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

OBJECTIVE: To determine costs of illness for adult diabetes mellitus (DM), including complications caused by DM. DESIGN: A population-based multicentre cross- sectional study including an interview and a physical examination of patients identified as having DM. The patients' medical records were analysed regarding diagnoses and complications attributable to DM. SETTING: Eight health care centres of six primary care districts in Southern Sweden. SUBJECTS: 1677 adults aged 25+, cared for at the health care centres, entered the study. MAIN OUTCOME MEASURES: Utilization of health care and care from relatives and the municipality, absence of short- and long-term sickness, cost of illness. RESULTS: The average annual direct and indirect costs for an adult with DM were calculated to be 61 700 Swedish Kronor (SEK) or 2.5 times higher than earlier estimates. The incremental cost of DM was 34 100 SEK. The cost distribution was 28% for health care, 31% for the municipality and relatives and 41% lost productivity. CONCLUSIONS: Calculations for the cost of illness of DM are underestimated if comorbidity caused by DM is not considered. When DM-related complications are included to identify the actual burden of disease to society, the cost of illness as a result of DM in Sweden is substantially higher than previously estimated.

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.

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] > or = 6.7 mmol/l) initially treated with diet alone, 144 (FBG still > or = 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, with FBG < 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.

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

Of 23 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose fasting blood glucose had not reached less than or equal to 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 less than or equal to 6.0 mmol.l-1 after addition of less than or equal to 20 mg glipizide daily. They had a sustained (greater than or equal to 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 less than 5 mg (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.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative efficacy of metformin and glibenclamide in patients with non-insulin-dependent diabetes mellitus.

Metformin and glibenclamide were compared in a randomized, double-blind trial in patients with non-insulin-dependent diabetes mellitus (NIDDM) using a parallel group design. The study was performed in primary health care, and the main purpose was to assess combination therapy with the two drugs as primary treatment versus conventional oral therapy. After a 2 months diet period patients were randomized to commence treatment with either metformin, glibenclamide or the combination of both. Patients randomized to monotherapy received the alternative drug in addition if the maximal dose i.e. 3 g metformin or 14 mg glibenclamide was insufficient to normalize the fasting blood glucose concentration (FBG). Randomization and dose escalation occurred at FBG greater than or equal to 6.7 mmol/l. The titrated dose was continued for 6 months, whereafter placebo was given for 2 weeks. Seventy-two patients were randomized to either the metformin group (n = 38) or the glibenclamide group (n = 34). Fifty-six completed 6 months treatment, twenty-eight in each randomized group. Glycaemic control was unchanged after diet alone in all groups. The improvement during drug treatment was highly significant (p less than 0.001), mean FBG difference (+/- SEM) 3.2 +/- 0.4 mmol/l and mean HbA1c difference (+/- SEM) 1.5 +/- 0.2% (n = 56). There were no significant differences between patients treated solely with metformin (n = 16) and glibenclamide (n = 17) or between patients treated with a combination of glibenclamide added to metformin (n = 12) and metformin added to glibenclamide (n = 11).(ABSTRACT TRUNCATED AT 250 WORDS)

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 less than or equal to 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 less than or equal to 6 mM for approximately 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.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Apart 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 hyperinsulinaemia, 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.(ABSTRACT TRUNCATED AT 400 WORDS)

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 less than or equal to 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 less than or equal to 6.0 mmol l-1. Nine patients (24%) maintained fasting blood glucose less than or equal to 6.0 mmol l-1 for greater than 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.

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

An 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.

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.

Therapeutic equivalence of sulfaisodimidine 2 g twice daily and 1 g four times daily in lower urinary tract infections.

The serum concentrations and clinical effects of sulfaisodimidine given during 12 days were examined in two groups of patients with uncomplicated lower urinary tract infection. Group I (n=12) received the drug in a conventional dosage, 1 g four times daily, and group II (n=14) in a dose of 2 g twice daily. The serum concentrations of sulfonamide at steady state (day 7) and one day after cessation of therapy (day 13) did not differ significantly between the groups. With the exception of one patient in group I, both subjective and objective symptoms vanished during treatment and remained absent for at least 4 weeks thereafter. Two patients in each group developed signs of sulfonamide allergy. Thus, the two regimens seemed to be equally efficient, and the risk of therapy failure due to low blood concentrations of sulfaisodimidine should not be greater when the drug is given in a dosage of 2 g twice daily than when it is administered in the conventional way. Hence, the latter, simpler regimen can be recommended.

Excretion of paracetamol in human breast milk.

Breast 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 found in 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.

Hemoglobin AI in community care.

In order to investigate the potential usefulness of knowing the blood concentrations of HbAI in primary care, HbAI was measured in diabetic subjects attending a primary care centre. The values were compared with concentration of HbAI in a reference group on non-diabetics. The reference group had a mean value in HbAI of 7.6+/-0.1% with a tendency to increased values with advancing age. The diabetic subjects had a mean value in HbAI of 10.8+/-0.2%. Diabetics under good control had lower values (10.2+/-0.2%), than patients under poor control (12.0+/-0.2%) (p less than 0.001). There was a correlation (r=0.50, p less than 0.001) between HbAI and fasting blood glucose levels. It is concluded that determination of HbAI can be an aid in the control of diabetics in primary care. However, the method requires good technical management, and the results are most reliable when the same person analyses all samples. The objective in diabetic therapy in this respect should no doubt be to depress the concentrations of HbAI towards normal values.

Serum tolbutamide and chlorpropamide concentrations in patients with diabetes mellitus.

A selective and sensitive gas chromatographic technique was used to measure the steady-state serum concentrations of tolbutamide and chlorpropamide in 97 patients with maturity-onset diabetes mellitus who had been taking these drugs (37 tolbutamide, 60 chlorpropamide) for at least a year. No other antidiabetic agents had been given. The serum tolbutamide concentrations varied widely between the patients (from close to zero to 370 mumol/l (100 mug/ml)), yet the variation in dosage was only sixfold (0.5-3.9 g daily). The serum chlorpropamide concentrations varied even more widely (from close to zero to 882 mumol/l (244 mug/ml)), though the dosage variation was fourfold (125-500 mg daily). There was no systematic relation between dosage and serum concentrations of the drugs.Only 2 (5.4%) of the tolbutamide-treated patients and 10 (16.7%) of the chlorpropamide-treated patients had normal fasting blood glucose concentrations (below 5.5 mmol/l (99 mg/100 ml)), and fewer than half had values below 8.0 mmol/l (144 mg/100 ml). In most cases, therefore, the treatment was insufficient.There was no significant difference in mean fasting blood glucose concentrations between the two treatment groups. The mean steady-state concentration of chlorpropamide, however, was significantly higher than that of tolbutamide. Thus, contrary to common belief, the intrinsic activity of chlorpropamide is apparently not greater than that of tolbutamide. The alleged greater potency of chlorpropamide seems to be related wholly to kinetic differences, such as the less extensive metabolic degradation and slower elimination of the drug.We conclude that treatment with sulphonylureas in conventional dosage is far from optimal and that monitoring the concentrations of these drugs in the blood may help to improve their efficacy.