Electrophysiological studies in newly onset type 2 diabetes without visible vascular retinopathy.

The purpose of this study was to investigate the early alterations of retinal function, assessed with electrophysiology, in newly onset type 2 diabetes patients without vascular retinopathy. Seventeen patients with newly diagnosed type 2 diabetes (duration 7±3 months), without any vascular retinopathy in fundus photographs, were examined with full-field electroretinogram (ERG) and multifocal ERG (mfERG). The results were compared with those of age-matched subjects without diabetes. In the dark-adapted full-field ERG, the a-wave and the 30-Hz flicker implicit times were delayed in diabetes patients compared to controls, P=0.001 and P=0.020. In the first-order kernel of the mfERG, the first positive wave, P1, was delayed in all areas measured. The electrophysiological examinations demonstrate early alterations of retinal function characterised by a delayed a-wave implicit time in the dark-adapted full-field ERG, representing the rod signalling, and alterations in the multifocal ERG reflecting cone and/or postreceptoral function.

Can sulphonylurea addition to lifestyle changes help to delay diabetes development in subjects with impaired fasting glucose? The Nepi ANtidiabetes StudY (NANSY).

The Nepi ANtidiabetes StudY (NANSY) is a 5-year randomized, double-blind, placebo-controlled trial in Swedish primary care, examining whether the development of type 2 diabetes (T2D) and retinopathy (separately reported) would be delayed in 40- to 70-year-old subjects with impaired fasting glucose (IFG) who, in addition to lifestyle changes, were treated with either placebo or low-dosage sulphonylurea (SU) (1-mg glimepiride; Amaryl). Of 274 subjects (163 men, 111 women), 138 were allocated to placebo (46.0% men, 56.8% women) and 136 to glimepiride (54.0% men, 43.2% women). The primary endpoint was conversion to diabetes. Average follow-up time was 3.71 years; 96 subjects converted to diabetes, 55 allocated to placebo and 41 to glimepiride (absolute difference 9.8%; p = 0.072). In conclusion, the study failed to support the notion that low-dose SU added to lifestyle changes in IFG subjects would help to delay the conversion to diabetes.

Retinopathy in subjects with impaired fasting glucose: the NANSY-Eye baseline report.

AIMS: Network for Pharmacoepidemiology (NEPI) Antidiabetes Study-Eye is a randomized placebo-controlled Swedish trial investigating if treatment with sulphonylurea, in addition to dietary regulation and increased exercise, delays the development of retinopathy in subjects with impaired fasting glucose (IFG). METHODS: Subjects were surveyed in primary care with repeated fasting blood glucose measurements. Those with a mean of two consecutive values >or=5.6 and <6.1 mmol/l were invited to participate. Baseline physical examination included blood pressure and body mass index (BMI). Fundus photos were taken in two fields using 35-mm diafilm. The alternative classification of the Wisconsin Epidemiologic Study of Diabetic Retinopathy was used to classify the retinopathy level. RESULTS: At baseline, 90 men and 64 women with IFG were photographed. Of these, 16 subjects (10%) had mild or very mild retinopathy. There was no difference in occurrence of retinopathy between subjects with known diagnosis of hypertension or not. However, subjects with retinopathy had significantly higher systolic (154 vs. 141 mmHg, p = 0.013) and diastolic (86 vs. 81 mmHg, p = 0.008) blood pressure levels independent of differences in age, sex and known hypertension. There was a corresponding difference in BMI, being greater in subjects with than in those without retinopathy (32.4 vs. 29.2 kg/m(2), p = 0.013). There were no associations between levels of fasting blood glucose or haemoglobin A1c, on the one hand, and retinopathy, on the other. CONCLUSION: Retinopathy may be present even before type 2 diabetes is manifest. It is associated with higher blood pressure levels and higher BMI values, that is, with predominant features of the metabolic syndrome.

Utilisation of antihyperglycaemic drugs in ten European countries: different developments and different levels.

AIMS/HYPOTHESIS: The aim of this study was to compare developments in the utilisation of antihyperglycaemic drugs (AHGDs) in ten European countries. SUBJECTS AND METHODS: Data on the yearly utilisation of insulin and oral AHGDs were collected from public registers in Denmark, Finland, Norway, Sweden, Belgium, England, Germany, Italy, Portugal and Spain, and were expressed as defined daily doses per 1,000 inhabitants per day. RESULTS: Total AGHD utilisation increased everywhere, but at different rates and levels. Insulin utilisation doubled in England and Germany, but hardly changed in Belgium, Portugal or Italy. Sulfonylurea utilisation doubled in Spain, England and Denmark but was reduced in Germany and Sweden. Metformin utilisation increased greatly everywhere. There were two- to three-fold differences in AHGD utilisation even between neighbouring countries. In Finland, there were more users of both insulin (+120%) and oral AHGDs (+80%) than in Denmark, and the daily oral AHGD doses were higher. In Denmark and Sweden, AHGD utilisation was equal in subjects aged <45 years, but in those >or=45 years of age, both insulin and oral AHGD utilisation were twice as high in Sweden. CONCLUSIONS/INTERPRETATION: The ubiquitous increase in AHGD utilisation, particularly metformin, seems logical, considering the increasing prevalence of type 2 diabetes and the results of the UK Prospective Diabetes Study. However, the large differences even between neighbouring countries are more difficult to explain, and suggest different habits and attitudes in terms of screening and management of type 2 diabetes.

Understanding adherence to official guidelines on statin prescribing in primary health care--a multi-level methodological approach.

OBJECTIVE: The aim was to investigate the role that municipalities and out-patient health care centres (HCCs) have in understanding adherence to official guidelines on statin prescribing. Our hypothesis was that after guideline publication, adherence to recommended statin prescription would increase and variance among HCCs and municipalities would decrease. Since multi-level regression analysis (MLRA) is a relatively new methodology in pharmacoepidemiology, we also aimed to explore the application of MLRA in our investigation. METHODS: We obtained data from the Swedish Corporation of Pharmacies record of sales regarding all initial prescriptions of statins issued between April and December 2003. We applied multi-level analysis on 34,514 individual prescriptions (level 1) nested within 226 HCCs (level 2), which in turn were nested within 33 municipalities (level 3). Temporal trends and gender differences were investigated by means of random slope analysis. Variance was expressed using median odds ratio (MOR) and interval odds ratio. RESULTS: HCCs appeared to be more relevant than municipalities for understanding the physicians' propensity to prescribe a recommended statin (MOR(HCC) = 1.96 and MOR(Municipality) = 1.41). Overall prevalence of adherence was very low (about 20%). After publication of the guidelines, prescription of recommended statins increased, and variance among HCCs decreased but only during the first 4 months of the observation period. CONCLUSION: The publication of official guidelines in the county of Scania exerted a positive influence on statin prescription but, at the end of the observation period, adherence was still low and practice variation high. These facts may reflect inefficient therapeutic traditions and suggest that more intensive interventions may be necessary to promote rational statin prescription.

Inverse association between plasma homocysteine, sulphonylurea exposure and physical activity: a community-based sample of type 2 diabetes patients in the Skaraborg hypertension and diabetes project.

AIM: This study aimed to investigate levels of Homocysteine (tHcy) and folate in a population-based sample of patients with type 2 diabetes. In particular, the study explored modifiable determinants such as treatment for diabetes, life style, glucose control and kidney function. PATIENTS AND METHODS: In a community-based surveillance of patients with type 2 diabetes, 196 men and 191 women were consecutively identified in primary care and characterized by cardiovascular disease (CVD) risk factors focusing on components in the metabolic syndrome. For categorical associations plasma tHcy was dichotomized using the upper 10 percentiles of the distribution. RESULTS: Treatment with sulphonylurea was associated with lower serum levels of tHcy compared to those on diet alone. The association was confined to women [odds ratio 0.14; confidence interval 0.03-0.8] and remained significant when differences in factors related to the metabolic syndrome, life style and previous CVD were accounted for, but was lost when adjusted for HbA1c. There was an inverse dose-related association between physical activity and plasma levels of tHcy (men p = 0.006, women p = 0.034), and a positive association with serum levels of creatinine (men p = 0.004, women p < 0.001). CONCLUSIONS: The association with physical activity might be one contributing explanation for its well-known protective effect on cardiovascular disease. The over risk for vascular complications in diabetic patients with kidney disease may be partially explained by high levels of tHcy and should be further explored. Prospective studies are particularly needed on various treatment for type 2 diabetes and tHcy to explore possible implications for clinical procedures and for public health.

Metabolic disorders associated with uncontrolled hypertension.

AIM: To examine the prevalence and characteristics of uncontrolled hypertension (HT). METHODS: A cross-sectional community-based study (1992-93) was carried out in Skara, Sweden, including 894 patients who consecutively underwent an annual follow-up at the hypertension outpatient clinic in primary care. Controlled HT was defined as diastolic blood pressure (DBP) < or =90 mmHg and systolic blood pressure (SBP) < or =160 mmHg and was used as reference. Uncontrolled DBP was defined as DBP >90 mmHg regardless of SBP level, and isolated uncontrolled SBP was defined as SBP >160 mmHg and DBP < or =90 mmHg. Proportions were age-standardized using the Skara population as reference. RESULTS: The prevalence of uncontrolled HT was 43% (isolated uncontrolled SBP 18% and uncontrolled DBP 25%). Both men and women with isolated uncontrolled SBP were older (73 years, CI: 70-75; and 73 years; CI: 72-75) than patients with controlled HT (64 years, CI: 63-66; and 65 years, CI: 64-66). Men and women with known cardiovascular disease (CVD) less often had isolated uncontrolled SBP (OR: 0.4, CI: 0.2-0.9; and OR: 0.5, CI: 0.3-0.9), whereas men and women with known diabetes more often had uncontrolled DBP (OR: 2.3, CI: 1.3-4.1; and OR: 3.3, CI: 1.9-5.7). Men with known CVD less often had uncontrolled DBP (OR: 0.5, CI: 0.3-1.0, p = 0.04), and men with fasting blood glucose >5.5 mmol/l more often had isolated uncontrolled SBP (OR: 1.9, CI: 1.0-3.5, p = 0.04). In women, the following high risk factor levels were associated with uncontrolled DBP: fasting blood glucose >5.5 mmol/l (OR: 1.4, CI: 1.1-1.8), fasting triglycerides > or =1.7 mmol/l (OR: 1.4, CI: 1.1-1.8), body mass index (BMI) >30 kg/m2 (OR: 1.5, CI: 1.1-1.9), waist/hip ratio (WHR) >0.85 cm/cm (OR: 1.7, CI: 1.3-2.2), insulin resistance (homeostasis model assessment (HOMA) >third quartile) (OR: 1.4, CI: 1.1-1.9) and microalbuminuria (OR: 3.2, CI: 1.7-6.2). CONCLUSION: Uncontrolled DBP is in both sexes related to type 2 diabetes, whereas isolated uncontrolled SBP is related to older age. In women, uncontrolled DBP, furthermore, is related to several other CVD risk factors of the metabolic syndrome. Patients with uncontrolled DBP should be carefully evaluated for metabolic disorders.

Glycaemic control, disease duration and beta-cell function in patients with Type 2 diabetes in a Swedish community. Skaraborg Hypertension and Diabetes Project.

AIMS: To examine determinants for glycaemic control in primary care patients with Type 2 diabetes. METHODS: In a community-based surveillance of primary care patients with Type 2 diabetes, 190 men and 186 women were consecutively identified and examined for cardiovascular risk factors. Insulin resistance and beta-cell function were estimated using homeostasis model assessment (HOMA). Good glycaemic control was defined as HbA(1c) < 6.5%. RESULTS: Following adjustment for age and gender, HbA(1c) > or = 6.5% was associated with duration of diabetes (10.6 vs. 6.4 years, P < 0.001), lower levels of serum insulin (6.3 vs. 8.0 mU/l, P = 0.012), higher serum triglyceride levels (2.0 vs. 1.7 mmol/l, P = 0.002) and impairment of beta-cell function (HOMA index 19.5 vs. 45.8, P < 0.001). The association between HbA(1c) levels and duration remained with adjustment for age, gender, waist-hip ratio (WHR) and serum triglycerides (odds ratio (OR) for HbA(1c) > or = 6.5% by 5 years diabetes duration = 1.7; 95% confidence interval (CI) 1.4--2.1) but was lost following additional adjustment for beta-cell function (OR for HbA(1c) > or = 6.5% = 1.3; 95% CI 0.96-1.7). In a separate linear regression with beta-cell function as the dependent variable there was a significant association with HbA1c after adjustments for differences in age, gender, WHR, serum triglyceride levels and diabetes duration (P < 0.001). CONCLUSIONS: Increasing HbA1c by time was associated with declining beta-cell function.

Diastolic blood pressure and area of residence: multilevel versus ecological analysis of social inequity.

STUDY OBJECTIVES: To study geographical differences in diastolic blood pressure and the influence of the social environment (census percentage of people with low educational achievement) on individual diastolic blood pressure level, after controlling for individual age and educational achievement. To compare the results of multilevel and ecological analyses. DESIGN: Cross sectional analysis performed by multilevel linear regression modelling, with women at the first level and urban areas at the second level, and by single level ecological regression using areas as the unit of analysis. SETTING: Malmö, Sweden (population 250 000). PARTICIPANTS: 15 569 women aged 45 to 73, residing in 17 urban areas, who took part in the Malmö Diet and Cancer Study (1991-1996). MAIN RESULTS: In the "fixed effects" multilevel analysis, low educational achievement at both individual (beta=1.093, SE=0.167) and area levels (beta=2.966, SE=1.250) were independently associated with blood pressure, although in the "random effects" multilevel analysis almost none of the total variability in blood pressure across persons was attributable to areas (intraclass correlation=0.3%). The ecological analysis also found an association between the area educational variable and mean diastolic blood pressure (beta=4.058, SE=1.345). CONCLUSIONS: The small intraclass correlation found indicated very marginal geographical differences and almost no influence of the urban area on individual blood pressure. However, these slight differences were enough to detect an effect of the social environment on blood pressure. The ecological study overestimated the associations found in the "fixed" effects multilevel analysis, and neither distinguished individual from area levels nor provided information on the intraclass correlation. Ecological analyses are inadequate to evaluate geographical differences in health.

Differences in pharmacotherapy and in glucose control of type 2 diabetes patients in two neighbouring towns: a longitudinal population-based study.

AIM: To compare prescribing, dosage and blood glucose levels in patients with type 2 diabetes in two communities with differences in anti-hyperglycaemic drug utilization. METHODS: A retrospective longitudinal (1984-1994) population-based study in two neighbour towns in southern Sweden. The mean prescribed daily dose was expressed as a fraction of the Defined Daily Dose (DDD) for each drug. RESULTS: In town A, prescribing of oral agents and insulin was predominantly made by one specialized diabetes clinician, while in town B it was spread among several different general practitioners and one specialist. Altogether 44 636 medical visits by 2348 patients were identified. In each town, about 40% of the patients were treated without anti-hyperglycaemic drugs, about 40% with oral agents and about 20% with insulin. However, there were pronounced between-town differences in dosage and glucose control. The mean prescribed daily dose of sulphonylurea monotherapy decreased gradually from approximately 0.7 to approximately 0.5 DDD in town B but remained approximately 0.8 DDD in town A. The proportion of patients on both sulphonylurea and metformin increased substantially in town A but not in town B. In these patients, the mean prescribed daily dose of sulphonylurea exceeded 1.0 DDD in both towns, although it decreased with time in town B. The mean prescribed daily dose of insulin increased from 1.05 to 1.2 DDD in town A but remained virtually unchanged at 0.95 DDD in town B. The mean fasting blood glucose was lower in town A than in town B both overall (7.7 vs. 8.8 mmol/l), in those treated without any anti-hyperglycaemic drugs (7.2 vs. 8.1 mmol/l), in those on sulphonylurea monotherapy (8.3 vs. 9.7 mmol/l) and in those treated with insulin (8.1 vs. 10.2 mmol/l). CONCLUSIONS: Glucose control in routine care was better when most patients were treated by a diabetes specialist and were exposed to more intense pharmacotherapy.

Variation in antibiotic use in the European Union.

Data on antibiotic use are not publicly available in most European Union countries. We obtained data for non-hospital antibiotic sales for 1997 from the 15 member states and analysed these according to the Anatomic Therapeutic Chemical classification system, and expressed them as defined daily doses per 1000 people per day. Sales of antibiotics varied more than four-fold: France (36.5), Spain (32.4), Portugal (28.8), and Belgium (26.7) had the highest sales, whereas the Netherlands (8.9), Denmark (11.3), Sweden (13.5), and Germany (13.6) had the lowest. There was also profound variation in use of different classes of antibiotics. Detailed knowledge of antibiotic use is necessary to implement national strategies for optimum antibiotic use, and to address the threat posed by resistant microorganisms.

Prescribing, prescription costs and adherence to formulary committee recommendations: long-term differences between physicians in public and private care.

BACKGROUND: In southern Sweden, many general practitioners (GPs) participate in an extensive postgraduate drug education programme, and many health centres are also fed back crude local drug statistics from pharmacists in the area. Private physicians and hospital physicians have not participated in these programmes. OBJECTIVE: The drug prescribing habits and costs of GPs, hospital physicians and private physicians were compared. METHODS: Each March, from 1990 to 1997, all prescriptions dispensed at the eight pharmacies in Växjö, a city and municipality in southern Sweden, were registered, specifying drug(s) prescribed, price, patient's age, sex and area of residence, and prescriber's place of work and category. RESULTS: Overall, the costs of prescribed drugs increased with time, even in 1997 when the prescribing volume was reduced due to changes in the reimbursement system. The cost increase was caused by increased prescribing of newer, more expensive drug alternatives. However, within each of the eleven major drug groups, the drugs prescribed by GPs were less expensive than those prescribed by hospital physicians and, particularly, private physicians. Moreover, even though GPs prescribed more and a wider range of drugs, they also had a higher degree of adherence to the recommendations by the formulary committee. CONCLUSION: GPs prescribed less expensive drugs and had a higher degree of adherence to the recommendations by the formulary committee than other categories of physicians. One reason for these differences may be that the GPs participated in regional and local educational activities aimed at the rationalisation of drug prescribing.

Association of outpatient utilisation of non-steroidal anti-inflammatory drugs and hospitalised heart failure in the entire Swedish population.

OBJECTIVE: Individual-based studies on restricted geographical settings have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may precipitate congestive heart failure. As NSAID use is very extensive, it might increase the occurrence of symptomatic heart failure in the general population. Therefore, in order to study the impact of NSAID utilisation (prescribed and over the counter) on hospitalised heart failure in an entire country (Sweden), we performed an ecological analysis, a design appropriate for studying large geographical areas. METHODS: We employed weighted (population size) ecological linear regression to study the association between outpatient utilisation of NSAIDs during 1989-1993 and hospitalised heart failure in 1993 in 283 of Sweden's 288 municipalities. Data were adjusted for age and gender proportions, socio-economic factors, latitude and utilisation of cardiovascular drugs, aspirin, low-dose aspirin and paracetamol. RESULTS: The unadjusted relative risk of hospitalised heart failure for each increase of one standard deviation of NSAID utilisation (5.8 defined daily doses/1000 inhabitants/day) was 1.23 [95% confidence interval (CI) 1.18, 1.27]. After adjustments, the relative risk was 1.08 (95% CI 1.04, 1.12); the corresponding values if aspirin (non-low-dose) was included as an NSAID were 1.26 (95% CI 1.23, 1.28) and 1.07 (95% CI 1.04, 1.10). There was no such adjusted association with the utilisation of paracetamol-0.95 (95% CI 0.92, 0.98). CONCLUSION: The NSAID--heart failure association already established by individual-based studies on restricted geographical settings was corroborated in the present ecological study based on the whole population of an entire country (Sweden). Efforts should be made to promote a rational use of NSAIDs in the general population.

Impaired glucose metabolism and obesity in Swedish patients with borderline isolated systolic hypertension: Skaraborg Hypertension and Diabetes Project.

AIM: To assess the prevalence of borderline isolated systolic hypertension (borderline ISH), and to examine its association with other cardiovascular risk factors. METHODS: A cross-sectional community-based study was carried out in 1993-1994 in Skara, Sweden, including 1109 randomly chosen subjects > or = 40 years old. Normotension (NT) was defined as systolic blood pressure (SBP) < 140 and diastolic blood pressure (DBP) < 90 mmHg, borderline ISH as SBP 140-159 and DBP < 90 mmHg and hypertension (HT) as SBP > or = 160 or DBP > or = 90 mmHg or ongoing treatment. RESULTS: The prevalence of borderline ISH (n = 203) by age was 4% in ages 40-49 years, 15% in ages 50-59 years, 28% in ages 60-69 years and 25% in ages 70-79 years. With borderline ISH as reference, normotensive subjects less often had fasting blood glucose > 5.5 mmol/l (odds ratio (OR): 0.4, 95% CI: 0.26-0.75), BMI > 27 kg/m2 (OR: 0.6, 95% confidence intervals (CI): 0.42-0.85) and known diabetes (OR: 0.4, 95% CI: 0.16-0.95). Hypertensive subjects more often had high density lipoprotein (HDL) cholesterol < 1.0 mmol/l (OR: 2.0, 95% CI: 1.35-2.99), a history of previous cardiovascular disease (CVD) (OR: 1.7, 95% CI: 1.01-2.72), known diabetes (OR: 2.4, 95% CI: 1.29-4.58) and microalbuminuria (men) (OR: 1.9, 95% CI: 1.15-3.11). CONCLUSION: Borderline ISH is a common condition. It is associated with a more unfavourable risk factor profile than that of normotensive subjects concerning primarily glucose metabolism and obesity. The prevalence of known diabetes increased with the degree of hypertension.

Effects and serum levels of glibenclamide and its active metabolites in patients with type 2 diabetes.

OBJECTIVE: To study the effects and serum levels of glibenclamide (Gb) and its active metabolites in patients on chronic Gb medication on different daily doses. MATERIAL AND METHODS: Fifty patients with type 2 diabetes on regular Gb therapy (1.75-14.0 mg daily). Blood samples were taken immediately before and 90 min after regular Gb intake. A standardized breakfast was served 30 min after drug intake. Serum insulin and proinsulin levels were determined by ELISA methods without cross-reactivities. Serum drug levels were determined by HPLC. Fischer's R to Z-test (correlation coefficients) and paired Student t-tests were used when comparing values within the entire group and unpaired non-parametric Mann-Whitney tests were used when comparing high and low dose levels. A p-value < 0.05 was considered significant. RESULTS: There were significant correlations between daily Gb dose, on the one hand, and, on the other, HbAlc (r = 0.55), Delta-insulin (r = - 0.59) and Delta-proinsulin (r = - 0.52) levels. Significant correlations between Gb therapy duration and insulin (r = - 0.40) and proinsulin (r = - 0.34) secretion and between Gb dose and ratio proinsulin/insulin (RPI) at both time points (r = 0.32 and 0.30) were also found. The RPI was lower after Gb intake. In patients on > or = 10.5 mg steady state serum metabolite levels (Ml and Ml + M2) were higher (29(0-120) and 33 (0-120) ng/ml) than those of Gb itself (18(0-64) ng/ml). A great inter-subject variability in Gb levels at both time points was seen. CONCLUSIONS: Our results indicate that, in patients on chronic medication, Gb is capable of stimulating both insulin and proinsulin secretion; the effect on insulin release is relatively greater. The effect was more pronounced in patients on a low Gb dose, either because of less impaired beta-cells in those receiving low doses, or due to reduced sulphonylurea sensitivity in those on high dosage (down-regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated; the metabolites may contribute to hypoglycaemic events.

The NEPI antidiabetes study (NANSY). 1: short-term dose-effect relations of glimepiride in subjects with impaired fasting glucose.

AIM: NANSY is a randomised, placebo-controlled Swedish-Norwegian study which aims to include 2 x 1112 male and female subjects with impaired fasting glucose (IFG), to assess whether conversion to type 2 diabetes can be delayed by addition of sulphonylurea to dietary regulation and increased exercise. This pilot study was conducted to find the optimum dose of glimepiride in NANSY. METHODS: In a double blind trial in primary care 25 IFG subjects were in random order exposed to single doses and one-week treatments with 0 (placebo), 0.5, 1.0 and 2.0 mg glimepiride once daily. The optimum dose was assessed by measuring blood glucose during oral 75 g glucose tolerance test (OGTT), comparing fasting blood glucose, and the area under the blood glucose curve (AUC), and by monitoring hypoglycaemic events. RESULTS: With single doses, there was a clear dose-response relationship for the reduction in AUC, with a statistically significant difference only between placebo (mean 1981, 95% confidence intervals (CI) 1883-2078) and 2 mg glimepiride (mean 1763, 95% CI 1665-1861). However, following 1-week treatments, the only significant difference was between placebo (mean 1934, 95% CI 1856-2012) and 1 mg glimepiride (mean 1714, 95% CI 1637-1792). Correspondingly, the only statistically significant difference in fasting blood glucose day 7 was between placebo (5.87 mmol/l, 95% CI 5.68-6.05 mmol/l) and 1 mg glimepiride (5.42 mmol/l, 95% CI 5.21-5.62 mmol/l). Chemical hypoglycaemia was common but hypoglycaemic symptoms were rare and similar between the active doses, and easily countered by the subjects. CONCLUSIONS: The sulphonylurea dose-effect curve may be bell-shaped, perhaps due to down regulation of sulphonylurea receptors during chronic exposure. Alternatively, the finding could be a rebound phenomenon, secondary to preceding hypoglycaemia. The optimum dose for NANSY was found to be 1 mg glimepiride.