diabetic foot

1. Gliclazide: revisiting evidence on a classic
therapy

2. Index
 EPIDEMIOLOGY:
 Global Burden and Rapid Growth in India
 SULFONYLUREAS (SUS)
 A Trusted Long Term Partner
 Is glycaemic control still relevant in the era of CVOTs?
 EXTRA-PANCREATIC BENEFITS OF GLICLAZIDE
 Effective and safety perspective of Gliclazide with other modern SUs
 SUS IN THE TREATMENT OF T2DM: a fresh look and new insights
 CARDIO-VASCULAR OUTCOMES IN LARGE STUDIES OF SUs
 CARDIO-RENAL OUTCOMES IN LARGE STUDIES OF GLICLAZIDE – ADVANCE Study
 PHARMACOECONOMIC ANALYSIS OF ADVANCE TRIAL
 JADE Register
 GLICLAZIDE EFFICACY: More than 3 Decades in T2DM Management

3.  I. Introduction
 Brief overview of diabetes and the role of medicationin its management
 Introductionto Gliclazideand its classificationas a sulfonylurea medication
 II. Mechanism of action of Gliclazide
 Overview of how Gliclazide works to lower blood sugar levels
 Explanationof the drug's effects on insulin secretion and glucose uptake
 III. Efficacy of Gliclazide
 Review of clinicaltrials and evidence supporting the use of Gliclazidein the treatmentof diabetes
 Comparison of Gliclazidewith other medications in its class and with newer drug classes
 IV. Safety profile of Gliclazide
 Discussion of common side effects of Gliclazide
 Analysis of the risk of hypoglycemia associated with Gliclazide compared to other diabetes medications
 V. Emerging evidence on Gliclazide
 Overview of recent studies on Gliclazide and its potential benefits beyond glycemic control
 Discussion of its cardiovascular and renal protective effects
 VI. Conclusion
 Summary of the key points presented in the talk
 Implications of the revisited evidence on the use of Gliclazide in diabetes management
 Future directions and potential areas for further research

4. 1. Diabetes Epidemiology:
Increasing Global Burden with
Rapid Growth in India

5. 77 millions
in India, 2019
Diabetes Epidemiology:
The World - Global Burden
537 million adults (20-79 years) are living with
diabetes - 1 in 10.
Over 3 in 4 adults with diabetes live in low- and
middle-income countries.
6.7 million deaths in 2021 - 1 every 5
seconds.
537 million adults (20-79 years) are living
with diabetes This number is predicted to
rise to 783 million by 2045.
Pradeepa R, Mohan V. Epidemiology of type 2 diabetes in India. Indian J Ophthalmol. 2021 Nov;69(11):2932-2938.

6. 2. Sulfonylureas (SUs):
A Trusted Long Term Partner

7. GLP-1R agonist
1920 1990 2000 2010
1970
Insulin SFU
Pramlintide
DPP-4
inhibitor
Bromocriptine
1950 1980
ADA Standards of Care
1989
TZD
Metformin
Rapid-acting
insulin
Meglitinide
Basal insulin
2014
αGlucosidase
inhibitor
SGLT-2 Inhibitor
Therapeutic Advances Over Past 20 Years
Sulfonylureas (SUs) have remained the main-stay of
pharmacotherapy in the management of type 2 diabetes since
1950

8. Ref.: Indian J Endocrinol Metab. 2015 May-Jun; 19(3): 314–316.
Gliclazide
Patented
(1966)
Gliclazide
Approved
(1972)
Medical Use
Gliclazide: 1972
Glimepiride: 1995
2. Sulfonylureas (SUs):
A Trusted Long Term Partner

9. • Lowering A1C by 0.5% conferred a significant HRR of 20%
(95% CI 4–33%) for MACE [1]
Population based study confirms, high HbA1c is associated
increased risk of MI, stroke, death & heart failure
• Strongest predictors regarding the risk of acute
myocardial infarction were the glycated hemoglobin
level [2]
Is glycemic control still an imperative
parameter in CVOTs?
In the era of CVOTs, glycemic control is a crucial component

10. EXTRA-PANCREATIC BENEFITS OF GLICLAZIDE

11. Gliclazide: Sulfonylurea with Pleotropic Benefits
Benefit Description
Anti-oxidant action Reduces oxidative stress, irrespective of glycemic control.
Protects beta-cell from free radical damage.
Normalizes lipid peroxides.
Anti-inflammatory
action
Unique azabicyclo-octyl ring leading to beta cell preservation [Structure-
Activity Relationship (SAR)]
Reduces monocyte adhesion and TNF alpha.
Cardiovascular
Protective action
Inhibits AGE-induced endothelial activation & Improves endothelial function
in T2DM
Significant reduction in left ventricular mass (LVM) in diabetes patients.
Awadhesh Kumar Singh & Ritu Singh (2016) Is gliclazide a sulfonylurea with difference? A review in 2016, Expert Review of Clinical Pharmacology, 9:6, 839-851,

12. Effective and safety perspective of Gliclazide
with other modern SUs
GLICLAZIDE MR GLIMEPIRIDE
8.40%
8.20%
7.20%
7.20%
Gliclazide non inferior to Glimepiride
Baseline 27 weeks
GLICLAZIDE MR GLIMEPIRIDE
3.70%
8.90%
% of pt with confirmed Hypoglycemia
% of pt with confirmed
Hypoglycemia
• Either as monotherapy or in combination
• Gliclazide MR is at least as effective as glimepiride
• Safety of gliclazide MR was significantly better
• Approx. 50% fewer confirmed hypoglycaemic episodes in
comparison with glimepiride.
N= 845
Duration 27 weeks
P<0.001
P<0.001
Eur J Clin Invest. 2004 Aug;34(8):535-42. doi: 10.1111/j.1365-2362.2004.01381.x. PMID: 15305887.

13. Safety of Gliclazide
Adapted from: J Family Med Prim Care.2020 Nov; 9(11): 5450–5457.
 Lowest risk of hypoglycemia between the newer generation SUs.
 Renal safe - No need for dose adjustment in renal dysfunction (CKD stages 3-5) ( NFK-
KDOQI)
 Safe in cardiac patients (SUR1 specific).
 Beta cell preservation due to unique Azabicyclo - Octyl ring in its structure.
 Weight neutral.
NKF: National Kidney Foundation;
KDOQI: Kidney Disease Outcomes Quality Initiative; SUR1: Sulfonylurea Receptor 1
Br J Clin Pharmacol (2016) 82 1291–1302; Sinha B et al.Consensus Statement on Dose Modifications of Anti Diabetic Agents
used in Patients with Diabetes and Chronic Kidney Disease; J Assoc Physicians India 2016;64

14. SUs in the treatment of T2DM: a fresh look and
new insights
 CV safety of SUs as well as more recent findings from large studies of SUs
 Mortality and Cardiovascular Risk
 TOSCA.IT
 CAROLINA trials
 ADVANCE
 CARDIO-RENAL OUTCOMES IN LARGE STUDIES OF GLICLAZIDE – ADVANCE STUDY
 Highlighting the differences in CV and hypoglycaemia risks among the various SUs.
 Finally, the impact of glycaemic control on CV outcomes is also discussed, where the data suggest that the recent
positive CV outcomes with some antihyperglycaemic agents may have been driven in part by improved glycaemic
control.
Diabetes Ther (2020) 11 (Suppl 1):S15–S22

15. Mortality and Cardiovascular Risk
European Heart Journal (2011) 32, 1900–1908

16. Mortality and Cardiovascular Risk
European Heart Journal (2011) 32, 1900–1908
Aim: To examine mortality and cardiovascular risk associated with all available ISs
compared with metformin.
Method: Nationwide study in Denmark
N = 107806; 9 Years
End Point: All-cause mortality, cardiovascular death

17. 1
Conclusion: Gliclazide was associated with a significantly lower risk for All Cause Death than other SUs.
Cardiovascular Safety
Mortality and cardiovascular risk

18. CARDIO-VASCULAR OUTCOMES IN LARGE
STUDIES OF SUs –TOSCA IT Trial
Study Design:
• Randomised phase IV trial
• Patients with T2DM aged 50–75 years with an HbA1c of 7.0–9.0%, BMI 20–45
kg/m2, on metformin ≥ 2 g/day, and had not experienced any acute CV
events in the past 6 months
Number of patients and treatment
• Add-on pioglitazone: 15–45 mg/day (n = 1535)
• Add-on SUs: glibenclamide 5–15 mg/day (n = 24), glimepiride
2–6 mg/day (n = 723) or gliclazide 30–120 mg/day (n = 745)
Median follow-up duration: 57.3 months
CV outcomes:
• First occurrence of all-cause death, non-fatal MI, nonfatal stroke or urgent coronary revascularisation:
• HR for add-on pioglitazone vs sulfonylurea 0.96, 95% CI 0.74–1.26 (p = 0.79)
• Incidence of hypoglycaemia: pioglitazone vs SU: 10% vs 34% (p0.0001)
Diabetes Ther (2020) 11 (Suppl 1):S15–S22

19. The largest morbidity-mortality trial ever performed in type 2 diabetes.
Cardiovascular Safety
ADVANCE

20. Aim: To investigate the relative risk of
hypoglycaemia with newer generation SUs are
added to metformin.
Method: A systematic review of RCTs lasting 12–
52 weeks to evaluate addition of SUs to
inadequate metformin monotherapy in T2DM.
End Point: HbA1c, Macrovascular and
Microvascular Events.
N = 11140;
Group A – Std Treatment Group B – Intensive Treatment
Conclusion: Intensive strategy with conventional agents can achieve mean A1C
levels of 6.5% safely with no increase in mortality
ADVANCE

21. CARDIO-VASCULAR OUTCOMES IN LARGE
STUDIES OF SUs –ADVANCE Trial
Study Design:
• Phase III RCT
• Patients with T2DM aged ≥ 55 years with a history of major macrovascular
or microvascular disease or ≥ 1 other risk factor for vascular disease
Number of patients and treatment
• Intensive control: gliclazide MR 30–120 mg/day /(n = 5571)
• Standard control: other SUs (n = 5569)
Median follow-up duration: 5 years
CV outcomes:
• Comparative risk with intensive versus standard therapy
• Cumulative incidence of CV death, MI, stroke: HR 0.94; 95% CI 0.84, 1.06 (p = 0.32)
• Significant decrease in major macrovascular and microvascular events (p = 0.01)
• Non-significant decrease in major macrovascular events (p = 0.32)
Diabetes Ther (2020) 11 (Suppl 1):S15–S22

22. Additional findings of the ADVANCE study included a significant
• 10% decrease in the primary endpoint of combined major macrovascular
and microvascular events with intensive versus standard therapy (p = 0.01);
• A non-significant 6% decrease in major macrovascular events (p = 0.32);
• A significant 14% decrease in major microvascular events (p = 0.015);
• A significant 21% reduced risk of nephropathy (p = 0.006)
Diabetes Obes Metab. 2020;22(Suppl. 2):5–11.
CARDIO-RENAL OUTCOMES IN LARGE STUDIES OF
GLICLAZIDE – ADVANCE Study

23. Examination of the renal outcomes:
• 9% reduction in new-onset microalbuminuria
• 30% reduction in macroalbuminuria (both p ≤ 0.012)
End-stage renal disease (ESRD; defined as renal transplant or dialysis) was also reduced by
• 65% at the end of the original study with intensive versus standard therapy (p = 0.0017)
• 43% after an additional 5 years of follow-up
Diabetes Obes Metab. 2020;22(Suppl. 2):5–11.
CARDIO-RENAL OUTCOMES IN LARGE STUDIES OF
GLICLAZIDE – ADVANCE Study

24. ADVANCE study: Benefits of intensive glucose
control with gliclazide MR
 Intensive glucose control reduced the risk of combined
major cardiovascular and microvascular events by 10%.
 This was primarily because of a significant 21%
reduction in the risk of new or worsening nephropathy
made up of new onset macroalbuminuria, end stage
kidney disease (ESKD), renal death and doubling of
creatinine to over 200 mcmol/L.7

25. Reductions in HbA1c were consistently observed
across a range of subgroups
 In the intensive group, HbA1c was
gradually reduced over 36 months
and then maintained for an average
of 5 years to produce a mean
HbA1c of 6.5% compared with 7.3%
in the standard group
Diabetes Obes Metab. 2020;22(Suppl. 2):5–11.

26. Effects were similar across different regions
 Effects were similar across different regions of the world
including Asia, Eastern Europe and the established
market economies of Australia, North America, the
United Kingdom and Western Europe combined
Diabetes Obes Metab. 2020;22(Suppl. 2):5–11.

27. New Update on use of SUs in Asian
Patients: JADE register
China Hong Kong India Indonesia Korea Malaysia Philippines Singapore Taiwan Thailand Vietnal
Aim: To explore clinical profiles and patterns of oral glucose lowering drug (OGLD) use in Asian
patients with T2D, with a focus on SUs including Gliclazide.
Method:
• 62512 patients from 11 countries
• Prospectively enrolled in the Joint Asia Diabetes Evaluation (JADE) Register between 2007 & 2019

28. SU is most prescribed drug in India
New Update on use of SUs in Asian
Patients: JADE register
Sulphonylureas (SUs) versus non-SUs Type of regimen in patients treated with SUs
SU + Metformin is most commonly
prescribed drug in India

29. New Update on use of SUs in Asian
Patients: JADE register
Results:
• Patients received one (37.5%) or two (44.2%) OGLDs
• Metformin was used by 84.1% of treated patients, followed by SUs (59.4%) and DPP-4 inhibitors (23.0%)
• In entire cohort, 59.4% of treated patients received SU based therapy with variations amongst countries/ regions
• Amongst SU users,
• Gliclazide users were more likely than Gliclazide non-users to achieve HbA1c < 7% (OR 1.09, 95% CI 1.02–1.17)
• Lower risk of self-reported hypoglycaemia (OR 0.81, 95% CI 0.72–0.92)
GLICLAZIDE GLIMEPIRIDE GLIBENCLAMIDE
47%
40.30%
8.40%
Commonly prescribed SU's
Commonly prescribed SU's
SU + METFORMIN SU + DPP-4I
79.50%
22.10%
Overall SU's regimens
Overall SU's regimens
In Asia, SUs are a popular OGLD class often combined with Metformin.
Good glycaemic control and safety profiles associated with the use of SUs, including gliclazide, support their position as a
key treatment option in patients with T2D.

30. Renal Safety

31. Renal Safety
• Target HbA1c < 7.0%, irrespective of the presence or absence of CKD.
• Lowering HbA1c levels to approximately 7.0% reduces the
development of Microalbuminuria. (Strong)

32. Journal of Diabetes Nursing
Volume 20 No 10 2016.
Recommendations
of Gliclazide in
CKD and Dialysis.
Renal Safety

33. Effectiveness of Gliclazide compare to
other OAD’s

34. Evidence in real-world Setting of Gliclazide with
other OAD’s
Aims:
To compare the effectiveness and safety of gliclazide modified
release (MR) to sitagliptin as type 2 diabetes mellitus (T2D)
treatments in a real-world patient population
Conclusions:
In this real-world study,
• Second-line gliclazide MR was more effective than sitagliptin in
• Reducing HbA1c
• Similar durability
• Persistence and low rates of hypoglycaemic events in individuals with
T2D on metformin treatment and HbA1c above the target of 7.0%
Diabetes Obes Metab. 2020;22:2417–2426.

35. Secondary Sulphonylureas failure: Gliclazide versus
Glibenclamide
• Initiation of insulin was significantly delayed with Gliclazide group than those in
Glibenclamide group (P<0.001 in each group).
• Independent variables affecting the period were average HbA1c levels during GCZ or
GBC treatment (hazard ratio=2.5 per %), other OHAs combined (hazard ratio=1.9 on
combination), and difference between GCZ and GBC groups (hazard ratio=0.5 on GCZ).
• These results imply that Gliclazide may be more protective against secondary beta cell
failure than GBC
Obejective:
• Retrospectively compared the periods until the onset of insulin treatment from the
onset of the diabetes from start of diabetes treatment, or from start of Glibenclamide
or Gliclazide treatment
Diabetes Research and Clinical Practice 70 (2005) 291- 297.

36. Secondary Sulphonylureas failure: SU’s
 Data from three clinical trials are presented, comparing the efficacy of
different sulfonylureas in the treatment of type II diabetes
Conclusion:
These trials suggest that gliclazide is a potent sulfonylurea with a low rate of
secondary failure and a low incidence of side effects and may be a better
choice in long-term sulfonylurea therapy
• Secondary failure rate over 5 years was assessed in 248 type II diabetic patients
randomly allocated to three different sulfonylureas and found to be lowest - with
gliclazide (7%) compared with glibenclamide (17.9%): p < 0.1) and glipizide (25.6%:
p < 0.005).
• Incidence of hypoglycemia was significantly higher with glibenclamide than with
gliclazide fp < 0.05).
Diabetes Research (Edinburgh, Scotland). 1990 Jan 1;13(1):19-21.