Gliclazide MR:

A novel formulation in T2DM treatment

Rezvan Salehidoost, M.D., Endocrinologist

Abidi Diabetes Master Class

AGENDA

Gliclazide molecule as a sulfonylurea

• Basic and clinical points

Review on available literatures

• Glc vs. other SUs

• ADVANCE study

• Glc MR vs. standard Glc

Take home message

Gliclazide Molecule

Basic and clinical points

Target organs and action mechanism of anti-diabetic drugs

Zhou K, et al. doi:10.1038/nrendo.2016.51

Mechanism of Action of Sulfonylureas

SUR1 KATP channels contain two high affinity binding sites, one accept sulfonyl moiety and one that

accept benzamide moiety.

Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic β-cells.

It was shown to provide cardiovascular protection as it does not bind to SUR-2A in the heart.

Diabetologia.2001; 44(8): 1019–25.

Gliclazide Pharmacokinetics

Well absorption

Peak plasma concentration occurring within 4 -6 hrs

Extensively (94%) bound to plasma proteins

Half-life: Approximately 10–12 hrs

Metabolized in the liver to inactive metabolites: oThe metabolites have no significant hypoglycaemic effect.

Use in pregnancy & lactation: o Category C

Gliclazide 80 mg: Datapharm Communications Ltd ;Summary of product characteristics 2013. Gliclazide 80 mg: Arrow Pharmaceuticals NZ Limited Fact Sheet 2006.

Gliclazide: Method of Administration

The total daily dose may vary from 40 to 320 mg taken orally.

The dose should be adjusted according to the individual patient’s response,

commencing with 40–80 mg daily (½ - 1 tablet) and increasing until adequate

control is achieved.

A single dose should not exceed 160 mg (2 tablets).

If > 160 mg/d are required, tablets should be taken twice daily according to

the main meals of the day.

Maximum Recommended Dose Starting Dose

320 mg/day 40-80 mg/day

(1/2-1 of 80 mg tablet)

Summary of product characteristics; Gliclazide 80 mg

Gliclazide MR: Dosage and administration

The daily dose of GLICLAZIDE MR may vary from 30-120 mg (1-4 tablets) once daily.

The recommended starting dose of GLICLAZIDE MR is 1 tablet per day (30 mg), even in elderly patients (> 65 years old).

A single daily dose provides effective blood glucose control.

Dose adjustment should be carried out in steps of 30 mg – Each step should last for at least two weeks.

Administration It is recommended that the medication be taken at breakfast time. The

tablets should be swallowed whole and must not be chewed or crushed.

Previously untreated patients should commence with a dose of 30 mg.

GLICLAZIDE MR can replace gliclazide 80 mg immediate release tablets.

GLICLAZIDE MR can replace an antidiabetic treatment without any transitional period.

PRODUCT MONOGRAPH; Gliclazide Modified Release Tablets 30 mg, AA PHARMA INC., June 25, 2010

Gliclazide Contraindications

Pregnancy

Type 1 diabetes

Diabetics undergoing surgery

Diabetics pre-coma and coma

Severe hepatic insufficiency

After severe trauma or during infections

Diabetes complicated by ketosis and acidosis

Patients known to have hypersensitivity to other Sus.

Summary of product characteristics; Gliclazide 80 mg

Review of

Clinical Evidences

Gliclazide vs. other Insulinotropic Agents

Chan S P., Colagiuri S. Diabetes Res Clin Pract 2015;110: 75-81.

Gliclazide vs. other SUs: HbA1c

Chan S P., Colagiuri S. Diabetes Res Clin Pract 2015;110: 75-81.

Gliclazide vs. other Sulfonylureas: Hypoglycemia

Chan S P., Colagiuri S. Diabetes Res Clin Pract 2015;110: 75-81.

Hypothetical Question on “SUs and Heart”

Considering the presence of Sulfonylurea Receptor (SUR) on myocardium and coronary vessels in addition to pancreas, it has been postulated that using SUs may lead to poor cardiac outcomes especially if used around the time of ischemic attacks. The mechanism may be:

• prevention of adequate coronary vasodilation, so causing a larger area of myocardial damage

• interference with ischemic preconditioning or possible arrhythmogenic effects.

• The objective of the present study was to evaluate the safety of the sulfonylureas most frequently used and to use trial sequential analysis (TSA) to analyze whether the available sample was powered enough to support the results.

Rados DV, et al. PLOS Medicine 2016;13(4): e1001992.

IF: 13.6

http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

Rados DV, et al. PLOS Medicine 2016;13(4): e1001992. https://doi.org/10.1371/journal.pmed.1001992 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

Forest plots for all-cause mortality of SUs according to comparator (placebo/diet or active comparators)

Rados DV, et al. PLOS Medicine 2016;13(4): e1001992. https://doi.org/10.1371/journal.pmed.1001992 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

Forest plots for cardiovascular mortality of SUs according to comparator (placebo/diet or active comparators)

Forest plots for all-cause and cardiovascular mortality of Sulfonylureas as an add-on to metformin

Rados DV, et al. PLOS Medicine 2016;13(4): e1001992. https://doi.org/10.1371/journal.pmed.1001992 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

Meta-Analysis: Conclusion

Sulfonylureas are not associated with increased risk for all-cause mortality, cardiovascular mortality, MI, or stroke. Current evidence supports the safety of SUs; an absolute risk of 0.5% could be firmly discarded.

Rados DV, et al. PLOS Medicine 2016;13(4): e1001992. https://doi.org/10.1371/journal.pmed.1001992 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

Clinical Data on Using

Gliclazide MR

Journal of Diabetes and Its Complications, 2000; 14(4):185-91.

Diamicron MR once daily is effective and well tolerated in T2DM: A double-blind, randomized, multinational study

Drouin P. J Diabetes Complications. 2000; 14(4): 185-91.

Study design: Diamicron MR vs. Diamicron in the treatment of T2DM

Drouin P. J Diabetes Complications. 2000; 14(4): 185-91.

Diamicron MR vs. Diamicron in the treatment of T2DM

Drouin P. J Diabetes Complications. 2000; 14(4): 185-91.

a) ∆HbA1c in all cases

d) ∆Weight in the whole & obese cases c) ∆FPG in all cases

b) ∆HbA1c in OAD naive cases

Canadian Journal of Diabetes. 2015; 39 (4):308 -16.

Clemens KK, et al. Canadian Journal of Diabetes. 2015; 39 (4):308 -16.

What to take home?

Take Home Message!

In comparison to the other SUs, Gliclazide seems to have:

• less hypoglycemia

• at least, similar efficacy

• better cardiovascular outcome

Gliclazide MR may increase adherence and facilitate its clinical usage.

After metformin, If you decide to use a sulfonylurea as the 2nd

drug in treating T2DM, Gliclazide should be logically the choice.

Safety profiles

Cardiovascular effects

Our experience in handling

Extra-glycemic effects

Side effects Effectiveness

In the era of growing number of diabetes medications and new data, we should consider

these factors to select the proper component for each individual patient:

The last, not the least…

Patient preference Cost Availability

Thanks for your attention