Background information of the condition
Type 2 Diabetes Mellitus: is a chronic disease in which the pancreas is not making, or the body is not appropriately using insulin. It is associated with increased risk of cardiovascular disease, limb amputation, retinopathy, nephropathy and neuropathy and premature death. If diet and exercise do not control symptoms from elevated blood sugar; drug therapy is added. The main oral anti-hyperglycaemic drugs are sulphonylureas (glibenclamide, glimepiride), meglitinide analogues (repaglinide, nateglinide), biguanides (metformin), alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) and thiazolidinediones (rosiglitazone, pioglitazone).
Effectiveness of therapy in type 2 diabetes mellitus
The United Kingdom Prospective Diabetes Study (UKPDS 33) trial assessed morbidity and mortality with 10-year treatment with sulfonylureas in people with type 2 diabetes. This study randomized newly diagnosed Type 2 diabetics (N = 3867) to conventional therapy or intensive therapy with sulfonylureas (chlorpropamide 100-500mg, glibenclamide 2.5 to 20mg and glipizide 2.5 to 10mg) or insulin. Conventional therapy included drug treatment only if fasting blood glucose was >15mmol/L or symptoms of hyperglycemia developed. Intensive treatment with glibenclamide predominantly reduced the microvascular complication, retinopathy requiring photocoagulation. Cardiovascular events were not significantly reduced; there was a trend towards reduction in total MI, 14.2% v 16.3%, p=0.052. There were no significant differences in clinical outcome between the different sulfonylureas or insulin. Over the first 10 years intensive therapy increased major hypoglycemic episodes: chlorpropamide (1%), glibenclamide (1.4%), insulin (1.8%) and conventional treatment (0.7%). Intensive therapy also caused greater weight gain than conventional therapy: insulin (4.0 kg), chlorpropamide (2.6 kg) and glibenclamide (1.7 kg).
In the same trial (UKPDS 34) 1704 overweight diabetic patients were randomized to metformin, conventional therapy or intensive treatment with sulfonylureas or insulin. Treatment with sulphonylureas and insulin had no significant benefit on the occurrence of microvascular or macrovascular end points over 10 years in this obese population.
Category (according to Product monograph): Gliclazide is a hypoglycemic agent of the sulfonylurea class.
Mechanism of action (according to Product Monograph): The hypoglycemic action of gliclazide is related to an improvement in insulin secretion from the functioning beta cells of the pancreas. It potentates the insulin release, improves the dynamics of insulin.
Indication (according to Health Canada): “for control of hyperglycemia in gliclazide responsive diabetes mellitus of stable, mild, non-ketosis prone, maturity onset or adult type which cannot be controlled by proper dietary management and exercise, or when insulin therapy is not appropriate”.
Dose: The recommended daily dosage is 80 to 320mg, starting with 160mg/day.
Duration: patients with diabetes mellitus require life-long therapy.
Methodology of systematic review
Research question: In DB, RCTs, does gliclazide provide a therapeutic advantage in terms of mortality and/or morbidity versus other sulfonylureas (glimepiride, glyburide, chlorpropamide and tolbutamide) in adult patients with Type 2 diabetes mellitus?
Assessment principles: Double blind randomized controlled trials of at least 3 months duration comparing glicazide to other sulfonylureas in patients with Type 2 diabetes will be included and critically appraised. Randomization and blinding are required for assessment of outcomes of diabetes treatments, as glucose control reflects not only drug therapy, but also patient dietary and exercise habits. As a result, even objective outcomes measures (for example biochemical markers of blood glucose) are subject to bias in open label trials.
The overall health impact will be assessed according to the following hierarchy: cause mortality (including diabetes-related death from myocardial infarction, stroke, peripheral vascular disease, renal disease, and hyper- or hypoglycaemia or sudden death); serious adverse events including diabetes-related morbidity: retinopathy, nephropathy, neuropathy, amputation, cardiovascular events (myocardial infarction, stroke, peripheral vascular disease), and hyper- or hypoglycemic episodes; diabetes-related symptoms (polyuria, polydypsia, polyphagia); and glycemic control including glycated haemoglobin (HbA1c and blood glucose levels).
Search strategy: Databases searched: (Medline, Embase and Cochrane Library from 1996 to January 2007), the manufacturer’s submission, and references of review articles.
Search findings: Four double blind randomized controlled trials comparing gliclazide vs glibenclamide met the inclusion criteria for critical appraisal.
- Jenning et al 2000: N=30 patients with retinopathy or incipient nephropathy for 6 months;
- Tessier et al1994: N=22 patients >65 years for 6 months;
- Baba et al 1983: N=289 patients for 6 months;
- Jerum et al 1987: N= 19 patients for 24 months).
One trial comparing gliclazide to glimepiride (Tsumura et al 1995, phase 3: N = 460 for 6 months) met the inclusion criteria for critical appraisal.
Gliclazide vs glibenclamide: 4 trials
Total serious adverse events were not reported in any of the trials. Mortality was not reported in 3 trials. Baba et al 1983 trial reported one death in glibenclamide treated patient due to heart disease.
One trial in 19 patients (Jerum et al 1987) reported on diabetic nephropathy and retinopathy and showed no significant difference between gliclazide versus glibenclamide over 2 years.
Two trials Tessier et al 1994 trial and Baba et al 983 reported on hypoglycemic events and showed no significant difference between gliclazide and glibenclamide in elderly patients experiencing hypoglycemic events. Diabetes-related symptoms are not reported in any trial. There were no significant differences in HbA1c in 3 trials (Jenning et al 2000, Tessier et al 1994, Jerum et al 1987). Baba et al 1983 did not report HbA1c values.
Gliclazide vs glimepiride: 1 trial
Tsumura et al 1995 did not report on mortality, serious adverse events and diabetes- related symptoms were not reported in trial. There was no significant difference in hypoglycemia or HbA1c between the two treatment groups. Total adverse events were not reported.
Summary and Conclusions:
No published double blind RCTs have assessed effectiveness of gliclazide therapy in terms of mortality or non-fatal serious adverse events in adult patients with non-insulin dependent diabetes mellitus. Gliclazide did not show a therapeutic advantage in terms of hypoglycemic episodes or HbA1c levels compared to glibenclamide or glimperide.
Therefore, there is insufficient evidence from double blind randomized trials that gliclazide provides a therapeutic advantage over other sulfonylurea drugs in adult patients with non- insulin dependent diabetes mellitus.
- UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with suphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-53.
- UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854-65.
- Product monograph (e-CPS, 2007).
- Jennings PE, Belch JJ. Free radical scavenging activity of sulfonylureas: a clinical assessment of the effect of gliclazide. Metabolism 2000, 49:23-26.
- Tessier D. Dawson K. Tetrault JP. Bravo G. Meneilly GS. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Diabet Med 1994, 11: 974-80, 1994.
- Baba S. Nakagawa S. Takebe K. Goto Y. Maezawa H. Takeda R. Sakamoto N. Fukui I. Comparison of gliclazide and glibenclamide treatment in non-insulin-dependent diabetes. J Exp Med 1983, 141: 693-706.
- Jerums G. Murray RM. Seeman E. Cooper ME. Edgley S. Marwick K. Larkins RG. Martin TJ. Lack of effect of gliclazide on early diabetic nephropathy and retinopathy: a two-year controlled study. Diabet Res Clin Pract 1987, 3: 71-80.
- Tsumura K. Clinical evaluation of glimepiride (HOE490) in NIDDM, including a double blind comparative study versus gliclazide. Diabet Res Clin Pract 1995, 28 Suppl:S147-9.