glimepride in TYPE 2 DM

1. Glimepiride use is associated with reduced
cardiovascular mortality in patients with Type 2
diabetes and Chronic heart failure: a prospective
study
Moderator : Dr Shanmukh T Kalsad
Presentor : Dr J A Deva

3. INTRODUCTION
• Diabetes is a metabolic disease characterized by chronic hyperglycaemia for
varying reasons and is a major chronic disease affecting several individuals
worldwide.
• According to the International Diabetes Federation, the number of patients with
diabetes worldwide has reached 537 million in 2021 and is expected to increase
to ∼783 million by 2045.
• Patients with diabetes have poorer cardiovascular outcomes and prognosis and
longer hospital stays than those without.
• CHF is also the most common cardiovascular complication of T2D, with a higher
incidence than myocardial infarction or stroke.
• The cardiovascular benefits of some hypoglycaemic drugs have long exceeded
glycaemic control

4. • 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.
• Glimepiride has good cardiovascular safety according to randomized controlled trials
(RCTs).
• The proportion of SUs used in patients with T2D and CHF is as high as 60.4%.
• 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, indicating the potential
cardiovascular effect of glimepiride.
• This prospective cohort study aimed to evaluate the effects of glimepiride on the clinical

5. METHODS
• STUDY DESIGN AND PATIENT INFORMATION
• In this cohort study, we collected information on inpatients clinically diagnosed with T2D
and CHF [left ventricular ejection fraction (LVEF)
• <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-2022and 2022 AHA/ ACC/HFSA Guideline for the
Management of Heart Failure;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.

8. DATA COLLECTION AND END POINTS
• Clinical data and laboratory results were obtained from the electronic
medical record database of the Tongji Hospital
• 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 myocardial infarction or stroke.
• 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.

9. MOLECULAR DOCKING OF GLIMIPRIDE WITH sEH AND
ELISA OF 14,15-EET, DHET AND RATIO OF EET/DHET
• To explore the possible docking mode and binding ability between glimepiride
(ligand) and sEH, we used AutoDock (version 4.2.6) to perform molecular 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.
• 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
• Using the 14,15-DHET ELISA kit to measure DHET of the two parts, the concentration of 14,15-
DHET and 14,15-EET would be obtained, and the ratio of them (14,15-EET/DHET) represented the

10. STATISTICAL ANALYSIS
• 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 analysis on the
observed baseline data and related treatments using a logistic regression model in the R
environment
• The optimal calliper width was set to 0.05
• Several matched variables were used
• Continuous variables between 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

11. RESULTS

12. DEMOGRAPHIC AND GENERAL CHARACTERISTICS

18. CLINICAL FOLLOWUP OUTCOME

20. SUBGROUP ANALYSIS

23. MOLECULAR DOCKING

25. POSSIBLE MECHANISMS UNDERLYING
CARDIOVASCULAR PROTECTION
• To further study the mechanism underlying the possible benefits of glimepiride,
we used molecular docking to predict the binding between glimepiride and sEH.
• We found that glimepiride had a good combination with sEH, with binding
energies of −8.51 kcal/mol.
• We further measured the EET and DHET (hydrolysis products of EETs catalyzed by
sEH) levels and found that glimepiride significantly increased the EET level,
decreased the DHET level, and significantly increased the EET/DHET ratio, which
indicated that glimepiride could inhibit sEH.

26. 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 reduce all-cause mortality,
cardiovascular mortality, hospitalizations and emergency visits for
heart failure, and hospitalizations for acute myocardial infarction or
stroke in patients with T2D and CHF and has similar 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

27. • CAROLINA trial results the cardiovascular safety of glimepiride is gradually
being recognized & also the increased incidence of hypoglycaemia caused by
long- term glimepiride use did not affect the cardiovascular risk
• 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)
• It was associated with lower all-cause mortality (HR, 0.77; 95% CI, 0.67–0.89)
and non-significant but similar trends in cardiovascular mortality (HR, 0.83;
95% CI, 0.65–1.05) compared with other second-generation SUs
• Compared with new hypoglycaemic drugs with cardiovascular protective
effects, dapagliflozin alone showed a similar efficacy to glimepiride
• 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
• Further, there was no intra-group difference in the risk of hospitalization for
heart failure between DPP-4 inhibitors and SUs.

28. • Other large prospective RCTs, Compared with glimepiride treatment,
liraglutide treatment for 18 weeks did not improve the longitudinal functional
reserve index (diastolic/systolic)
• In other placebo-controlled studies, liraglutide significantly improved cardiac
function by reducing the left ventricular load
• The indifference between these findings indirectly indicates the potential
protective effect of glimepiride on cardiac function
• Glimepiride can protect endothelial cells from atherosclerosis by inhibiting
endothelial cell- mediated low-density lipoprotein oxidation
• Compared with glimepiride, empagliflozin did not improve the endothelial
function in patients with T2D, although it reduced the body fluid volume
• 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

29. • Our results suggest that glimepiride may inhibit sEH activity to reduce EET
degradation to DHET. As endogenous cardioprotective factors, EET can
effectively inhibit inflammation, endothelial dysfunction, cardiac remodelling,
and fibrosis,which may be an underlying mechanism of the cardiovascular
protective effect of glimepiride.
• 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.It
may also alleviate insulin resistance by inducing PPAR γ activity.
• Glimepiride may have a more significant cardiovascular protective effect in
patients with a large left ventricle (LVD: ≥50 mm) and previous blood glucose
control (HbA1c level: <8%)
• 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.
• High-dose glimepiride (2–4 mg/day) has greater cardiovascular protective advantages than
low-dose glimepiride (1 mg/day)

30. 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.

31. STUDY LIMITATIONS
• Although 1:1 PSM and Cox regression 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 information 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.