Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Variants in the VDR Gene May Influence 25(OH)D Levels in Type 1 Diabetes Mellitus in a Brazilian Population.

Vitamin D has been considered a strong contributing factor to type 1 diabetes mellitus (T1DM). Many studies have investigated polymorphisms in the VDR gene in association with T1DM in different populations, but there are still conflicting findings. This study aimed to evaluate the association of four variants in the VDR gene (rs7975232, rs1544410, rs731236, and rs2228570) with T1DM risk and vitamin D levels within a population from North Region, Brazil, as well as the influence of genomic ancestry on T1DM. A total of 65 T1DM patients and 83 non-T1DM patients were enrolled in this study. VDR gene polymorphisms were assessed using Sanger sequencing analysis. Genomic ancestry was analyzed using a set of 61 ancestry-informative markers. T1DM patients showed higher European genomic contribution and lower Native American genomic contribution when compared to non-T1DM patients. T1DM patients with AA genotype in rs1544410 or CC genotype in rs731236 had significantly lower 25(OH)D levels compared to the other two genotypes (p = 0.013 and p = 0.02, respectively), while T1DM with TT genotype in rs2228570 had higher 25(OH)D levels compared to CC + TC in the same polymorphism (p = 0.011). Our findings suggest that the association between 25(OH)D and T1DM may be modified by VDR variants, possibly influencing the development of this autoimmune disease.

HLA Genotypes and Type 1 Diabetes and Its Relationship to Reported Race/Skin Color in Their Relatives: A Brazilian Multicenter Study.

We aimed to investigate the relationship between HLA alleles in patients with type 1 diabetes from an admixed population and the reported race/skin color of their relatives. This cross-sectional, multicenter study was conducted in public clinics in nine Brazilian cities and included 662 patients with type 1 diabetes and their relatives. Demographic data for patients and information on the race/skin color and birthplace of their relatives were obtained. Typing of the HLA-DRB1, -DQA1, and -DQB1 genes was performed. Most studied patients reported having a White relative (95.17%), and the most frequently observed allele among them was DRB1*03:01. Increased odds of presenting this allele were found only in those patients who reported having all White relatives. Considering that most of the patients reported having a White relative and that the most frequent observed allele was DRB1*03:01 (probably a European-derived allele), regardless of the race/skin color of their relatives, we conclude that the type 1 diabetes genotype comes probably from European, Caucasian ethnicity. However, future studies with other ancestry markers are needed to fill the knowledge gap regarding the genetic origin of the type 1 diabetes genotype in admixed populations such as the Brazilian.

Nocturnal blood pressure fall as predictor of diabetic nephropathy in hypertensive patients with type 2 diabetes.

BACKGROUND: Hypertensive patients with reduced blood pressure fall (BPF) at night are at higher risk of cardiovascular events (CVE). METHODS: We evaluated in hypertensive diabetic patients, if a reduced nocturnal BPF can precedes the development of diabetic nephropathy (DN). We followed 70 patients with normal urinary albumin excretion (UAE) for two years. We performed 24-hours ambulatory BP monitoring in baseline and at the end of the study. RESULTS: Fourteen (20%) patients (GI) developed DN (N = 11) and/or CVE (n = 4). Compared to the remaining 56 patients (GII) in baseline, GI had similar diurnal systolic (SBP) and diastolic BP (DBP), but higher nocturnal SBP (138 +/- 15 vs 129 +/- 16 mmHg; p < 0.05) and DBP (83 +/- 12 vs 75 +/- 11 mmHg; p < 0,05). Basal nocturnal SBP correlated with occurrence of DN and CVE (R = 0.26; P < 0.05) and with UAE at the end of the study (r = 0.3; p < 0.05). Basal BPF (%) correlated with final UAE (r = -0.31; p < 0.05). In patients who developed DN, reductions occurred in nocturnal systolic BPF (12 +/- 5 vs 3 +/- 6%, p < 0,01) and diastolic BPF (15 +/- 8 vs 4 +/- 10%, p < 0,01) while no changes were observed in diurnal SBP (153 +/- 17 vs 156 +/- 16 mmHg, NS) and DBP (91 +/- 9 vs 90 +/- 7 mmHg, NS). Patients with final UAE < 20 microg/min, had no changes in nocturnal and diurnal BP. CONCLUSIONS: Our results suggests that elevations in nocturnal BP precedes DN and increases the risk to develop CVE in hypertensive patients with T2DM.

Effect of Once-Weekly Exenatide on Clinical Outcomes According to Baseline Risk in Patients With Type 2 Diabetes Mellitus: Insights From the EXSCEL Trial.

Background In the EXSCEL (Exenatide Study of Cardiovascular Event Lowering), exenatide once-weekly resulted in a nonsignificant reduction in major adverse cardiovascular events ( MACEs ) and a nominal 14% reduction in all-cause mortality in 14 752 patients with type 2 diabetes mellitus (T2 DM ) with and without cardiovascular disease. Whether patients at increased risk for events experienced a comparatively greater treatment benefit with exenatide is unknown. Methods and Results In the EXSCEL population, we created risk scores for MACEs and all-cause mortality using step-wise selection of baseline characteristics. A risk score was calculated for each patient, and a time-to-event model for each end point was developed including the risk score, treatment assignment, and risk-treatment interaction. Interaction P values evaluating for a differential treatment effect by baseline risk were reported. Over a median follow-up of 3.2 years (interquartile range, 2.2, 4.4), 1091 (7.4%) patients died and 1744 (11.8%) experienced a MACE . Independent predictors of MACEs and all-cause mortality included age, sex, comorbidities (eg, previous cardiovascular event), body mass index, blood pressure, hemoglobin A1c, and estimated glomerular filtration rate. The all-cause mortality and MACE risk models had modest discrimination with optimism-corrected c-indices of 0.73 and 0.71, respectively. No interaction was observed between treatment effect and risk profile for either end point (both interactions, P>0.1). Conclusions Baseline characteristics (eg, age, previous cardiovascular events) and routine laboratory values (eg, hemoglobin A1c, estimated glomerular filtration rate) provided modest prognostic value for mortality and MACEs in a broad population of patients with type 2 diabetes mellitus. Exenatide's effects on mortality and MACEs were consistent across the spectrum of baseline risk. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01144338.

The impact of ethnicity, educational and economic status on the prescription of insulin therapeutic regimens and on glycemic control in patients with type 1 diabetes. A nationwide study in Brazil.

AIMS: Establish the relationship between demographic, educational and economic status on insulin therapeutic regimens (ITRs) and on glycemic control in patients with type 1 diabetes. METHODS: This was a cross-sectional, multicenter study with 1760 patients conducted between August 2011 and August 2014 in 10 Brazilian cities. RESULTS: Patients were stratified according to ITRs as follows: only NPH insulin (group 1, n=80(4.5%)); only long-acting insulin analogs (group 2, n=6(0.3%)); continuous subcutaneous insulin infusion (CSII) (group 3, n=62(3.5%)); NPH plus regular insulin (group 4, n=710(40.3%)); NPH plus ultra-rapid insulin analogs (group 5, n=259(14.8%)); long-acting insulin analogs plus regular insulin (group 6, n=25(4.4%)) and long-acting plus ultra-rapid insulin analogs (group 7, n=618 (35.1%)). As group A (provided free of charge by the government) we considered groups 1 and 4, and as group B (obtained through lawsuit or out-of-pocket) groups 2, 3 and 7. Multivariate logistic analysis showed that independent variables related to group B were older age, more years of school attendance, higher economic status and ethnicity (Caucasians). The independent variables related to better glycemic control were older age, higher adherence to diet, higher frequency of self-monitoring of blood glucose, more years of school attendance and belonging to group B. CONCLUSIONS: In Brazilian National Health Care System, prescriptions of insulin analogs or CSII are more frequent in Caucasian patients with type 1 diabetes, with higher economic status and more years ofschool attendance. Among these variables years of school attendance was the only one associated with better glycemic control.

Hyperglycemia and nocturnal systolic blood pressure are associated with left ventricular hypertrophy and diastolic dysfunction in hypertensive diabetic patients.

BACKGROUND: The aim of this study was to determine if hypertensive type 2 diabetic patients, when compared to patients with essential hypertension have an increased left ventricular mass index (LVMI) and a worse diastolic function, and if this fact would be related to 24-h pressoric levels changes. METHODS: Ninety-one hypertensive patients with type 2 diabetes mellitus (DM) (group-1 [G1]), 59 essential hypertensive patients (group-2 [G2]) and 26 healthy controls (group-3 [G3]) were submitted to 24-h Ambulatory Blood Pressure Monitoring (ABPM) and echocardiography (ECHO) with Doppler. We calculated an average of fasting blood glucose (AFBG) values of G1 from the previous 4.2 years and a glycemic control index (GCI) (percentual of FBG above 200 mg/dl). RESULTS: G1 and G2 did not differ on average of diurnal systolic and diastolic BP. However, G1 presented worse diastolic function and a higher average of nocturnal systolic BP (NSBP) and LVMI (NSBP = 132 +/- 18 vs 124 +/- 14 mmHg; P < 0.05 and LVMI = 103 +/- 27 vs 89 +/- 17 g/m2; P < 0.05, respectively). In G1, LVMI correlated with NSBP (r = 0.37; P < 0.001) and GCI (r = 0.29; P < 0.05) while NSBP correlated with GCI (r = 0.27; P < 0.05) and AFBG (r = 0.30; P < 0.01). When G1 was divided in tertiles according to NSBP, the subgroup with NSBP> or =140 mmHg showed a higher risk of LVH. Diabetics with NSBP> or =140 mmHg and AFBG>165 mg/dl showed an additional risk of LVH (P < 0.05; odds ratio = 11). In multivariate regression, both GCI and NSBP were independent predictors of LVMI in G1. CONCLUSION: This study suggests that hyperglycemia and higher NSBP levels should be responsible for an increased prevalence of LVH in hypertensive patients with Type 2 DM.

[Endogenous hyperinsulinism: review and follow-up of 24 cases]. / Hiperinsulinismo endógeno: revisão e seguimento de 24 casos.

Hypoglycemia due to endogenous hyperinsulinism (EH) is diagnosed in a symptomatic patient with low levels of plasma glucose concomitant with elevated plasma insulin and C-peptide. Causes of EH are pancreatic islet-cells disease, use of insulin secretagogues, and autoimmune hypoglycemia. In this review, the authors studied 24 patients with hypoglycemia due to endogenous hyperinsulinism in order to describe aspects of diagnosis and treatment. Our study demonstrated that after 12 hours of fasting (mini-fasting test; at least three samples), all patients presented the diagnostic criteria for EH. Additionally, we found that 11 of 12 patients (91.7%) who underwent glucagon test achieved glucose levels less than 50 mg/dL and below baseline after 120 minutes. Mini-fasting (3 samples) and glucagon test may be useful to prevent prolonged fasting test to clarify the diagnosis of endogenous hyperinsulinism.

Diabetes mellitus and spinal epidural abscess: clinical or surgical treatment?

Spinal epidural abscess (SEA) is an uncommon condition and its most important predisposing factor is diabetes mellitus. Although the treatment of choice is prompt surgical abscess evacuation, followed by antibiotic therapy, successful conservative treatment of SEA has been reported in some cases. We describe a SEA case in a 23-year old white woman with diabetes for 14 years, who was successfully treated only with antibiotics, and achieved full recovery at the fourth month of follow-up.

Autonomic neuropathy tests correlate with left ventricular mass and cardiac diastolic function in normotensive patients with type 2 diabetes mellitus and without left ventricular hypertrophy.

BACKGROUND: Hypertensive diabetic patients, when compared with essential hypertensive patients, have a higher left ventricular mass index (LVMI) and an impaired cardiac diastolic function (CDF). Autonomic neuropathy (AN) could contribute to this finding. OBJECTIVE: To evaluate the relationship between AN tests, and LVMI and CDF in normotensive patients with type 2 diabetes mellitus (DM2) and without AN symptoms or left ventricular hypertrophy. METHODS: In 21 normotensive patients with DM2 (group 1) and 16 control subjects (group 2), LVMI and CDF were evaluated using atrial deceleration time, isovolumic relaxation time, E wave, A wave and E/A wave ratio. AN tests performed included a deep breathing test, Valsalva manoeuvre and lying-to-standing test. RESULTS: Groups did not differ in clinical and echocardiographic characteristics. None of the patients in either group presented with left ventricular hypertrophy. In group 1, there were correlations between the deep breathing test and LVMI (r=-0.6; P<0.01) and between the deep breathing test and E/A wave ratio (r=0.4; P<0.05). No correlations were found in the control group. CONCLUSION: In DM2 patients, AN tests correlated with LVMI and CDF before left ventricular hypertrophy, hypertension, impaired CDF and diabetic AN symptoms were present. The present study suggests that AN tests could be regularly performed in DM2 patients. Any abnormalities in tests should be followed by a cardiac evaluation.

Diabetes mellitus and spinal epidural abscess: clinical or surgical treatment? / Diabetes melito e abscesso epidural espinhal: tratamento clínico ou cirúrgico?

Spinal epidural abscess (SEA) is an uncommon condition and its most important predisposing factor is diabetes mellitus. Although the treatment of choice is prompt surgical abscess evacuation, followed by antibiotic therapy, successful conservative treatment of SEA has been reported in some cases. We describe a SEA case in a 23-year old white woman with diabetes for 14 years, who was successfully treated only with antibiotics, and achieved full recovery at the fourth month of follow-up.

O abscesso epidural espinhal (AEE) é uma doença incomum e o diabetes melito é o seu fator predisponente mais importante. O tratamento de escolha é a imediata drenagem cirúrgica, seguida de antibioticoterapia, entretanto, casos já foram relatados em que o AEE foi tratado clinicamente com sucesso. Descrevemos um caso de AEE em um paciente diabético tratado satisfatoriamente com uso isolado de antibióticos e que evoluiu com recuperação total no quarto mês de seguimento.

Doença de basedow graves associada à acidose tubular renal e paralisia periódica tireotóxica: relato de um caso e revisäo da literatura / Graves' basedow disease associated acidosis renal tubular and thyrotoxic periodic paralysis: report of a case and review of the literature

Doenças tireoidianas autoimunes (DTA) tem sido associadas esporadicamente à acidose tubular renal tipo 1 (ART-1). Apresentamos o segundo caso descrito na literatura, de nosso conhecimento, de doenças de Basedow-Graves associada à ATR e à paralisia periódica tiretóxica (PPT). Os níveis de pH sanguíneo e de eletrólitos nao se normalizaram com a correçao da disfunçao tireodiana. A paralisia revertou com a administraçao de grandes quantidades de potássio (300-445 mEq/dia) e a acidose com ingestao de bicarbonato (15g/24h). Nefrocalcinose bilateral estava presente com hipercalciúria (310-603 mg/24 h) e diabetes insípidus nefrogênico (Osmolaridade urinárias= 347 mOsm após DDAVP). Aventa-se um mecanismo autoimune na gênese da ATR-1à semelhança do que ocorre na doença tireodiana associada. (Arq Bras Endocrinol Metab 1994; 38/1:35-38).