Fezolinetant for the treatment of vasomotor symptoms associated with menopause: a meta-analysis.

This systematic review and meta-analysis investigated the efficacy and safety of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms (VMS) associated with menopause. PubMed, Cochrane Library, Embase and Web of Science were searched for randomized controlled trials (RCTs) published from inception to June 2023, comparing fezolinetant to placebo in postmenopausal women suffering from moderate-to-severe VMS. The mean difference and risk ratio were calculated for continuous and binary outcomes, respectively. R software was used for the statistical analysis, and RoB-2 (Cochrane) to assess the risk of bias. We performed subgroup analysis based on different dosing regimens. Five RCTs comprising 3302 patients were included. Compared with placebo, at 12-week follow-up, fezolinetant significantly reduced the daily frequency of moderate-to-severe VMS (weighted mean difference [WMD] - 2.36; 95% confidence interval [CI] - 2.92, -1.81) and daily severity of moderate-to-severe VMS (WMD -0.22; 95% CI -0.31, -0.13). Also, fezolinetant significantly improved the quality of life (WMD -0.42; 95% CI -0.58, -0.26) and sleep disturbance (WMD -1.10; 95% CI -1.96, -0.24). There were no significant differences between groups in adverse events. These findings support the efficacy and safety of fezolinetant for the treatment of VMS related to menopause.

2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetes.

BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.

The 2021-2022 position of Brazilian Diabetes Society on diabetic kidney disease (DKD) management: an evidence-based guideline to clinical practice. Screening and treatment of hyperglycemia, arterial hypertension, and dyslipidemia in the patient with DKD.

BACKGROUND: Diabetic kidney disease is the leading cause of end-stage renal disease and is associated with increased morbidity and mortality. This review is an authorized literal translation of part of the Brazilian Diabetes Society (SBD) Guidelines 2021-2022. This evidence-based guideline provides guidance on the correct management of Diabetic Kidney Disease (DKD) in clinical practice. METHODS: The methodology was published elsewhere in previous SBD guidelines and was approved by the internal institutional Steering Committee for publication. Briefly, the Brazilian Diabetes Society indicated 14 experts to constitute the Central Committee, designed to regulate methodology, review the manuscripts, and make judgments on degrees of recommendations and levels of evidence. SBD Renal Disease Department drafted the manuscript selecting key clinical questions to make a narrative review using MEDLINE via PubMed, with the best evidence available including high-quality clinical trials, metanalysis, and large observational studies related to DKD diagnosis and treatment, by using the MeSH terms [diabetes], [type 2 diabetes], [type 1 diabetes] and [chronic kidney disease]. RESULTS: The extensive review of the literature made by the 14 members of the Central Committee defined 24 recommendations. Three levels of evidence were considered: A. Data from more than 1 randomized clinical trial or 1 metanalysis of randomized clinical trials with low heterogeneity (I2 < 40%). B. Data from metanalysis, including large observational studies, a single randomized clinical trial, or a pre-specified subgroup analysis. C: Data from small or non-randomized studies, exploratory analyses, or consensus of expert opinion. The degree of recommendation was obtained based on a poll sent to the panelists, using the following criteria: Grade I: when more than 90% of agreement; Grade IIa 75-89% of agreement; IIb 50-74% of agreement, and III, when most of the panelist recommends against a defined treatment. CONCLUSIONS: To prevent or at least postpone the advanced stages of DKD with the associated cardiovascular complications, intensive glycemic and blood pressure control are required, as well as the use of renin-angiotensin-aldosterone system blocker agents such as ARB, ACEI, and MRA. Recently, SGLT2 inhibitors and GLP1 receptor agonists have been added to the therapeutic arsenal, with well-proven benefits regarding kidney protection and patients' survival.

Parents' cardiovascular risk factors are related to overweight and obesity in young Brazilians with type 1 diabetes.

AIM: To identify family background characteristics and cardiovascular disease (CVD) risk factors linked to overweight and obesity in Brazilian with type 1 diabetes (T1D). METHODS: We performed cross-sectional anthropometric and laboratory analyses in young individuals with T1D. RESULTS: Among 181 participants, 87 were women and 94 were men (64%/78% normal weight, 27%/15% overweight and 9%/7% obese). Obese men were older; were more likely to be Black; had higher triglyceride levels and diastolic blood pressure (BP), lower estimated glucose disposal rate (eGDR) and higher prevalence of first-degree relatives (FDR) with hypertension and early CVD. Overweight and obese women were more likely to have lower eGDR, and obese women were more likely to have FDR with obesity. CONCLUSION: One third of young people with T1D were overweight or obese. Excess weight was associated with family history (FH) of obesity for women and FH of early CVD or hypertension for men. BMI was related to decreased insulin sensitivity in both genders, but only men with T1D had metabolic impairment. Our data highlight the importance of considering family background in individuals with T1D.

The first series of cases of ketosis-prone type 2 diabetes (flatbush diabetes) in Brazilian adults.

Ketosis-prone type 2 diabetes (KPD) is an emerging form of diabetes mellitus characterized by unprovoked ketoacidosis, absence of autoimmunity and beta-cell dysfunction. The KPD may improve after initial glycemic compensation and evolve to exogenous insulin independence, most cases were observed in populations with African or Hispanic backgrounds. We reviewed the literature on KPD and, to date, only one case of KPD has been described in Brazil's multi-ethnic population. A group of adult Brazilian KPD patients without autoimmunity and insulinopenia was identified for this study. We report a retrospective study of four KPD cases (3 males) evaluated in southeast Brazil, the patients were overweight or obese, age between the third and fifth decades of life, had a family history of type 2 diabetes, hyperglycemia (809.5 ± 344.2 mg/dL), acidosis (pH 7.21 ± 0.07; normal range (nr): 7.35-7.45 and bicarbonate 9.1 ± 6.2; nr: 22-26 mEq/mL), ketonuria (142.5 ± 114.4 mg/dL; nr: absence), absence of glutamic acid decarboxylase antibodies (GAD-65), and beta-cell function reserve (C-peptide 1.19 ± 0.53 ng/mL - nr: 1.1-4.4 ng/mL) on diagnosis. After glycemic compensation, there was increase of C-peptide (2.21 ± 0.41) indicating the recovery of beta-cell function and the time to insulin independence was 7.7 ± 3.5 months. They evolved after the period of glucotoxicity with insulin withdrawal and could be treated with oral antidiabetic therapy. This is the first case series of KPD described in Brazil being characterized by ketoacidosis at diagnosis, absence of autoimmunity, recovery of beta-cell function and insulin independence.

Awareness of hypoglycemia and spectral analysis of heart rate variability in type 1 diabetes.

AIMS: To investigate the relationship of unawareness of hypoglycemia with spectral analysis of heart rate variability (HRV) and clinical variables in type 1 diabetes (T1D) individuals. METHODS: Participants with type 1 diabetes mellitus (type 1 diabetes) were prospectively assessed for hypoglycemia awareness using the Pedersen-Bjergaard method and were classified as normal hypoglycemia awareness, impaired hypoglycemia awareness and hypoglycemia unawareness. Indices of HRV in frequency domain were evaluated and Ewing tests were used for the diagnosis of cardiovascular autonomic neuropathy (CAN). RESULTS: Ninety-eight participants with T1D (mean age 26 years, average diabetes duration 13 years, and mean HbA1c 8.4%) were included in this study. The prevalence of hypoglycemia unawareness was 28%. No significant difference was observed on the prevalence of CAN among groups of different hypoglycemia awareness (p = 0.740). On regression analyses, abnormal results of HRV in frequency domain were not associated with unawareness of hypoglycemia. On univariable regression analysis, age, diabetes duration and estimated creatinine clearance were associated with unawareness of hypoglycemia. CONCLUSION: CAN as assessed by Ewing tests and spectral analysis of HRV is not associated with unawareness of hypoglycemia. There is association of age, diabetes duration and renal deficit with unawareness of hypoglycemia.

Modifiable Variables Are Major Risk Factors for Posttransplant Diabetes Mellitus in a Time-Dependent Manner in Kidney Transplant: An Observational Cohort Study.

Modifiable and nonmodifiable risk factors for developing posttransplant diabetes mellitus (PTDM) have already been established in kidney transplant setting and impact adversely both patient and allograft survival. We analysed 450 recipients of living and deceased donor kidney transplants using current immunosuppressive regimen in the modern era and verified PTDM prevalence and risk factors over three-year posttransplant. Tacrolimus (85%), prednisone (100%), and mycophenolate (53%) were the main immunosuppressive regimen. Sixty-one recipients (13.5%) developed PTDM and remained in this condition throughout the study, whereas 74 (16.5%) recipients developed altered fasting glucose over time. Univariate analyses demonstrated that recipient age (46.2 ± 1.3vs. 40.7 ± 0.6 years old, OR 1.04; P = 0.001) and pretransplant hyperglycaemia and BMI ≥ 25 kg/m2 (32.8% vs. 21.6%, OR 0.54; P = 0.032 and 57.4% vs. 27.7%, OR 3.5; P < 0.0001, respectively) were the pretransplant variables associated with PTDM. Posttransplant transient hyperglycaemia (86.8%. 18.5%, OR 0.03; P = 0.0001), acute rejection (P = 0.021), calcium channel blockers (P = 0.014), TG/HDL (triglyceride/high-density lipoprotein cholesterol) ratio ≥ 3.5 at 1 year (P = 0.01) and at 3 years (P = 0.0001), and tacrolimus trough levels at months 1, 3, and 6 were equally predictors of PTDM. In multivariate analyses, pretransplant hyperglycaemia (P = 0.035), pretransplant BMI ≥ 25 kg/m2 (P = 0.0001), posttransplant transient hyperglycaemia (P = 0.0001), and TG/HDL ratio ≥ 3.5 at 3-year posttransplant (P = 0.003) were associated with PTDM diagnosis and maintenance over time. Early identification of risk factors associated with increased insulin resistance and decreased insulin secretion, such as pretransplant hyperglycaemia and overweight, posttransplant transient hyperglycaemia, tacrolimus trough levels, and TG/HDL ratio may be useful for risk stratification of patients to determine appropriate strategies to reduce PTDM.

A Systematic Review of Treatment of Painful Diabetic Neuropathy by Pain Phenotype versus Treatment Based on Medical Comorbidities.

BACKGROUND: Painful diabetic neuropathy (PDN) is a serious, polymorphic, and prevalent complication of diabetes mellitus. Most PDN treatment guidelines recommend a selection of drugs based on patient comorbidities. Despite the large numbers of medications available, most randomized clinical trials (RCTs) conducted so far have yielded unsatisfactory outcomes. Therefore, treatment may require a personalized approach based on pain phenotype or comorbidities. METHODS: To evaluate whether or not a patient's pain phenotype or comorbidities can influence the response to a specific PDN treatment, we conducted a systematic review using two different approaches: pain phenotype and associated comorbidities-based treatment. RESULTS: Out of 45 identified papers, 7 were thoroughly reviewed. We found four RCTs stratified according to pain phenotype with three main results: (1) paroxysmal pain had a better response to pregabalin; (2) the preservation of thermal sensation or nociception anticipated a positive response to the topical treatment of pain; and, (3) after a failure to duloxetine (60 mg/day), the patients with evoked pain or severe deep pain had a better response to association of duloxetine/pregabalin while those with paresthesia/dysesthesia benefited from duloxetine monotherapy (120 mg/day). By contrast, the other three papers provided weak and even contradictory evidence about PDN treatment based on comorbidities. CONCLUSION: Although more studies are needed to provide an adequate recommendation for clinical practice, our systematic review has provided some evidence that PDN phenotyping may optimize clinical outcomes and could, in the future, lead to both less empirical medicine and more personalized pain therapeutics.

Cardiovascular autonomic neuropathy contributes to sleep apnea in young and lean type 1 diabetes mellitus patients.

Knowledge about association between sleep apnea and cardiovascular autonomic neuropathy (CAN) in type 1 diabetes mellitus (T1DM) might give some insight into the pathogenesis of this condition in these patients. In obese patients, excessive central adiposity, including a large neck circumference, can contribute to obstructive sleep apnea (OSA). Its presence in non-obese patients, however, indicates that it could be correlated with autonomic neuropathy. The aim of this study was to compare the prevalence of OSA in young and lean T1DM patients with and without CAN. We studied 20 adult, non-obese, T1DM patients who were divided into two groups according to the results of the cardiovascular autonomic reflex tests (CARTs). These two groups (9 with CAN and 11 without CAN) were compared to a control group of 22 healthy individuals, who were matched by age and BMI. A polysomnography was performed and sleep was analyzed. The CAN+ group had a significantly higher prevalence of sleep apnea compared to the other groups (67% CAN+; 23% CAN-; 4.5% controls: CAN+ vs. Control; p = 0.006 and CAN+ vs. CAN-; p = 0.02). The CAN- group had higher sleep efficiency compared to the CAN+ group, demonstrating impaired sleep architecture in diabetics with this chronic complication. In conclusion, OSA may be related to the presence of CAN in young and lean T1DM patients. It could contribute to worse the prognosis and reducing the quality of life of these patients without specific treatment of these conditions.

Pancreas transplantation alone in children: a case report.

Pancreas transplantation (PT) is a relatively uncommon therapy for non-uremic type 1 diabetes, as the severity of diabetes must warrant the risk of immunosuppression. In pediatric diabetic patients, who are less likely to display uremia because of the duration of diabetes, there is very little experience with pancreas transplantation alone (PTA). This report describes a 13-yr-old male PTA recipient. This patient was initially diagnosed with type 1 diabetes mellitus at the age of four yr. Following a multidisciplinary evaluation, PTA was found to be indicated based on a history of severe labile diabetes and hypoglycemic unawareness resulting in frequent episodes of hypoglycemia and hospital admissions. Because of the failure of medical management of the patient's diabetes, a whole organ bladder and systemic drained PTA was performed. Immunosuppression included thymoglobulin, tacrolimus, mycophenolate mofetil, and steroids. Early outcome was uneventful and patient was discharged 12 d after surgery normoglycemic and insulin-free. An episode of acute rejection (Maryland grade II) 20-d post-transplant was successfully treated with corticosteroids. A second and more severe episode of rejection (Maryland grade IV) occurred 13 months post-transplant, requiring treatment with thymoglobulin and conversion from steroid to sirolimus. On tacrolimus, sirolimus, and mycophenolic acid, he remains euglycemic and insulin-free 38 months after PTA. His quality-of-life is judged to be superior to his insulin dependent state prior to transplantation. According to the medical literature, this is the youngest patient ever to undergo PTA.

Selective approach for venous drainage in right iliac vein and cava vein for combined pancreas-kidney transplantation.

In this paper, the authors evaluate if the use of a venous drainage system in the cava vein (instead of the external iliac vein) presents differences in pancreatic transplantation. Between December 2000 and 2004, 105 pancreas-kidney transplants were performed. Patients in group A (n=49) underwent complete liberation of the right iliac vein for venous drainage. In group B (n=56), the venous drainage system was placed in the cava vein or in the confluence. Analyzed clinical parameters included: insulin replacement, vascular thrombosis in the graft, intraabdominal collections, graft loss, reoperation, and deaths. When compared to the external iliac vein, venous drainage to the cava vein did not result in significant differences. Venous drainage to the cava vein is a valuable alternative when the right iliac fossa has been previously approached. It is a practical, rapid procedure and it is not necessary to expose the internal iliac vein.

Glycemic control in adult type 1 diabetes patients from a brazilian country city: comparison between a multidisciplinary and a routine endocrinological approach.

OBJECTIVE: To evaluate the metabolic control of a cohort of adult type 1 diabetes mellitus (T1DM) patients assisted in a public Diabetes Center (DC) that follows the rules of a national diabetes society. METHODS: We compared for one year the metabolic control and the characteristics of 175 T1DM patients attended by a multidisciplinary team in a DC (test group) with 30 patients assisted only by endocrinologists at a public endocrinology outpatient center (control group). RESULTS: The test group presented a larger proportion of well-controlled patients (p= 0.002). The proportions (test x control group) were as follows: 51.4% x 16.7% in the subgroup with A1C < 7%; 21.7% x 36.7% in the subgroup with A1C between 7.1% and 8.0%; and 26.9% x 46.7% in the subgroup with A1C > 8%. Patients assisted in the DC presented a likelihood 4.38 times higher of reaching levels of A1C up to 7%. CONCLUSIONS: This study shows the effectiveness of a DC and emphasizes the importance of education, adherence and multidisciplinarity as cornerstones for the treatment, showing that in developing countries it is possible to treat T1DM with satisfactory results.

Effects of Eurocollins solution as aortic flush for the procurement of human pancreas.

BACKGROUND: Belzer solution is considered to be the best preservation media used for pancreas transplantation; however, its high cost accounts for approximately 14.5% of all resources allocated by the Brazilian government toward each pancreatic transplant. The objective of the present study was to test a reduction of Belzer solution during pancreas harvest, thereby lowering procedural cost. METHODS: The patients received pancreas-kidney transplantations during the period from January 2003 to August 2004. Patients were divided into two groups. Patients assigned to Group A (n=30) received only Belzer solution (2 L through the aorta artery), whereas patients in Group B (n=16) were perfused first with 1 L of Eurocollins solution followed by 1 L of Belzer solution. The two groups were assessed for differences in the following clinical parameters: the need for insulin replacement or antifungal and anticytomegalovirus treatment, pancreatitis, acute cellular rejection, graft vascular thrombosis, fistulas, intra-abdominal collection, graft loss, deaths, pancreatic ischemia time, and average hospitalization time. RESULTS: No statistically significant differences were observed in any of the parameters analyzed (P<0.05). The use of Eurocollins solution, followed by Belzer solution during pancreas harvesting, did not result in differences in graft survival or functionality, postsurgical complications, or patient survival and hospitalization time, when compared to the use of Belzer solution alone. CONCLUSIONS: Perfusion with 1 L of Eurocollins solution followed by 1 L of Belzer solution during pancreas harvesting seems to be a simple and efficient alternative for reducing the costs of the harvesting process.