Croatian guidelines for the pharmacotherapy of type 2 diabetes

INTRODUCTION: The Croatian Association for Diabetes and Metabolic Disorders of the Croatian Medical Association has issued in 2011 the first national guidelines for the nutrition, education, self-control, and pharmacotherapy of diabetes type 2. According to the increased number of available medicines and new evidence related to the effectiveness and safety of medicines already involved in the therapy there was a need for update of the existing guidelines for the pharmacotherapy of type 2 diabetes in the Republic of Croatia. PARTICIPANTS: as co-authors of the Guidelines there are listed all members of the Croatian Association for Diabetes and Metabolic Diseases, as well as other representatives of professional societies within the Croatian Medical Association, who have contributed with comments and suggestions to the development of the Guidelines. EVIDENCE: These guidelines are evidence-based, according to the GRADE system (eng. Grading of Recommendations, Assessment, Development and Evaluation), which describes the level of evidence and strength of recommendations. CONCLUSIONS: An individual patient approach based on physiological principles in blood glucose control is essential for diabetes' patients management. Glycemic targets and selection of the pharmacological agents should be tailored to the patient, taking into account the age, duration of disease, life expectancy, risk of hypoglyce- mia, comorbidities, developed vascular and other complications as well as other factors. Because of all this, is of national interest to have a practical, rational and applicable guidelines for the pharmacotherapy of type 2 diabetes.

Core Standards of the EUBIROD Project. Defining a European Diabetes Data Dictionary for Clinical Audit and Healthcare Delivery.

BACKGROUND: A set of core diabetes indicators were identified in a clinical review of current evidence for the EUBIROD project. In order to allow accurate comparisons of diabetes indicators, a standardised currency for data storage and aggregation was required. We aimed to define a robust European data dictionary with appropriate clinical definitions that can be used to analyse diabetes outcomes and provide the foundation for data collection from existing electronic health records for diabetes. METHODS: Existing clinical datasets used by 15 partner institutions across Europe were collated and common data items analysed for consistency in terms of recording, data definition and units of measurement. Where necessary, data mappings and algorithms were specified in order to allow partners to meet the standard definitions. A series of descriptive elements were created to document metadata for each data item, including recording, consistency, completeness and quality. RESULTS: While datasets varied in terms of consistency, it was possible to create a common standard that could be used by all. The minimum dataset defined 53 data items that were classified according to their feasibility and validity. Mappings and standardised definitions were used to create an electronic directory for diabetes care, providing the foundation for the EUBIROD data analysis repository, also used to implement the diabetes registry and model of care for Cyprus. CONCLUSIONS: The development of data dictionaries and standards can be used to improve the quality and comparability of health information. A data dictionary has been developed to be compatible with other existing data sources for diabetes, within and beyond Europe.

Depression in Croatian Type 2 diabetic patients: prevalence and risk factors. A Croatian survey from the European Depression in Diabetes (EDID) Research Consortium.

AIMS: To determine the prevalence rate of and risk factors for depression in Croatian Type 2 diabetic patients. METHODS: Depressive mood was examined in 384 randomly selected outpatients with Type 2 diabetes. Center for Epidemiological Studies Depression Scale (CES-D) and Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) were used to identify depressive disturbances. The groups with CES-D > or = 16 and < 16 were compared with respect to demographic, psychological and clinical characteristics. Regression analysis was used to determine risk factors for depression. RESULTS: Of the examined patients, 22% had CES-D scores > or = 16, and in 33% of them clinical depression was confirmed by the psychiatric interview. Depressed patients compared with the non-depressed ones reported more diabetes-related problems and poorer well-being (t = 6.71, P < 0.001 and t = 11.98, P < 0.001, respectively). Multiple regression analysis indicated female gender, experienced support and the level of emotional well-being to predict depression (R = 0.74, F = 15.3, P < 0.001). CONCLUSIONS: The obtained data indicate that the prevalence rate in Croatian Type 2 diabetic patients is comparable to findings from other cultural settings. Depressive symptoms can be predicted by psychological rather than disease-related variables. Psychological care for diabetic patients may be necessary to prevent depressive symptomatology.

A pilot study of mitochondrial DNA point mutation A3243G in a sample of Croatian patients having type 2 diabetes mellitus associated with maternal inheritance.

In this work, patients having type 2 diabetes mellitus and diabetic mothers were tested for the presence of mitochondrial DNA point mutation A3243G. This mutation is associated with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), diabetes and deafness. Twenty-two diabetic persons were screened. DNA was isolated from peripheral blood lymphocytes and from swabs of oral mucosa. The mitochondrial DNA point mutation A3243G was detected using PCR-RFLP test. The mutation was detected in oral mucosal DNA of two patients (but not from lymphocyte DNA). One patient was a man with hearing and visual impairments and proteinuria; the other was a woman having proteinuria but no hearing impairment. The mutation was not detectable in oral mucosal DNA from the control persons: 20 diabetic patients having diabetic fathers and 22 healthy, nondiabetic volunteers. The incidence of mitochondrial DNA point mutation A3243G in this study of Croatian diabetic patients is in line with data in the literature.

Estimation of physical activity by different questionnaires in overweight subjects and patients with Type 2 diabetes mellitus: relationship with anthropometric and metabolic variables.

AIM: This study assessed the level of physical activity in overweight and obese subjects, and overweight and obese patients with Type 2 diabetes mellitus (T2DM). It also compared their physical activity level with that of the general population and investigated benefits of physical activity on anthropometric and metabolic parameters and blood pressure in the studied groups of patients using Baecke's questionnaire and the Lipid Research Clinics Physical Activity (LRC PA) questionnaire. The two questionnaires were also compared in the evaluation of benefits. METHODS: Physical activity level and other parameters (body weight, body height, body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, lipoprotein and creatinine concentrations in the blood, concentration of fasting glucose and HbA1c in the blood, albuminuria-to-creatinuria ratio) of 136 subjects and their relationships were investigated during their out-patient visits. RESULTS: No difference in physical activity level was found among the four groups of investigated patients. The comparison between the level of physical activity in the investigated patients and the general population obtained by Baecke's questionnaire revealed a lower sports index in all groups of investigated men and obese women with diabetes mellitus. Our results confirm the benefit of physical activity on a high number of investigated parameters in the studied patients. The Baecke's questionnaire was found to estimate the effects of physical activity on metabolic and anthropometric parameters, as well as blood pressure, better than the LRC PA questionnaire, especially the two-point scoring system. CONCLUSIONS: LRC PA and especially Baecke's questionnaires are valuable aids in the estimation of physical activity level and its benefits in overweight and obese patients and patients with T2DM.

Twice daily biphasic insulin aspart improves postprandial glycaemic control more effectively than twice daily NPH insulin, with low risk of hypoglycaemia, in patients with type 2 diabetes.

OBJECTIVE: Biphasic insulin aspart 30 (BIAsp30) is a dual release formulation, containing 30% soluble and 70% protamine-crystallized insulin aspart. This study compared the glycaemic control and safety profiles achieved with either twice daily BIAsp30 or NPH insulin in patients with type 2 diabetes not optimally controlled by oral hypoglycaemic agents (OHAs), NPH insulin or a combination of both. METHODS: In this 16-week multinational, parallel-group, double-blind trial, 403 such patients were randomized to receive either BIAsp30 or NPH insulin immediately before breakfast and evening meals. OHAs were discontinued at randomization. Efficacy was assessed by glycosylated haemoglobin (HbA1c) and self-recorded daily 8-point blood glucose (BG) profiles. Hypoglycaemic and other adverse events were the chosen safety parameters. RESULTS: HbA1c concentration decreased by >0.6% (p < 0.0001 vs. baseline) in both groups, with metabolic control continuing to improve throughout the trial without reaching a stable level. Patients who switched from once or twice daily NPH monotherapy to twice daily BIAsp30 achieved a significantly greater reduction in HbA1c (0.78%) than those randomized to twice daily NPH insulin (0.58%; p = 0.03). BIAsp30 decreased mean daily postprandial glycaemic exposure to a greater extent than NPH insulin (mean difference = 0.69 mmol/l; p < 0.0001), reflecting greater decreases in the postbreakfast and postdinner increments (of 1.26 and 1.33 mmol/l, respectively), although postlunch increment was relatively increased (by 0.56 mmol/l). Despite the greater reduction in overall postprandial glycaemic exposure in the BIAsp30 group, the overall safety profile of BIAsp30 was equivalent to that of NPH insulin with <2% of patients experiencing major hypoglycaemia, and approximately 33% reporting minor hypoglycaemic episodes, in both groups. CONCLUSION: Twice daily BIAsp30 reduced postprandial glucose exposure to a significantly greater extent than NPH insulin and was at least as effective at reducing HbA1c in patients with type 2 diabetes. Both insulins were well tolerated. In patients poorly controlled on OHAs or NPH alone, glycaemic control can be improved by switching to twice daily BIAsp30, without increasing hypoglycaemic risk.

Relationship between autonomic neuropathy, 24-hr blood pressure and retinopathy in normoalbuminuric and normotensive type 1 diabetic patients.

In order to investigate factors related to the development of retinopathy in 122 normotensive and normoalbuminuric patients 24 hr-blood pressure (BP) measurement and autonomic tests based on standard, vector and spectral analysis of heart rate variation (HRV) were performed. Retinopathy was found in 47 patients with significantly longer duration of diabetes and prevalence of autonomic neuropathy (9.5 +/- 5.5; 59.6%) in comparison with 75 patients without retinopathy (5.29 +/- 4.9; 16%), (p < 0.05). Patients were matched according to age, gender, HbA1c and 24-hr urinary albumin excretion rate. Maximal night systolic, mean night and day diastolic BPs were significantly higher in patients with retinopathy (118.94 +/- 11; 62.94 +/- 8.1; 74.3 +/- 7.2 mmHg) as compared to patients without it (115.03 +/- 8.9; 59.65 +/- 7.1; 71.75 +/- 5.7) (p = 0.03). Maximal night systolic BP was inversely related to power high frequency (HF; r = -0.28, p = 0.05) and deep breathing CV (r = -0.23, p = 0.02). Mean night diastolic BP was inversely related to power mid frequency (r = -0.21, p = 0.03), HF (r = -0.32, p = 0.005), CV deep breathing (r = -0.27, p = 0.005) and mean circular resultant deep breathing (r = -0.24, p = 0.003); mean day diastolic BP to power HF (r = -0.22, p = 0.02). In multiple regression analysis retinopathy was associated with the duration of diabetes (beta = 0.53) and autonomic neuropathy (beta = 0.28) (p < 0.001). Autonomic neuropathy was related to BP elevation and retinopathy in normotensive and normoalbuminuric Type 1 diabetic patients.

Effects of a fixed mixture of 25% insulin lispro and 75% NPL on plasma glucose during and after moderate physical exercise in patients with type 2 diabetes.

OBJECTIVE: To compare the plasma glucose (PG) response with a fixed mixture of 25% insulin lispro and 75% NPL (Mix25), prior to a meal and 3 h before exercise, to human insulin 30/70 (30/70) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Thirty-seven patients were treated in a randomized, open-label, 8-week, two-period crossover study. Mix25 was injected 5 min before breakfast and dinner throughout the study, as was 30/70 on inpatient test days and on outpatient dose titration days. Following the 4-week outpatient phase, patients were hospitalized, and exercised at a heart rate of 120 beats/min on a cycle ergometer two times for 30 min, separated by 30 min rest, starting 3 h after a 339 kcal breakfast. RESULTS: The 2-h postprandial PG was significantly lower with Mix25 ((mean +/- SEM) 10.5 +/- 0.4 mmol/l vs 11.6 +/- 0.4 mmol/l; p = 0.016). Maximum decrease in PG from onset of exercise to end of exercise was significantly less with Mix25 (-3.6 +/- 0.29 mmol/l vs -4.7 +/- 0.31 mmol/l; p = 0.001). The maximum decrease in PG over 6 h, after exercise onset, was significantly less with Mix25 (-4.3 +/- 0.4 mmol/l vs -5.9 +/- 0.4 mmol/l; p < 0.001). The frequency of hypoglycemia (blood glucose (BG) < 3 mmol/l or symptoms) during the inpatient test was not different between treatments. During the outpatient phase, the frequency of patient-recorded hypoglycemia was significantly lower with Mix25 (0.7 +/- 0.2 episodes/30 d vs 1.2 +/- 0.3 episodes/30 d; p = 0.042). CONCLUSIONS: Mix25 resulted in better postprandial PG control without an increase in exercise-induced hypoglycemia. The smaller decrease in PG during the postprandial phase after exercise may suggest a lower risk of exercise-induced hypoglycemia with Mix25 than with human insulin 30/70, especially for patients in tight glycemic control.

Relationship between autonomic function, 24-h blood pressure, and albuminuria in normotensive, normoalbuminuric patients with Type 1 diabetes.

We performed a battery of cardiovascular reflex tests, 24-h ambulatory blood pressure (AMBP) and 24-h urinary albumin excretion (UAE) in 116 normoalbuminuric and normotensive patients with Type 1 diabetes. Tests of heart rate variation (HRV) included the coefficient of variation (CV) and the low-frequency (LF), mid-frequency (MF), and high-frequency (HF) bands of spectral analysis at rest, HRV during deep breathing (CV, mean circular resultant--MCR), Valsalva ratio, and maximum/minimum 30:15 ratio. Autonomic neuropathy, characterized as an abnormality of more than two tests, was found in 33 patients. Patients with neuropathy compared to those without neuropathy showed significantly higher mean day and night diastolic blood pressure (dBP), mean systolic night blood pressure (sBP), and mean day and night heart rate (HR). Mean night dBP was inversely related to MF, HF, and HRV during deep breathing; mean day dBP and mean night sBP to HF; mean night HR to CV at rest, MF, HF, HRV during deep breathing, 30:15 ratio; mean day HR to HF, HRV during deep breathing, Valsalva, and 30:15 ratio. Mean 24-h UAE was not significantly different in neuropathic than in nonneuropathic patients. UAE was inversely related to CV at rest and HF. In the stepwise multiple regression analysis, reduced MF, HF, HRV during deep breathing, and high levels of UAE and HbA1c were associated with high night dBP. Autonomic neuropathy is already present in normotensive Type 1 diabetic patients at the normoalbuminuric stage and related to BP and albuminuria.

Intramuscular injection of insulin lispro or soluble human insulin: pharmacokinetics and glucodynamics in Type 2 diabetes.

AIM: The aim of the study was to compare the pharmacokinetics and glucodynamics of insulin lispro and soluble human insulin following intramuscular (i.m.) injection in patients with Type 2 diabetes with secondary failure of sulphonylureas. METHODS: Single 15-U i.m. doses of insulin lispro or soluble human insulin were administered to 16 patients in a two-way, randomized, crossover design. Glucodynamic and pharmacokinetic parameters were determined over 6 h after insulin injection using clamp techniques. RESULTS: Insulin C(max) was significantly higher (971 +/- 217 vs. 659 +/- 141 pmol/l, P < 0.001) and T(max) was significantly shorter (46.9 +/- 27 vs. 94.7 +/- 50.1 min, P = 0.002) with insulin lispro. Glucose infusion rate (GIR) curves showed clear separation 20 min after injection and were significantly greater for insulin lispro during the 40-60, 60-80 and 80-100-minute time intervals. Total glucose infused was only approximately 5% larger with insulin lispro during the 6-h follow-up, due to lower insulinaemia at later time points. The glucose R(max) and TR(max) were not statistically different between insulin treatments. CONCLUSION: This study shows that i.m. injection of insulin lispro is followed by its more rapid absorption, which results in stronger metabolic effect in the first 2 h when compared with soluble human insulin under the same test conditions. Diabet. Med. 18, 562-566 (2001)

[New diagnostic criteria and classification of diabetes mellitus]. / Novi dijagnosticki kriteriji i klasifikacija secerne bolesti.

World Health Organisation (WHO) has recently proposed new diagnostic criteria and classification of diabetes mellitus. A major change in diagnostic criteria is lowering of diagnostic fasting plasma glucose level: level of 7.0 mM/L or more in two separate samples is sufficient for the diagnosis. Diagnostic criteria for plasma glucose in 120-min. of oral glucose tolerance test are unchanged. Newly recommended fasting level seems to correlate better with 120-min. value and to be a good marker of increased cardiovascular risk. The new classification describes impaired glucose regulation with two stages: impaired fasting glycaemia (plasma glucose of 6.1-7.0 mM/L) which is a new category and impaired glucose tolerance. Both subcategories are not real clinical entities, but markers of diabetic and cardiovascular risk. Diabetes mellitus, as a clinical entity, is separated in four classes: type 1, type 2, other specific types and gestational diabetes. Gestational diabetes includes any glucose intolerance in pregnancy. The Croatian Board for Diabetes Mellitus recommends acceptance of these criteria and classification for clinical use in the country and suggests that OGTT be performed for metabolic syndrome detection in cases of impaired fasting glycaemia.

Different risk factors of microangiopathy in patients with type I diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study.

AIMS/HYPOTHESIS: To identify factors associated with early development of and late protection from microvascular complications in subjects with Type I (insulin-dependent) diabetes mellitus. METHODS: The frequency of microvascular complications and their relation to risk factors were studied in 300 Type I diabetic subjects with short duration of disease (< or = 5 years) compared with 1062 subjects with long duration (> or = 14 years). Microvascular disease was defined as the presence of either retinopathy (assessed from centrally-graded retinal photographs) or urinary albumin excretion rate of more than 20 micrograms/min. RESULTS: The prevalence of microvascular disease was 25% in the short duration group. In the long duration group 18% had no evidence of microvascular complications. In the short duration group factors associated with early development of complications were cigarette smoking and a family history of hypertension. Subjects free of microvascular complications in spite of long duration of diabetes had better glycaemic control, lower blood pressure, better lipid profile and lower von Willebrand factor levels. CONCLUSION/INTERPRETATION: At the early stages of Type I diabetes, cigarette smoking and genetic susceptibility to hypertension are important risk factors for microvascular complications. At a later stage, additional risk factors are poorer glycaemic control, higher blood pressure, and an unfavourable lipid profile possibly associated with endothelial dysfunction. Many of these factors are amenable to long-term intervention which should be started as soon as possible in the course of the disease.

[The diabetic foot. The Croatian model--national consensus (clinical recommendations for diagnosis, prevention and therapy)]. / Dijabeticko stopalo. Hrvatski model--nacionalno usuglaseno misljenje (klinicke preporuke za dijagnostiku, prevenciju i lijecenje).

Diabetic foot occurs due to the loss of protective sense and circulation disorder and a marked proneness to infections. Mechanical stress of bone growths frequently leads to ulcerations. The prevention and timely treatment of diabetic foot requires the participation of both patients and all health care levels. This consensus is given for the purpose of procedure standardization. Education is the basis of prevention and should be carried out with every patient suffering from diabetes mellitus and those with a sensory defect in particular. Appropriate footwear significantly contributes to prevention and treatment of ulcers. As regards the treatment, the necessity of surgical approach with a long term and often manifold antibiotic therapy should be pointed out. Infections are usually mixed. The deeper the ulceration, the more likely the infection with anaerobes and Gram-negative bacteria occurs in addition to Gram-positive ones which are normally present in surface lesions. Strict metabolic control is a precondition for successful treatment. In conclusion, diabetic foot is a major health problem which requires multidisciplinary approach with permanent patient education as its essential part, and a specific cooperation of all levels and different health care specialties.

Changes of autoantibodies against oxidatively modified low density lipoproteins during long-term LDL-apheresis.

The oxidation of low-density lipoproteins (LDL) is considered a key event in the initiation of atherosclerosis. The aim of this study was to follow-up the biological marker of in vivo LDL oxidation (oxidatively modified LDL autoantibody titres) during long-term LDL-apheresis treatment. A patient suffering from severe combined hyperlipidaemia underwent LDL-apheresis biweekly and was followed for two years. The significant reduction of baseline total cholesterol (58%), total triglycerides (80%), LDL-cholesterol (48%), apoprotein B (50%) and apolipoprotein (a) (61%) may be considered as a good response to the treatment. The titre of autoantibodies (IgG) against oxidatively modified LDL (malondialdehyde-derived LDL) was followed throughout the study and showed dynamic changes. The measured values were multiple compared as mean+/-SD over each semester of apheresis application: I semester 70.0+/-8.3 U/ml, n = 12; II semester 58.0+/-13.8 U/ml, n = 12; III semester 37.6+/-6.0 U/ml, n=12; IV semester 34.3+/-7.0 U/ml, n = 12; ANOVA: I vs. II semester p<0.083, II vs. III semester p<0.00053, III vs. IV semester p<0.248. In parallel to the changes in this biochemical parameter, regression of numerous xanthomas was clinically observed. In spite of this, the presence of oxidised-LDL (oxLDL) antibodies was enhanced in comparison to antibody titre detected in a group of age-matched normolipaemic healthy controls (n = 15; 19.4+/-8.6; p<0.01). Classical lipoprotein parameters were correlated with the titre of autoantibodies against oxLDL and showed low correlation coefficients: total cholesterol vs. oxLDLab, r = 0.36; triglycerides vs. oxLDLab, r = 0.43; LDL cholesterol vs. oxLDLab, r = 0.14; HDL cholesterol vs. oxLDLab, r = -0.33; apo B vs. oxLDLab, r = 0.25; apo (a) vs. oxLDLab, r = -0.05. Our study showed an additional benefit of LDL-apheresis therapy. The production of autoantibodies against oxLDL was reduced during the treatment, indicating a lower level of the atherogenic antigen.

Reduction of diffusion capacity for carbon monoxide in diabetic patients.

Diabetes can cause the development of pulmonary complications due to collagen and elastin changes, as well as microangiopathy. This study demonstrates the relationship between pulmonary complications and other chronic complications in diabetes. Twenty-seven patients with diabetes, aged 21 to 62 years, who had had the disease from 3 to 32 years, were included in this study. The protein excretion rate (PER) and the diffusion capacity of the lung for carbon monoxide (DLCO) were included as parameters of the severity of complications. PER was determined by the Biuret method. DLCO was measured by the single-breath method and was corrected by the measurement of alveolar volume (VA). The values of DLCO as corrected by VA (DLCO/VA) were included in the statistical evaluation of the results. The variables of age, duration of diabetes, and complication parameters were included in a multiple regression model with forward, stepwise selection to assess their value in predicting DLCO/VA. The variables were found to be significant predictors of DLCO/VA (R2 = 0.46, adjusted R2 = 0.32, p < 0.022). However, proteinuria was the only significant independent predictor of DLCO/VA. This finding indicates that both renal and pulmonary complications of diabetes share a similar microangiopathic background.

Quality of life following a change in therapy for diabetes mellitus.

OBJECTIVE: The study objective was to evaluate and compare quality-of-life (QOL) parameters between patients with type 2 (non-insulin-dependent) diabetes mellitus who changed therapy from an oral hypoglycaemic agent (OHA) to insulin and those who remained on an OHA. DESIGN: The World Health Organization Quality of Life Questionnaire (WHOQOL) was used to assess quality of life among 2 groups of patients with type 2 diabetes mellitus at baseline and after a 2-month follow-up period. SETTING: The study was conducted in the outpatient department of the Vuk Vrhovac Clinic, a referral centre for registration, treatment and follow-up of patients with diabetes mellitus in Zagreb, Croatia. PARTICIPANTS AND INTERVENTIONS: 32 consecutively recruited patients with type 2 diabetes mellitus who were switched from an OHA to insulin therapy (group 1) were compared with 28 patients who remained on OHA (group 2) with respect to QOL issues. The patient groups were comparable in terms of gender, age, duration of disease, education and family status. However, patients in group 1 had glycosylated haemoglobin (HbA1c) values greater than 9.5% on average during a period of approximately 6 months, which was the criterion used for switching to insulin therapy. MAIN OUTCOME MEASURES AND RESULTS: At baseline, various QOL ratings were higher among patients in group 2 than group 1, indicating better quality of life with respect to overall quality of life (t = -2.31, p = 0.03), physical health (t = -2.36, p = 0.02), psychological state (t = -2.01, p = 0.05) and level of independence (t = -2.75, p = 0.001), while no differences were found between groups with respect to the social domain, personal beliefs and environmental QOL aspects. After the follow-up period, the groups were comparable in all QOL aspects other than overall quality of life (t = -2.18, p = 0.03) and level of independence (t = -3.49, p = 0.001), both of which remained higher for patients in group 2. No changes in QOL parameters were detected within group 2 from baseline to the end of the 2-month follow-up period, whereas patients in group 1 showed significant improvement in psychological QOL determinants (t = -2.14, p = 0.04). CONCLUSION: Results of the study indicate that introducing insulin therapy in patients with type 2 diabetes mellitus and sustained elevated HbA1c levels might positively affect their quality of life.

Total plasma antioxidants in first-degree relatives of patients with insulin-dependent diabetes.

Insulin-dependent diabetes mellitus (IDDM) is a chronic disorder that results from autoimmune destruction of the pancreatic beta-cells. Recent evidence suggests that oxidative damage, resulting from both cytokine-induced production of toxic free radicals and low antioxidant capacity of the beta-cell plays a significant role in the pathogenesis of IDDM. Islet cell antibodies (ICA) have been the best validated marker of risk for the development of IDDM in predisposed individuals, i.e. first-degree relatives of patients with IDDM. We investigated the total plasma antioxidant status (TAS) in both ICA-positive and ICA-negative first-degree relatives of patients with IDDM, to assess the level of overall protection against oxidative damage. TAS was significantly lowered in ICA-positive when compared to both ICA-negative and healthy subjects (p < 0.001), while no significant difference was found in comparison to recently diagnosed patients with IDDM. TAS values were not significantly influenced by gender, age and smoking habits in all groups, as well as by ICA titers in the group of ICA-positive subjects. Results indicate that prediabetic condition, apart from well-established immunological and metabolic alterations, could be associated with biochemical changes revealing complex disturbances of the antioxidative defence system. Although TAS is a functional rather than specific marker, its measurement is likely to be a valuable tool for understanding the mechanisms of specific beta-cell injury.

Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment.

The pharmacokinetics, efficacy and safety of glimepiride were investigated in a single- and a multiple-dose open study in patients with non-insulin-dependent diabetes mellitus and renal impairment and an initial creatinine clearance above 10 ml/ min. Patients were divided into three groups with creatinine clearance above 50 ml/min, 20-50 ml/min and under 20 ml/min. Fifteen fasting patients received a single dose of 3 mg glimepiride and serial blood and urine samples were taken over 24 h for pharmacokinetic and efficacy analyses. A further 16 patients received glimepiride over a 3-month period, an initial dose of 1 mg glimepiride being adjusted within the range 1 to 8 mg to achieve good glucose control. Pharmacokinetic evaluation was done on day 1 and after 3 months. Mean relative total clearance and mean volume of distribution of both single (41.6 ml/ min and 8.47 litres, respectively, when creatinine clearance was above 50 ml/min) and multiple doses of glimepiride increased in proportion to the degree of renal impairment (to 91.1 ml/min and 14.98 litres, respectively, when creatinine clearance was below 20 ml/min, single dose), whereas the terminal halflife and mean time remained unchanged. Lower relative total clearance and renal clearance of both glimepiride metabolites correlated significantly with lower creatinine clearance values. Of the 16 patients 12 required between 1 and 4 mg glimepiride to stabilize their fasting blood glucose. Glimepiride was well-tolerated and there were no drug-related adverse events. In conclusion glimepiride is safe, effective and has clearly-definable pharmacokinetics in diabetic patients with renal impairment. The increased plasma elimination of glimepiride with decreasing kidney function is explainable on the basis of altered protein binding with an increase in unbound drug.