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Efficacy and Safety of Pioglitazone Versus Glimepiride After Metformin and Alogliptin Combination Therapy
Efficacy and Safety of Pioglitazone Versus Glimepiride After Metformin and Alogliptin Combination Therapy
Efficacy and Safety of Pioglitazone Versus Glimepiride After Metformin and Alogliptin Combination Therapy
Drug/Regimen
Diabetes Metab J 2020;44:67-77
https://doi.org/10.4093/dmj.2018.0274
pISSN 2233-6079 · eISSN 2233-6087 JOURNAL
D IA B ET E S & MET A BOL I SM
Background: There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus
(T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of
piogli- tazone or glimepiride when added to metformin plus alogliptin treatment for T2DM.
Methods: This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean
patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to
also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted
based on the investi- gator’s judgement.
Results: Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period
(pio- glitazone: –0.81%, P<0.001; glimepiride: –1.05%, P<0.001). However, the pioglitazone-treated group exhibited
significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model
assessment of insulin re- sistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin
markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001).
Conclusion: Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of
pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance,
and hypoglycemia risk) relative to the addition of glimepiride.
Corresponding author: In Joo Kim https://orcid.org/0000-0003-1307-6146 This is an Open Access article distributed under the terms of the Creative Commons
Division of Endocrinology and Metabolism, Department of Internal Medicine and Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/)
Biomedical Research Institute, Pusan National University Hospital, Pusan which permits unrestricted non-commercial use, distribution, and reproduction in any
National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan 49241, medium, provided the original work is properly cited.
Korea
E-mail: injkim@pusan.ac.kr
*Jeong Mi Kim and Sang Soo Kim contributed equally to this study as first
authors.
†
Current affiliation: Department of Internal Medicine, Isam Hospital, Busan, Copyright © 2020 Korean Diabetes Association https://e-
Korea dmj.org
Received: Dec. 21, 2018; Accepted: Feb. 17, 2019
Kim JM, et al.
METHODS
Study design
This multicenter, randomized, open-label, parallel design,
68 Diabetes Metab J 2020;44:67-77 https://e-dmj.org
Dual combination treatment and third-line therapy
Data collection
The baseline and follow-up examinations included a
physical examination, laboratory testing, medical review,
and an in- person interview to collect information
regarding medical conditions. Self-reported historical data
(“yes” or “no”) regard- ing diabetic retinopathy and
diabetic neuropathy were collect- ed at the screening. The
conventional method was used to cal- culate BMI (kg/m2).
Serum specimens were typically collected after an 8-hour
overnight fast and stored at –70°C after pro- cessing.
Treatments
Participants were randomly assigned to receive either
piogli- tazone (15 mg/day) or glimepiride (2 mg/day) in
addition to their current treatment using metformin plus
alogliptin. After 12 weeks of treatment, the doses could be
adjusted to 30 mg/day for pioglitazone or 4 mg/day for
glimepiride, based on the in- vestigator’s decision.
135 Randomized
69 Intention-to-treat population Pioglitazone 15 mg every
66 Intention-to-treat
day population Glimepiride 2 mg every day
7 Withdrawal of consent
2 Adverse event/serious adverse event 1 Investigator’s judgement 7 Withdrawal of consent 1 Investigator’s judgement
1 Did not meet inclusion/exclusion criteria
At week 12
At week 12 Glimepiride 1 mg every day in 7 patients Glimepiride 3 mg every day in 3 patients Glimepiride 4 m
Pioglitazone 30 mg every day in 13 patients
Glimepiride Pioglitazone
Glimepiride Pioglitazone
9
a 6
8
7 5
Mean HbA1c (%)
6 P=0.029 P=0.630
Mean HOIMA-IR
P=0.054
5 4
4
3 3
2
2
1
0
1
0 12 26 0 12 26
Time (wk) A Time (wk) B
140
50 130
120
45 P=0.007
110
40 100
90
35
80
0 12 26 0 12 26
Time (wk) C Time (wk) D
Fig. 2. Changes in the measured variables at 12 weeks and 26 weeks. Mean±standard error values at baseline, 12 weeks, and
26 weeks were calculated for (A) glycosylated hemoglobin (HbA1c), (B) homeostatic model assessment of insulin
resistance (HOMA-IR), (C) high density lipoprotein cholesterol (HDL-C), and (D) triglycerides during 26-week treatments
using glimepiride (closed triangles) or pioglitazone (closed quadrangles) for patients with type 2 diabetes mellitus who were
concur- rently receiving combination therapy using alogliptin and metformin. aP<0.05.
magnitude of the change in HDL-C levels when we
upper respiratory tract infection (10/69, 14.49%) in the
compared the pioglitazone and glimepiride groups in the PP
piogli- tazone group and hypoglycemia (16/66, 24.24%) in
population (5.57±9.58 mg/dL vs. 0.94±8.47 mg/dL,
the glimepiride group. The glimepiride group was more
P=0.007) (Table 2, Fig. 2C).
likely than the pioglitazone group to experience AEs that
Triglyceride levels also decreased significantly in both
were rated as be- ing possibly/probably/definitely related to
groups (pioglitazone: 132.84±72.15 mg/dL to 113.02±51.47
the study drug (i.e., adverse drug reactions) (pioglitazone:
mg/dL, P=
eight patients [11.59%], glimepiride: 23 patients [34.85%];
0.034; glimepiride: 146.17±71.58 mg/dL to 130.72±67.03
P=0.003). The most fre- quently reported adverse drug
mg/dL, P=0.043). However, there was no significant inter-
reaction was hypoglycemia, which was significantly more
group differ- ence in the magnitude of these changes (–
common in the glimepiride group (pioglitazone: 1/69
19.83±69.69 mg/dL vs. –15.45±56.76 mg/dL, P=0.711)
[1.45%], glimepiride: 14/66 [21.21%]; P= 0.001). Two
(Table 2, Fig. 2D).
patients in the pioglitazone group discontinued the study
because of AEs. Two patients in the pioglitazone group
Safety
reported experiencing trauma-related fractures (serious
Table 3 shows the safety outcomes for each treatment. A
AEs), with one case involving a femoral fracture after a fall
total of 122 patients (90.4%) reported at least one
from second-floor stairs and the second case involving a
treatment-emer- gent AE (pioglitazone: 64/69 patients
toe fracture after unintentionally kicking a table leg. A third
[92.75%], glimepiride: 58/66 patients [87.88%]; P=0.504).
pa-
The most frequent AEs were
DISCUSSION
CONFLICTS OF INTEREST
AUTHOR CONTRIBUTIONS
ORCID
ACKNOWLEDGMENTS
None
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