The increasing burden of type 2 diabetes (T2D), in relation to alarming rise in the prevalence; challenges in the diagnosis, prevention, and treatment; as well as the substantial impact of disease on longevity and quality of life, is a major concern in healthcare worldwide. Sulfonylureas (SUs) have been a cornerstone of T2D pharmacotherapy for over 60 years as oral antidiabetic drugs (OADs), while the newer generation SUs, such as gliclazide modified release (MR), are known to be associated with low risk of hypoglycemia in addition to the cardiovascular neutrality. This scoping review aimed to specifically address the current position of gliclazide MR among other SUs in the contemporary treatment paradigm for T2D and to provide a practical guidance document to assist clinicians in using gliclazide MR in real-life clinical practice. The main topics addressed in this paper include the role of early and sustained glycemic control and use of SUs in T2D management, the properties of gliclazide MR in relation to its effectiveness and safety, the use of gliclazide therapy in special populations, and the place of SUs as a class and gliclazide MR specifically in the current T2D treatment algorithm.

Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors.

To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin.

MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions.

Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers.

We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP).

There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking.

Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK).

The National Institute for Health Research Health Technology Assessment programme.

The risk of hypoglycaemia may differ among sulphonylureas (SUs), but evidence from head-to-head comparisons is sparse. Performing a network meta-analysis to use indirect evidence from randomized controlled trials (RCTs), we compared the relative risk of hypoglycaemia with newer generation SUs when added to metformin.

A systematic review identified RCTs lasting 12-52 weeks and evaluating SUs added to inadequate metformin monotherapy (≥1000 mg/day) in type 2 diabetes. Adding RCTs investigating the active comparators from the identified SU trials, we established a coherent network. Hypoglycaemia of any severity was the primary end point.

Thirteen trials of SUs and 14 of oral non-SU antihyperglycaemic agents (16 260 patients) were included. All reported hypoglycaemia only as adverse events. Producing comparable reductions in HbA_1C of -0.66 to -0.84% (-7 to -9 mmol/mol), the risk of hypoglycaemia was lowest with gliclazide compared to glipizide (OR 0.22, CrI: 0.05 to 0.96), glimepiride (OR 0.40, CrI: 0.13 to 1.27), and glibenclamide (OR 0.21, CrI: 0.03 to 1.48). A major limitation is varying definitions of hypoglycaemia across studies.

When added to metformin, gliclazide was associated with the lowest risk of hypoglycaemia between the newer generation SUs. Clinicians should consider the risk of hypoglycaemia agent-specific when selecting an SU agent.

Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide. Whether sulphonylureas show better, equal or worse therapeutic effects in comparison with other antidiabetic interventions for patients with T2DM remains controversial.

To assess the effects of sulphonylurea monotherapy versus placebo, no intervention or other antidiabetic interventions for patients with T2DM.

We searched publications in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS and CINAHL (all until August 2011) to obtain trials fulfilling the inclusion criteria for our review.

We included clinical trials that randomised patients 18 years old or more with T2DM to sulphonylurea monotherapy with a duration of 24 weeks or more.

Two authors independently assessed the risk of bias. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were other patient-important outcomes and metabolic variables. Where possible, we used risk ratios (RR) with 95% confidence intervals (95% CI) to analyse the treatment effect of dichotomous outcomes. We used mean differences with 95% CI to analyse the treatment effect of continuous outcomes. We evaluated the risk of bias. We conducted trial sequential analyses to assess whether firm evidence could be established for a 10% relative risk reduction (RRR) between intervention groups.

We included 72 randomised controlled trials (RCTs) with 22,589 participants; 9707 participants randomised to sulphonylureas versus 12,805 participants randomised to control interventions. The duration of the interventions varied from 24 weeks to 10.7 years. We judged none of the included trials as low risk of bias for all bias domains. Patient-important outcomes were seldom reported.First-generation sulphonylureas (FGS) versus placebo or insulin did not show statistical significance for all-cause mortality (versus placebo: RR 1.46, 95% CI 0.87 to 2.45; P = 0.15; 2 trials; 553 participants; high risk of bias (HRB); versus insulin: RR 1.18, 95% CI 0.88 to 1.59; P = 0.26; 2 trials; 1944 participants; HRB). FGS versus placebo showed statistical significance for cardiovascular mortality in favour of placebo (RR 2.63, 95% CI 1.32 to 5.22; P = 0.006; 2 trials; 553 participants; HRB). FGS versus insulin did not show statistical significance for cardiovascular mortality (RR 1.36, 95% CI 0.68 to 2.71; P = 0.39; 2 trials; 1944 participants; HRB). FGS versus alpha-glucosidase inhibitors showed statistical significance in favour of FGS for adverse events (RR 0.63, 95% CI 0.52 to 0.76; P = 0.01; 2 trials; 246 participants; HRB) and for drop-outs due to adverse events (RR 0.28, 95% CI 0.12 to 0.67; P = 0.004; 2 trials; 246 participants; HRB).Second-generation sulphonylureas (SGS) versus metformin (RR 0.98, 95% CI 0.61 to 1.58; P = 0.68; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 0.92, 95% CI 0.60 to 1.41; P = 0.70; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.79 to 1.18; P = 0.72; 4 trials; 1642 participants; HRB), meglitinides (RR 1.44, 95% CI 0.47 to 4.42; P = 0.52; 7 trials; 2038 participants; HRB), or incretin-based interventions (RR 1.39, 95% CI 0.52 to 3.68; P = 0.51; 2 trials; 1503 participants; HRB) showed no statistically significant effects regarding all-cause mortality in a random-effects model. SGS versus metformin (RR 1.47; 95% CI 0.54 to 4.01; P = 0.45; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 1.30, 95% CI 0.55 to 3.07; P = 0.55; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.73 to 1.28; P = 0.80; 4 trials; 1642 participants; HRB) or meglitinide (RR 0.97, 95% CI 0.27 to 3.53; P = 0.97; 7 trials, 2038 participants, HRB) showed no statistically significant effects regarding cardiovascular mortality. Mortality data for the SGS versus placebo were sparse. SGS versus thiazolidinediones and meglitinides did not show statistically significant differences for a composite of non-fatal macrovascular outcomes. SGS versus metformin showed statistical significance in favour of SGS for a composite of non-fatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93; P = 0.02; 3018 participants; 3 trials; HRB). The definition of non-fatal macrovascular outcomes varied among the trials. SGS versus metformin, thiazolidinediones and meglitinides showed no statistical significance for non-fatal myocardial infarction. No meta-analyses could be performed for microvascular outcomes. SGS versus placebo, metformin, thiazolidinediones, alpha-glucosidase inhibitors or meglitinides showed no statistical significance for adverse events. SGS versus alpha-glucosidase inhibitors showed statistical significance in favour of SGS for drop-outs due to adverse events (RR 0.48, 95% CI 0.24 to 0.96; P = 0.04; 9 trials; 870 participants; HRB). SGS versus meglitinides showed no statistical significance for the risk of severe hypoglycaemia. SGS versus metformin and thiazolidinediones showed statistical significance in favour of metformin (RR 5.64, 95% CI 1.22 to 26.00; P = 0.03; 4 trials; 3637 participants; HRB) and thiazolidinediones (RR 6.11, 95% CI 1.57 to 23.79; P = 0.009; 6 trials; 5660 participants; HRB) for severe hypoglycaemia.Third-generation sulphonylureas (TGS) could not be included in any meta-analysis of all-cause mortality, cardiovascular mortality or non-fatal macro- or microvascular outcomes. TGS versus thiazolidinediones showed statistical significance regarding adverse events in favour of TGS (RR 0.88, 95% CI 0.78 to 0.99; P = 0.03; 3 trials; 510 participants; HRB). TGS versus thiazolidinediones did not show any statistical significance for drop-outs due to adverse events. TGS versus other comparators could not be performed due to lack of data.For the comparison of SGS versus FGS no meta-analyses of all-cause mortality, cardiovascular mortality, non-fatal macro- or microvascular outcomes, or adverse events could be performed.Health-related quality of life and costs of intervention could not be meta-analysed due to lack of data.In trial sequential analysis, none of the analyses of mortality outcomes, vascular outcomes or severe hypoglycaemia met the criteria for firm evidence of a RRR of 10% between interventions.

There is insufficient evidence from RCTs to support the decision as to whether to initiate sulphonylurea monotherapy. Data on patient-important outcomes are lacking. Therefore, large-scale and long-term randomised clinical trials with low risk of bias, focusing on patient-important outcomes are required.

Hypoglycaemia is a side effect caused by some therapies for type 2 diabetes, which can cause physical, social and psychological harm. Hypoglycaemia also prevents attainment of treatment goals and satisfactory glycaemic control.

The risk of hypoglycaemia associated with commonly prescribed therapies, including metformin, sulphonylureas, dipeptidyl peptidase-4 enzyme (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists and thiazolidinediones, is reviewed in this paper (insulin-induced hypoglycaemia is not included). Other medications that are frequently co-prescribed in type 2 diabetes are also discussed, including anti-hypertensive drugs, antibiotics and fibrates, along with various important patient-related risk factors.

Hypoglycaemia is a common and potentially dangerous side effect of some medications used for type 2 diabetes. The risk of hypoglycaemia should always be considered when selecting and implementing a therapy, with a focus on the individual. Future research into new therapies should measure the frequency of hypoglycaemia prospectively and accurately. Hypoglycaemia has been shown to be a potentially life-threatening metabolic stress; therefore therapies that effectively manage diabetes without the risk of hypoglycaemia are likely to be favoured in the future.

To determine if therapeutic management programmes for type 2 diabetes that include self-monitoring of blood glucose (SMBG) result in greater reductions in glycated haemoglobin (HbA1c) compared with programmes without SMBG in non-insulin requiring patients.

Multicentre, randomized, parallel-group trial. A total of 610 patients were randomized to SMBG or non-SMBG groups. Patients in both groups received the same oral antidiabetic therapy using a gliclazide modified release (MR)-based regimen for 27 weeks. The primary efficacy end-point was the difference between groups in HbA1c at the end of observation.

A total of 610 patients were randomized: 311 to the SMBG group and 299 to the non-SMBG group. HbA1c decreased from 8.12 to 6.95% in the SMBG group and from 8.12 to 7.20% in the non-SMBG group; between-group difference was 0.25% (95% CI: 0.06, 1.03; p = 0.0097). Symptoms suggestive of mild to moderate hypoglycaemia was the most commonly reported adverse event, reported by 27 (8.7%) and 21 (7.0%) patients in the SMBG and non-SMBG groups, respectively; the incidence of symptomatic hypoglycaemia was lower in the SMBG group.

In patients with type 2 diabetes, the application of SMBG as an adjunct to oral antidiabetic agent therapy results in further reductions in HbA1c.

The purpose of this study was to develop an extended release tablet formulation containing gliclazide as a model drug by optimization technique. A central composite design was employed with pH-dependent matrix forming polymers like keltone-HVCR (X1) and eudragit-EPO (X2) as independent variables. Five dependent variables were considered: hardness, percent drug release after 1 hr, percent drug release after 6 hr, diffusion exponent and time required for 50% of drug release. Response surface methodology and multiple response optimization utilizing a quadratic polynomial equation were used to obtain an optimal formulation. The results indicate that Factor X1 along its interaction with Factor X2 was found to be significantly affecting the studied response variables. An optimized formulation, containing 8 mg of keltone-HVCR and 14.10mg of eudragit-EPO, provides a sufficient hardness (> 4.5 kg/cm2) and optimal release properties. The desirability function was used to optimize the response variables, each having a different target and the observed responses were highly agreed with experimental values. The release kinetics of gliclazide from optimized formulation followed zero-order release pattern. The dissolution profiles of optimized formulation before and after stability studies were evaluated by using similarity factor (f2) and were found to be similar. The results demonstrate the feasibility of the model in the development of extended release dosage form.

Gliclazide-modified release (gliclazide MR) is a new formulation of the sulfonylurea gliclazide designed for once-daily administration. The hydrophilic matrix of hypromellose-based polymer in the new formulation induces a progressive drug release, which parallels the 24-h glycaemic profile in type 2 diabetic patients. The aim of this study was to compare the efficacy and safety of gliclazide MR (once-daily administration) versus gliclazide (twice-daily administration) in Chinese type 2 diabetic patients.

Sixty-three type 2 diabetic Chinese patients who had been on diet control alone or on treatment with metformin or on low dose of sulfonylurea were randomized to either gliclazide MR taken once daily or gliclazide taken twice daily. Dosage of metformin was maintained throughout the study, and the sulfonylurea was stopped. The dose of gliclazide MR was increased at 1-month intervals from 30 mg to 120 mg, while that of gliclazide from 80 mg to 320 mg until metabolic control was achieved [fasting plasma glucose (FPG) < or = 7.7 mmol/l] or the maximum dose reached. Efficacy was mainly evaluated by levels of haemoglobin A1c (HbA1c) and FPG.

The mean baseline characteristics of the full analysis set 1 (FAS1) (HbA1c, n = 58) and the FAS2 (FPG, n = 61) were comparable in both groups. The levels of HbA1c decreased similarly in both groups over the treatment period: -1.6 +/- 1.6% (p < 0.001) on gliclazide MR (n = 31) and -1.6 +/- 1.4% (p < 0.001) on gliclazide (n = 27). Decrease in HbA1c was observed irrespective of pre-existing therapy for diabetes: -2.3 +/- 1.5% for patients on diet alone; -0.6 +/- 1.3% for patients switched from sulfonylurea to study drug and -1.4 +/- 0.8% for patients on metformin in combination with study drug. FPG decreased significantly from 177.5 +/- 63.5 to 136.7 +/- 42.2 (p < 0.001, n = 32) on gliclazide MR and not significant from 188.2 +/- 62.6 to 163.7 +/- 67.9 (p = 0.059, n = 29) on gliclazide. Both treatments were very well tolerated with no major hypoglycaemic episodes requiring external assistance; only three patients experienced mild hypoglycaemic episodes.

Once-daily gliclazide MR showed a better trend in improving blood glucose control in comparison with gliclazide in type 2 diabetic Chinese patients irrespective of the pre-existing anti-diabetic treatment. The safety profiles of gliclazide MR and gliclazide were similar with a small number of patients having reported hypoglycaemic episodes. Once-daily dosing with gliclazide MR should improve patient compliance, an important factor in long-term glycaemic control.

Sulphonylureas are widely used in the management of type 2 diabetes. The effectiveness of treatment with oral antidiabetic drugs depends largely on patient compliance. The objective of the DIACOM (effect of DosIng frequency of oral Antidiabetic agents on the COMpliance and biochemical control of type 2 diabetes) study was to compare the compliance of patients treated with once-daily (od) or twice-daily (bid) sulphonylureas.

One hundred and five patients, previously treated with glibenclamide, were randomized to receive gliclazide in modified-release formulation (MR) once daily or glibenclamide twice daily for 16 weeks, using an electronic monitoring system (MEMS).

A significant difference in compliance was observed between the two groups. The overall compliance was 93.5+/-14.0% in the once-daily gliclazide MR group and 87.2+/-21.1% in the twice-daily glibenclamide group (p<0.05), and the correct number of doses was taken on 86.3+/-15.4 and 66.9+/-29.0% of treatment days respectively (p<0.0001). The percentage of missed doses was 9.3+/-12.5% in the once-daily group and 17.5+/-18.0% in the twice-daily group (p<0.01). The percentage of doses taken in the correct time window and correct inter-dose interval was higher in the once-daily group, as was therapeutic coverage. Patients in the gliclazide MR group also achieved significantly better glycaemic control [fasting plasma glucose and glycated haemoglobin (HbA(1c))] than those treated with glibenclamide (p<0.0001).

The study demonstrates that patient compliance with once-daily gliclazide MR is significantly better than with twice-daily glibenclamide. Consistently better efficacy was observed for short-term (fasting glucose) and long-term glycaemic control (HbA(1c)) in the once-daily group. These results demonstrate the possible therapeutic advantages of once-daily agents over twice-daily agents in the treatment of type 2 diabetes.

To evaluate the efficacy and safety of gliclazide modified release (MR), alone or combined with other oral antidiabetic drug(s) over 2 years in type 2 diabetic patients.

Two consecutive periods: (i) a 10-month, double-blind comparative study, where 800 type 2 diabetic patients were randomized either to gliclazide MR (30-120 mg) once daily or to gliclazide (80-320 mg) twice daily. All the patients were then treated with gliclazide MR for a 2-month switch period; (ii) 549 patients were subsequently enrolled in a 12-month, open-label period on gliclazide MR alone or in combination according to glycaemic control, 507 of whom completed the study.

Glycated haemoglobin (HbA1c) significantly decreased from baseline over 2 years by -0.46 +/- 1.08% in the whole cohort of 2-year completed patients, -0.95% in the subgroup of diet-failed patients and by -0.34% in the subgroup of patients pretreated with one oral antidiabetic drug. HbA1c was reduced by -0.43 +/- 1.02% and by -0.51 +/- 1.16%, when gliclazide MR was used in monotherapy and in combination therapy, respectively. The overall incidence of symptoms suggestive of hypoglycaemia was 4.8 episodes/100 patient-year, with no severe episode. This incidence was similarly low in elderly patients and patients with impaired renal function.

Gliclazide MR alone or in combination with another oral antidiabetic drug significantly improved glycaemic control in type 2 diabetic patients over 2 years with a very good safety profile, notably in the elderly and in patients with impaired renal function.

Progressive beta-cell failure is a characteristic feature of type 2 diabetes; consequently, beta-cell secretagogues are useful for achieving sufficient glycaemic control. The European GUIDE study is the first large-scale head-to-head comparison of two sulphonylureas designed for once-daily administration used under conditions of everyday clinical practice.

Eight hundred and forty-five type 2 diabetic patients were randomized to either gliclazide modified release (MR) 30-120 mg daily or glimepiride 1-6 mg daily as monotherapy or in combination with their current treatment (metformin or an alpha-glucosidase inhibitor) according to a double-blind, 27-week, parallel-group design. Efficacy was evaluated by HbA1c and safety by hypoglycaemic episodes using the European Agency definition.

HbA1c decreased similarly in both groups from 8.4% to 7.2% on gliclazide MR and from 8.2% to 7.2% on glimepiride. Approximately 50% of the patients achieved HbA1c levels less than 7%, and 25% less than 6.5%. The mean difference between groups of the final HbA1c was -0.06% (noninferiority test P < 0.0001). No hypoglycaemia requiring external assistance occurred. Hypoglycaemia with blood glucose level < 3 mmol L(-1) occurred significantly less frequently (P = 0.003) with gliclazide MR (3.7% of patients) compared with glimepiride (8.9% of patients). The distribution of the sulphonylurea doses was similar in both groups.

This study provides new insights into therapeutic strategies using sulphonylureas. It shows that gliclazide MR is at least as effective as glimepiride, either as monotherapy or in combination. The safety of gliclazide MR was significantly better, demonstrating approximately 50% fewer confirmed hypoglycaemic episodes in comparison with glimepiride.

Gliclazide modified release (MR) is a new formulation of the drug gliclazide and is given once daily. The specifically designed hydrophilic matrix of gliclazide MR leads to a progressive drug release that parallels the 24-hour glycemic profile in type 2 diabetic patients. Development studies showed a sustained efficacy over 2 years coupled with a very good acceptability. Gliclazide MR acts selectively on adenosine triphosphate-dependent potassium (K(ATP)) channels of the pancreatic beta cell. No interaction with cardiovascular K(ATP) channels has been shown, indicating that the drug can be safely used in patients with ischemic heart disease. In addition, gliclazide MR shows the ability to inhibit key mechanisms in diabetic angiopathy, independently of glycemic control.

Hypoglycaemic agents such as sulphonylureas and the newer group of "glinides" stimulate insulin secretion by closing ATP-sensitive potassium (K(ATP)) channels in pancreatic beta cells, but have varying cross-reactivity with related channels in extrapancreatic tissues such as heart, vascular smooth and skeletal muscle. Experiments on the structure-function relationships of recombinant K(ATP) channels and the phenotypes of mice deficient in different K(ATP) channel subunits have provided important insights into the mechanisms underlying sulphonylurea selectivity, and the potential consequences of K(ATP) channel blockade outside the pancreatic beta cell. The different pharmacological properties of K(ATP) channels from beta cells compared with those from cardiac, smooth and skeletal muscle, are accounted for by the expression of alternative types of sulphonylurea receptor, with non-identical drug binding sites. The sulphonylureas and glinides are found to fall into two groups: one exhibiting selectivity for beta cell sulphonylurea receptors (SUR1), and the other blocking cardiovascular and skeletal muscle sulphonylurea receptors (SUR2) with potencies similar to their action on SUR1. In seeking potential side effects of K(ATP) channel inhibitors in humans, it is essential to take these drug differences into account, along with the probability (suggested by the studies on K(ATP) channel knockout mice) that the effects of extrapancreatic K(ATP) channel inhibition might be either subtle or rare. Further studies are still required before a final decision can be made on whether non-selective agents are appropriate for the therapy of Type 2 diabetes.

To study the relationship between the pharmacokinetics (PK) of gliclazide and its long-term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability.

A PKPD database of 634 Type 2 diabetic patients with a total of 5,258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease-progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR.

Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half-life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l(-1) year(-1) (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1-year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control.

This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long-term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control.

Gliclazide modified release (MR) is a new formulation of the drug gliclazide and is given once daily. The hydrophilic matrix of hypromellose-based polymer in the new formulation effects a progressive release of the drug which parallels the 24-hour glycaemic profile in untreated patients with type 2 diabetes mellitus. The formulation shows high bioavailability and its absorption profile is unaffected by coadministration with food. Mean plasma glucose levels are significantly reduced over a 24-hour period in patients with type 2 diabetes mellitus treated with gliclazide MR once daily, in both fasting and postprandial states. No cardiovascular ATP-sensitive potassium channel interaction has been observed at therapeutic concentrations of gliclazide MR. Gliclazide MR has also demonstrated antioxidant properties that are independent of glycaemic control. In a randomised, double-blind, multicentre study, gliclazide MR 30 to 120 mg once daily showed similar efficacy to gliclazide immediate release (IR) 80 to 320 mg/day (in divided doses for doses >80 mg) in patients with type 2 diabetes mellitus over a 10-month period, reducing glycosylated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) to a similar extent. The drug appeared most efficacious in patients who had previously been treated by diet alone, where significant reductions in HbA(1c) from baseline of 0.9% and 0.95% were seen at 10 and 24 months. Similarly, a sustained effect of gliclazide MR was observed in a subgroup of elderly patients defined a priori; HbA(1c) was decreased to a similar degree to that observed in the general study population. Gliclazide MR showed similar tolerability to gliclazide IR after 10 months' treatment in the randomised trial. The most commonly observed adverse events were arthralgia, arthritis, back pain and bronchitis (each <5%). Bodyweight remained stable. In this study no episodes of nocturnal hypoglycaemia or hypoglycaemia requiring third party assistance were observed during treatment with gliclazide MR. Episodes of symptomatic hypoglycaemia were infrequent, occurring in approximately 5% of patients.