DM) is a progressive disease that
glucose; HbA1c, glycated haemoglobin; HDL-C, high-density lipoprotein cholester- involves b-cell dysfunction, and b-cell failure requires insulin to
ol; ITT, intention to treat; LDL-C, low-density lipoprotein cholesterol; OADs, oral achieve optimal glycaemic control. Basal insulin and premixed
antidiabetic drugs; SBP, systolic blood pressure; SD, standard deviation; SGLT2, insulin play important roles in poorly controlled T2DM [1,2]. If
sodium–glucose cotransporter 2; T2DM, type 2 diabetes mellitus; UACR, urine
prandial glycaemic levels are inadequately controlled by basal
albumin-to-creatinine ratio.
* Corresponding author at: MacKay Memorial Hospital, No. 92, Section 2,
insulin, then basal/prandial regimens or premixed insulin can be
Zhongshan North Road, Taipei City 10449, Taiwan. used to further lower glycated haemoglobin (HbA1c) [3,4]. Never-
E-mail address: [email protected] (Y.-H. Zeng). theless, many patients with T2DM are still not able to achieve their
https://doi.org/10.1016/j.diabet.2020.08.001
1262-3636/ C 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
S.-C. Liu et al. / Diabetes & Metabolism 47 (2020) 101184
Fig. 1. Flow chart of patient recruitment into the study. ITT, intention-to-treat.
or 25 mg of empagliflozin (n = 53), of whom 103 (97%) completed Mean changes in systolic blood pressure (SBP) from baseline were
all 24 weeks of treatment. Baseline characteristics were balanced 1.4 1.2 mmHg with linagliptin (P = 0.247) and 5.0 1.6 mmHg with
across the two groups (Table 1), except for a male predominance empagliflozin (P = 0.003). The mean difference between the linagliptin
and higher C-peptide levels in the empagliflozin group. Mean and empagliflozin groups in terms of SBP-adjusted mean change from
patient age was 59.1 10.2 years in the linagliptin group, and
58 10.4 years in the empagliflozin group. At baseline, HbA1c values Table 1
were 9.0 1.2% and 9.4 1.5% in the linagliptin and empagliflozin Participants’ baseline characteristics.
groups, respectively. The mean daily insulin dose was
Linagliptin Empagliflozin
66.2 22.5 units in the linagliptin group and 65.5 23.1 units in (n = 53) (n = 53)
the empagliflozin group. Most of the patients recruited for the study
Male gender [n (%)] 15 (28.3) 26 (49.1)*
had normal kidney function (mean eGFR: 83.9 34.9 mL/min/ Age (years) 59.1 10.2 58 10.4
1.73 m2 in the linagliptin group, and 81.4 26.7 mL/min/1.73 m2 Diabetes duration (years) 11.1 6.2 12.6 6.1
in the empagliflozin group). History of hypertension [n (%)] 28 (52.8) 31 (58.5)
History of hyperlipidaemia [n (%)] 49 (92.5) 45 (84.9)
Weight (kg) 70.6 10.5 71.5 12.5
Efficacy
Body mass index (kg/m2) 27.9 3.5 27.8 4.8
Systolic blood pressure (mmHg) 131.3 13.0 133.0 10.2
At week 24, mean HbA1c changes from baseline were Diastolic blood pressure (mmHg) 73.9 8.4 76.5 8.3
0.06 0.17% with linagliptin (P = 0.713) and 1.01 0.16% with HbA1c (%) 9.0 1.2 9.4 1.5
empagliflozin (P < 0.001), with a significantly greater reduction in the Fasting plasma glucose (mg/dL) 173.9 60.8 186.6 73.5
Creatinine (mg/dL) 0.85 0.23 0.91 0.27
empagliflozin group [mean difference: 0.88%, 95% confidence eGFR (mL/min/1.73 m2) 83.9 34.9 81.4 26.7
interval (CI): 1.33, 0.43; P < 0.001; Table 2; Fig. 2A and B]. UACR (mg/g) 145 277 233 498
Mean FPG changes from baseline were 12.6 8.2 mg/dL with Alanine aminotransferase (IU/L) 27.6 24.2 22.9 17.2
linagliptin (P = 0.129) and 54.3 10.4 mg/dL with empagliflozin Uric acid (mg/dL) 5.1 1.2 5.5 1.7
Total cholesterol (mg/dL) 188.5 42.8 185.7 42.8
(P < 0.001), with a significantly greater reduction in the empagliflozin
Triglyceride (mg/dL) 182 170 160 117
group (mean difference: 57.6 mg/dL, 95% CI: 78.74, 36.44; LDL cholesterol (mg/dL) 99.9 29.0 100.6 31.5
P < 0.001; Table 2, Fig. 2C). HDL cholesterol (mg/dL) 49.2 10.3 52.0 13.7
There was a non-significant increase in body weight from Blood beta-ketone (mmol/L) 0.19 0.14 0.21 0.24
baseline with linagliptin (0.2 0.2 kg; P = 0.349), whereas a C-peptide (ng/mL) 1.26 0.78 1.67 0.99*
Metformin dose (mg) 668 400 571 224
reduction in body weight was observed with empagliflozin Total insulin dose (units/day) 66.2 22.5 65.5 23.1
( 1.5 0.4 kg; P < 0.001). The mean difference between the lina-
Data are mean SD unless otherwise indicated.
gliptin and empagliflozin groups in terms of mean body weight *
P < 0.05.
change from baseline at 24 weeks was 1.8 kg (95% CI: 2.63, 0.89; HbA1c, glycated haemoglobin; eGFR, estimated glomerular filtration rate; LDL/HDL,
P < 0.001; Table 2, Fig. 2D). low-density/high-density lipoprotein; UACR, urine albumin-to-creatinine ratio.
S.-C. Liu et al. / Diabetes & Metabolism 47 (2020) 101184
Table 2
Comparison of trial outcome measures with empagliflozin vs linagliptin added to premixed insulin.
HbA1c (%) 9.0 (1.2) 0.06 (0.17) 0.713 9.4 (1.5) 1.01 (0.16) <0.001 0.88 ( 1.33, 0.43) <0.001
FPG (mg/dL) 173.9 (60.8) 12.6 (8.2) 0.129 186.6 (73.5) 54.3 (10.4) <0.001 57.6 ( 78.74, 36.44) <0.001
Weight (kg) 70.6 (10.5) 0.2 (0.2) 0.349 71.5 (12.5) 1.5 (0.4) <0.001 1.8 ( 2.63, 0.89) <0.001
SBP (mmHg) 131.3 (13.0) 1.4 (1.2) 0.247 133.0 (10.2) 5.0 (1.6) 0.003 6.0 ( 9.80, 2.15) 0.003
DBP (mmHg) 73.9 (8.4) 1.5 (1.1) 0.188 76.5 (8.3) 2.0 (1.3) 0.117 2.3 ( 5.31, 0.70) 0.132
Creatinine (mg/dL) 0.85 (0.23) 0.03 (0.01) 0.018 0.91 (0.27) 0.05 (0.02) 0.065 0.02 ( 0.04, 0.07) 0.597
eGFR (mL/min/1.73 m2) 83.9 (34.9) 2.9 (1.8) 0.108 81.4 (26.7) 2.4 (2.0) 0.233 0.3 ( 5.01, 5.65) 0.905
UACR (mg/g) 145.2 (276.9) 3.4 (30.0) 0.910 232.5 (498.1) 50.3 (27.6) 0.075 34.4 ( 108.08, 39.34) 0.357
ALT (IU/L) 27.6 (24.2) 0.2 (2.0) 0.916 22.9 (17.2) 1.5 (1.5) 0.328 2.9 ( 6.82, 1.05) 0.149
Uric acid (mg/dL) 5.1 (1.2) 0.25 (0.10) 0.010 5.5 (1.7) 0.20 (0.20) 0.328 0.18 ( 0.27, 0.62) 0.439
Total cholesterol (mg/dL) 188.5 (42.8) 0.7 (4.7) 0.881 185.7 (42.8) 1.7 (6.1) 0.779 0.5 ( 13.43, 14.48) 0.940
Triglyceride (mg/dL) 181.8 (170.1) 18.1 (17.7) 0.311 160.2 (116.5) 12.6 (13.1) 0.344 37.7 ( 78.06, 2.64) 0.067
LDL cholesterol (mg/dL) 99.9 (29.0) 1.6 (3.3) 0.631 100.6 (31.5) 2.2 (4.4) 0.618 3.3 ( 6.66, 13.31) 0.510
HDL cholesterol (mg/dL) 49.2 (10.3) 2.5 (0.9) 0.007 52.0 (13.7) 1.6 (1.3) 0.215 1.5 ( 1.47, 4.46) 0.319
Blood beta-ketone (mmol/L) 0.19 (0.14) 0.02 (0.04) 0.605 0.21 (0.24) 0.05 (0.03) 0.176 0.04 ( 0.06, 0.13) 0.429
C-peptide (ng/mL) 1.26 (0.78) 0.17 (0.09) 0.052 1.67 (0.99) 0.12 (0.43) 0.784 0.02 ( 0.86, 0.90) 0.961
Total insulin dose (units/day) 66.2 (22.5) 1.7 (1.0) 0.084 65.5 (23.1) 1.0 (0.9) 0.274 2.7 ( 5.21, 0.10) 0.042
a
Data are means (SD).
b
Data are means (SE) or mean difference (95% CI).
DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; HbA1c, glycated haemoglobin; LDL/HDL, low-density/high-density
lipoprotein; SBP, systolic blood pressure; UACR, urine albumin-to-creatinine ratio.
baseline at 24 weeks was 6.0 mmHg (95% CI: 9.8, 2.15; P = 0.003; premixed insulin therapy in patients with poorly controlled T2DM.
Table 2, Fig. 2E). The results reveal that treatment with empagliflozin for 24 weeks
Both treatment groups showed non-significant changes in daily led to a significant reduction in HbA1c, FPG, body weight and SBP,
insulin dose over the 24 weeks of the study (1.7 1.0 U/day in the and a mild decrease in total daily insulin dose, compared with
linagliptin group, 1.0 0.9 U/day in the empagliflozin group), with linagliptin.
significantly greater insulin dose reductions with empagliflozin Our study has also shown that the addition of empagliflozin to
compared with linagliptin ( 2.7 U/day, 95% CI: 5.21, 0.10; premixed insulin therapy reduced HbA1c by 1.01% after 24 weeks.
P = 0.042; Table 2, Fig. 2F). This is similar to reports from earlier trials wherein empagliflozin
reduced HbA1c by 0.78–1.02% at weeks 16–18 in patients with
Safety inadequately controlled T2DM on regimes of basal insulin or
multiple daily injections of insulin [12]. In addition, direct
Data on AEs are presented in Table 3; the frequency of AEs during comparisons between the SGLT2 and DPP-4 inhibitors in the
the 24-week study period was similar in the two treatment groups. present study reveal that HbA1c reduction at week 24 was
No deaths were reported during treatment. However, one AE, significantly greater with empagliflozin than with linagliptin.
diabetic ketoacidosis, led to discontinuation of the study in the These results are consistent with an indirectly comparative
empagliflozin group: the probable cause was cessation of insulin meta-analysis [16] that reported that SGLT2 inhibitors were
therapy. In addition, one male patient experienced an event superior to DPP-4 inhibitors for HbA1c reduction (weighted
consistent with UTI during empagliflozin treatment, and urine mean difference: 0.24%, 95% CI: 0.43, 0.05%; P = 0.02). Such a
culture confirmed Acinetobacter baumannii infection, whereas one difference was also observed when considering an indirect
female patient experienced UTI during linagliptin treatment, and comparison between SGLT2 inhibitors and DPP-4 inhibitors
blood and urine cultures showed Escherichia coli infection. However, added to metformin [17]. Although one previous study [18]
neither of these two events led to discontinuation of the study drugs. reported that the addition of linagliptin to basal insulin and
Hypoglycaemia-related events were observed in 12 patients metformin improved glycaemic control, in the present study,
(22.6%) in the linagliptin group and 16 patients (30.2%) in the there were no such significant changes in HbA1c in the linagliptin
empagliflozin group, but these rates were not statistically group. One possible reason for this discrepancy could be that, as
significantly different (P = 0.51). Five events in each treatment the participants recruited for our study were predominantly
group were classified as documented symptomatic hypoglycae- patients with inadequately controlled T2DM using premixed
mia, while the others were classified as probable symptomatic insulin, they had markedly impaired b-cell function and required
hypoglycaemia. Ultimately, no severe hypoglycaemia was repor- larger total daily insulin dosages at baseline. More important, the
ted, and no patients discontinued the study due to hypoglycaemia. glucose-lowering efficacy of SGLT2 inhibitors is thought to
Changes in laboratory values from baseline are shown in Table depend on the filtered glucose load and, as such, will decrease
2. No major differences in mean changes from baseline for with deterioration of GFR [10,19]. Indeed, empagliflozin has
creatinine, eGFR, alanine aminotransferase (ALT), uric acid, total proved more efficacious in reducing HbA1c levels in patients with
cholesterol, high-density lipoprotein (HDL) cholesterol, low- preserved GFR [20]. As per our study design, patients with
density lipoprotein (LDL) cholesterol and triglycerides were noted eGFR < 45 mL/min/1.73 m2 were excluded due to the known
with either linagliptin or empagliflozin at week 24. indications for empagliflozin use. Thus, our results are more
applicable to patients with preserved GFR and use of the higher
Discussion dose of empagliflozin (25 mg).
In contrast to the (non-significant) body weight gain observed
The present study compared the efficacy and safety of an SGLT2 in the linagliptin group, body weight in the empagliflozin group
inhibitor (empagliflozin) and DPP-4 inhibitor (linagliptin) added to was reduced by 1.5 kg. Weight gain can worsen insulin resistance,
S.-C. Liu et al. / Diabetes & Metabolism 47 (2020) 101184
Fig. 2. Efficacy parameters with 5-mg linagliptin compared with 25-mg empagliflozin: (A) mean HbA1c at baseline and at 12 and 24 weeks; (B) change in mean HbA1c after
24 weeks; (C) change in mean fasting glucose after 24 weeks; (D) change in mean body weight after 24 weeks; (E) change in mean systolic blood pressure after 24 weeks; and
(F) change in mean total insulin doses after 24 weeks. P values were derived using analysis of covariance (ANCOVA) to evaluate treatment differences.
causing the patient to require higher insulin doses that, in turn, for cases of severe hyperglycaemia or hypoglycaemia, whereas a
lead to more weight gain [21]. The fact that empagliflozin is slight increment in insulin doses was observed in the linagliptin
beneficial for weight control is yet another reason to consider its group. In addition, empagliflozin resulted in a greater reduction of
use as an add-on to premixed insulin. In our empagliflozin group, SBP than linagliptin, similar to the findings of a previous study, the
there were minimal reductions in total daily insulin doses due to mechanism of which may be related to weight loss, osmotic
the lack of proactive adjustment of insulin doses by protocol except diuresis and/or reduced arterial stiffness [22,23].
S.-C. Liu et al. / Diabetes & Metabolism 47 (2020) 101184
Table 3
Safety assessment for up to 24 weeks of follow-up.
The incidence of hypoglycaemia was not significantly higher in to non-Asian patients should be viewed with caution. Finally, the
the empagliflozin group than in the linagliptin group and was number of study participants was relatively small, and large-scale
similar to that seen in previous trials [11–13]. The possible long-term RCTs are now needed to confirm the findings of our
mechanism behind the lower hypoglycaemic rate with linagliptin present study.
may be related to the glucose-dependent enhancement of insulin In conclusion, this study was the first to directly compare an
secretion [24] and greater a-cell sensitivity of DPP-4 inhibitors to SGLT2 inhibitor and DPP-4 inhibitor as add-on therapeutic options
hypoglycaemia [25,26]. However, diabetic ketoacidosis, an AE, led for T2DM patients who are already receiving premixed insulin
to discontinuation of some study patients in the empagliflozin therapy. In Asian patients with inadequately controlled T2DM
group: the probable cause was the interruption of insulin use despite a premixed insulin regimen, the addition of empagliflozin
during holiday travel. Moreover, there was no significant differ- can result in better effects than the addition of linagliptin in terms
ence in mean levels of blood ketone bodies between the two of glycaemic control, body weight, SBP and total daily insulin
treatment groups, which may be explained by the absence of doses. Moreover, no unexpected safety or tolerability issues were
insulin dose decreases in the empagliflozin group. identified with empagliflozin treatment.
A UTI was experienced in one patient (1.9%) in each treatment
Disclosure of interest
group, which is lower than the rate observed in other clinical trials
[11–13]; the possible reasons for this could be the small study All authors declare that: (i) no support, financial or otherwise, was received from
population size and short duration of the present study. A previous any organization that may have had an interest in the submitted work; and (ii) no
other relationships or activities have influenced the performance of this study.
study found that reductions in ALT with empagliflozin were more
prominent in participants with the highest ALT levels at baseline
and minimal in those with the lowest levels at baseline [27]. In our Contributors
present study, ALT levels at baseline in the empagliflozin group
were within the normal range and, therefore, there were no S.-C.L. conceived the study and designed the trial. Y.-H.Z.
significant reductions in ALT levels in contrast to the reports of conducted the trial investigation and collected data. C.-C.L. was
other studies [28]. responsible for medical oversight during the trial. Y.-H.Z.
Although a small decrease in eGFR was observed at week 24 in performed all data analyses and interpreted the results. F.-J.S
both our treatment groups, empagliflozin slowed the decline in checked all of the statistical analyses. All authors critically
eGFR and decreased albuminuria compared with a placebo in Asian reviewed this report and approved the study. S.-C.L. and Y.-H.Z.
patients in the BI 10773 (Empagliflozin) Cardiovascular Outcome took the final decision to submit this final version of the
Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG manuscript for publication.
OUTCOME) trial [29]. In the Cardiovascular Safety and Renal
Microvascular Outcome Study with Linagliptin (CARMELINA) Acknowledgements
randomized clinical trial [30], progression of albuminuria was
less frequently seen in the linagliptin group than in the placebo We are grateful to the trial investigators, staff and participants
group. Overall, there was no increased risk of renal function for their invaluable contributions.
deterioration with either of these two drugs.
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