Sulphonylureas act by binding to sulphonylurea receptors on pancreatic β-cells, leading to increased secretion of insulin [4]. Gliclazide is a second generation sulphonylurea that is widely used in the treatment of patients with Type 2 diabetes because it has similar efficacy to other sulphonylureas but a lower risk of hypoglycaemia [5,6]. Nateglinide is a rapid-onset insulinotropic agent unrelated to sulphonylureas [7,8]. Because its effect on insulin secretion subsides when glucose levels fall, nateglinide has less potential to elicit hypoglycaemia than sulphonylureas [9]. Furthermore, nateglinide has minimal or no effect on body weight, also probably because its insulinotropic effects are limited to the postprandial period and thus nateglinide does not increase overall insulin exposure [10].

Eligible patients received either nateglinide (Starlix, Novartis Pharma, Basel, Switzerland) or gliclazide in combination with metformin during the 24-week period. Randomization to treatment was by a computer-generated schedule via an interactive voice-responding system that assigned randomization on a study-centre basis with a block size of 4. A double-dummy technique, using identical-looking nateglinide and placebo tablets and identical-looking gliclazide and placebo capsules, was used to blind study medication assignment. Treatment regimens of nateglinide and gliclazide were started at the lowest levels (60 mg three times a day before meals and 80 mg once per day, respectively) and were titrated to the next dose level on a monthly basis up to a maximum of 180 mg before meals and 240 mg per day, respectively, during the first 3 months. Dose levels of study medication were increased if the fasting plasma glucose (FPG) level was > 7 mmol/l, if the patient had not experienced any confirmed hypoglycaemic events (symptomatic and/or asymptomatic events with plasma glucose concentration ≤ 4.0 mmol/l) and if the patient had not experienced more than three hypoglycaemic events in the past month.

Efficacy was determined from the change in HbA_1c levels from baseline to end point. Treatments were also assessed for the percentage of patients reaching a treatment target (end point HbA_1c < 7% and/or a decrease ≥ 0.5% HbA_1c), FPG and body weight after 24 weeks of double-blind treatment. At baseline and after 24 weeks, patients attended the clinic after an overnight fast and received a standard breakfast consisting of 180 ml orange juice (grapefruit juice was not allowed), 60 g of bread (white, wheat or rye), 20 g jam or preserves, 10 g butter or margarine, 120 ml whole milk (3–4% fat) or the equivalent amount of cheese plus 120 ml water, and decaffeinated coffee or tea if desired. The meal was consumed within 15 min and blood samples were taken at 0, 15, 30, 60, 90, 120, 180 and 240 min. Glucose and insulin concentrations were measured and excursions were calculated from the difference between fasting and postprandial levels; the area under the glucose curve from 0 to 4 h (AUC_{0−4 h}), adjusted for pre-meal values, was calculated for patients who had at least six measurements. In addition, insulin secretion index was calculated as: homeostatis model assessment (HOMA)-B = [20 × fasting insulin (mU/l)]/[fasting glucose (mmol/l) – 3.5].

Determinations of HbA_1c and glucose and insulin from the meal tests were carried out at two central laboratories, one in Europe and one in the USA. Additionally, all patients were provided with glucose-monitoring devices and supplies, and were instructed on their use. Hypoglycaemic events were analysed according to whether they were asymptomatic, symptomatic or confirmed events; number of hypoglycaemic clinical symptoms and incidence rate (number of symptoms per 100 patients per month) were also determined. Symptoms suggestive of hypoglycaemia were tachycardia, palpitations, shakiness, sweating and dizziness, hunger, blurred vision, impairment of motor function, confusion or inappropriate behaviour. An event was considered as confirmed if the self-monitored plasma glucose value obtained at the time of the event was ≤ 4.0 mmol/l (corresponding to blood glucose value of ≤ 3.6 mmol/l) or if hypoglycaemia was classified as grade 2 (i.e. an episode with sufficient neurological impairment that the patient was unable to initiate self-treatment and required assistance or hospitalization). The incidence rate of hypoglycaemic events per 100 patients per month was calculated as [(total number of events across all patients)/(total duration on treatment in days)] × 30 × 100. All adverse events were recorded; they were defined as serious if they were fatal, life-threatening, required prolonged hospitalization, resulted in persistent or significant disability/incapacity, constituted a congenital anomaly/birth defect or were considered medically significant. For each adverse event, the relationship to study drug treatment was classified by the investigator as suspected or not suspected.

During the study, 33 patients discontinued treatment prematurely; 13 (9.8%) patients from the nateglinide group (two as a result of adverse events, one lost to follow-up, nine who withdrew consent and one because of an unsatisfactory therapeutic effect) and 20 (15.5%) patients from the gliclazide group (eight due to adverse events, four lost to follow-up, six who withdrew consent and two because of protocol violations).

The mean metformin doses at study entry were comparable (1921 and 1812 mg/day in the nateglinide and gliclazide groups, respectively). The majority of patients in the nateglinide group (59.4%) were titrated up to the highest dose level (180 mg three times/day), compared with 35.7% of patients in the gliclazide group attaining the highest dose level (240 mg/day).

The number of patients showing an improvement in HbA_1c was similar for both treatments. However, fewer patients in the nateglinide combination group achieved the target HbA_1c of less than 7.0% at end point than in the gliclazide group. A small difference in baseline HbA_1c, slightly higher in nateglinide plus metformin (7.66%) compared with gliclazide plus metformin (7.57%), may account for this result. Supporting this, the composite efficacy criteria, i.e. merging an improvement of at least 0.5% or achieving an HbA_1c less than 7.0%, showed the treatments were comparable.

The changes in FPG concentrations mirrored those observed for HbA_1c. Measures of post-meal glucose control and prandial insulin secretion were either significantly better in the group of patients treated with nateglinide plus metformin or showed a corresponding trend. Control of postprandial hyperglycaemia is believed to have more of an impact on both micro- and macrovascular risk factors than reduction of elevated fasting glucose levels [15]. In a meta-analysis of studies of mortality in relation to glycaemia, the 2-h blood glucose level was more predictive of all-cause and cardiovascular death than FPG [16].

Nateglinide and gliclazide were both well tolerated and the incidence of adverse events was similar in either group. The number of hypoglycaemic events, particularly asymptomatic events, was higher than seen in previous trials with nateglinide. However, this was likely to be because of the recommendation given to patients in the study to measure blood glucose regularly, independent of whether they were experiencing symptoms of hypoglycaemia. Also, the threshold value used to define hypoglycaemia was 4.0 mmol/l, which was relatively high compared with the level used routinely in many other clinical trials.