Correction: The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials.

[This corrects the article DOI: 10.1371/journal.pmed.1001992.].

Endothelial nitric oxide synthase gene polymorphisms and risk of diabetic nephropathy: a systematic review and meta-analysis.

BACKGROUND: Nitric oxide (NO) has numerous functions in the kidney, including control of renal and glomerular hemodynamics, by interfering at multiple pathological and physiologically critical steps of nephron function. Endothelial NOS (eNOS) gene has been considered a potential candidate gene to diabetic nephropathy (DN) susceptibility. Endothelial nitric oxide synthase gene (eNOS-3) polymorphisms have been associated with DN, however some studies do not confirm this association. The analyzed polymorphisms were 4b/4a, T-786C, and G986T. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was used in this report. Case-control studies that had diabetic patients with DN as cases and diabetic patients without nephropathy as controls, as well as that evaluated at least one of the three polymorphisms of interest were considered eligible. All studies published up until December 31st, 2012 were identified by searching electronic databases. Hardy-Weinberg equilibrium assessment was performed. Gene-disease association was measured using odds ratio estimation based on the following genetic contrast/models: (1) allele contrast; (2) additive model; (3) recessive model; (4) dominant model and (4) co-dominant model. RESULTS: Twenty-two studies were eligible for meta-analysis (4b/a: 15 studies, T-786C: 5 studies, and G984T: 12 studies). Considering 4b/a polymorphism, an association with DN was observed for all genetic models: allele contrast (OR = 1.14, CI: 1.04-1.25); additive (OR = 1.77, CI: 1.37-2.28); recessive (OR = 1.77, CI: 1.38-2,27); dominant (OR = 1.12, CI: 1.01-1.24), with the exception for co-dominance model. As well, T-786C polymorphism showed association with all models, with exception for co-dominance model: allele contrast (OR = 1.22, CI: 1.07-1.39), additive (OR = 1.52, CI: 1.18-1.97), recessive (OR = 1.50, CI: 1.16-1.93), and dominant (OR = 1.11, CI: 1.01-1.23). For the G894T polymorphism, an association with DN was observed in allelic contrast (OR = 1.12, CI: 1.03-1.25) and co-dominance models (OR = 1.13, CI: 1.04-1.37). CONCLUSIONS: In the present study, there was association of DN with eNOS 4b/a and T-786C polymorphism, which held in all genetic models tested, except for co-dominance model. G894T polymorphism was associated with DN only in allele contrast and in co-dominance model. This data suggested that the eNOS gene could play a role in the development of DN.

All-cause mortality and cardiovascular safety of basal insulin treatment in patients with type 2 diabetes mellitus: A systematic review with meta-analysis and trial sequential analysis.

AIM: To evaluate the risk of all-cause and cardiovascular mortality, acute myocardial infarction, and stroke associated with insulin treatment in patients with type 2 diabetes. METHODS: A systematic review with meta-analysis of randomized clinical trials (RCTs) was performed. EMBASE, Cochrane, and PubMed databases were searched for RCTs reporting mortality or cardiovascular events and comparing basal insulin to any treatment in patients with type 2 diabetes. Data were summarized with Mantel-Haenzel relative risk (RR). Trial sequential analysis (TSA) was used to evaluate the reliability of the results considering a 20% relative risk difference between treatments. PROSPERO Registry: CRD42018087336. RESULTS: In total, 2351 references were identified, and 26 studies (24348 patients) were included. Most studies evaluated glargine insulin (69%), compared insulin to GLP-1 analogs (57%), and evaluated add-on therapy with metformin (77%). Insulin was not associated with increased all-cause mortality (RR 0.99; 95% confidence interval (CI) 0.92-1.06), cardiovascular mortality (RR 1.01; 95% CI 0.91-1.13), myocardial infarction (RR 1.02; 95% CI 0.92-1.15), or stroke (RR 0.87; 95% CI 0.68-1.12). Insulin treatment increased severe hypoglycemia risk (RR 2.98; 95% CI 2.47-3.61). All analyses had low statistical heterogeneity. TSA confirmed these findings: optimal sample size (myocardial infarction), futility boundary (all-cause mortality, cardiovascular mortality, and stroke) and harm boundary (hypoglycemia) were reached. CONCLUSION: Treatment with basal insulin of patients with type 2 diabetes does not increase the risk of cardiovascular events or death. Despite the increased risk of hypoglycemia, these findings reinforce that insulin is a safe option in the treatment of type 2 diabetes.

Metabolic effects of antihyperglycemic agents and mortality: meta-analysis of randomized controlled trials.

The effects of antihyperglycemic medications on cardiovascular events and mortality are heterogeneous and their effects on intermediate factors might explain these differences. This systematic review explores the relationship between metabolic factors, mechanism of action, and mortality effects of antihyperglycemic medications in type 2 diabetes. Randomized trials assessing the effects of antihyperglycemic medications on all-cause or cardiovascular mortality in type 2 diabetes were included. Myocardial infarction, stroke, and heart failure were secondary outcomes. The effects of medications on HbA1c, severe hypoglycemia (SH), body weight, systolic blood pressure (SBP), and mechanism of action were evaluated. Meta-analyses and meta-regressions were performed grouping studies according to the above-cited factors. All-cause mortality was lower for medications that reduced HbA1c, SH, body weight, and SBP. Decreased cardiovascular mortality was associated with lower HbA1c, SH, SBP. Myocardial infarction and stroke were also associated with favorable metabolic profile. These findings were not confirmed in meta-regression models. Medications associated with lower SH, body weight and SBP had a lower risk of heart failure. In conclusion, medications with better metabolic profile were associated with reduced all-cause and cardiovascular mortality. These findings are based on indirect comparisons and must be applied cautiously.

Portuguese-Brazilian evidence-based guideline on the management of hyperglycemia in type 2 diabetes mellitus.

BACKGROUND: In current management of type 2 diabetes (T2DM), cardiovascular and renal prevention have become important targets to be achieved. In this context, a joint panel of four endocrinology societies from Brazil and Portugal was established to develop an evidence-based guideline for treatment of hyperglycemia in T2DM. METHODS: MEDLINE (via PubMed) was searched for randomized clinical trials, meta-analyses, and observational studies related to diabetes treatment. When there was insufficient high-quality evidence, expert opinion was sought. Updated positions on treatment of T2DM patients with heart failure (HF), atherosclerotic CV disease (ASCVD), chronic kidney disease (CKD), and patients with no vascular complications were developed. The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: In non-pregnant adults, the recommended HbA1c target is below 7%. Higher levels are recommended in frail older adults and patients at higher risk of hypoglycemia. Lifestyle modification is recommended at all phases of treatment. Metformin is the first choice when HbA1c is 6.5-7.5%. When HbA1c is 7.5-9.0%, dual therapy with metformin plus an SGLT2i and/or GLP-1RA (first-line antidiabetic agents, AD1) is recommended due to cardiovascular and renal benefits. If an AD1 is unaffordable, other antidiabetic drugs (AD) may be used. Triple or quadruple therapy should be considered when HbA1c remains above target. In patients with clinical or subclinical atherosclerosis, the combination of one AD1 plus metformin is the recommended first-line therapy to reduce cardiovascular events and improve blood glucose control. In stable heart failure with low ejection fraction (< 40%) and glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2, metformin plus an SGLT-2i is recommended to reduce cardiovascular mortality and heart failure hospitalizations and improve blood glucose control. In patients with diabetes-associated chronic kidney disease (CKD) (eGFR 30-60 mL/min/1.73 m2 or eGFR 30-90 mL/min/1.73 m2 with albuminuria > 30 mg/g), the combination of metformin and an SGLT2i is recommended to attenuate loss of renal function, reduce albuminuria and improve blood glucose control. In patients with severe renal failure, insulin-based therapy is recommended to improve blood glucose control. Alternatively, GLP-1RA, DPP4i, gliclazide MR and pioglitazone may be considered to reduce albuminuria. In conclusion, the current evidence supports individualizing anti-hyperglycemic treatment for T2DM.

Risk factors for micro and macrovascular disease in black and white patients with type 2 diabetes mellitus.

BACKGROUND: The prevalence of chronic complications in type 2 diabetes mellitus (DM) is higher in black patients. The reason for this finding is still unknown. The objective of this study was to analyze the micro and macrovascular risk factor profile of type 2 DM patients without advanced diabetic nephropathy according to ethnicity. METHODS: A cross-sectional multicentric regional study was conducted evaluating 780 patients. All patients were submitted to clinical and laboratory evaluation. Ethnicity was self-reported as white (n = 585) or black (n = 195). RESULTS: Black patients had lower triglycerides [115 (35-892) vs. 152 (34-1236) mg/dl; P <0.001] and higher HDL-cholesterol levels than whites (48.3 +/- 13.5 vs. 44.8 +/- 12.1 mg/dl; P = 0.002).White and black patients did not differ regarding fasting plasma glucose, A1c test, total and LDL cholesterol, blood pressure levels, insulin and HOMA-IR. There were no differences between groups regarding medication in use (statin: 18.5 vs. 19.3%, P = 1.000; fibrates: 1.5 vs. 0.7%, P = 0.680; angiotensin converting enzyme inhibitors: 39.5 vs. 43.8%, P = 0.375; acetylsalicylic acid: 29.9 vs. 27.7%, P = 0.673). CONCLUSIONS: There were no differences in the prevalence of the classic micro and macrovascular risk factors between ethnic groups. The study of non-conventional risk factors and genetic factors is essential to understand determinants of the worst outcomes presented by the African-Brazilian population.

Thyroid ultrasound features and risk of carcinoma: a systematic review and meta-analysis of observational studies.

BACKGROUND: Thyroid nodules are a common finding in the general population, and their detection is increasing with the widespread use of ultrasound (US). Thyroid cancer is found in 5-15% of cases depending on sex, age, and exposure to other risk factors. Some US parameters have been associated with increased risk of malignancy. However, no characteristic seems sufficiently reliable in isolation to diagnose malignancy. The objective of this meta-analysis was to evaluate the diagnostic performance of US features for thyroid malignancy in patients with unselected thyroid nodules and nodules with indeterminate fine-needle aspiration (FNA) cytology. METHODS: Electronic databases were reviewed for studies published prior to July 2012 that evaluated US features of thyroid nodules and reported postoperative histopathologic diagnosis. A manual search of references of review and key articles, and previous meta-analyses was also performed. A separate meta-analysis was performed including only nodules with indeterminate cytology. Analyzed features were solid structure, hypoechogenicity, irregular margins, absence of halo, microcalcifications, central vascularization, solitary nodule, heterogeneity, taller than wide shape, and absence of elasticity. RESULTS: Fifty-two observational studies (12,786 nodules) were included. Nine studies included nodules with indeterminate cytology as a separate category, comprising 1851 nodules. In unselected nodules, all US features were significantly associated with malignancy with an odds ratio varying from 1.78 to 35.7, and microcalcifications, irregular margins, and a taller than wide shape had high specificities (Sp; 87.8%, 83.1%, 96.6%) and positive likelihood ratios (LHR; 3.26, 2.99, 8.07). Absence of elasticity was the single feature with the best diagnostic performance (sensitivity 87.9%, Sp 86.2%, and positive LHR 6.39). The presence of central vascularization was the most specific US feature in nodules with indeterminate cytology (Sp 96% and positive LHR 2.13). CONCLUSIONS: US features in isolation do not provide reliable information to select nodules that should have a FNA performed. A combination of US characteristics with higher likelihood ratios and consequently with higher post-test probabilities of malignancy-microcalcifications, or a taller than wide shape, or irregular margins, or absence of elasticity-will probably identify nodules with an increased risk for malignancy. Further studies are required to standardize elastography techniques and evaluate outcomes, especially in nodules with an indeterminate cytology.

Late afternoon blood pressure increase is associated with diabetic retinopathy in normotensive type 2 diabetes mellitus patients.

AIMS: To identify if the variability of blood pressure (BP) is associated with diabetic retinopathy (DR) in normotensive type 2 DM patients. METHODS: Sixty-five normotensive type 2 DM patients that had 24-h ambulatory BP monitoring (ABPM) were grouped according any degree of DR. RESULTS: Fourteen (21%) patients had DR. Office BP and 24-h BP parameters did not differ between groups. At late afternoon period, patients with DR had higher increment in both systolic (11.3+/-12.7mmHg vs. 1.0+/-11.4mmHg, P=0.006) and diastolic (6.7+/-8.6mmHg vs. -0.73+/-10.0mmHg, P=0.017) BP levels than those without. Multivariate logistic analyses were performed with DR as a dependent variable. Each 1mmHg increment in systolic BP at the late afternoon period was associated with a 10.2% increase in DR prevalence [OR 1.102 (CI 95% 1.011-1.202, P=0.027)], after adjustments for A1C test, DM duration, age, albuminuria and current smoking. CONCLUSIONS: In conclusion, in normotensive type 2 DM patients, BP increase at late afternoon is associated to DR independently from confounder factors or other ABPM parameters.

Risk factors for micro and macrovascular disease in black and white patients with type 2 Diabetes mellitus / Comparação de fatores de risco para complicações micro e macrovasculares em pacientes com Diabetes mellitus tipo 2 negros e brancos

BACKGROUND: The prevalence of chronic complications in type 2 diabetes mellitus (DM) is higher in black patients. The reason for this finding is still unknown. The objective of this study was to analyze the micro and macrovascular risk factor profile of type 2 DM patients without advanced diabetic nephropathy according to ethnicity. METHODS: A cross-sectional multicentric regional study was conducted evaluating 780 patients. All patients were submitted to clinical and laboratory evaluation. Ethnicity was self-reported as white (n = 585) or black (n = 195). RESULTS: Black patients had lower triglycerides [115 (35-892) vs. 152 (34-1236) mg/dl; P <0.001] and higher HDL-cholesterol levels than whites (48.3 ± 13.5 vs. 44.8 ± 12.1 mg/dl; P = 0.002).White and black patients did not differ regarding fasting plasma glucose, A1c test, total and LDL cholesterol, blood pressure levels, insulin and HOMA-IR. There were no differences between groups regarding medication in use (statin: 18.5 vs. 19.3 percent, P = 1.000; fibrates: 1.5 vs. 0.7 percent, P = 0.680; angiotensin converting enzyme inhibitors: 39.5 vs. 43.8 percent, P = 0.375; acetylsalicylic acid: 29.9 vs. 27.7 percent, P = 0.673). CONCLUSIONS: There were no differences in the prevalence of the classic micro and macrovascular risk factors between ethnic groups. The study of non-conventional risk factors and genetic factors is essential to understand determinants of the worst outcomes presented by the African-Brazilian population.

OBJETIVO: A prevalência das complicações crônicas do Diabetes mellitus (DM) é maior nos negros. A razão para esse achado é desconhecida. O objetivo desse estudo é analisar os fatores de risco para doença micro e macrovascular em pacientes com DM tipo 2 de acordo com a etnia. MÉTODOS: Foi realizado estudo transversal avaliando 780 pacientes. Todos pacientes realizaram avaliação clinico/ laboratorial. A etnia foi autoreferida em branca (n = 585) ou negra (n = 195). RESULTADOS: Os pacientes negros apresentaram níveis menores de triglicerídeos [115 (35-892) vs. 152 (34-1236) mg/dl; P <0.001] e maiores de HDL colesterol que os brancos (48.3 ± 13.5 vs. 44.8 ± 12.1 mg/dl; P = 0.002). Não houve diferença entre os grupos quanto à glicemia de jejum, teste A1c, LDL e colesterol total, níveis pressóricos, insulina e Homa-ir. Não houve diferença no uso de medicações (estatinas: 18.5 vs. 19.3 por cento, P = 1.000; fibratos: 1.5 vs. 0.7 por cento, P = 0.680; inibidores da enzima conversora da angiotensina: 39.5 vs. 43.8 por cento, P = 0.375; acido acetilsaliscílico: 29.9 vs. 27.7 por cento, P = 0.673). CONCLUSÃO: Não houve diferença na prevalência dos fatores de risco convencionais para doença micro e macrovascular entre os grupos étnicos. O estudo de fatores não-convencionais e genéticos é essencial para a elucidação dos determinantes dos piores desfechos apresentados pela população diabética afrobrasileira.