Per-Olof Bitzén

Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study.

OBJECTIVE To assess and compare the therapeutic efficacy and safety of metformin (M) and sulfonylurea (glyburide, G), alone and in various combinations, in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Of 165 patients (fasting blood glucose [FBG] ≥ 6.7 mmol/l) initially treated with diet alone, 144 (FBG still ≥6.7 mmol/l) were randomized to double-blind, double-dummy controlled treatment with M, G, or primary combination therapy (MG). The dose was titrated, withFBG <6.7 mmol/l as target, using, at most, six dose levels. The first three dose levels comprised increasing single-drug therapy (M or G) or primary combination at increasing but low dosage (MGL), and the second three levels were composed of various high-dose combinations, i.e., add-on therapy (M/G or G/M) and primary combination escalated to high dosage (MGH). Medication was maintained for 6 months after completed dose titration. RESULTS The FBG target was achieved in 9% of patients after diet alone. Single-drug therapy was insufficient in 36% and MGL in 25% (NS) of the randomized patients. There was further improvement in glucose control by the high-dose combinations. Mean FBG ± SE was reduced (P = 0.001) from 9.1 ± 0.4 to 7.0 ± 0.2 mmol/l in those maintained on single-drug treatment or low-dose primary combination. Those treated with different high-dose combinations had a large mean FBG reduction, from 13.3 ± 0.8 to 7.8 ± 0.6 mmol/l. HbA1c levels showed corresponding reductions, and glycemic levels rose after drug discontinuation. Fasting C-peptide rose during treatment with G and MGL but not with M, while fasting insulin was not significantly changed. Meal-stimulated C-peptide and insulin levels were unchanged by M but increased by G and, to a lesser extent, by MGL. There were no significant insulin or C-peptide differences between the different high-dose combinations (M/G, G/M, and MGH). Body weight did not change following treatment with M or combination but increased by 2.8 ± 0.7 kg following G alone. Blood pressure was unchanged. Overall effects on plasma lipids were small, with no significant differences between groups. Drug safety was satisfactory, even if the reporting of (usually modest) adverse events was high; the profile, but not the frequency, differed between groups. CONCLUSIONS Dose-effect titrated treatment with either metformin or glyburide promotes equal degrees of glycemic control. The former, but not the latter, is able to achieve this control without increasing body weight or hyperinsulinemia. Near-normal glycemia can be obtained by a combination of metformin and sulfonylurea, even in advanced NIDDM.

Sulphonylurea antidiabetic drugs. An update of their clinical pharmacology and rational therapeutic use

SummaryApart from the amelioration of symptoms, a major aim of the treatment of non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) should be the prevention of cardiovascular complications. These are associated with the chronic hyperglycaemia that is characteristic of NIDDM, and the risk of complications is already increased in subjects with impaired glucose tolerance (IGT). For these reasons, and because hyperglycaemia appears to be a self-perpetuating condition, treatment should be introduced as early as possible and should be aimed at normalisation of blood glucose. To enable early detection and intervention, screening is necessary. As diet regulation alone rarely suffices to normalise blood glucose, addition of sulphonylurea drugs is indicated in many cases. If introduced in the IGT phase, sulphonylureas drugs combined with diet regulation may postpone the development of IGT to manifest NIDDM, and may reduce the increased risk of cardiovascular morbidity and mortality.Sulphonylureas stimulate insulin release, possibly via interaction with receptors in the pancreatic B cells. In addition, such treatment enhances the reduced insulin action. This might be a primary effect but is also a consequence of the increased access to insulin and the subsequent reduction of hyperglycaemia. Sulphonylureas may enhance insulin availability by reducing insulin clearance. Effects on blood lipids are probably secondary phenomena.Fast and short acting sulphonylureas may improve the impaired meal-induced acute insulin release. If combined with weight-reducing diet regulation and introduced early, such treatment can maintain (near) normal blood glucose levels and an improved insulin action for several years without increasing basal insulin secretion, without chronic hyper-insulinaemia, and without weight increase. If not combined with diet regulation, sulphonylurea therapy is likely to fail. If introduced when NIDDM is advanced, the efficacy of these drugs is limited, with secondary failures developing at a rate of 5 to 10% per year. Continuous (24-hour-a-day) exposure to drug treatment could possibly desensitise the B cell to sulphonylurea stimulation.‘Second-generation’ sulphonylurea drugs have a higher potency than ‘first-generation’ drugs, but this need not signify a greater clinical efficacy. The effect of several of these drugs may be increased if they are ingested half an hour before meal(s). Short acting sulphonylureas may be safer than long acting ones, which seem more likely to cause long lasting and fatal hypoglycaemia, at least in elderly patients. Hypoglycaemia may be augmented by the concomitant use of alcohol, aspirin, sulphonamides and trimethoprim, and by intercurrent illness with decreased caloric intake. Thiazides and β-blockers may counteract the efficacy of sulphonylurea drugs.

Cost of illness of adult diabetes mellitus underestimated if comorbidity is not considered

Norlund A, Apelqvist J, Bitzén P.‐O, Nyberg P, Scherstén (Swedish Council on Technology Assessment in Health Care, Stockholm; and University Hospital; and Dalby/Lund, University of Lund, Lund, Sweden) Cost of illness of adult diabetes mellitus underestimated if comorbidity is not considered. J Intern Med 2001; 250: 57–65.

Excretion of paracetamol in human breast milk

SummaryBreast milk and plasma levels of paracetamol were monitored in 3 lactating women after ingestion of a single 500 mg dose of paracetamol. The paracetamol concentrations were consistently lower in milk, with a mean milk/plasma AUC ratio of 0.76. This value was in close agreement with the milk/plasma partition ratio of 0.81 foundin vitro, and could be related to quantitative binding differences between the two fluids. The half-lives of paracetamol in plasma and breast milk were almost identical, with an overall mean of 2.7 h. As less than 0.1% of the maternal dose would be present in 100 ml milk, breast feeding need not be discontinued due to paracetamol treatment in conventional dosage.

Assessment of Laboratory Methods for Detection of Unsuspected Diabetes in Primary Health Care

In order to assess different methods for early detection of unsuspected diabetes, urine and venous blood samples were collected at random from 1082 patients visiting a primary health care centre in southern Sweden. Blood glucose was analysed by the hexokinase method along with the Dextrostix-Eyetone reflectance meter. Urine glucose was determined by Clinistix, Diastix, Neostix, Rediatest, Clinitest and quantitatively by the hexokinase method. Patients fulfilling the criteria of a positive screen were subjected to a diagnostic investigation with an oral glucose tolerance test. Out of 89 positive screenees, 37 patients were classified as diabetics, showing a prevalence of diabetes in the study population of 3.4% according to the WHO criteria. Impaired glucose tolerance was found in 14 patients. In a control group of 56 patients, randomly selected among negative screenees, no cases of diabetes were found. Random blood glucose measurement by the hexokinase method, using 7 mmol/l as a screening level, had a significantly higher sensitivity (95%) than all urine glucose methods (59-30%) with comparable specificity (97-99%). Use of the Dextrostix-Eyetone reflectance meter resulted in a decrease in sensitivity to 75% without any change in specificity or predictability, compared with the hexokinase method. Urine testing for glucose was found to be a suboptimal method for early case finding of diabetes among patients receiving primary health care.

The influence of glipizide on early insulin release and glucose disposal before and after dietary regulation in diabetic patients with different degrees of hyperglycaemia.

SummaryAn early defect in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and the preceding phase of impaired glucose tolerance (IGT) is a reduction in early insulin release and hence a prolonged elevation of postprandial blood glucose. We therefore assessed whether a rapidly acting sulphonylurea (glipizide 5 mg 0.5 h before a test meal) could correct these disturbances in 38 IGT/NIDDM subjects, whose early insulin release and postprandial blood glucose elevations remained unimproved after 10 weeks of dietary regulation.We also assessed whether the efficacy of glipizide was dependent upon the ambient blood glucose concentration, and if early systemic availability of the drug was important for the blood glucose lowering effect.A single dose of glipizide normalized early insulin release and hence reduced the postprandial blood glucose increase that was not lowered by dietary regulation.The efficacy of glipizide was dependent upon the early systemic availability of the drug, but early systemic availability and efficacy were independent of the extent of blood glucose elevation, at least within a range of 6–12 mmol·l−1 of fasting blood glucose.

Efficacy of Dietary Regulation in Primary Health Care Patients with Hyperglycaemia Detected by Screening

The efficacy of dietary regulation was examined in 38 consecutive primary health care patients with hyperglycaemia detected on screening. Ten weeks of dietary regulation reduced overall mean fasting blood glucose from 8.2 to 6.5 mmol ***l−1. Fasting blood glucose fell more (from 12.3 to 7.6 mmol l−1 and from 8.4 to 6.6 mmol l−1) in the two quartiles initially above the median (7.15 mmol l−1), than in the lower quartiles (6.7 to 6.1 mmol l−1 and 5.7 to 5.8 mmol l−1), even though weight reduction was similar. The reduction in blood glucose correlated (r = 0.87) with the degree of fasting hyperglycaemia before treatment. Sixteen patients (42%) reached or maintained fasting blood glucose ≤ 6.0 mmol l−1 and they had a milder degree of glucose intolerance, a higher insulin response to a meal and a greater reduction in weight than the 22 patients (58%) who did not reach ≤ 6.0 mmol l−1. Nine patients (24%) maintained fasting blood glucose ≤ 6.0 mmol l−1 for > 5 years, and showed a considerable improvement of insulin action. Dietary regulation improved glucose control mainly by reducing fasting hyperglycaemia; neither the delay in early insulin release nor the associated elevation and prolongation of the post‐prandial glucose excursions were reduced.

Long-term effects of glipizide on insulin secretion and blood glucose control in patients with non-insulin-dependent diabetes mellitus

SummaryOf 23 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose fasting blood glucose had not reached ≤6.0 mmol·l−1 after 10 weeks of dietary regulation, 15, who had had a weight reduction of −2.8 kg by dietary control, did achieve a fasting blood glucose ≤6.0 mmol·l−1 after addition of ≤20 mg glipizide daily. They had a sustained (≥2 years) increase in meal-induced insulin secretion (32% increase in postprandial C-peptide AUC), and a sustained reduction in postprandial hyperglycaemia (34% reduction in AUC). Ten of the patients took a mean daily dose <5mg (4.8 mg) and had a sustained increase in insulin secretion rate (increased C-peptide slope). The 15 patients had no elevation of basal insulin secretion and no impairment of weight reduction. The remaining 8 subjects, who showed little or no weight reduction on dietary control, had little or no reduction in fasting blood glucose despite long-term treatment with 20 mg glipizide daily, a less sustained increase in meal-induced insulin secretion, a smaller reduction of postprandial hyperglycaemia, and an increase in body weight. On diagnosis the 8 subjects did not differ from the other 15 subjects in age, body weight, blood glucose, HbA1c, C-peptide or insulin, nor in their glucose and insulin responses to a test dose of glipizide; the main reason for the apparent drug failure appeared to be deficient compliance with dietary regulation rather than a primary inability to respond to sulphonylurea treatment. The findings indicate that glipizide is able to promote and maintain increased meal-induced insulin secretion and near-normal fasting and non-fasting blood glucose levels without continuous B cell stimulation. However, these improvements prevail mainly in subjects who persist with hypocaloric dietary regulation.

Will Sulfonylurea Treatment of Impaired Glucose Tolerance Delay Development and Complications of NIDDM

The chronic hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) evolves gradually and is usually preceded by more transient hyperglycemia, classified as impaired glucose tolerance (IGT). Already in this phase, there is an increased risk of cardiovascular complications, and many IGT subjects, like NIDDM patients, often display several of the metabolic and circulatory disturbances that are associated with hyperglycemia, e.g., insulin resistance, hyperinsulinemia and/or hyperproinsulinemia, delayed insulin release, dyslipidemia, and hypertension. Therefore, and because untreated hyperglycemia is a self-perpetuating condition, early detection and early intervention may be necessary to prevent the progression and complications of NIDDM. This in turn would necessitate screening procedures, and the therapeutic goal should include both euglycemia and normalization of plasma insulin, plasma lipids, and blood pressure. A study in the German Democratic Republic indicated that the mortality in screening-detected NIDDM patients did not differ from that in patients detected in routine care. In a Swedish study on screening-detected NIDDM subjects, only those who had IGT rather than manifest NIDDM could maintain fasting blood glucose ≤6 mM for 5 yr by hypocaloric dietary regulation alone. In those with screening-detected NIDDM, the delayed acute insulin release and net postprandial hyperglycemia were improved by addition of glipizide, and most managed to attain and maintain fasting blood glucose ≤6 mM for ∼2 yr after such addition. However, after 4 yr, there was an increase in blood glucose, suggesting that preventive intervention either may not be possible or may have to start in the IGT phase. In another Swedish study, the combination of dietary advice and tolbutamide seemed to delay the progression of IGT to NIDDM, lower cholesterol and triglyceride levels and blood pressure, and reduce cardiovascular morbidity and mortality. However, no preventive effect was seen in two similar British studies. Moreover, only a few untreated IGT subjects progress to manifest NIDDM. Hence, routine screening for IGT and subsequent therapeutic intervention cannot be recommended, but more studies are needed.

Increased prevalence of large bites in 12-lead vectorcardiograms of diabetic patients

The vectorcardiographic (VCG) bites in diabetic patients were compared with those in nondiabetic control subjects using automated analysis of the conventional electrocardiogram (ECG). A 12-lead ECG was recorded from each of the 154 patients with non-insulin-dependent diabetes mellitus and 128 control subjects. The orthogonal leads X, Y, and Z were derived from the 12-lead ECG, from which a so-called 12-lead VCG was calculated for each of the 282 participants. A computer-based method for the detection and quantification of bites was applied to the 12-lead VCGs. Bite amplitudes in the horizontal loop had an average of 0.062 +/- 0.089 mV in the diabetic group, and 0.039 +/- 0.045 mV in the control group (P < .01). In the sagittal plane, the mean bite amplitude was also greater in the diabetic group than in the control group: 0.095 +/- 0.084 versus 0.069 +/- 0.058 mV, respectively (P < .01). A bite greater than 0.1 mV in the horizontal or sagittal planes was found in 56 diabetic patients (36%) and 27 control subjects (21%) with (P < .05) considered significant. In conclusion, the results of this study suggest that automated analysis of the 12-lead VCG can be valuable in diagnosing diabetic cardiomyopathy.