Drug Summary – Gliclazide Modified-Release

(Refer to: Drug Review - Sulphonylureas for full text and references)

Mode of action	Gliclazide modified-release is a sulphonylurea (SU) and insulin secretagogue that binds selectively to the sulphonylurea receptor-1A (SUR1A) binding-site of KATP channels on pancreatic beta cells resulting in membrane depolarisation, calcium influx and exocytosis of stored insulin
Glycaemic efficacy and indications	When used as monotherapy or as add-on to other non-insulin glucose lowering drugs the mean HbA1C reduction is -1% with sustained efficacy beyond 2 years
Cardiovascular outcome trials	The ADVANCE study, using a gliclazide modified-release intensive treatment strategy achieved an HbA1C target of 6.5% (vs. 7.3% for conventional treatment) and demonstrated a significant reduction in microvascular outcomes (and therefore also the combined microvascular and macrovascular outcomes), driven mainly by the reduction in the incidence of nephropathy There have been no dedicated cardiovascular safety studies with any sulphonylurea. Meta-analyses of observational and random is  ed controlled trials consistently demonstrate that gliclazide has a better cardiovascular safety profile than glibenclamide and glimepiride
Hypoglycaemia	Gliclazide modified-release increases the risk of hypoglycaemia when used as monotherapy or combination therapy, but this is significantly lower when compared to glibenclamide and glimepiride The rates of hypoglycaemia increase with lower glycaemic targets
Weight	Weight change ranges from 0 to +1.5 kg. Mean weight gain in a meta-analysis of RCTs was 0.5kg
Non-glycaemic benefits	Gliclazide modified-release increases peripheral insulin sensitivity, decreases hepatic glucose production, inhibits platelet aggregation and adhesion, increases t-PA activity and has antioxidant effects. There are also reports of possibly a lower cancer risk compared to other SUs and insulin
Side Effects and Precautions	Side-effects apart from hypoglycaemia and weight gain are rare. Cross-reactivity with sulphonamide antibiotic allergy is uncommon and is not a contra-indication Do not use with advanced liver disease because of hepatic metabolism
Dosing and prescribing	The usual starting dose for gliclazide modified-release is 30 to 60 mg administered once daily with the morning meal Consider starting with the higher (60 mg) dose when the HbA1C target is more than 0.5% from the prevailing HbA1C level, or if the patient is has symptomatic hyperglycaemia The dose can be escalated by 30 to 60mg every one to four weeks, guided by fasting glucose levels The maximum dose is 120 mg administered once daily with the morning meal If mild hypoglycaemia occurs unexpectedly reduce the dose by 30 to 60 mg A single episode of severe hypoglycaemia or recurrent episodes of mild hypoglycaemia would be a strong indication to switch to an alternative glucose lowering drug The 60 mg tablets are scored and can be broken to improve cost effectiveness
Renal dosing	Current guidelines recommend that gliclazide modified-release can be used at all stages of chronic kidney disease using standard dosing guidelines Caution is advised however, when the eGFR is < 30 ml/min/1.73m2, and these patients with CKD stage 3 or worse should be managed with specialist supervision
Cost of cheapest formulation at maximum dose	R 93.00 for 120 mg (Single exit price as at March 2017)

 

(See Strength of Recommendations Taxonomy (SORT) for explanation of Grade A-C)

SEMDSA 2017 Recommendations for sulphonylureas
The sulphonylurea of choice should be gliclazide modified-release because: It has equivalent efficacy compared to other sulphonylureas It is consistently associated with lower rates of hypoglycaemia and better cardiovascular and renal safety relative to other sulphonylureas It has proven benefits for long-term microvascular disease outcomes	A
Glibenclamide must not be used at primary care level	A
Consider gliclazide modified-release as initial monotherapy when metformin is not tolerated or is contraindicated	B
Consider gliclazide modified-release as add-on (dual therapy) to metformin (or other initial drug therapy) in most patients not achieving or maintaining their glycaemic targets	A
If not already in use, consider gliclazide modified-release as a third glucose lowering drug	A
To convert treatment from another sulphonylurea to gliclazide modified-release, use the following dose conversion: Glibenclamide 5 mg ≈ Gliclazide modified-release 30 mg Glimepiride 1-2 mg ≈ Gliclazide modified-release 30 mg	C
Only continue gliclazide modified-release beyond stage 3 chronic kidney disease (when the eGFR is less 30 ml/min/m2) with specialist supervision	C
Circumstances where gliclazide MR may be preferred to other treatment options: Gliclazide MR should be the preferred second drug for the majority of patients with type 2 diabetes At diagnosis when rapid control of hyperglycaemic symptoms is required	C
Circumstances where gliclazide MR may not be the preferred option: The individualised glycaemic target is ≤ 6.5% (as the risk of hypoglycaemia may be unacceptably high with this target) There is a history of severe hypoglycaemia or hypoglycaemia unawareness There is a history of recurrent hypoglycaemia (any degree) despite dose adjustments The risk of hypoglycaemia is high and/or its consequences are severe The patient has advanced liver disease

 

Caution:

Do not persist with any chosen treatment if the HbA1C has not decreased by > 0.5% after six months

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