Metabolic syndrome as a risk indicator for periodontal disease and tooth loss.

OBJECTIVES: The aim of the present study was to evaluate the association of metabolic syndrome (MS) with periodontitis (PE) and tooth loss (TL). MATERIALS AND METHODS: A cross-sectional study was conducted with 363 individuals who underwent full-mouth periodontal examination, and the association between MS and PE was evaluated considering three outcomes: severe periodontitis, mean probing depth ≥2.4 mm, and mean clinical attachment loss ≥2.0 mm. The prevalence ratio (PR) between MS and PE was calculated using a model adjusted for gender, age, smoking, years of education, and socioeconomic status. RESULTS: The adjusted model showed a PR for severe periodontitis of 1.17 (95 % CI 0.83-1.65). There was no significant association between MS and PE defined as mean probing depth ≥2.4 mm. MS was significantly associated with PE defined as mean attachment loss ≥2 mm in individuals aged 41-60 years (PR 1.47, 95 % CI 1.05-2.06). In addition, MS was associated with TL (>6 teeth) (PR 1.23, 95 % CI 1.02-1.49) for all ages, both in crude and adjusted analyses. CONCLUSIONS: We concluded that there is a weak association of MS with both attachment loss and TL. CLINICAL RELEVANCE: Patients with MS seem to have a higher risk of attachment loss and tooth loss and should be screened for periodontal disease.

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

BACKGROUND: Sulfonylureas are an effective and inexpensive treatment for type 2 diabetes. There is conflicting data about the safety of these drugs regarding mortality and cardiovascular outcomes. The objective of the present study was to evaluate the safety of the sulfonylureas most frequently used and to use trial sequential analysis (TSA) to analyze whether the available sample was powered enough to support the results. METHODS AND FINDINGS: Electronic databases were reviewed from 1946 (Embase) or 1966 (MEDLINE) up to 31 December 2014. Randomized clinical trials (RCTs) of at least 52 wk in duration evaluating second- or third-generation sulfonylureas in the treatment of adults with type 2 diabetes and reporting outcomes of interest were included. Primary outcomes were all-cause and cardiovascular mortality. Additionally, myocardial infarction and stroke events were evaluated. Data were summarized with Peto odds ratios (ORs), and the reliability of the results was evaluated with TSA. Forty-seven RCTs with 37,650 patients and 890 deaths in total were included. Sulfonylureas were not associated with all-cause (OR 1.12 [95% CI 0.96 to 1.30]) or cardiovascular mortality (OR 1.12 [95% CI 0.87 to 1.42]). Sulfonylureas were also not associated with increased risk of myocardial infarction (OR 0.92 [95% CI 0.76 to 1.12]) or stroke (OR 1.16 [95% CI 0.81 to 1.66]). TSA could discard an absolute difference of 0.5% between the treatments, which was considered the minimal clinically significant difference. The major limitation of this review was the inclusion of studies not designed to evaluate safety outcomes. CONCLUSIONS: Sulfonylureas are not associated with increased risk for all-cause mortality, cardiovascular mortality, myocardial infarction, or stroke. Current evidence supports the safety of sulfonylureas; an absolute risk of 0.5% could be firmly discarded. REVIEW REGISTRATION: PROSPERO CRD42014004330.

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.].

Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study.

BACKGROUND: For patients with type 2 diabetes who do not achieve target glycaemic control with conventional insulin treatment, advancing to a basal-bolus insulin regimen is often recommended. We aimed to compare the efficacy and safety of long-acting glucagon-like peptide-1 receptor agonist dulaglutide with that of insulin glargine, both combined with prandial insulin lispro, in patients with type 2 diabetes. METHODS: We did this 52 week, randomised, open-label, phase 3, non-inferiority trial at 105 study sites in 15 countries. Patients (aged ≥18 years) with type 2 diabetes inadequately controlled with conventional insulin treatment were randomly assigned (1:1:1), via a computer-generated randomisation sequence with an interactive voice-response system, to receive once-weekly dulaglutide 1·5 mg, dulaglutide 0·75 mg, or daily bedtime glargine. Randomisation was stratified by country and metformin use. Participants and study investigators were not masked to treatment allocation, but were unaware of dulaglutide dose assignment. The primary outcome was a change in glycated haemoglobin A1c (HbA1c) from baseline to week 26, with a 0·4% non-inferiority margin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01191268. FINDINGS: Between Dec 9, 2010, and Sept 21, 2012, we randomly assigned 884 patients to receive dulaglutide 1·5 mg (n=295), dulaglutide 0·75 mg (n=293), or glargine (n=296). At 26 weeks, the adjusted mean change in HbA1c was greater in patients receiving dulaglutide 1·5 mg (-1·64% [95% CI -1·78 to -1·50], -17·93 mmol/mol [-19·44 to -16·42]) and dulaglutide 0·75 mg (-1·59% [-1·73 to -1·45], -17·38 mmol/mol [-18·89 to -15·87]) than in those receiving glargine (-1·41% [-1·55 to -1·27], -15·41 mmol/mol [-16·92 to -13·90]). The adjusted mean difference versus glargine was -0·22% (95% CI -0·38 to -0·07, -2·40 mmol/mol [-4·15 to -0·77]; p=0·005) for dulaglutide 1·5 mg and -0·17% (-0·33 to -0·02, -1·86 mmol/mol [-3·61 to -0·22]; p=0·015) for dulaglutide 0·75 mg. Five (<1%) patients died after randomisation because of septicaemia (n=1 in the dulaglutide 1·5 mg group); pneumonia (n=1 in the dulaglutide 0·75 mg group); cardiogenic shock; ventricular fibrillation; and an unknown cause (n=3 in the glargine group). We recorded serious adverse events in 27 (9%) patients in the dulaglutide 1·5 mg group, 44 (15%) patients in the dulaglutide 0·75 mg group, and 54 (18%) patients in the glargine group. The most frequent adverse events, arising more often with dulaglutide than glargine, were nausea, diarrhoea, and vomiting. INTERPRETATION: Dulaglutide in combination with lispro resulted in a significantly greater improvement in glycaemic control than did glargine and represents a new treatment option for patients unable to achieve glycaemic targets with conventional insulin treatment. FUNDING: Eli Lilly and Company.

Increased protein intake is associated with uncontrolled blood pressure by 24-hour ambulatory blood pressure monitoring in patients with type 2 diabetes.

OBJECTIVE: To analyze possible associations of dietary components, especially protein intake, with blood pressure (BP) during ambulatory BP monitoring (ABPM) in patients with type 2 diabetes. METHODS: In this cross-sectional study, BP of outpatients with type 2 diabetes was evaluated by 24-hour ABPM (Spacelabs 90207) and usual diet by 3-day weighed diet records. Patients were divided into 2 groups according to their daytime ABPM: uncontrolled BP (systolic BP ≥ 135 mmHg or diastolic BP ≥ 85 mmHg) and controlled BP (systolic BP < 135 mmHg and diastolic BP < 85 mmHg). Logistic regression models unadjusted and adjusted for possible confounders (covariates) were used to analyze the association of protein and uncontrolled BP. RESULTS: A total of 121 patients with type 2 diabetes aged 62.3 years, 54.5% of whom were women, were studied. The uncontrolled BP group had higher glycated hemoglobin (HbA1C) values (8.4 ± 2.0 vs 7.6 ± 1.3%; p = 0.04) and consumed more protein (20.0 ± 3.8 vs 18.2 ± 3.6% of energy; p = 0.01) and meat, (2.6 [1.45, 2.95] vs 2.0 [1.49, 2.90] g/kg weight; p = 0.04) than the controlled BP group. In a multivariate analysis, protein intake (% of energy) increased the chance for uncontrolled BP (odds ratio [OR] = 1.16; 95% confidence interval [CI], 1.02, 1.30; p = 0.02), adjusted for body mass index (BMI), HbA1C, low-density lipoprotein (LDL) cholesterol, number of antihypertensive medications, and ethnicity. Meat consumption higher than 3.08 g/kg weight/day more than doubled the chance for uncontrolled BP (OR = 2.53; 95% CI, 1.01, 7.60; p = 0.03). CONCLUSION: High protein intake and meat consumption were associated with high daytime ABPM values in patients with type 2 diabetes. Reducing meat intake might represent an additional dietary intervention in hypertensive patients with type 2 diabetes.

Contrasting effects of preexisting hyperglycemia and higher body size on hospital mortality in critically ill patients: a prospective cohort study.

BACKGROUND: Obesity and diabetes mellitus are well-defined risk factors for cardiovascular mortality. The impact of antecedent hyperglycemia and body size on mortality in critical ill patients in intensive care units (ICUs) may vary across their range of values. Therefore, we prospectively analyzed the relationship between in-hospital mortality and preexisting hyperglycemia and body size in critically ill ICU patients to understand how mortality varied among normal, overweight, and obese patients and those with low, intermediate, and high glycated hemoglobin (HbA1c) levels. METHODS: Medical history, weight, height, physiologic variables, and HbA1c were obtained during the first 24 h for patients who were consecutively admitted to the high complexity ICU of Hospital de Clínicas de Porto Alegre, Brazil, from April to August 2011. The relationships between mortality and obesity and antecedent hyperglycemia were prospectively analyzed by cubic spline analysis and a Cox proportional hazards model. RESULTS: The study comprised 199 patients. The overall hospital mortality rate was 43.2% during a median 16 (8-28) days of follow-up. There was a progressive risk of in-hospital mortality with higher HbA1c levels, with the relationship becoming significant at HbA1c >9.3% compared with lower levels (hazard ratio 1.74; 95% confidence interval with Bonferroni correction 1.49-2.80). In contrast, mean body mass index (BMI) was higher in survivors than in nonsurvivors (27.2 kg/m2 ± 7.3 vs. 24.7 kg/m2 ± 5.0 P = 0.031, respectively). Cubic spline analysis showed that these relationships differed nonlinearly through the spectrum of BMI values. In a Cox proportional hazards model adjusted for Acute Physiology and Chronic Health Evaluation II score and HbA1c, the risk of in-hospital mortality progressively decreased with increasing BMI (BMI <20 vs. 20-23.9 kg/m2, P = 0.032; BMI <20 vs. 24-34.9 kg/m2, P = 0.010; BMI <20 vs. ≥35 kg/m2, P = 0.032). CONCLUSIONS: Our findings suggest that significant hyperglycemia prior to ICU admission is a risk factor for in-hospital mortality. Conversely, increasing BMI may confer an advantageous effect against mortality in critical illness independently of previous glycemic control.

Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial.

BACKGROUND: Management of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population. METHODS: This was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight. RESULTS: A total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg). CONCLUSIONS: Dapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00528879.

Association study of sorbitol dehydrogenase -888G>C polymorphism with type 2 diabetic retinopathy in Caucasian-Brazilians.

Diabetic retinopathy (DR) is a common chronic complication of diabetes and remains the leading cause of blindness in working-aged people. Hyperglycemia increases glucose flux through the polyol pathway, in which aldose reductase converts glucose into intracellular sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase (SDH). The accelerated polyol pathway triggers a cascade of events leading to retinal vascular endothelial dysfunction and the eventual development of DR. Polymorphisms in the gene encoding aldose reductase have been consistently associated with DR. However, only two studies have analyzed the relationship between polymorphisms in the gene encoding SDH (SORD) and DR. In this case-control study, we investigated whether the -888G > C polymorphism (rs3759890) in the SORD gene is associated with the presence or severity of DR in 446 Caucasian-Brazilians with type 2 diabetes (241 subjects with and 205 subjects without DR). The -888G > C polymorphism was also examined in 105 healthy Caucasian blood donors, and the genotyping of this polymorphism was carried out by real-time PCR. The genotype and allele frequencies of the -888G > C polymorphism in patients with type 2 diabetes were similar to those of blood donors (G allele frequency = 0.16 in both groups of subjects). Similarly, the genotype and allele frequencies in patients with DR or the proliferative form of DR were similar to those of patients without this complication (P > 0.05 for all comparisons). Thus, our findings suggest that the -888G > C polymorphism in the SORD gene is not involved in the pathogenesis of DR in type 2 diabetes.

Improvement of the metabolic syndrome profile by soluble fibre - guar gum - in patients with type 2 diabetes: a randomised clinical trial.

A diet rich in fibre seems to protect against the metabolic syndrome (MetS), but there is scarce information about the role of fibre intake in patients with the MetS and diabetes. The aim of the present study was to evaluate the effects of soluble fibre from partially hydrolysed guar gum (PHGG) on the MetS and cardiovascular risk factors in patients with type 2 diabetes. In the present randomised controlled clinical trial, forty-four patients with type 2 diabetes (males 38·6 %, age 62 (SD 9) years, diabetes duration 14·2 (SD 9·6) years) and the MetS underwent clinical, laboratory and dietary evaluations at baseline, 4 and 6 weeks. All patients followed their usual diet and the intervention group (n 23) received an additional 10 g/d of PHGG. In the intervention group, waist circumference (WC), glycated Hb (HbA1c), 24 h urinary albumin excretion (UAE) and serum trans-fatty acids (FA) were reduced in comparison with baseline after 4 and 6 weeks: WC 103·5 (SD 9·5) to 102·1 (SD 10) to 102·3 (SD 9·7) cm; HbA1c 6·88 (SD 0·99) to 6·64 (SD 0·94) to 6·57 (SD 0·84) %; 24 h UAE 6·8 (interquartile range 3·0-17·5) to 4·5 (interquartile range 3·0-10·5) to 6·2 (interquartile range 3·0-9·5) mg; trans-FA 71 (interquartile range 46-137) to 67 (interquartile range 48-98) to 57 (interquartile range 30-110) mg/l (P< 0·05 for all). The only change in the control group was weight reduction: 77·0 (SD 13·5) to 76·2 (SD 13·3) to 76·1 (SD 13·4) kg (P= 0·005). Other MetS components (blood pressure, TAG, HDL-cholesterol, fasting plasma glucose), total and LDL-cholesterol, C-reactive protein and endothelin-1 did not change in either group. In patients with type 2 diabetes and the MetS, the addition of PHGG to the usual diet improved cardiovascular and metabolic profiles by reducing WC, HbA1c, UAE and trans-FA.

The presence of the -866A/55Val/Ins haplotype in the uncoupling protein 2 (UCP2) gene is associated with decreased UCP2 gene expression in human retina.

Uncoupling protein 2 (UCP2) is a mitochondrial transporter present in the inner membrane of mitochondria, and it uncouples substrate oxidation from ATP synthesis, thereby dissipating the membrane potential energy and consequently decreasing ATP production by mitochondrial respiratory chain. As a consequence of the uncoupling, UCP2 decreases the reactive oxygen species (ROS) formation by mitochondria. ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Recently, our group reported that the -866A/55Val/Ins haplotype (-866G/A, Ala55Val and Ins/Del polymorphisms) of the UCP2 gene was associated with increased risk for DR in patients with DM. The purpose of this study was to analyze the effect of this haplotype on UCP2 gene expression in human retina. In addition, MnSOD2 gene expression was also investigated according to different UCP2 haplotypes. This cross-sectional study included 188 cadaveric cornea donors. In a subset of 91 retinal samples differentiated according to the presence of the mutated UCP2 haplotype and risk alleles of the -866G/A and Ins/Del polymorphisms, UCP2 and MnSOD2 gene expressions were measured by semi-quantitative RT-qPCR. Mutated UCP2 haplotype carriers (homozygous + heterozygous) had a lower UCP2 gene expression than reference haplotype carriers (8.4 ± 7.6 vs. 18.8 ± 23.7 arbitrary units; P = 0.046). Accordingly, UCP2 gene expression was decreased in -866A carriers when compared with G/G carriers (P = 0.010). UCP2 gene expression did not differ between Ins allele carriers and Del/Del carriers (P = 0.556). Interestingly, subjects carrying the heterozygous UCP2 haplotype showed increased MnSOD2 gene expression (P = 0.025). This is the first report suggesting that the presence of the -866A/55Val/Ins haplotype is associated with decreased UCP2 gene expression in human retina. Possibly, MnSOD2 expression might influence the UCP2 effect in the protection against oxidative stress.

The role of Dietary Approaches to Stop Hypertension (DASH) diet food groups in blood pressure in type 2 diabetes.

The role of each Dietary Approaches to Stop Hypertension (DASH) diet component in blood pressure (BP) of patients with diabetes is still uncertain. The aim of the present study was to evaluate possible associations of the recommended food groups of the DASH diet eating plan with BP values in patients with type 2 diabetes. In the present cross-sectional study, 225 patients with type 2 diabetes (age 61·1 (SD 10·4) years; diabetes duration 13·1 (SD 9·1) years; males 48·4 %; BMI 28·5 (SD 4·3) kg/m(2); HbA1c 7·1 (SD 1·3) %; systolic BP 136·7 (SD 20·0) mmHg; diastolic BP 78·4 (SD 11·8) mmHg) without dietary counselling during the previous 6 months had their dietary intake assessed by 3 d weighed-diet records. Patients were divided into two groups according to BP tertiles: LOW BP (first tertile) and HIGH BP (second plus third tertiles). Multivariate logistic regression models demonstrated that the daily intake of 80 g of fruits per 4184 kJ (1000 kcal) (OR 0·781; 95 % CI 0·617, 0·987; P = 0·039) or 50 g of vegetables per 4184 kJ (1000 kcal) (OR 0·781; 95 % CI 0·618, 0·988; P = 0·040) reduced the chance of the presence of HIGH mean BP (MBP ≥ 92 mmHg) by 22 % each, adjusted for possible confounders. In conclusion, fruit and vegetables were the food groups of the DASH diet associated with reduced BP values in patients with type 2 diabetes, and their consumption might play a protective role against increased BP values.

Albuminuria is not associated with bacteriuria in patients with type 2 diabetes mellitus: a meta-analysis of observational studies.

BACKGROUND/AIMS: It has been recommended that urinary albumin be measured in sterile urine for the proper diagnosis of diabetic nephropathy. However, the association between bacteriuria and urinary albumin is controversial. METHODS: A systematic review and meta-analysis was performed to investigate the association of albuminuria and bacteriuria in patients with diabetes. Medline and Embase were searched (beginning in 1950 until November 2010). Data were extracted independently by two investigators. The pooled OR estimates were calculated using the random effects model. RESULTS: We identified 305 studies in the database searches. A total of seven studies were included, providing data from 1,552 patients (mean age 56.4 years). The OR of bacteriuria for the presence of micro- and/or macroalbuminuria was 1.60 (95% CI: 0.97-2.66, I(2) = 66.6%) as compared to patients without bacteriuria. Funnel plots and the Egger regression test suggested no significant asymmetry in the analysis (p = 0.21). In a sensitivity analysis including the five studies (1,197 participants) that evaluated microalbuminuria as the outcome, the OR of bacteriuria for microalbuminuria was 1.22 (95% CI: 0.68-2.19). CONCLUSION: In conclusion, no association was identified between albuminuria and bacteriuria considering the current literature. Further prospective studies of a large diabetic population are needed to clarify such an association.

Effect of antihyperglycemic agents added to metformin and a sulfonylurea on glycemic control and weight gain in type 2 diabetes: a network meta-analysis.

BACKGROUND: Few studies have examined the effect of adding a third antihyperglycemic drug when blood glucose control is not achieved by using metformin and a sulfonylurea. PURPOSE: To compare the efficacy of add-on antihyperglycemic drugs in patients with type 2 diabetes that is not controlled with metformin and a sulfonylurea. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, LILACS, and ClinicalTrials.gov electronic databases. STUDY SELECTION: Randomized trials at least 24 weeks in duration. Studies evaluated the effects of adding a third antihyperglycemic drug to treatment of adults aged 18 years or older with type 2 diabetes and a hemoglobin A(1c) (HbA(1c)) level greater than 7.0% who were already receiving a combination of metformin and a sulfonylurea. DATA EXTRACTION: Primary end points were change in HbA(1c) level, change in weight, and frequency of severe hypoglycemia. DATA SYNTHESIS: Eighteen trials involving 4535 participants that lasted a mean of 31.3 weeks (24 to 52 weeks) were included. Compared with placebo, drug classes did not differ in effect on HbA(1c) level (reduction ranging from -0.70% [95% credible interval {CrI}, -1.33% to -0.08%] for acarbose to -1.08% [CrI, -1.41% to -0.77%] for insulin). Weight increase was seen with insulins (2.84 kg [CrI, 1.76 to 3.90 kg]) and thiazolidinediones (4.25 kg [CrI, 2.76 to 5.66 kg]), and weight loss was seen with glucagon-like peptide-1 agonists (-1.63 kg [CrI, -2.71 to -0.60 kg]). Insulins caused twice the absolute number of severe hypoglycemic episodes than noninsulin antihyperglycemic agents. LIMITATIONS: Most of the trials were short term, and trial quality varied. With so few trials relative to antihyperglycemic agents, investigators relied on indirect comparisons, which increased the uncertainty of the findings and conclusions. CONCLUSION: There is no clear difference in benefit between drug classes when adding a third agent to treatment of patients with type 2 diabetes who are already receiving metformin and a sulfonylurea. The most appropriate option should depend on each patient's clinical characteristics. PRIMARY FUNDING SOURCE: Conselho Nacional de Desenvolvimento Científico e Tecnológico and Coordenacao de Aperfeicoamento de Pessoal de Nível Superior.

The rs7204609 polymorphism in the fat mass and obesity-associated gene is positively associated with central obesity and microalbuminuria in patients with type 2 diabetes from Southern Brazil.

OBJECTIVE: Single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) gene, especially the common rs9939609 (A/T) SNP, are associated with body mass index (BMI), diabetes, and metabolic syndrome (MetS). MetS is highly prevalent in patients with type 2 diabetes and has been associated with chronic diabetic complications. Therefore, the aim of this study was to evaluate possible associations of the scarcely investigated rs7204609 (C/T) polymorphism, as well as the rs9939609 (A/T) polymorphism, with MetS and chronic diabetic complications in type 2 diabetic patients from Southern Brazil. DESIGN: This was a cross-sectional study. PATIENTS AND METHODS: A total of 236 patients with type 2 diabetes (age: 60.0 ± 10.3 years; diabetes duration: 12.7 ± 8.2 years; 53.4% women) were genotyped for the FTO rs7204609 and rs9939609 polymorphisms (ABI PRISM 7000 Real-Time PCR System). Patients underwent clinical, laboratory, and nutritional evaluation. MetS was defined according to the 2009-Joint Interim Statement. RESULTS: Carriers of C allele of the rs7204609 polymorphism (CT/CC genotypes, n = 35) were at increased risk for the presence of MetS (odds ratio [OR] = 4.56; 95% CI: 1.04 to 19.9), elevated waist circumference (OR = 8.66; 95% CI: 1.12 to 66.7), BMI: ≥ 30 kg/m(2) (OR = 3.71; 95% CI: 1.71 to 8.02), and microalbuminuria (OR = 2.30; 95% CI: 1.08 to 4.88), adjusted for gender and diabetes duration (P < .05 for all models). The rs9939609 polymorphism was not associated with MetS, elevated waist circumference or BMI, or diabetic complications. Daily energy and nutrient intakes did not differ according to the presence of the polymorphisms. CONCLUSIONS: The C allele of the rs7204609 polymorphism in the FTO gene increased the chance for the presence of MetS, especially central obesity, and microalbuminuria, independently of energy and nutrient intakes in this sample of type 2 diabetic patients from Southern Brazil.

Endothelin-1 and endothelin a receptor immunoreactivity is increased in patients with diabetic nephropathy.

BACKGROUND: Endothelin-1 (ET-1) is associated with progression of renal disease, acting as a vasoconstrictor and growth factor for mesangial cells. ET-1 and endothelin A receptor (ET-RA) might have a role in the development of diabetic nephropathy (DN). The aims of this study were to determine ET-1 and ET-RA expressions in patients with DN and to correlate these expressions with renal function and proteinuria. MATERIALS AND METHODS: This is a cross-sectional study comprising 13 patients with type 2 diabetes mellitus and DN, 10 patients with proteinuric IgA nephropathy, and 13 samples of normal kidney from tumor nephrectomies. Demographic and selected data were collected from medical charts. The distribution and intensity of ET-1 and ET-RA immunostaining in renal biopsies were determined by immunohistochemistry and these correlated with the estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: Patients with DN and IgA nephropathy on biopsy had markedly increased staining for ET-1 in endothelial cells of glomerular and peritubular capillaries when compared with controls (p < 0.001). ET-RA staining was also more intense and more diffuse in DN and IgA nephropathy than in controls (p = 0.019) and was restricted to tubular epithelial cells. A positive correlation was observed between ET-1 expression and proteinuria (r = 0.634, p = 0.027), but both ET-1 and ET-RA expressions did not correlate with eGFR. CONCLUSION: In this preliminary report, the higher expressions of ET-1 and ET-RA found in both DN and IgA nephropathy suggest a potential role for the endothelin system in DN as well as in other nondiabetic glomerular diseases.

Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis.

The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI -0.66 to -0.59) and body weight by 0.60 kg (95% CI -0.64 to -0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.

Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Correction of hyperglycaemia and prevention of glucotoxicity are important objectives in the management of type 2 diabetes. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces renal glucose reabsorption in an insulin-independent manner. We assessed the efficacy and safety of dapagliflozin in patients who have inadequate glycaemic control with metformin. METHODS: In this phase 3, multicentre, double-blind, parallel-group, placebo-controlled trial, 546 adults with type 2 diabetes who were receiving daily metformin (>/=1500 mg per day) and had inadequate glycaemic control were randomly assigned to receive one of three doses of dapagliflozin (2.5 mg, n=137; 5 mg, n=137; or 10 mg, n=135) or placebo (n=137) orally once daily. Randomisation was computer generated and stratified by site, implemented with a central, telephone-based interactive voice response system. Patients continued to receive their pre-study metformin dosing. The primary outcome was change from baseline in haemoglobin A(1c)(HbA(1c)) at 24 weeks. All randomised patients who received at least one dose of double-blind study medication and who had both a baseline and at least one post-baseline measurement (last observation carried forward) were included in the analysis. Data were analysed by use of ANCOVA models. This trial is registered with ClinicalTrials.gov, number NCT00528879. FINDINGS: 534 patients were included in analysis of the primary endpoint (dapagliflozin 2.5 mg, n=135; dapagliflozin 5 mg, n=133; dapagliflozin 10 mg, n=132; placebo, n=134). At week 24, mean HbA(1c) had decreased by -0.30% (95% CI -0.44 to -0.16) in the placebo group, compared with -0.67% (-0.81 to -0.53, p=0.0002) in the dapagliflozin 2.5 mg group, -0.70% (-0.85 to -0.56, p<0.0001) in the dapagliflozin 5 mg group, and -0.84% (-0.98 to -0.70, p<0.0001) in the dapagliflozin 10 mg group. Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin (2-4%) and placebo groups (3%). Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (2.5 mg, 11 patients [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) than in the placebo group (seven [5%]). 17 patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group). INTERPRETATION: Addition of dapagliflozin to metformin provides a new therapeutic option for treatment of type 2 diabetes in patients who have inadequate glycaemic control with metformin alone. FUNDING: Bristol-Myers Squibb and AstraZeneca.

High dietary glycemic index and low fiber content are associated with metabolic syndrome in patients with type 2 diabetes.

OBJECTIVE: To investigate possible associations of dietary glycemic index (GI) and fiber content with metabolic syndrome (MetS) in patients with type 2 diabetes. METHODS: In this cross-sectional study, 175 outpatients with type 2 diabetes (aged 61.1 ± 9.7 years; HbA(1c) 7.3% ± 1.4%; diabetes duration of 11 years [range, 5-17]) had food intake assessed by 3-day weighed-diet records. Dietary GI (according to FAO/WHO) and fiber content were categorized as high or low based on median values. MetS was defined according to the 2009 Joint Interim Statement. RESULTS: Patients with MetS (n = 109) had higher 24-hour GI (60.0% ± 6.3% vs 57.5% ± 6.4%), higher breakfast GI (59.8% ± 8.0% vs 55.0% ± 9.9%), and lower fiber intake at 24 hours (17.0 ± 6.6 g vs 21.2 ± 8.0 g), breakfast (1.9 [1.2-3.2] vs 3.1 [1.8-4.9] g), lunch (6.2 [3.9-8.0] vs 7.5 [4.7-9.4] g), and dinner (3.3 [2.1-5.2] vs 4.9 [3.1-6.4] g; p < 0.05 for all comparisons) than patients without MetS. In multivariate analyses, high GI (~60%) of 24 hours (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.10-4.11; p = 0.025), breakfast (OR, 2.20; 95% CI, 1.15-4.21; p = 0.017), and lunch (OR, 2.46; 95% CI, 1.28-4.74; p = 0.007) was associated with MetS. Breakfast (OR, 2.14; 95% CI, 1.04-4.41; p = 0.039) and dinner (OR, 2.27; 95% CI, 1.15-4.49; p = 0.019) with low fiber content were also associated with MetS. When high GI and low fiber intake were combined into the same variable, associations with MetS were maintained. CONCLUSIONS: Increased dietary GI and reduced fiber content were positively associated with MetS, mainly due to breakfast intake, in patients with type 2 diabetes.

Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis.

CONTEXT: Regular exercise improves glucose control in diabetes, but the association of different exercise training interventions on glucose control is unclear. OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled clinical trials (RCTs) assessing associations of structured exercise training regimens (aerobic, resistance, or both) and physical activity advice with or without dietary cointervention on change in hemoglobin A(1c) (HbA(1c)) in type 2 diabetes patients. DATA SOURCES: MEDLINE, Cochrane-CENTRAL, EMBASE, ClinicalTrials.gov, LILACS, and SPORTDiscus databases were searched from January 1980 through February 2011. STUDY SELECTION: RCTs of at least 12 weeks' duration that evaluated the ability of structured exercise training or physical activity advice to lower HbA(1c) levels as compared with a control group in patients with type 2 diabetes. DATA EXTRACTION: Two independent reviewers extracted data and assessed quality of the included studies. DATA SYNTHESIS: Of 4191 articles retrieved, 47 RCTs (8538 patients) were included. Pooled mean differences in HbA(1c) levels between intervention and control groups were calculated using a random-effects model. Overall, structured exercise training (23 studies) was associated with a decline in HbA(1c) level (-0.67%; 95% confidence interval [CI], -0.84% to -0.49%; I(2), 91.3%) compared with control participants. In addition, structured aerobic exercise (-0.73%; 95% CI, -1.06% to -0.40%; I(2), 92.8%), structured resistance training (-0.57%; 95% CI, -1.14% to -0.01%; I(2), 92.5%), and both combined (-0.51%; 95% CI, -0.79% to -0.23%; I(2), 67.5%) were each associated with declines in HbA(1C) levels compared with control participants. Structured exercise durations of more than 150 minutes per week were associated with HbA(1c) reductions of 0.89%, while structured exercise durations of 150 minutes or less per week were associated with HbA(1C) reductions of 0.36%. Overall, interventions of physical activity advice (24 studies) were associated with lower HbA(1c) levels (-0.43%; 95% CI, -0.59% to -0.28%; I(2), 62.9%) compared with control participants. Combined physical activity advice and dietary advice was associated with decreased HbA(1c) (-0.58%; 95% CI, -0.74% to -0.43%; I(2), 57.5%) as compared with control participants. Physical activity advice alone was not associated with HbA(1c) changes. CONCLUSIONS: Structured exercise training that consists of aerobic exercise, resistance training, or both combined is associated with HbA(1c) reduction in patients with type 2 diabetes. Structured exercise training of more than 150 minutes per week is associated with greater HbA(1c) declines than that of 150 minutes or less per week. Physical activity advice is associated with lower HbA(1c), but only when combined with dietary advice.

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.