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.

Gene expression profiles displayed by peripheral blood mononuclear cells from patients with type 2 diabetes mellitus focusing on biological processes implicated on the pathogenesis of the disease

Patients with type 2 diabetes mellitus (T2DM) exhibit insulin resistance associated with obesity and inflammatory response, besides an increased level of oxidative DNA damage as a consequence of the hyperglycemic condition and the generation of reactive oxygen species (ROS). In order to provide information on the mechanisms involved in the pathophysiology of T2DM, we analyzed the transcriptional expression patterns exhibited by peripheral blood mononuclear cells (PBMCs) from patients with T2DM compared to non-diabetic subjects, by investigating several biological processes: inflammatory and immune responses, responses to oxidative stress and hypoxia, fatty acid processing, and DNA repair. PBMCs were obtained from 20 T2DM patients and eight non-diabetic subjects. Total RNA was hybridized to Agilent whole human genome 4x44K one-color oligo-microarray. Microarray data were analyzed using the GeneSpring GX 11.0 software (Agilent). We used BRB-ArrayTools software (gene set analysis - GSA) to investigate significant gene sets and the Genomica tool to study a possible influence of clinical features on gene expression profiles. We showed that PBMCs from T2DM patients presented significant changes in gene expression, exhibiting 1320 differentially expressed genes compared to the control group. A great number of genes were involved in biological processes implicated in the pathogenesis of T2DM. Among the genes with high fold-change values, the up-regulated ones were associated with fatty acid metabolism and protection against lipid-induced oxidative stress, while the down-regulated ones were implicated in the suppression of pro-inflammatory cytokines production and DNA repair. Moreover, we identified two significant signaling pathways: adipocytokine, related to insulin resistance; and ceramide, related to oxidative stress and induction of apoptosis. In addition, expression profiles were not influenced by patient features, such as age, gender, obesity, pre/post-menopause age, neuropathy, glycemia, and HbA(1c) percentage. Hence, by studying expression profiles of PBMCs, we provided quantitative and qualitative differences and similarities between T2DM patients and non-diabetic individuals, contributing with new perspectives for a better understanding of the disease. (C) 2012 Elsevier B.V. All rights reserved.

Classification of the severity of diabetic neuropathy: a new approach taking uncertainties into account using fuzzy logic

OBJECTIVE: This study proposes a new approach that considers uncertainty in predicting and quantifying the presence and severity of diabetic peripheral neuropathy. METHODS: A rule-based fuzzy expert system was designed by four experts in diabetic neuropathy. The model variables were used to classify neuropathy in diabetic patients, defining it as mild, moderate, or severe. System performance was evaluated by means of the Kappa agreement measure, comparing the results of the model with those generated by the experts in an assessment of 50 patients. Accuracy was evaluated by an ROC curve analysis obtained based on 50 other cases; the results of those clinical assessments were considered to be the gold standard. RESULTS: According to the Kappa analysis, the model was in moderate agreement with expert opinions. The ROC analysis (evaluation of accuracy) determined an area under the curve equal to 0.91, demonstrating very good consistency in classifying patients with diabetic neuropathy. CONCLUSION: The model efficiently classified diabetic patients with different degrees of neuropathy severity. In addition, the model provides a way to quantify diabetic neuropathy severity and allows a more accurate patient condition assessment.

Color vision impairment in type 2 diabetes assessed by the D-15d test and the Cambridge Colour Test

Color vision impairment emerges at early stages of diabetes mellitus type 2 (DM2) and may precede diabetic retinopathy or the appearance of vascular alterations in the retina. The aim of the present study was to compare the evaluation of the color vision with two different tests - the Lanthony desaturated D-15d test (a traditional color arrangement test), and the Cambridge Colour Test (CCT) (a computerized color discrimination test) - in patients diagnosed with DM2 without clinical signs of diabetic retinopathy (DR), and in sex- and age-matched control groups. Both color tests revealed statistically significant differences between the controls and the worst eyes of the DM2 patients. In addition, the degree of color vision impairment diagnosed by both tests correlated with the disease duration. The D-15d outcomes indicated solely tritan losses. In comparison, CCT outcomes revealed diffuse losses in color discrimination: 13.3% for best eyes and 29% for worst eyes. In addition, elevation of tritan thresholds in the DM2 patients, as detected by the Trivector subtest of the CCT, was found to correlate with the level of glycated hemoglobin. Outcomes of both tests confirm that subclinical losses of color vision are present in DM2 patients at an early stage of the disease, prior to signs of retinopathy. Considering the advantages of the CCT test compared to the D-15d test, further studies should attempt to verify and/or improve the efficiency of the CCT test.

Evaluation of plasma homocysteine level according to the C677T and A1298C polymorphism of the enzyme MTHRF in type 2 diabetic adults

Objective: To determine plasma homocysteine levels during fasting and after methionine overload, and to correlate homocysteinemia according to methylenetetrahydrofolate reductase (MTHFR) polymorphism in type 2 diabetic adults. Subjects and methods: The study included 50 type 2 diabetic adults (DM group) and 52 healthy subjects (Control group). Anthropometric data, and information on food intake, serum levels of vitamin B 12, folic acid and plasma homocysteine were obtained. The identification of C677T and A1298C polymorphisms was carried out in the MTHFR gene. Results: There was no significant difference in homocysteinemia between the two groups, and hyperhomocysteinemia during fasting occurred in 40% of the diabetic patients and in 23% of the controls. For the same polymorphism, there was not any significant difference in homocysteine between the groups. In the Control group, homocysteinemia was greater in those subjects with C677T and A1298C polymorphisms. Among diabetic subjects, those with the A1298C polymorphism had lower levels of homocysteine compared with individuals with C677T polymorphism. Conclusion: The MTHFR polymorphism (C677T and A1298C) resulted in different outcomes regarding homocysteinemia among individuals of each group (diabetic and control). These data suggest that metabolic factors inherent to diabetes influence homocysteine metabolism. Arq Bras Endocrinol Metab. 2012;56(7):429-34

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.

Surgical Treatment of Type 2 Diabetes in Patients with BMI Below 35: Mid-term Outcomes of the Laparoscopic Ileal Interposition Associated with a Sleeve Gastrectomy in 202 Consecutive Cases

The objective of this study was to evaluate the mid-term outcomes of the laparoscopic ileal interposition into the jejunum (JII-SG) or into the duodenum (DII-SG) associated with sleeve gastrectomy for type 2 diabetes mellitus (T2DM) patients with BMI below 35. The procedures were performed on 202 consecutive patients. Mean age was 52.2 +/- 7.5. Mean duration of T2DM was 9.8 +/- 5.2 years. Insulin therapy was used by 41.1%. Dyslipidemia was observed in 78.2%, hypertension in 67.3%, nephropathy in 49.5%, retinopathy in 31.2%, coronary heart disease in 11.9%, and other cardiovascular events in 12.9%. Mean follow-up was 39.1 months (range, 25-61). Early and late mortality was 0.99% and 1.0%, respectively. Early reoperation was performed in 2.5%. Early and late major complications were 8.4% and 3.5%. Early most frequent complications were pneumonia and ileus. Intestinal obstruction was diagnosed in 1.5%. Mean BMI decreased from 29.7 to 23.5 kg/m(2), mean fasting glucose from 202.1 to 112.2 mg/dl, and mean postprandial glucose from 263.3 to 130 mg/dl. Triglycerides diminished from a mean of 273.4 to 110.3 mg/dl and cholesterol from a mean of 204.7 to 160.1 mg/dl. Hypertension was resolved in 87.5%. Mean hemoglobin A(1c) (HbA(1c)) decreased from 8.7 to 6.2% after the JII-SG and to 5.9% following the DII-SG. HbA(1c) below 7% was seen in 89.9% of the patients and below 6.5% in 78.3%. Overall, 86.4% of patients were off antidiabetic medications. Both JII-SG and DII-SG demonstrated to be safe, effective, and long-lasting alternatives for the treatment of T2DM patients with BMI < 35. Beyond glycemic control, other benefits were achieved.

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.

Interference of different types of seats on postural control system during a forward-reaching task in individuals with paraplegia

We aimed to evaluate the influence of different types of wheelchair seats on paraplegic individuals' postural control using a maximum anterior reaching test. Balance evaluations during 50, 75, and 90% of each individual's maximum reach in the forward direction using two different cushions on seat (one foam and one gel) and a no-cushion condition were carried out on 11 individuals with a spinal cord injury (SCI) and six individuals without SCI. Trunk anterior displacement and the time spent to perform the test were assessed. No differences were found for the three types of seats in terms of trunk anterior displacement and the time spent to perform the test when intragroup comparisons were made in both groups (P > 0.05). The intergroup comparison showed that body displacement was less prominent and the time spent to perform the test was more prolonged for individuals with SCI (P < 0.05), which suggests a postural control deficit. The seat type did not affect the ability of the postural control system to maintain balance during the forward-reaching task.

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.

Analysis of the mRNA expression of the S100 beta protein in adipocytes of patients with diabetes mellitus, type 2

Objective: This study aims to explore the possible relationship between the expression level of S100 beta protein mRNA with diabetes mellitus type 2 in adipocytes from patients with this disease in comparison with normoglycemic individuals. Materials and methods: Samples of adipose tissue of eight patients from the coronary section of the Institute Dante Pazzanese of Cardiology (IDPC), four in Group Diabetes and four of Normoglycemic group, were evaluated by RT-PCR real time. Results: An increase around 15 times values, between the threshold cycle (Delta Ct), of mRNA expression of S100 beta protein in adipocytes of the diabetes group was observed in comparison to the control group (p = 0.015). Conclusion: Our results indicate, for the first time, that there is coexistence of increased expression of the S100 beta and the type 2 diabetes mellitus gene. Arq Bras Endocrinol Metab. 2012;56(7):435-40

A modified laparoscopic sleeve gastrectomy for the treatment of diabetes mellitus type 2 and metabolic syndrome in obesity

BACKGROUND: Ghrelin is a gastrointestinal peptide hormone (a 28-amino acid peptide) produced primarily by X/A cells in the oxyntic glands of the stomach fundus and cells lining the duodenum cavern. It suppresses insulin secretion and action and commands a significant role in regulating food intake. The aim of the present study was to show that modified laparoscopic sleeve gastrectomy (MLSG), in which a significant part of the gastric fundus and body of the stomach is removed up to 1 inch from the pylorus vein, may contribute to decreasing circulating ghrelin levels. METHODS: A study population consisting of 150 individuals was monitored after undergoing a MLSG, with individuals chosen based on a documented history of diabetes mellitus type 2 and metabolic syndrome, clinical results determining a body mass index (BMI) of 35 to 60 kg/m(2), peptide C level greater than 1, negative anti-glutamic acid decarboxylase, negative anti-insulin, and confirmed stability of drug/insulin treatment and glycosylated hemoglobin greater than 6.5% for at least 24 and 3 months, respectively, before enrollment. RESULTS: Twenty-four months after surgery, 150 patients (86.6%) presented with normal glycemic levels between 77 and 99 mg/dL. All patients improved average serum insulin levels by 9 mU/L and average glycosylated hemoglobin levels by 5.1% (normal range, 4%-6%). All patients tested negative for Helicobacter pylori and stopped using insulin, with 3 patients prescribed twice-daily use of an oral hypoglycemiant. In 14% of cases, patients experienced partial hair loss with low serum zinc levels and were prescribed oral zinc reposition and topical hair stimulants. The average weight loss recorded was 44.6% for patients with a BMI less than 45 kg/m(2) and 58% for patients with a BMI greater than 50 kg/m(2). CONCLUSIONS: The MLSG is a safe procedure with a low morbidity rate (2.7%) (4 cases of fistula and 2 of bleeding) and no surgical mortality in this study. This surgery can promote control of diabetes mellitus type 2 and aid the treatment of exogenous overweight and morbidly obese individuals. The results of this study show that only through resection of the ghrelin-producing gastric area can most obesity cases and diabetes type II conditions be reverted to nonobese and controlled diabetes. (c) 2012 Elsevier Inc. All rights reserved.

Ecosystem approach and the Fuzzy logic: a dialectical proposal for information on Environmental Health

The ever-growing production and the problematization of Environmental Health have shown the need to apprehend complex realities and deal with uncertainties from the most diversified instruments which may even incorporate local aspects and subjectivities by means of qualitative realities, while broadening the capacity of the information system. This paper presents a view on the reflection upon some challenges and possible convergences between the ecosystemic approach and the Fuzzy logic in the process of dealing with scientific information and decision-making in Environmental Health.

Identifying common and specific microRNAs expressed in peripheral blood mononuclear cell of type 1, type 2, and gestational diabetes mellitus patients

Abstract Background Regardless the regulatory function of microRNAs (miRNA), their differential expression pattern has been used to define miRNA signatures and to disclose disease biomarkers. To address the question of whether patients presenting the different types of diabetes mellitus could be distinguished on the basis of their miRNA and mRNA expression profiling, we obtained peripheral blood mononuclear cell (PBMC) RNAs from 7 type 1 (T1D), 7 type 2 (T2D), and 6 gestational diabetes (GDM) patients, which were hybridized to Agilent miRNA and mRNA microarrays. Data quantification and quality control were obtained using the Feature Extraction software, and data distribution was normalized using quantile function implemented in the Aroma light package. Differentially expressed miRNAs/mRNAs were identified using Rank products, comparing T1DxGDM, T2DxGDM and T1DxT2D. Hierarchical clustering was performed using the average linkage criterion with Pearson uncentered distance as metrics. Results The use of the same microarrays platform permitted the identification of sets of shared or specific miRNAs/mRNA interaction for each type of diabetes. Nine miRNAs (hsa-miR-126, hsa-miR-1307, hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-144, hsa-miR-199a-5p, hsa-miR-27a, hsa-miR-29b, and hsa-miR-342-3p) were shared among T1D, T2D and GDM, and additional specific miRNAs were identified for T1D (20 miRNAs), T2D (14) and GDM (19) patients. ROC curves allowed the identification of specific and relevant (greater AUC values) miRNAs for each type of diabetes, including: i) hsa-miR-1274a, hsa-miR-1274b and hsa-let-7f for T1D; ii) hsa-miR-222, hsa-miR-30e and hsa-miR-140-3p for T2D, and iii) hsa-miR-181a and hsa-miR-1268 for GDM. Many of these miRNAs targeted mRNAs associated with diabetes pathogenesis. Conclusions These results indicate that PBMC can be used as reporter cells to characterize the miRNA expression profiling disclosed by the different diabetes mellitus manifestations. Shared miRNAs may characterize diabetes as a metabolic and inflammatory disorder, whereas specific miRNAs may represent biological markers for each type of diabetes, deserving further attention.

Angiotensin II type 2 receptor (AT2R) is associated with increased tolerance of the hyperthyroid heart to ischemia-reperfusion

Background Thyroid hormone induces cardiac hypertrophy and preconditions the myocardium against Ischemia/Reperfusion (I/R) injury. Type 2 Angiotensin II receptors (AT2R) are shown to be upregulated in cardiac hypertrophy observed in hyperthyroidism and this receptor has been reported to mediate cardioprotection against ischemic injury. Methods The aim of the present study was to evaluate the role of AT2R in the recovery of myocardium after I/R in isolated hearts from T3 treated rats. MaleWistar rats were treated with triiodothyronine (T3; 7 μg/100 gBW/day, i.p.) in the presence or not of a specific AT2R blocker (PD123,319; 10 mg/Kg) for 14 days, while normal rats served as control. After treatment, isolated hearts were perfused in Langendorff mode; after 30 min of stabilization, hearts were subjected to 20 min of zero-flow global ischemia followed by 25 min, 35 min and 45 min of reperfusion. Results T3 treatment induced cardiac hypertrophy, which was not changed by PD treatment. Post-ischemic recovery of cardiac function was increased in T3-treated hearts after 35 min and 45 min of reperfusion as compared to control and the ischemic contracture was accelerated and intensified. AT2R blockade was able to return the evaluated functional parameters of cardiac performance (LVDP, +dP/dtmáx and −dP/dtmin) to the control condition. Furthermore, AT2R blockade prevented the increase in AMPK expression levels induced by T3, suggesting its possible involvement in this process. Conclusion AT2R plays a significant role in T3-induced cardioprotection.