European Journal of Preventive Cardiology (2022) 00, 1–14 FULL RESEARCH PAPER

https://doi.org/10.1093/eurjpc/zwac312 Heart failure and cardiomyopathies

Glimepiride use is associated with reduced

cardiovascular mortality in patients with type 2

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

diabetes and chronic heart failure:
a prospective cohort study
Wu He 1†, Gang Yuan2†, Yu Han1, Yongcui Yan1, Gen Li1, Chengcheng Zhao1,
Jingshan Shen3, Xiangrui Jiang3, Chen Chen1, Li Ni1*, and Dao Wen Wang1*
1
Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Genetics and
Molecular Mechanisms of Cardiological Disorders, 1095# Jiefang Ave., Wuhan 430030, China; 2Department of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji
Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China; and 3CAS Key Laboratory of Receptor Research, and Drug Discovery and
Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road., Shanghai, 201203, China

Received 17 October 2022; revised 4 December 2022; accepted 23 December 2022; online publish-ahead-of-print 27 December 2022

Aims Glimepiride has good cardiovascular safety. However, whether glimepiride benefits clinical cardiovascular outcomes is
unclear.
............................................................................................................................................................................................
Methods A total of 21 451 inpatients with type 2 diabetes (T2D) and chronic heart failure (CHF) were analysed, including 638 who
and results received glimepiride treatment and 20 813 who did not. Propensity score matching yielded 509 pairs (glimepiride and non-
glimepiride groups), and both groups were followed up. Kaplan–Meier and Cox regression analyses were used to compare
all-cause mortality, cardiovascular mortality, hospitalizations and emergency visits for heart failure, and hospitalizations for
acute myocardial infarction or stroke. During follow-up, the all-cause mortality [adjusted hazard ratio (HR), 0.47; 95% con-
fidence interval (CI), 0.35–0.63; P < 0.001], cardiovascular mortality (adjusted HR, 0.34; 95% CI, 0.24–0.48; P < 0.001), and
number of hospitalizations and emergency visits for heart failure (adjusted HR, 0.42; 95% CI, 0.36–0.50; P < 0.001) and hos-
pitalizations for acute myocardial infarction or stroke (adjusted HR, 0.53; 95% CI, 0.38–0.73; P < 0.001) were significantly
lower in the glimepiride group; the conclusion remained similar in all subgroups. Furthermore, high-dose glimepiride use
(2–4 mg/day) was associated with lower cardiovascular mortality than low-dose (1 mg/day) (adjusted HR, 0.55; 95% CI,
0.31–0.99; P = 0.047). Glimepiride exhibited good molecular docking with soluble epoxide hydrolase (sEH) and increased
the level epoxyeicosatrienoic acid (EET).
............................................................................................................................................................................................
Conclusion Long-term continuous glimepiride use is associated with better survival, fewer hospitalizations and emergency visits for
heart failure, and fewer hospitalizations for acute myocardial infarction or stroke in patients with T2D and CHF. High-
dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride. The cardiovascular protective
effect of glimepiride may be related to the EET level increase through sEH inhibition.
............................................................................................................................................................................................
Trial ClinicalTrials.gov NCT05538819. https://www.clinicaltrials.gov/ct2/show/NCT05538819
registration
-Lay
- - - - - -summary
-------------------------------------------------------------------------------------------------------------------------------------------------------
Long-term continuous glimepiride use is associated with better survival, fewer hospitalizations, and emergency visits for
heart failure. High-dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride.

* Corresponding author. Tel: +86 134 0719 2299, Fax: +86 27 6937 8422, Email: dwwang@tjh.tjmu.edu.cn (D.W.W.), Email: nili@tjh.tjmu.edu.cn (L.N.)
†
These authors contributed equally to this article.
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits
non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
2 W. He et al.
Graphical Abstract
............................................................................................................................................................................................
Keywords Glimepiride • Type 2 diabetes • Chronic heart failure • Mortality • Cardiovascular mortality
Introduction
Diabetes is a metabolic disease characterized by chronic hypergly-
caemia for varying reasons and is a major chronic disease affecting
several individuals worldwide.1 According to the International
Diabetes Federation, the number of patients with diabetes world-
wide has reached 537 million in 2021 and is expected to increase
to ∼783 million by 2045. Patients with diabetes have poorer cardio-
vascular outcomes and prognosis and longer hospital stays than
those without.2
Thirty years ago, Dzau and Braunwald3 introduced the concept of a con-
tinuum of cardiovascular diseases and defined them as a series of events
caused by numerous related and unrelated risk factors, thus developing
to end-stage heart disease through many pathophysiological pathways
and processes. The continuum of cardiovascular diseases begins with dia-
betes, hypertension, and dyslipidaemia, which can eventually lead to chron-
ic heart failure (CHF) and cardiovascular mortality.3 Patients with type 2
diabetes (T2D) have a high incidence of clinical heart failure and subclinical
left ventricular dysfunction.4 Although treatment strategies for hypergly-
caemia have somewhat progressed, the possibility of heart failure caused
by T2D remains high as the prevalence of hyperglycaemia increases and
the population ages.5 T2D is a risk factor for CHF events and increases
the morbidity and mortality risks in patients with CHF.6 CHF is also the
most common cardiovascular complication of T2D, with a higher inci-
dence than myocardial infarction or stroke.7 T2D and CHF share a com-
mon pathophysiological mechanism in patients with diabetes and heart
failure; therefore, managing their synergistic effects is important.6
Although stable and continuous glycaemic control, rather than intensive
hypoglycaemia, may improve the prognosis of patients with T2D and
CHF,8 not all hypoglycaemic drugs can improve cardiovascular prognosis.9
Additionally, the cardiovascular benefits of some hypoglycaemic drugs
have long exceeded glycaemic control;10 therefore, the choice of hypogly-
caemic drugs may affect CHF prognosis and related cardiovascular
outcomes.2
Since the first sulfonylurea (SU; tolbutamide) was commercially
launched in Germany in 1956, SUs, as the oldest oral hypoglycaemic
Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023
drugs, have been developed for three generations and are commonly
used for patients with T2D.11,12 In 2008, the US Food and Drug
Administration and European Drug Administration required cardiovas-
cular safety certification for all hypoglycaemic drugs, resulting in in-
creased related clinical trials.7 Currently, data on the relationship
between SUs and cardiovascular outcomes are limited, and the cardio-
vascular effects remain controversial in observational studies.13,14
Third-generation SUs, such as glimepiride, are widely used for treating
T2D because of their definite hypoglycaemic efficacy, relatively low risk
of hypoglycaemia, convenient daily use, and low price.11 Glimepiride has
good cardiovascular safety according to randomized controlled trials
(RCTs).15 The proportion of SUs used in patients with T2D and
CHF is as high as 60.4%.16 Although some studies have shown that
SUs are neutral in terms of hospitalization rates and adverse cardiovas-
cular events in patients with CHF,17 no standard RCT of glimepiride has
been conducted to study its effect on the prognosis of patients with
T2D and confirmed CHF.7 In addition, our team has focused on the
study of arachidonic acids—epoxygenases/epoxyeicosatrienoic acids
(EETs)—soluble epoxide hydrolase (sEH)/dihydroxyeicosatrienoic
acids (DHETs) system for many years. We found that glimepiride might
have the effects of inhibiting sEH to increase EET and reduce DHET.
Increased EET production exerts protective effects on the heart,18–20
indicating the potential cardiovascular effect of glimepiride.
This prospective cohort study aimed to evaluate the effects of glime-
piride on the clinical outcomes of patients with T2D and CHF and pro-
vide theoretical evidence for the clinical application of glimepiride in
these patients. We also predicted the molecular docking of glimepiride
with sEH and evaluated the effects of glimepiride on the EET level to
explore the potential mechanism.
Methods
Study design and patient information
In this cohort study, we collected information on inpatients clinically diag-
nosed with T2D and CHF [left ventricular ejection fraction (LVEF):
Glimepiride use is associated with reduced cardiovascular mortality in patients with T2D and CHF
<50%; N-terminal pro-brain natriuretic peptide (NT-proBNP) level:
>125 pg/mL; and/or left ventricular diameter (LVD): ≥50 mm] at the
Tongji Hospital of Tongji Medical College, Huazhong University of
Science and Technology from 1 April 2012 to 1 April 2022. All patients
were re-diagnosed according to the Classification and Diagnosis of
Diabetes: Standards of Medical Care in Diabetes-202221 and 2022 AHA/
ACC/HFSA Guideline for the Management of Heart Failure;22 those who did
not meet the diagnostic criteria, lacked echocardiographic and
NT-proBNP data, aged <18 years or used SUs other than glimepiride
were excluded. All data were collected from the electronic medical record
database of the Tongji Hospital.
This study included 21 451 inpatients aged >18 years with T2D and CHF.
According to regular glimepiride use (continuous use of glimepiride after
discharge), the patients were divided into glimepiride and non-glimepiride
groups. A 1:1 propensity score matching (PSM) analysis was used to balance
the confounding factors between the glimepiride treatment and clinical out-
comes. The PSM cohort (509:509) was followed up using a telephone ques-
tionnaire directly or at an outpatient clinic at our cardiac centre. The
follow-up deadline was 1 July 2022. According to the follow-up results,
the glimepiride group was subdivided into high-dose (2–4 mg/day) and low-
dose (1 mg/day) groups.
The study was conducted in accordance with the Declaration of Helsinki
principles and approved by the Research Ethics Committee of Tongji
Medical College (no. TJ-IRB20220604). Owing to the retrospective nature
and anonymity of the study, the ethics committee waived the need for writ-
ten informed consent.
Data collection and endpoint definitions
Clinical data and laboratory results were obtained from the electronic med-
ical record database of the Tongji Hospital, which were independently ex-
amined by three researchers to obtain the basic information and baseline
data of each patient. The primary outcomes were cardiovascular mortality
and hospitalizations and emergency visits for heart failure. The secondary
outcomes were all-cause mortality and hospitalizations for acute myocar-
dial infarction or stroke. Follow-up work was conducted independently
by three researchers, and the results were reviewed and checked by an-
other researcher. Follow-up included evaluation of whether and when
the end of the event occurred. Clinical endpoints that occurred in other
hospitals or communities were also included in our follow-up.
Molecular docking of glimepiride with soluble
epoxide hydrolase and enzyme-linked
immunosorbent assay of
14,15-epoxyeicosatrienoic,
14,15-dihydroxyeicosatrienoic and
14,15-epoxyeicosatrienoic/
dihydroxyeicosatrienoic
To explore the possible docking mode and binding ability between glimepir-
ide (ligand) and sEH, we used AutoDock (version 4.2.6) to perform molecu-
lar docking based on molecular model technology and PyMOL (version
2.4.1) to visualize the docking results. A binding energy of less than
‘−5 kcal/mol’ represents a better binding interaction between molecules.23
An enzyme-linked immunosorbent assay (ELISA) was used to measure the
concentration of 14,15-DHET and further obtained the concentration of
14,15-EET and the activity of sEH of H9c2 cells according to the manual.24
Briefly, H9c2 samples should be collected and homogenized by Western/IP
lysis buffer with a final concentration of 0.1 mM of TPP (triphenylpho-
sphine, Shanghai, China). After acidification, the samples were extracted
three times with ethyl acetate and pooled the collected organic phases
and evaporate under argon gas. Then, dissolve the above dried up residue
in 20 μL of ethanol and separate them to two parts solution whose volumes
are 9 and 11 μL. Finally, 250 μL 1× sample dilution was added into the less
one to make a solution and stored at 4°C. For the other part, 11 μL of acet-
ic acid was added for EET hydrolyzing to DHET at room temperature for
18 h. After the reaction, 1.5× volume of water was put into and repeat
the extraction process mentioned above. Using the 14,15-DHET ELISA
kit to measure DHET of the two parts, the concentration of
3
14,15-DHET and 14,15-EET would be obtained, and the ratio of them
(14,15-EET/DHET) represented the activity of sEH.
Statistical analysis and mapping
Statistical analysis and mapping were performed using SPSS (version 24.0, IBM,
Armonk, NY, USA), R (version 3.5.1, R Foundation for Statistical Computing,
Vienna, Austria), and GraphPad Prism (version 9.0, San Diego, CA, USA). To
reduce the influence of confounding covariates, we performed a 1:1 PSM ana-
lysis on the observed baseline data and related treatments using a logistic re-
gression model in the R environment. The matched variables included age,
Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023
sex, smoking status, drinking status, disease history (e.g. hypertension, coronary
artery disease, cardiomyopathy, chronic obstructive pulmonary disease, chron-
ic kidney disease, and atrial fibrillation), basic vital signs (temperature, respira-
tory rate, pulse rate, and diastolic and systolic blood pressures), and cardiac
function-related indicators on admission [LVEF, LVD, NT-proBNP level,
high-sensitivity-cardiac troponin I level, and New York Heart Association
(NYHA) functional classification], diabetes-related indicators on admission
(fasting blood glucose and glycated haemoglobin/haemoglobin A1c levels),
other clinical laboratory indicators (routine blood test result, blood biochem-
istry profile, and coagulation function), and other commonly used drugs [gli-
nides, metformin, thiazolidinediones, α-glucosidase, dipeptidyl peptidase
(DPP)-4 inhibitors, sodium/glucose cotransporter-2 inhibitors, glucagon-like
peptide-1 agonists, insulin, angiotensin-converting enzyme inhibitors or angio-
tensin receptor blockers, angiotensin receptor–neprilysin inhibitors (ARNIs),
diuretic, digitalis, calcium channel blockers, antiplatelet drugs, anticoagulant
drugs, statins, and nitrates] in the glimepiride and non-glimepiride groups.
The optimal calliper width was set to 0.05.
The distribution and homoscedasticity of each dataset were tested using
D’Agostino and Pearson’s omnibus normality. Continuous variables be-
tween different groups were expressed as medians and interquartile ranges
(IQRs), and the Kruskal–Wallis test with FDR correction was performed on
non-parametric datasets. The classified variables between different groups
were expressed as counts and percentages and analysed using the chi-
square test or Fisher’s exact test. Survival analysis methods, including
Kaplan–Meier curve and Cox proportional hazard model analyses, were
used to compare the time of endpoint events between the glimepiride
and non-glimepiride groups and different subgroups.
Results
Demographic and general characteristics
This study included 28 944 patients with T2D and CHF from the Tongji
Hospital. Of them, 7493 (25.9%) were excluded. Ultimately, 21 451 pa-
tients were included, of whom 638 (men: 60.0%) and 20 813 (men:
67.3%) were classified into the glimepiride and non-glimepiride groups,
respectively (Figure 1). The baseline characteristics of the groups after
PSM are shown in Table 1. The median ages of the glimepiride (men:
66.8%) and non-glimepiride groups (men: 66.8%) were 67 (IQR, 58–
75) and 66 years (IQR, 59–74), respectively. There were no significant
differences in any baseline characteristics between the groups [n = 509
for each group, P > 0.05, standardized mean difference (SMD) < 0.1].
Laboratory indices and echocardiographic
data
The baseline cardiac function-related indicators, diabetes-related indi-
cators, and other laboratory results (routine blood test result, blood
biochemistry profile, infection-related indicators, and coagulation func-
tion) before and after PSM in the glimepiride and non-glimepiride
groups are shown in Table 2. After PSM, there was no significant differ-
ence in the examination and test results between the groups (P > 0.05,
SMD < 0.1, except for activated partial thromboplastin time).
Treatments
All patients experienced hypoglycaemia and heart failure. Except for gli-
nides, ARNIs, diuretics, digitalis, antiplatelet drugs, anticoagulant drugs,
4 W. He et al.
Figure 1 The flowchart of study design.
and statins, there were significant differences in the use of other drugs
(P < 0.05). To study the effects of glimepiride in the patients with T2D
complicated by heart failure, PSM analysis was performed on all drugs
included to balance other treatments associated with the clinical out-
comes (Table 3). All drug treatments were well matched between
the groups (P > 0.05, SMD < 0.1).
Clinical outcomes during hospitalization
Among the entire cohort, 738 patients died during hospitalization
(3.4%), of whom 7 (0.9%) in the glimepiride group and 731 in the non-
glimepiride group (3.5%) died (P = 0.001). A total of 2118 patients de-
veloped hypoglycaemia during hospitalization (9.9%, blood glucose le-
vel: <70 mg/dL), including 66 in the glimepiride group (10.3%) and
2052 in the non-glimepiride group (9.9%, P = 0.685). The median hos-
pital stay in the glimepiride and non-glimepiride groups was both 9 days
(P = 0.482). The in-hospital cardiovascular mortality rates were 3.4 and
0.9%, respectively (P < 0.001). In the PSM analysis, there was no
significant difference in the in-hospital cardiovascular mortality (P =
0.087), in-hospital hypoglycaemia incidence (P = 0.597), or hospital
stay (P = 0.242) between the groups (Table 4). The Kaplan–Meier
survival curve and multivariate analyses among all patients showed
that the glimepiride group had a lower in-hospital cardiovascular mor-
tality [log-rank P < 0.001; adjusted hazard ratio (HR), 0.47; 95% confi-
dence interval (CI), 0.22–0.98; P = 0.045] than the non-glimepiride
group (Figure 2A). The Kaplan–Meier survival curve and multivariate
Cox regression analyses among the PSM cohort showed no significant
difference in the in-hospital cardiovascular mortality between the
groups (log-rank P = 0.095) (Figure 2B).
Clinical follow-up outcomes of the
propensity score matching cohort
The primary and secondary endpoint outcomes were evaluated during
follow-up after PSM (follow-up deadline: 1 April 2022, median follow-up
period: 34.1 months). A total of 150 cardiovascular mortalities (46 and
104 in the glimepiride and non-glimepiride groups, respectively) and 586
Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023
hospitalizations and emergency visits for heart failure (238 and 348, re-
spectively) occurred in 1018 patients. The Kaplan–Meier survival curve
and proportional Cox regression analyses (none of which violated the
proportional hazard hypothesis) showed that the cardiovascular mor-
tality (log-rank P < 0.001; crude HR, 0.37; 95% CI, 0.26–0.53) and num-
ber of hospitalizations and emergency visits for heart failure (log-rank
P < 0.001; crude HR, 0.44; 95% CI, 0.37–0.52; P < 0.001) were signifi-
cantly lower in the glimepiride group than in the non-glimepiride group.
When the multivariate Cox model was used to adjust the unbalanced
confounding factors, the glimepiride group still had a lower cardiovascu-
lar mortality (adjusted HR, 0.34; 95% CI, 0.24–0.48; P < 0.001) and fewer
hospitalizations and emergency visits for heart failure (adjusted HR, 0.42;
95% CI, 0.36–0.50; P < 0.001) than the non-glimepiride group (Figure 3B
and C). Moreover, long-term glimepiride use reduced the incidence of
secondary endpoint events. Glimepiride use was associated with lower
all-cause mortality (adjusted HR, 0.47; 95% CI, 0.35–0.63; P < 0.001) and
fewer hospitalizations for acute myocardial infarction or stroke
(adjusted HR, 0.53; 95% CI, 0.38–0.73; P < 0.001) than non-glimepiride
use (Figure 3A and D).
The subgroup analysis of the primary endpoints was based on strati-
fied factors and the selection of pre-specified subgroups. The results
showed a consistent effect across the subgroups stratified according
to sex (male or female), smoking status (yes or no), coronary heart dis-
ease (CHD) (yes or no), age (<65 or ≥65 years), LVEF (<40 or ≥40%),
LVD (<50 or ≥50 mm), NYHA classification (II or III and IV), HbA1c
level (<8 or ≥8%), and renal function (estimated glomerular filtration
rate of <60 or ≥60 mL/min/1.73 m2) (Figure 4). Furthermore, the sig-
nificant differences between the subgroups were mainly reflected in
the LVD and HbA1c level. Glimepiride treatment was more effective
in reducing the cardiovascular mortality (adjusted HR, 0.26; 95% CI,
0.16–0.41; P < 0.001 in the >50 mm LVD subgroup; adjusted HR,
0.23; 95% CI, 0.14–0.38; P < 0.001 in the <8% HbA1c level subgroup)
and number of hospitalizations and emergency visits for heart failure
(adjusted HR, 0.37; 95% CI, 0.30–0.46; P < 0.001 in the >50 mm LVD
subgroup; adjusted HR, 0.35; 95% CI, 0.29–0.44; P < 0.001 in the
<8% HbA1c level subgroup) in the patients with an LVD of >50 mm
and HbA1c level of ≥8% than in the other patients (Figure 4).
Table 1 Baseline characteristics of patients with type 2 diabetes mellitus and heart failure

All patient Unmatched PSM (1:1)

.................................................................. ....................................................................
(n = 21 451)
Glimepiride Non-glimepiride SMD P Glimepiride Non-glimepiride SMD P
(n = 638) (n = 20 813) (n = 509) (n = 509)
..........................................................................................................................................................................................................
Gender: male (%) 14 440 (67.3) 440 (69.0) 14 000 (67.3) 0.036 0.367 340 (66.8) 340 (66.8) <0.001 >0.999
Age, years 67 (58–75) 66 (57–74) 67 (58–75) 0.053 0.080 67 (58–75) 66 (59–74) 0.083 0.315
Age ≥65 years (%) 12 182 (56.8) 355 (55.6) 11 827 (56.8) 0.024 0.553 300 (58.9) 288 (56.6) 0.048 0.446
Age <65 years (%) 9269 (43.2) 283 (44.4) 8986 (43.2) 0.024 0.553 209 (41.1) 221 (43.4) 0.048 0.446
Smoking (%) 8550 (39.9) 277 (43.4) 8273 (39.7) 0.075 0.062 213 (41.8) 215 (42.2) 0.008 0.899
Drinking (%) 3830 (17.9) 145 (22.7) 3685 (17.7) 0.131 0.001 100 (19.6) 103 (20.2) 0.015 0.814
NYHA Class II (%) 11 672 (54.5) 409 (64.1) 11 263 (54.1) 0.201 <0.001 330 (64.8) 338 (66.4) 0.033 0.598
NYHA Class III/IV (%) 9779 (45.6) 229 (35.9) 9550 (45.9) 0.201 <0.001 179 (35.2) 171 (33.6) 0.033 0.598
Original comorbidities (%)
Hypertension (%) 15 353 (71.6) 463 (72.6) 14 890 (71.5) 0.023 0.570 387 (76.0) 387 (76.0) <0.001 >0.999
CHD (%) 11 671 (54.4) 363 (56.9) 11 308 (54.3) 0.052 0.200 289 (56.8) 274 (53.8) 0.059 0.344
Cardiomyopathy (%) 3512 (16.4) 94 (14.7) 3418 (16.4) 0.046 0.256 67 (13.2) 53 (10.4) 0.085 0.174
COPD (%) 1223 (5.7) 26 (4.1) 1197 (5.8) 0.072 0.072 22 (4.3) 25 (4.9) 0.028 0.654
CKD (%) 3984 (18.6) 72 (11.3) 3912 (18.8) 0.193 <0.001 56 (11.0) 66 (13.0) 0.061 0.335
Atrial fibrillation (%) 1600 (7.5) 33 (5.2) 1567 (7.5) 0.090 0.026 30 (5.9) 24 (4.7) 0.044 0.401
Vital signs
Temperature (°C) 36.5 (36.3–36.6) 36.5 (36.3–36.6) 36.5 (36.3–36.6) 0.078 0.038 36.5 (36.3–36.6) 36.5 (36.3–36.6) 0.083 0.272
Glimepiride use is associated with reduced cardiovascular mortality in patients with T2D and CHF

Respiratory rate, breaths/min 20 (20–20) 20 (19–20) 20 (20–20) 0.055 0.070 20 (19–20) 20 (20–20) 0.029 0.818
Pulse, beats/min 80 (75–90) 80 (74–90) 80 (75–90) 0.057 0.148 80 (73–87) 80 (73–88) 0.018 0.870
Systolic blood pressure, mmHg 133 (120–147) 133 (121–145) 133 (120–147) 0.043 0.636 134 (123–146) 133 (123–147) 0.026 0.926
Diastolic blood pressure, 79 (71–86) 80 (72–86) 79 (71–86) 0.024 0.275 80 (72–86) 80 (73–86) 0.045 0.590
mmHg

Data were presented as median and interquartile range (Q1–Q3).

NYHA class, New York Heart Association functional classification; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; CKD, chronic kidney disease; IQR, interquartile range; SMD, standardized mean difference.
5

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

 6

Table 2 Laboratory results and echocardiographic data in patients with type 2 diabetes mellitus and heart failure

All patient Unmatched PSM (1:1)

.................................................................... ...................................................................
(n = 21 451)
Glimepiride Non-glimepiride SMD P Glimepiride Non-glimepiride SMD P
(n = 638) (n = 20 813) (n = 509) (n = 509)
...........................................................................................................................................................................................................
Cardiac function related indicators
LVEF 41 (38–44) 42 (39–44) 41 (38–44) 0.082 0.262 42 (39–44) 42 (39–44) 0.060 0.551
LVD 51 (46–55) 51 (47–54) 51 (46–55) 0.030 0.662 51 (47–53) 51 (47–54) 0.037 0.467
NT-proBNP 1709 (963–4358) 1372 (897–2313) 1728 (966–4460) 0.344 <0.001 1378 (890–2308) 1260 (834–3754) 0.080 0.064
hscTnI 42.27 (12.30–301.52) 33.43 (9.10–275.14) 42.70 (12.40–301.99) 0.004 0.003 33.41 (8.80–213.95) 25.00 (7.60–172.10) 0.027 0.108
Diabetes-related index
Glucose, mmol/L 8.68 (6.66–11.78) 9.32 (6.99–12.43) 8.66 (6.64–11.76) 0.066 0.002 9.44 (6.99–12.41) 9.03 (6.86–12.51) 0.034 0.403
HbA1c, % 7.1 (6.4–8.0) 7.6 (6.8–8.6) 7.1 (6.4–8.0) 0.277 <0.001 7.5 (6.8–8.5) 7.3 (6.7–8.4) 0.056 0.115
Routine blood test
Red blood cell count, ×1012/L 4.14 (3.56–4.63) 4.32 (3.81–4.78) 4.13 (3.55–4.63) 0.262 <0.001 4.29 (3.81–4.75) 4.26 (3.91–4.69) 0.030 0.359
Haemoglobin g/L 123 (105–139) 130 (114–144) 124 (105–139) 0.286 <0.001 130 (114–142) 129 (114–142) 0.010 0.726
Haematocrit, % 37.1 (31.8–41.3) 38.1 (34.4–42.3) 37.1 (31.6–41.3) 0.253 <0.001 38.5 (34.6–41.8) 38.2 (34.3–41.9) 0.015 0.611
White cell count, ×109/L 7.24 (5.65–9.41) 7.15 (5.67–9.00) 7.24 (5.65–9.42) 0.092 0.170 7.01 (5.56–8.94) 6.58 (5.50–8.42) 0.079 0.065
Neutrophil count, ×109/L 4.95 (3.57–7.05) 4.60 (3.43–6.44) 4.96 (3.43–6.44) 0.146 0.002 4.46 (3.33–6.26) 4.24 (3.36–5.95) 0.057 0.147
Lymphocyte count, ×109/L 1.36 (0.94–1.83) 1.51 (1.10–2.03) 1.35 (0.94–1.82) 0.253 <0.001 1.53 (1.12–2.04) 1.51 (1.11–1,91) 0.099 0.170
Monocyte count, ×109/L 0.51 (0.38–0.68) 0.51 (0.40–0.65) 0.51 (0.38–0.68) 0.002 0.992 0.50 (0.40–0.64) 0.52 (0.38–0.67) 0.029 0.797
Platelet count, ×109/L 192 (150–235) 195 (159–238) 192 (149–235) 0.091 0.031 193 (159–236) 192 (154–231) 0.036 0.580
Blood biochemistry
Alanine aminotransferase, U/L 19 (13–31) 20 (14–31) 19 (13–31) 0.047 0.097 20 (14–30) 19 (13–30) 0.047 0.313
Aspartate aminotransferase, U/L 22 (16–33) 20 (15–29) 20 (14–31) 0.074 <0.001 20 (15–28) 20 (16–28) 0.030 0.893
Lactate dehydrogenase, U/L 203.4 (169.2–254.0) 190.0 (164.0–230.1) 204.0 (169.8–254.7) 0.198 <0.001 190.0 (163.0–227.4) 187.0 (161.0–224.1) 0.041 0.705
Total bilirubin, µmol/L 8.8 (6.3–11.9) 8.6 (6.5–11.6) 8.8 (6.23–11.9) 0.036 0.557 8.6 (6.5–11.4) 8.8 (6.4–11.7) 0.018 0.571
Total protein, g/L 58.3 (51.2–67.7) 59.5 (52.6–69.4) 58.2 (51.1–67.6) 0.161 <0.001 59.3 (52.4–68.6) 59.5 (52.5–69.2) 0.044 0.559
Globulin, g/L 29.7 (26.6–33.3) 29.6 (26.6–32.9) 29.8 (26.6–33.3) 0.017 0.529 29.2 (26.3–32.6) 29.1 (26.4–32.6) 0.013 0.939
Albumin, g/L 38.2 (33.6–41.7) 40.2 (36.6–42.6) 38.2 (33.6–41.6) 0.308 <0.001 40.2 (36.5–42.6) 39.6 (36.3–43.0) 0.009 0.748
Alkaline phosphatase, U/L 76 (62–96) 74 (60–90) 76 (62–96) 0.172 0.003 74 (61–88) 72 (59–91) 0.023 0.510
Total cholesterol, mmol/L 3.67 (2.97–4.49) 3.74 (3.15–4.49) 3.66 (2.97–4.49) 0.028 0.037 3.74 (3.15–4.50) 3.58 (3.00–4.50) 0.044 0.126
Triglyceride, mmol/L 1.46 (1.06–2.12) 1.58 (1.18–2.24) 1.45 (1.06–2.12) 0.028 <0.001 1.59 (1.17–2.27) 1.54 (1.07–2.27) 0.029 0.336
LDL, mmol/L 2.15 (1.60–2.81) 2.29 (1.71–2.80) 2.15 (1.60–2.81) 0.067 0.012 2.23 (1.70–2.79) 2.17 (1.59–2.81) 0.055 0.133
HDL, mmol/L 0.88 (0.72–1.05) 0.89 (0.76–1.04) 0.88 (0.72–1.05) 0.034 0.113 0.90 (0.76–1.05) 0.90 (0.77–1.05) 0.009 0.961
Creatinine, μmol/L 86 (69–121) 78 (66–96) 86 (69–122) 0.280 <0.001 79 (66–96) 79 (67–95) 0.003 0.652

Continued
W. He et al.

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

Table 2 Continued

All patient Unmatched PSM (1:1)

.................................................................... ...................................................................
(n = 21 451)
Glimepiride Non-glimepiride SMD P Glimepiride Non-glimepiride SMD P
(n = 638) (n = 20 813) (n = 509) (n = 509)
...........................................................................................................................................................................................................
Blood urea nitrogen, mmol/L 6.76 (5.12–9.65) 6.30 (4.80–7.80) 6.78 (5.14–9.70) 0.298 <0.001 6.34 (4.98–7.87) 6.00 (4.90–7.81) 0.059 0.239
eGFR, mL/min 74.7 (49.9–92.4) 84.1 (64.5–97.8) 74.3 (49.1–92.2) 0.356 <0.001 81.5 (62.8–95.9) 82.4 (66.5–95.7) 0.044 0.480
C-reactive protein, mg/L 9.54 (2.60–41.09) 6.41 (2.05–29.6) 9.65 (2.60–41.60) 0.150 <0.001 6.10 (1.96–26.00) 6.02 (2.05–31.55) 0.062 0.336
Sodium, mmol/L 139.2 (136.7–141.4) 139.6 (137.3–141.4) 139.2 (136.6–141.4) 0.091 0.011 139.7 (137.4–141.5) 139.7 (137.1–141.5) 0.031 0.745
Potassium, mmol/L 4.10 (3.80–4.42) 4.03 (3.77–4.26) 4.10 (3.80–4.42) 0.188 <0.001 4.04 (3.81–4.28) 4.10 (3.78–4.30) <0.001 0.421
Chlorine, mmol/L 101.9 (98.9–104.4) 101.9 (99.4–104.2) 101.9 (98.9–104.4) 0.037 0.490 102.0 (99.9–104.5) 102.2 (99.4–104.3) 0.005 0.683
Magnesium, mmol/L 0.83 (0.78–0.88) 0.82 (0.78–0.87) 0.83 (0.78–0.88) 0.117 0.039 0.82 (0.78–0.87) 0.82 (0.77–0.86) 0.068 0.485
Calcium, mmol/L 2.22 (2.12–2.31) 2.26 (2.18–2.32) 2.22 (2.12–2.31) 0.246 <0.001 2.26 (2.18–2.32) 2.26 (2.17–2.33) 0.009 0.594
Lactic acid, mmol/L 2.07 (1.72–2.61) 2.04 (1.69–2.50) 2.07 (1.72–2.61) 0.135 0.076 2.01 (1.68–2.50) 2.01 (1.74–2.45) 0.008 0.873
Coagulation function
APTT 38.1 (35.1–42.1) 37.1 (34.3–40.6) 38.1 (35.1–42.2) 0.179 <0.001 37.1 (34.4–40.8) 37.3 (34.7–41.6) 0.115 0.228
Prothrombin time, s 13.8 (13.1–14.9) 13.5 (12.9–14.4) 13.8 (13.1–14.9) 0.161 <0.001 13.5 (12.9–14.4) 13.5 (12.9–14.4) 0.029 0.832
Prothrombin activity, % 90 (78–101) 94 (83–104) 90 (78–101) 0.229 <0.001 93 (83–104) 94 (83–104) 0.009 0.901
Thrombin time, s 16.8 (16.0–17.6) 16.7 (16.0–17.0) 16.8 (16.0–17.6) 0.103 0.078 16.6 (15.9–17.4) 16.7 (16.0–17.4) 0.055 0.838
International normalized ratio 1.07 (0.99–1.18) 1.04 (0.98–1.12) 1.07 (0.99–1.18) 0.163 <0.001 1.04 (0.98–1.12) 1.04 (0.97–1.14) 0.024 0.636
Fibrinogen, mg/L 3.79 (3.10–4.85) 3.68 (3.09–4.65) 3.80 (3.10–4.86) 0.025 0.215 3.59 (3.04–4.41) 3.64 (3.05–4.49) 0.040 0.575
D-dimer, mg/L 0.95 (0.47–2.05) 0.70 (0.39–1.41) 0.96 (0.48–2.07) 0.181 <0.001 0.68 (0.37–1.42) 0.74 (0.38–1.51) 0.002 0.553

Data were presented as medians and interquartile range (Q1–Q3).

LVEF, left ventricular ejection fraction; LVD, left ventricular diameter; NT-proBNP, N-terminal pro-brain natriuretic peptide; hsc-TnI, high-sensitivity-cardiac troponin I; HbA1c, glycated haemoglobin/haemoglobin A1c; LDL, low-density
lipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; eGFR, estimated glomerular filtration rate; APTT, activated partial thromboplastin time.
Glimepiride use is associated with reduced cardiovascular mortality in patients with T2D and CHF
7

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

8 W. He et al.

Table 3 Comparison of treatment of patients with type 2 diabetes and chronic heart failure between the glimepiride
and non-glimepiride groups

All patient Unmatched PSM (1:1)

......................................................... .......................................................
(n = 21 451)
Glimepiride Non-glimepiride SMD P Glimepiride Non-glimepiride SMD P
(n = 638) (n = 20 813) (n = 509) (n = 509)
.........................................................................................................................................................
Glinides 726 (3.4) 14 (2.2) 712 (3.4) 0.068 0.091 13 (2.6) 16 (3.1) 0.035 0.572
Metformin 5252 (24.5) 317 (49.7) 4935 (23.7) 0.607 <0.001 246 (48.3) 244 (47.9) 0.008 0.900

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

Thiazolidinediones 417 (1.9) 45 (7.1) 89.2 (1.8) 0.377 <0.001 34 (6.7) 42 (8.3) 0.060 0.340
α-glucosidase 7000 (32.6) 338 (60.8) 6612 (31.8) 0.623 <0.001 293 (57.6) 299 (58.7) 0.024 0.703
DPP4i 2126 (9.9) 121 (19.0) 2005 (9.6) 0.313 <0.001 97 (19.1) 107 (21.0) 0.049 0.434
SGLT2i 1998 (9.3) 83 (4.2) 1915 (9.2) 0.131 0.001 67 (13.2) 80 (15.7) 0.073 0.246
GLP1a 176 (0.8) 11 (1.7) 165 (0.8) 0.102 0.010 10 (2.0) 14 (2.8) 0.052 0.409
Insulin 14 115 (65.8) 396 (62.1) 13 719 (65.9) 0.081 0.044 322 (63.3) 334 (65.6) 0.049 0.432
β-blocker 8971 (41.8) 326 (51.1) 8645 (41.5) 0.194 <0.001 244 (47.9) 239 (47.0) 0.020 0.754
ACEI/ARB 10 323 (48.1) 391 (61.3) 9932 (47.7) 0.272 <0.001 307 (60.3) 302 (60.3) 0.020 0.749
ARNI 1307 (6.1) 32 (5.0) 1275 (6.1) 0.046 0.248 20 (3.9) 19 (3.7) 0.010 0.870
Diuretic 11 241 (52.4) 311 (48.7) 10 930 (52.5) 0.076 0.060 240 (47.2) 220 (43.2) 0.079 0.208
Digitalis 2124 (9.9) 50 (7.8) 2074 (10.0) 0.071 0.076 40 (7.9) 42 (8.3) 0.014 0.818
CCB 8962 (41.8) 291 (45.6) 8671 (41.7) 0.080 0.046 243 (47.7) 241 (47.3) 0.008 0.900
Antiplatelet drugs 10 971 (58.9) 376 (58.9) 10 595 (50.9) 0.164 <0.001 304 (59.7) 290 (57.0) 0.056 0.373
Anticoagulant 10 253 (47.8) 271 (42.5) 9982 (48.0) 0.110 0.006 218 (42.8) 230 (45.2) 0.048 0.449
drugs
Statins 11 566 (53.9) 416 (65.2) 11 150 (53.6) 0.233 <0.001 335 (65.8) 330 (64.8) 0.021 0.742
Nitrates 8287 (38.6) 252 (39.5) 8035 (38.6) 0.018 0.648 205 (40.3) 208 (40.9) 0.012 0.844

DPP4i, ipeptidyl peptidase 4 inhibitors; SGLT2i, sodium/glucose cotransporter-2 inhibitors; GLP1a, glucagon-like peptide-1 agonists; ARNI, angiotensin receptor-neprilysin inhibitors;
CCB, Calcium channel blockers.

The glimepiride group was subdivided into the low-dose and high-
dose groups. A survival analysis of the primary and secondary clinical
endpoints was performed in the high-dose, low-dose, and non-
glimepiride groups. The Kaplan–Meier survival curve and multivariate
Cox model analyses (none of which violated the proportional hazard
hypothesis) showed that the all-cause mortality (log-rank P = 0.016; ad-
justed HR, 0.54; 95% CI, 0.34–0.87; P = 0.010) and cardiovascular mor-
tality (log-rank P = 0.041; adjusted HR, 0.55; 95% CI, 0.31–0.99; P =
0.047) were significantly lower in the high-dose group than in the low-
dose group. The cardiovascular mortality (log-rank P = 0.009; adjusted
HR, 0.51; 95% CI, 0.32–0.82; P = 0.005), number of hospitalizations and
emergency visits for heart failure (log-rank P < 0.001; adjusted HR, 0.49;
95% CI, 0.39–0.62; P < 0.001), and number of hospitalizations for acute
myocardial infarction or stroke (log-rank P = 0.048; adjusted HR, 0.59;
95% CI, 0.38–0.93; P = 0.024) were significantly lower in the low-dose
group than in the non-glimepiride group (Figure 5).
Possible mechanisms underlying
cardiovascular protection: glimepiride can
increase the epoxyeicosatrienoic level by
inhibiting soluble epoxide hydrolase
To further study the mechanism underlying the possible benefits of gli-
mepiride, we used molecular docking to predict the binding between
glimepiride and sEH. We found that glimepiride had a good combin-
ation with sEH, with binding energies of −8.51 kcal/mol (Figure 6).
We further measured the EET and DHET (hydrolysis products of

Table 4 Comparison of clinical outcomes during hospitalization of patients with type 2 diabetes mellitus and heart
failure between glimepiride and non-glimepiride groups

All patients Unmatched PSM (1:1)

.............................................. .............................................
(n = 21 451)
Glimepiride Non-glimepiride P Glimepiride Non-glimepiride P
(n = 638) (n = 20 813) (n = 509) (n = 509)
.........................................................................................................................................................
Hospitalization time (days)a 9 (6–14) 9 (6–14) 9 (6–14) 0.482 9 (5–14) 9 (6–15) 0.242
In-hospital hypoglycaemia, n (%) 2118 (9.9) 66 (10.3) 2052 (9.9) 0.685 52 (10.2) 47 (9.2) 0.597
In-hospital cardiovascular mortality, n (%) 738 (3.4) 7 (0.9) 731 (3.5) <0.001 5 (1.0) 12 (2.4) 0.087

Data were presented as medians and interquartile range (Q1–Q3).

a
Hospitalization time contained discharged and dead patients.
Glimepiride use is associated with reduced cardiovascular mortality in patients with T2D and CHF 9

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

Figure 2 The Kaplan–Meier survival curve of in-hospital cardiovascular mortality for type 2 diabetes and chronic heart failure patients with and with-
out glimepiride treatment. (A) Kaplan–Meier survival curve of in-hospital cardiovascular mortality for all type 2 diabetes and chronic heart failure pa-
tients with and without glimepiride treatment. (B) Kaplan–Meier survival curve of in-hospital cardiovascular mortality for propensity score matching
patients with and without glimepiride treatment.

EETs catalyzed by sEH) levels and found that glimepiride significantly in-
creased the EET level, decreased the DHET level, and significantly
increased the EET/DHET ratio, which indicated that glimepiride could
inhibit sEH.
Discussion
In this prospective cohort study, we evaluated the effects of glimepiride
treatment on the clinical prognosis of patients with T2D and CHF. In
the glimepiride group, there was no particular bias in the prescription
of glimepiride. Due to the relatively low cost and relatively good clinical
efficiency and safety of glimepiride, these 638 participants chose to use
glimepiride for a long time. Our results suggest that glimepiride can re-
duce all-cause mortality, cardiovascular mortality, hospitalizations and
emergency visits for heart failure, and hospitalizations for acute myo-
cardial infarction or stroke in patients with T2D and CHF and has simi-
lar effects in different subgroups of concern. Additionally, high-dose
glimepiride further reduced the cardiovascular mortality and number
of hospitalizations and emergency visits for heart failure compared
with low-dose glimepiride.
Although previous studies and opinions have questioned and criti-
cized the cardiovascular safety of SUs,14,25 they have not been widely
recognized because of the small scale of the study and lack of distinction
between specific SUs and other defects. Further, owing to the
CAROLINA trial results (NCT01243424), the cardiovascular safety
of glimepiride is gradually being recognized.15,26,27 Glimepiride was
non-inferior to placebo in terms of major cardiovascular adverse events
(HR, 1.04; 95% CI, 0.850–1.274), all-cause mortality (HR, 1.08; 95% CI,
0.880–1.317), cardiovascular mortality (HR, 0.96; 95% CI, 0.732–
1.259), and non-cardiovascular mortality (HR, 1.24; 95% CI, 0.893–
1.733).26 It was associated with lower all-cause mortality (HR, 0.77;
95% CI, 0.67–0.89) and non-significant but similar trends in cardiovas-
cular mortality (HR, 0.83; 95% CI, 0.65–1.05) compared with other
second-generation SUs.28 Compared with new hypoglycaemic drugs
with cardiovascular protective effects, dapagliflozin alone showed a
similar efficacy to glimepiride.29 In patients with T2D, daily liraglutide
administration for background therapy with metformin was similar to
glimepiride in achieving blood glucose control and inducing weight
loss and hypoglycaemia.30 Further, there was no intra-group difference
in the risk of hospitalization for heart failure between DPP-4 inhibitors
and SUs.31
Owing to treatment concept changes and the urgency of investigat-
ing T2D combined with CHF, SUs are being re-evaluated, of which gli-
mepiride is undoubtedly the most promising.16,30 Unfortunately, few
large prospective RCTs have studied the effects between glimepiride
and placebo on the prognosis of patients with T2D and CHF.
Compared with glimepiride treatment, liraglutide treatment for 18
weeks did not improve the longitudinal functional reserve index (dia-
stolic/systolic), which was the main outcome in a previous study.32 In
other placebo-controlled studies, liraglutide significantly improved car-
diac function by reducing the left ventricular load.33 The indifference
between these findings indirectly indicates the potential protective ef-
fect of glimepiride on cardiac function. Glimepiride can protect
endothelial cells from atherosclerosis by inhibiting endothelial cell-
mediated low-density lipoprotein oxidation.34 Compared with glimepir-
ide, empagliflozin did not improve the endothelial function in patients
with T2D, although it reduced the body fluid volume.35 However, this
cannot deny the cardiovascular protective effects of glimepiride. The
CANDLE trial showed that among patients with T2D and CHF, the
NT-proBNP level did not show a significant downward trend in the
canagliflozin group compared with that in the glimepiride group.36
10 W. He et al.

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

Figure 3 The Kaplan–Meier survival curve of the clinical outcomes for type 2 diabetes and chronic heart failure patients with and without glimepiride
treatment. (A) Kaplan–Meier survival curve for all-cause mortality between glimepiride group and non-glimepiride group. (B) Kaplan–Meier survival
curve for cardiovascular mortality between glimepiride group and non-glimepiride group. (C) Kaplan–Meier survival curve for hospitalizations and
emergency visits for heart failure between glimepiride group and non-glimepiride group. (D) Kaplan–Meier survival curve for hospitalization for acute
myocardial infarction or stroke between glimepiride group and non-glimepiride group.

Our results suggest that glimepiride may inhibit sEH activity to re-
duce EET degradation to DHET. As endogenous cardioprotective fac-
tors, EET can effectively inhibit inflammation, endothelial dysfunction,
cardiac remodelling, and fibrosis,18–20 which may be an underlying
mechanism of the cardiovascular protective effect of glimepiride.
Glimepiride inhibits NLRP3 inflammasome activation,37 which might
be related to the EET level increase. It can play a cardioprotective
role in the diabetic heart by promoting ischaemic preconditioning
(IPC).38 Traditional SUs bind to the SUR2 receptor of cardiomyocytes,
closing the KATP channel on the mitochondria and thus affecting IPC,
whereas glimepiride specifically binds to SUR1 receptors and does not
affect the KATP channel of cardiomyocyte mitochondria.38,39
Glimepiride can also act on vascular endothelial cells, upregulate
eNOS activity through the PI3K-Akt-dependent pathway, and inhibit
cytokine-induced NF-κB activation to reduce oxidative stress and cell
dysfunction.40–42 It may also alleviate insulin resistance by inducing
PPAR γ activity.43 Although high-quality RCTs are lacking to confirm
the cardiovascular effects of glimepiride, these basic experimental
Glimepiride use is associated with reduced cardiovascular mortality in patients with T2D and CHF 11

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

Figure 4 Primary efficacy end-point events in select prespecified subgroups. (A) Cardiovascular mortality in subgroups. (B) Hospitalizations and
emergency visits for heart failure in subgroups.

results support the potential cardiovascular protective effects of glime- of hypoglycaemia during hospitalization. The CAROLINA trial also
piride from different angles. showed that the increased incidence of hypoglycaemia caused by long-
Herein, glimepiride did not reduce the hospital stay or mortality in term glimepiride use did not affect the cardiovascular risk.15 In the com-
the matched populations but did not significantly increase the incidence parison of the follow-up endpoint events, the cardiovascular protective
12 W. He et al.

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

Figure 5 The Kaplan–Meier survival curve of the clinical outcomes for type 2 diabetes and chronic heart failure patients with high/low dose and
without glimepiride treatment. (A) Kaplan–Meier survival curve for all-cause mortality between high/low-dose of glimepiride group and non-glimepiride
group. (B) Kaplan–Meier survival curve for cardiovascular mortality between high/low-dose of glimepiride group and non-glimepiride group. (C ) Kaplan–
Meier survival curve for hospitalizations and emergency visits for heart failure between high/low-dose of glimepiride group and non-glimepiride group.
(D) Kaplan–Meier survival curve for hospitalization for acute myocardial infarction or stroke between high/low-dose of glimepiride group and non-
glimepiride group.

effect of long-term glimepiride use was gradually highlighted.
Glimepiride significantly reduced the risk of cardiovascular adverse
events in the patients with T2D and CHF and had protective effects
in all subgroups. Notably, glimepiride may have a more significant car-
diovascular protective effect in patients with a large left ventricle
(LVD: ≥50 mm) and previous blood glucose control (HbA1c level:
<8%), which may be the focus of glimepiride studies in the future.
Further, because different glimepiride doses have different effects on
the prognosis of patients with T2D and CHF, a higher but normal
dose of glimepiride (2–4 mg/day) is recommended for long-term use.
However, the effect of glimepiride at higher doses (>4 mg/day) needs
to be verified in further clinical studies.
In summary, our results suggest that long-term continuous glimepir-
ide treatment is associated with reduced cardiovascular mortality and
hospitalizations and emergency visits for heart failure in patients with
T2D and CHD, especially in those with a large left ventricle and previous
blood glucose control. In addition, high-dose glimepiride (2–4 mg/day)
has greater cardiovascular protective advantages than low-dose
Glimepiride use is associated with reduced cardiovascular mortality in patients with T2D and CHF 13

Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023

Figure 6 Molecular docking of glimepiride with soluble epoxide hydrolase and effects of glimepiride on epoxyeicosatrienoic and dihydroxyeicosa-
trienoic relative levels. (A) Molecular docking of glimepiride with soluble epoxide hydrolase. (B) Effects of different concentrations of glimepiride on the
relative level of epoxyeicosatrienoic by enzyme-linked immunosorbent assay. (C ) Effects of different concentrations of glimepiride on the relative level
of dihydroxyeicosatrienoic by enzyme-linked immunosorbent assay. (D) Effects of different concentrations of glimepiride on the relative level of epox-
yeicosatrienoic/dihydroxyeicosatrienoic by enzyme-linked immunosorbent assay. *P < 0.05, **P < 0.01, ***P < 0.001.

glimepiride (1 mg/day). These clinical results may be related to the sEH
inhibition by glimepiride, thus reducing EET degradation.
Study limitations
Our study had several limitations. First, it is ideal to conduct RCTs to
study the effects between glimepiride and placebo. In this study, not
all clinical indicators and treatments were well matched to study the ef-
fects of glimepiride on all patients. Although 1:1 PSM and Cox regres-
sion analyses were performed to balance the confounding factors
related to the clinical outcomes, there were still some unexpected
biases (e.g. living environment, psychological factors, occupation, and
education) that were uncertain and could not be completely corrected.
Second, although many individuals participated in the follow-up, call in-
formation asymmetry caused by personal selective bias and real-time
call signal interference could not be completely excluded. Third, all
included patients were Chinese. Finally, the cohort study could
not determine the causal relationship between glimepiride treatment
and endpoint events. Further prospective RCTs are needed in the
future.
Authors’ contribution
W.H. and G.Y. designed the study, collected and analysed data, per-
formed the statistical analysis, and wrote the manuscript. Y.H., Y.Y.
and G.L. completed the follow-up, data collation, and verification.
C.Z. carried out the basic experiments. J.S., X.J. and C.C. were respon-
sible for quality control and carding ideas. D.W.W. and L.N. designed
the project, edited the manuscript, and supervised the study. All
authors gave final approval and agree to be accountable for all aspects
of work ensuring integrity and accuracy.
14
Acknowledgements
The authors would like to thank all the patients, their families, and all inves-
tigators involved in this study.
Funding
The author(s) disclosed receipt of the following financial support for the re-
search, authorship, and/or publication of this article. This work was sup-
ported in part by the projects of National Natural Science Foundation of
China (81790624, 82070354, 81470519 and C-0052), Program for
Huazhong University of Science and Technology Academic Frontier Youth
Team (2019QYTD08), and Top-Notch Talent Program of Tongji Hospital
(2021YBJRC005).
Conflict of interest: None declared.
Data availability
The data underlying this article will be shared on reasonable request to the
corresponding author.
References
1. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus
and its complications. Nat Rev Endocrinol 2018;14:88–98.
2. Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-
lowering agents in patients with diabetes. Eur J Heart Fail 2017;19:43–53.
3. Dzau V, Braunwald E. Resolved and unresolved issues in the prevention and treatment
of coronary artery disease: a workshop consensus statement. Am Heart J 1991;121:
1244–1263.
4. Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus. Circ Res 2019;124:121–141.
5. Karwi QG, Ho KL, Pherwani S, et al. Concurrent diabetes and heart failure: interplay and
novel therapeutic approaches. Cardiovasc Res 2022;118:686–715.
6. Dunlay SM, Givertz MM, Aguilar D, et al. Type 2 diabetes mellitus and heart failure: a
scientific statement from the American Heart Association and the Heart Failure
Society of America: this statement does not represent an update of the 2017 ACC/
AHA/HFSA heart failure guideline update. Circulation 2019;140:e294–e324.
7. Nassif M, Kosiborod M. Effect of glucose-lowering therapies on heart failure. Nat Rev
Cardiol 2018;15:282–291.
8. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in
veterans with type 2 diabetes. N Engl J Med 2009;360:129–139.
9. Liakos A, Tsapas A, Bekiari E. Some glucose-lowering drugs reduce risk for major ad-
verse cardiac events. Ann Intern Med 2020;173:Jc9.
10. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond
glycaemic control. Nat Rev Cardiol 2020;17:761–772.
11. Korytkowski MT. Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepir-
ide. Pharmacotherapy 2004;24:606–620.
12. Vaccaro O, Masulli M, Nicolucci A, et al. Effects on the incidence of cardiovascular
events of the addition of pioglitazone versus sulfonylureas in patients with type 2 dia-
betes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre
trial. Lancet Diabetes Endocrinol 2017;5:887–897.
13. Wang J, Wu HY, Chien KL. Cardioprotective effects of dipeptidyl peptidase-4 inhibitors
versus sulfonylureas in addition to metformin: a nationwide cohort study of patients
with type 2 diabetes. Diabetes Metab 2021;48:101299.
14. Packer M. Are physicians neglecting the risk of heart failure in diabetic patients who are
receiving sulfonylureas? Lessons from the TOSCA.IT trial. Eur J Heart Fail 2018;20:49–51.
15. Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs glimepiride on major
adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA ran-
domized clinical trial. JAMA 2019;322:1155–1166.
16. Lin SN, Phang KK, Toh SH, Chee KH, Zaman Huri H. Heart failure with type 2 diabetes
mellitus: association between antihyperglycemic agents, glycemic control, and ejection
fraction. Front Endocrinol (Lausanne) 2020;11:448.
17. Cintra RM, Nogueira AC, Bonilha I, et al. Glucose-lowering drugs and hospitalization for
heart failure: a systematic review and additive-effects network meta-analysis with more
than 500 000 patient-years. J Clin Endocrinol Metab 2021;106:3060–3067.
18. Wang B, Wu L, Chen J, et al. Metabolism pathways of arachidonic acids: mechanisms and
potential therapeutic targets. Signal Transduct Target Ther 2021;6:94.
19. Shi Z, He Z, Wang DW. CYP450 epoxygenase metabolites, epoxyeicosatrienoic acids,
as novel anti-inflammatory mediators. Molecules 2022 Jun 16;27:3873.
W. He et al.
20. Zhang M, Shu H, Chen C, et al. Epoxyeicosatrienoic acid: a potential therapeutic target of
heart failure with preserved ejection fraction. Biomed Pharmacother 2022;153:113326.
21. American Diabetes Association Professional Practice Committee. Classification and
diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care 2022;
45:S17–S38.
22. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the
management of heart failure: a report of the American College of Cardiology/
American Heart Association joint committee on clinical practice guidelines. Circulation
2022;145:e895–e1032.
23. Gaillard T. Evaluation of AutoDock and AutoDock Vina on the CASF-2013 benchmark.
J Chem Inf Model 2018;58:1697–1706.
Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac312/6961537 by guest on 31 January 2023
24. He Z, Zhang X, Chen C, et al. Cardiomyocyte-specific expression of CYP2J2 prevents
development of cardiac remodelling induced by angiotensin II. Cardiovasc Res 2015;105:
304–317.
25. Inoue T, Maeda Y, Sonoda N, et al. Hyperinsulinemia and sulfonylurea use are independ-
ently associated with left ventricular diastolic dysfunction in patients with type 2 dia-
betes mellitus with suboptimal blood glucose control. BMJ Open Diabetes Res Care
2016;4:e000223.
26. Ghosh S, Mukhopadhyay P, Pandey P, Chatterjee P, Pandit K. Cardiovascular safety of
glimepiride: an indirect comparison from CAROLINA and CARMELINA. Diab Vasc Dis
Res 2020;17:1479164120973653.
27. Riddle MC. A verdict for glimepiride: effective and not guilty of cardiovascular harm.
Diabetes Care 2019;42:2161–2163.
28. Douros A, Dell’Aniello S, Yu OHY, Suissa S. Comparative cardiovascular and hypogly-
caemic safety of glimepiride in type 2 diabetes: a population-based cohort study.
Diabetes Obes Metab 2020;22:254–262.
29. Muller-Wieland D, Kellerer M, Cypryk K, et al. Efficacy and safety of dapagliflozin or da-
pagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with
type 2 diabetes. Diabetes Obes Metab 2018;20:2598–2607.
30. Nauck M, Frid A, Hermansen K, et al. Efficacy and safety comparison of liraglutide, gli-
mepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD
(liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009;32:84–90.
31. Fadini GP, Saragoni S, Russo P, et al. Intraclass differences in the risk of hospitalization for
heart failure among patients with type 2 diabetes initiating a dipeptidyl peptidase-4 in-
hibitor or a sulphonylurea: results from the OsMed Health-DB registry. Diabetes Obes
Metab 2017;19:1416–1424.
32. Nyström T, Santos-Pardo I, Hedberg F, et al. Effects on subclinical heart failure in type 2
diabetic subjects on liraglutide treatment vs. glimepiride both in combination with met-
formin: a randomized open parallel-group study. Front Endocrinol (Lausanne) 2017;8:325.
33. Bizino MB, Jazet IM, Westenberg JJM, et al. Effect of liraglutide on cardiac function in pa-
tients with type 2 diabetes mellitus: randomized placebo-controlled trial. Cardiovasc
Diabetol 2019;18:55.
34. Shakuto S, Oshima K, Tsuchiya E. Glimepiride exhibits prophylactic effect on athero-
sclerosis in cholesterol-fed rabbits. Atherosclerosis 2005;182:209–217.
35. Tamura H, Kondo Y, Ito K, et al. Comparison of the effects of empagliflozin and glime-
piride on endothelial function in patients with type 2 diabetes: a randomized controlled
study. PLoS One 2022;17:e0262831.
36. Tanaka A, Hisauchi I, Taguchi I, et al. Effects of canagliflozin in patients with type 2 dia-
betes and chronic heart failure: a randomized trial (CANDLE). ESC Heart Fail 2020;7:
1585–1594.
37. Lowes DJ, Hevener KE, Peters BM. Second-generation antidiabetic sulfonylureas inhibit
Candida albicans and candidalysin-mediated activation of the NLRP3 inflammasome.
Antimicrob Agents Chemother 2020 Jan 27;64:e01777–19.
38. Hausenloy DJ, Wynne AM, Mocanu MM, Yellon DM. Glimepiride treatment facilitates
ischemic preconditioning in the diabetic heart. J Cardiovasc Pharmacol Ther 2013;18:
263–269.
39. Müller G. The molecular mechanism of the insulin-mimetic/sensitizing activity of the
antidiabetic sulfonylurea drug Amaryl. Mol Med 2000;6:907–933.
40. Schiekofer S, Rudofsky G Jr, Andrassy M, et al. Glimepiride reduces mononuclear acti-
vation of the redox-sensitive transcription factor nuclear factor-kappa B. Diabetes Obes
Metab 2003;5:251–261.
41. Jojima T, Suzuki K, Hirama N, Uchida K, Hattori Y. Glimepiride upregulates eNOS ac-
tivity and inhibits cytokine-induced NF-kappaB activation through a phosphoinoside
3-kinase-Akt-dependent pathway. Diabetes Obes Metab 2009;11:143–149.
42. Ueba H, Kuroki M, Hashimoto S, et al. Glimepiride induces nitric oxide production in
human coronary artery endothelial cells via a PI3-kinase-Akt dependent pathway.
Atherosclerosis 2005;183:35–39.
43. Inukai K, Watanabe M, Nakashima Y, et al. Glimepiride enhances intrinsic peroxisome
proliferator-activated receptor-gamma activity in 3T3-L1 adipocytes. Biochem Biophys
Res Commun 2005;328:484–490.