LIRAGLUTIDE: NEW RESULTS IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS

New drugs for type 2 diabetes that act on incretin metabolism have been shown to improve glycemic control, reduce body weight and have a low risk for hypoglycemia. Among these, liraglutide is the first glucagon-like peptide 1 (GLP-1) analogue approved for subcutaneous, once-daily administration. According to results from clinical trials, liraglutide is on attractive alternative for the early treatment of type 2 diabetes. The results of the LEAD (Liraglutide Effect and Action in Diabetes) study program demonstrated the efficacy and safety of liraglutide in terms of reduction of glycated hemoglobin (HbA(tc)) levels, significant loss of body weight that was maintained over the long term, better control of the lipid profile and systolic arterial pressure, reduction of the risk for hypoglycemia and reduction of cardiovascular risk. Moreover, the drug was demonstrated to be safe and can be co-administered with oral antidiabetic agents. The product's tolerability has been demonstrated, with nausea as the most common adverse event, which waned from the fourth week of treatment.

Maternal Moderate Physical Training during Pregnancy Attenuates the Effects of a Low-Protein Diet on the Impaired Secretion of Insulin in Rats: Potential Role for Compensation of Insulin Resistance and Preventing Gestational Diabetes Mellitus

The effects of pregestational and gestational low-to-moderate physical training on insulin secretion in undernourished mothers were evaluated. Virgin female Wistar rats were divided into four groups as follows: control (C, n = 5); trained (T, n = 5); low-protein diet (LP, n = 5); trained with a low-protein diet (T + LP, n = 5). Trained rats ran on a treadmill over a period of 4 weeks before mate (5 days week(-1) and 60 min day(-1), at 65% of VO2max). At pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8% casein diet, and controls were provided with a 17% casein diet. At third day after delivery, mothers and pups were killed and islets were isolated by collagenase digestion of pancreas and incubated for a further 1 h with medium containing 5.6 or 16.7 mM glucose. T mothers showed increased insulin secretion by isolated islets incubated with 16.7 mM glucose, whereas LP group showed reduced secretion of insulin by isolated islets when compared with both C and LP + T groups. Physical training before and during pregnancy attenuated the effects of a low-protein diet on the secretion of insulin, suggesting a potential role for compensation of insulin resistance and preventing gestational diabetes mellitus.

BDKRB2+9/-9 Polymorphism Is Associated with Higher Risk for Diabetes Mellitus in the Brazilian General Population

Some mechanisms have been proposed to explain the role of bradykinin on glucose homeostasis and some studies reported that the BDKRB2 +9/-9 polymorphism was associated to the transcriptional activity of the receptor. In this scenario, the main aim of this study was to evaluate the association of the BDKRB2 +9/-9 polymorphism with diabetes mellitus risk in the Brazilian general population. This study included 1,032 subjects of the general urban population. Anthropometrical, blood pressure, biochemical, and genotype analyses for the BDKRB2 +9/-9 bp insertion/deletion polymorphism were performed. Individuals carrying +9/+9 or +9/-9 genotypes had higher glucose values (84.5 mg/dL versus 80.6 mg/dL, resp.) and higher frequency of diabetes mellitus (7.6% versus 3.6%, resp.) compared to individuals carrying -9/-9, adjusting for age and gender. In addition, higher diabetes mellitus risk was associated to presence of the +9/+9 or +9/-9 genotypes (OR = 1.91; 95% CI = 1.09-4.19; P = 0.03). Our data suggest that the BDKRB2 +9/-9 polymorphism may act as a genetic modulator of glucose homeostasis. It was previously associated to insulin sensitivity, glucose uptake, and insulin secretion, and, in this study, data suggest that the polymorphism may increase susceptibility to chronic metabolic conditions such as diabetes in the Brazilian population.

Role of glycated hemoglobin in the care of diabetes mellitus

Introduction: Persistently high glycemic levels are extremely harmful to the organism and can lead patients to several complications of diabetes mellitus. Glycated hemoglobin represents the glycemic levels for what patient is chronically exposed. Methods: Two virtual databases were surveyed in two languages: Portuguese and English. 12 articles were selected and reviewed. Results and discussion: The HbA1c is used since 1958 in the assessment of glycemic control in diabetic patients. It is formed by a chemical reaction between hemoglobin A and acarbohydrate. Each percentage point of glycated hemoglobin represents approximately 35mg/dL in patient's averageglycemia. Conclusion: The glycated hemoglobin should be measured at least twice per year in patients with diabetes in general. In case of change of hypoglycemic therapy, this frequency should be doubled.

Correlates of the incidence of disability and mortality among older adult Brazilians with and without diabetes mellitus and stroke

Background: The combined effect of diabetes and stroke on disability and mortality remains largely unexplored in Brazil and Latin America. Previous studies have been based primarily on data from developed countries. This study addresses the empirical gap by evaluating the combined impact of diabetes and stroke on disability and mortality in Brazil. Methods: The sample was drawn from two waves of the Survey on Health and Well-being of the Elderly, which followed 2,143 older adults in Sao Paulo, Brazil, from 2000 to 2006. Disability was assessed via measures of activities of daily living (ADL) limitations, severe ADL limitations, and receiving assistance to perform these activities. Logistic and multinomial regression models controlling for sociodemographic and health conditions were used to address the influence of diabetes and stroke on disability and mortality. Results: By itself, the presence of diabetes did not increase the risk of disability or the need for assistance; however, diabetes was related to increased risks when assessed in combination with stroke. After controlling for demographic, social and health conditions, individuals who had experienced stroke but not diabetes were 3.4 times more likely to have ADL limitations than those with neither condition (95% CI 2.26-5.04). This elevated risk more than doubled for those suffering from a combination of diabetes and stroke (OR 7.34, 95% CI 3.73-14.46). Similar effects from the combination of diabetes and stroke were observed for severe ADL limitations (OR 19.75, 95% CI 9.81-39.76) and receiving ADL assistance (OR 16.57, 95% CI 8.39-32.73). Over time, older adults who had experienced a stroke were at higher risk of remaining disabled (RRR 4.28, 95% CI 1.53, 11.95) and of mortality (RRR 3.42, 95% CI 1.65, 7.09). However, risks were even higher for those who had experienced both diabetes and stroke. Diabetes was associated with higher mortality. Conclusions: Findings indicate that a combined history of stroke and diabetes has a great impact on disability prevalence and mortality among older adults in Sao Paulo, Brazil.

Therapeutic communication between health workers and patients concerning diabetes mellitus care

The objective of this cross-sectional study was to analyze therapeutic communication techniques used by health workers with patients under care for diabetes mellitus. Data were collected in 2010 in a public facility in the interior of Ceara, Brazil using video camera equipment and direct observation. Results showed that the most frequently used techniques within the "expression" group were: asking questions, voicing interest, and using descriptive phrases. The most frequently used technique within the "clarification" group was: asking the patient to specify the agent of action. Finally, in regard to the "validation" group, only the technique "summarizing content of the interaction" was employed. The conclusion is that despite the use of communication techniques on the part of professionals, there is still an alarming gap concerning communication skills. Such skills should be allied with technical expertise to enable the delivery of qualified care to individuals with diabetes mellitus.

Minimal change disease associated with type 1 and type 2 diabetes mellitus

A 19-year-old female with type 1 diabetes for four years, and a 73-year-old female with type 2 diabetes for twenty years developed sudden-onset nephrotic syndrome. Examination by light microscopy, immunofluorescence, and electron microscopy (in one case) identified minimal change disease (MCD) in both cases. There was a potential causative drug (meloxicam) for the 73-year-old patient. Both patients were treated with prednisone and responded with complete remission. The patient with type 1 diabetes showed complete remission without relapse, and the patient with type 2 diabetes had two relapses; complete remission was sustained after associated treatment with cyclophosphamide and prednisone. Both patients had two years of follow-up evaluation after remission. We discuss the outcomes of both patients and emphasize the role of kidney biopsy in diabetic patients with an atypical proteinuric clinical course, because patients with MCD clearly respond to corticotherapy alone or in conjunction with other immunosuppressive agents. Arq Bras Endocrinol Metab. 2012;56(5):331-5

Relationship among social support, treatment adherence and metabolic control of diabetes mellitus patients

This cross-sectional and quantitative study aimed to analyze the relationship among social support, adherence to non-pharmacological (diet and physical exercise) and pharmacological treatments (insulin and/or oral anti-diabetic medication) and clinical and metabolic control of 162 type 2 diabetes mellitus patients. Data were collected through instruments validated for Brazil. Social support was directly correlated with treatment adherence. Adherence to non-pharmacological treatment was inversely correlated with body mass index, and medication adherence was inversely correlated with diastolic blood pressure. There were no associations between social support and clinical and metabolic control variables. Findings indicate that social support can be useful to achieve treatment adherence. Studies with other designs should be developed to broaden the analysis of relations between social support and other variables.

The Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial: Clinical and angiographic profile at study entry

Background The optimal revascularization strategy for diabetic patients with multivessel coronary artery disease (MVD) remains uncertain for lack of an adequately powered, randomized trial. The FREEDOM trial was designed to compare contemporary coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI) with drug-eluting stents in diabetic patients with MVD against a background of optimal medical therapy. Methods A total of 1,900 diabetic participants with MVD were randomized to PCI or CABG worldwide from April 2005 to March 2010. FREEDOM is a superiority trial with a mean follow-up of 4.37 years (minimum 2 years) and 80% power to detect a 27.0% relative reduction. We present the baseline characteristics of patients screened and randomized, and provide a comparison with other MVD trials involving diabetic patients. Results The randomized cohort was 63.1 +/- 9.1 years old and 29% female, with a median diabetes duration of 10.2 +/- 8.9 years. Most (83%) had 3-vessel disease and on average took 5.5 +/- 1.7 vascular medications, with 32% on insulin therapy. Nearly all had hypertension and/or dyslipidemia, and 26% had a prior myocardial infarction. Mean hemoglobin A1c was 7.8 +/- 1.7 mg/dL, 29% had low-density lipoprotein <70 mg/dL, and mean systolic blood pressure was 134 +/- 20 mm Hg. The mean SYNTAX score was 26.2 with a symmetric distribution. FREEDOM trial participants have baseline characteristics similar to those of contemporary multivessel and diabetes trial cohorts. Conclusions The FREEDOM trial has successfully recruited a high-risk diabetic MVD cohort. Follow-up efforts include aggressive monitoring to optimize background risk factor control. FREEDOM will contribute significantly to the PCI versus CABG debate in diabetic patients with MVD. (Am Heart J 2012;164:591-9.)

Effect of Type 2 Diabetes Mellitus on the Pharmacokinetics of Metformin in Obese Pregnant Women

Background and Objective The use of metformin throughout gestation by women with polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus (T2DM) significantly reduces the number of first-trimester spontaneous abortions and the rate of occurrence of gestational diabetes and hypertensive syndromes. Metformin is taken up into renal tubular cells by organic cation transport 2 (OCT2) and eliminated unchanged into the urine. The objective of this study was to analyse the influence of T2DM on the pharmacokinetics of metformin in obese pregnant women and in a control group of non-diabetic obese pregnant women with PCOS. Methods Eight non-diabetic obese pregnant women with PCOS and nine obese pregnant women with T2DM taking oral metformin 850 mg every 12 h were evaluated throughout gestation. Serial blood samples were collected over a 12-h period during the third trimester of pregnancy. Steady-state plasma concentrations of metformin were determined by high-performance liquid chromatography with a UV detector. The pharmacokinetic results of the two groups, reported as median and 25th and 75th percentile, were compared statistically using the Mann Whitney test, with the level of significance set at p < 0.05. Results The pharmacokinetic parameters detected for PCOS versus T2DM patients, reported as median, were, respectively: elimination half-life 3.75 versus 4.00 h; time to maximum concentration 2.00 versus 3.00 h; maximum concentration 1.42 versus 1.21 mu g/mL; mean concentration 0.53 versus 0.56 mu g/mL; area under the plasma concentration time curve from time zero to 12 h 6.42 versus 6.73 mu g.h/mL; apparent total oral clearance 105.39 versus 98.38 L/h; apparent volume of distribution after oral administration 550.51 versus 490.98 L; and fluctuation (maximum minimum concentration variation) of 179.56 versus 181.73%. No significant differences in pharmacokinetic parameters were observed between the groups. Conclusion T2DM in the presence of insulin use does not influence the pharmacokinetics of metformin in pregnant patients, demonstrating the absence of a need to increase the dose, and consequently does not influence the OCT2-mediated transport in pregnant women with PCOS.

Cost-effectiveness and budget impact of saxagliptine as additional therapy to metformin for the treatment of diabetes mellitus type 2 in the Brazilian private health system

Cost-effectiveness and budget impact of saxagliptine as additional therapy to metformin for the treatment of diabetes mellitus type 2 in the Brazilian private health system Objectives: To compare costs and clinical benefits of three additional therapies to metformin (MF) for patients with diabetes mellitus type 2 (DM2). Methods: A discrete event simulation model seas built to estimate the cost-utility ratio (cost per quality-adjusted life years [QALY)) of saxagliptine as an additional therapy to MF when compared to rosiglitazone or pioglitazone. A budget impact model (BIM) was built to simulate the economic impact of saxagliptine use in the context of the Brazilian private health system. Results: The acquiring medication costs for the hypothetical patient group analyzed in a time frame of three years, were R$ 10,850,185, R$ 14,836,265 and R$ 14,679,099 for saxagliptine, pioglitazone and rosiglitazone, respectively. Saxagliptine showed lower costs and greater effectiveness in both comparisons, with projected savings for the first three years of R$ 3,874 and R$ 3,996, respectively. The BIM estimated cumulative savings of R$ 417,958 with the repayment of saxagliptine in three years from the perspective of a health plan with 1,000,000 covered individuals. Conclusion: From the perspective of private paying source, the projection is that adding saxagliptine with MF save costs when compared with the addition of rosiglitazone or pioglitazone in patients with DM2 that have not reached the HbA1c goal with metformin monotherapy. The BIM of including saxagliptine in the reimbursement lists of health plans indicated significant savings on the three-year horizon.

Autoantibodies and High-Risk HLA Susceptibility Markers in First-Degree Relatives of Brazilian Patients with Type 1 Diabetes Mellitus: A Progression to Disease Based Study

The objective of this study was to determine the frequencies of autoantibodies to heterogeneous islet-cell cytoplasmic antigens (ICA), glutamic acid decarboxylase(65) (GAD(65)A), insulinoma-associated antigen-2 (IA-2A) and insulin (IAA)-and human leukocyte antigen (HLA) class II markers (HLA-DR and -DQ) in first degree relatives of heterogeneous Brazilian patients with type I diabetes(T1DM). A major focus of this study was to determine the influence of age, gender, proband characteristics and ancestry on the prevalence of autoantibodies and HLA-DR and -DQ alleles on disease progression and genetic predisposition to T1DM among the first-degree relatives. IAA, ICA, GAD(65)A, IA-2A and HLA- class II alleles were determined in 546 first-degree-relatives, 244 siblings, 55 offspring and 233 parents of 178 Brazilian patients with T1DM. Overall, 8.9% of the relatives were positive for one or more autoantibodies. IAA was the only antibody detected in parents. GAD(65) was the most prevalent antibody in offspring and siblings as compared to parents and it was the sole antibody detected in offspring. Five siblings were positive for the IA-2 antibody. A significant number (62.1%) of siblings had 1 or 2 high risk HLA haplotypes. During a 4-year follow-up study, 5 siblings (expressing HLA-DR3 or -DR4 alleles) and 1 offspring positive for GAD(65)A progressed to diabetes. The data indicated that the GAD(65) and IA-2 antibodies were the strongest predictors of T1DM in our study population. The high risk HLA haplotypes alone were not predictive of progression to overt diabetes.

Metformin, but not glimepiride, improves carotid artery diameter and blood flow in patients with type 2 diabetes mellitus

OBJECTIVE: To compare the effects of glimepiride and metformin on vascular reactivity, hemostatic factors and glucose and lipid profiles in patients with type 2 diabetes. METHODS: A prospective study was performed in 16 uncontrolled patients with diabetes previously treated with dietary intervention. The participants were randomized into metformin or glimepiride therapy groups. After four months, the patients were crossed over with no washout period to the alternative treatment for an additional four-month period on similar dosage schedules. The following variables were assessed before and after four months of each treatment: 1) fasting glycemia, insulin, catecholamines, lipid profiles and HbA(1) levels; 2) t-PA and PAI-1 (antigen and activity), platelet aggregation and fibrinogen and plasminogen levels; and 3) the flow indices of the carotid and brachial arteries. In addition, at the end of each period, a 12-hour metabolic profile was obtained after fasting and every 2 hours thereafter. RESULTS: Both therapies resulted in similar decreases in fasting glucose, triglyceride and norepinephrine levels, and they increased the fibrinolytic factor plasminogen but decreased t-PA activity. Metformin caused lower insulin and pro-insulin levels and higher glucagon levels and increased systolic carotid diameter and blood flow. Neither metformin nor glimepiride affected endothelial-dependent or endothelial-independent vasodilation of the brachial artery. CONCLUSIONS: Glimepiride and metformin were effective in improving glucose and lipid profiles and norepinephrine levels. Metformin afforded more protection against macrovascular diabetes complications, increased systolic carotid artery diameter and total and systolic blood flow, and decreased insulin levels. As both therapies increased plasminogen levels but reduced t-PA activity, a coagulation process was likely still ongoing.

Benefits on quality of life concomitant to metabolic improvement in intervention program for prevention of diabetes mellitus

To evaluate whether an interdisciplinary intervention program on lifestyle results in better quality of life (QoL) and lower frequencies of depression and binge eating disorder (BED) in individuals at risk for type 2 diabetes mellitus. A total of 177 individuals (32.2% men, age 55.4 +/- A 12.5 years) at risk for diabetes were allocated to a 9-month traditional (TI) or intensive interdisciplinary intervention (II) on dietary habits and physical activity including psychoeducative groups. They were submitted to questionnaires and clinical and laboratory examinations. Predictors of non-adherence were analyzed by logistic regression. Only individuals submitted to II had blood pressure and plasma glucose levels reduced. Frequencies of depression reduced in both interventions but of BED only in II (28.0-4.0%, P < 0.001). Increments in the scores of SF-36 domains (physical functioning: 11.1 +/- A 14.0 vs. 5.3 +/- A 13.0, role-emotional: 20.4 +/- A 40.2 vs. 6.2 +/- A 43.8, P = 0.05) were greater in the II than in TI, respectively. Changes in SF-36 correlated with decreases in anthropometry, blood pressure and glucose levels, depression and BED scores. Male gender was independently associated with non-adherence to the II. In addition to metabolic benefits, an interdisciplinary approach may induce desirable extrametabolic effects, favoring the control of psychiatric disorders and improving the QoL of individuals at risk for diabetes.

Effect of Cholecalciferol as Adjunctive Therapy With Insulin on Protective Immunologic Profile and Decline of Residual beta-Cell Function in New-Onset Type 1 Diabetes Mellitus

Objective: To evaluate the effect of vitamin D-3 on cytokine levels, regulatory T cells, and residual beta-cell function decline when cholecalciferol (vitamin D-3 administered therapeutically) is given as adjunctive therapy with insulin in new-onset type 1 diabetes mellitus (T1DM). Design and Setting: An 18-month (March 10, 2006, to October 28, 2010) randomized, double-blind, placebo-controlled trial was conducted at the Diabetes Center of Sao Paulo Federal University, Sao Paulo, Brazil. Participants: Thirty-eight patients with new-onset T1DM with fasting serum C-peptide levels greater than or equal to 0.6 ng/mL were randomly assigned to receive daily oral therapy of cholecalciferol, 2000 IU, or placebo. Main Outcome Measure: Levels of proinflammatory and anti-inflammatory cytokines, chemokines, regulatory T cells, hemoglobin A(1c), and C-peptide; body mass index; and insulin daily dose. Results: Mean (SD) chemokine ligand 2 (monocyte chemoattractant protein 1) levels were significantly higher (184.6 [101.1] vs 121.4 [55.8] pg/mL) at 12 months, as well as the increase in regulatory T-cell percentage (4.55%[1.5%] vs 3.34%[1.8%]) with cholecalciferol vs placebo. The cumulative incidence of progression to undetectable (<= 0.1 ng/mL) fasting C-peptide reached 18.7% in the cholecalciferol group and 62.5% in the placebo group; stimulated C-peptide reached 6.2% in the cholecalciferol group and 37.5% in the placebo group at 18 months. Body mass index, hemoglobin A(1c) level, and insulin requirements were similar between the 2 groups. Conclusions: Cholecalciferol used as adjunctive therapy with insulin is safe and associated with a protective immunologic effect and slow decline of residual beta-cell function in patients with new-onset T1DM. Cholecalciferol may be an interesting adjuvant in T1DM prevention trials.