Luis Henrique Santos Canani

Standards of Medical Care in Diabetes--2008: response to Hirsch, Inzucchi, and Kirkman.

The American Diabetes Association (ADA) has released a Standards of Medical Care in Diabetes Position Statement for 2008 (1). In this document, it is stated that aspirin therapy should be used as a primary prevention strategy in diabetic patients at increased cardiovascular (CV) risk, including those who are >40 years old or have additional risk factors. The recommendation is based on evidence graded “A,” which is defined by the ADA as “evidence from well-conducted, randomized controlled trials that are adequately powered or compelling nonexperimental evidence.” As this indication seemed very …

Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes

OBJECTIVE Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS We genotyped ∼360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes-associated complications. RESULTS A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P < 1 × 10−5. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR] = 1.45, P = 5.0 × 10−7). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR = 1.36, P = 3.1 × 10−6). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR] = 1.33, P = 0.02, and HR = 1.32, P = 0.01, respectively). We demonstratedexpression of both FRMD3 and CARS in human kidney. CONCLUSIONS We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes.

Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in Type 2 diabetes.

Aims  To investigate the association of features of the metabolic syndrome with the prevalence of chronic complications.

Diabetic Retinopathy Predicts All-Cause Mortality and Cardiovascular Events in Both Type 1 and 2 Diabetes: Meta-analysis of observational studies

OBJECTIVE The prognostic significance of diabetic retinopathy (DR) for death and cardiovascular (CV) outcomes is debated. We investigated the association of DR with all-cause mortality and CV events in patients with diabetes by a systematic review and meta-analysis. RESEARCH DESIGN AND METHODS The electronic databases Medline and Embase were searched for cohort studies that evaluated DR in type 2 or type 1 diabetic patients and reported total mortality and/or fatal and nonfatal CV events, including myocardial infarction, angina pectoris, coronary artery bypass graft, ischemic changes on a conventional 12-lead electrocardiogram, transient ischemic attack, nonfatal stroke, or lower leg amputation. Data extraction was performed by two reviewers independently. Pooled effect estimates were obtained by using random-effects meta-analysis. RESULTS The analysis included 20 studies that fulfilled the inclusion criteria, providing data from 19,234 patients. In patients with type 2 diabetes (n = 14,896), the presence of any degree of DR increased the chance for all-cause mortality and/or CV events by 2.34 (95% CI 1.96–2.80) compared with patients without DR. In patients with type 1 diabetes (n = 4,438), the corresponding odds ratio was 4.10 (1.50–11.18). These associations remained after adjusting for traditional CV risk factors. DR was also predictive of all-cause mortality in type 2 diabetes (odds ratio 2.41 [1.87–3.10]) and type 1 diabetes (3.65 [1.05–12.66]). CONCLUSIONS The presence of DR was associated with an increased risk of all-cause mortality and CV events in both type 2 and type 1 diabetic patients.

Prevalência de complicações micro e macrovasculares e de seus fatores de risco em pacientes com diabetes melito do tipo 2 em atendimento ambulatorial

BACKGROUND: Type 2 diabetes (DM2) has been related to the development of macroangiopatic [coronary heart disease (CHD), peripheral vascular disease (PVD) and stroke] and microangiopatic [retinopathy, nephropathy, and distal sensory neuropathy (DSN)] complications. The aims of this study were to analyze prevalence of complications in DM2 patients and to estimate their associated risk factors. METHODS: Cross-sectional study, including 927 out patients with DM2 from three medical centers in Rio Grande do Sul: Hospital de Clinicas de Porto Alegre (n = 475), Grupo Hospitalar Conceicao (n = 229) and Hospital Sao Vicente de Paula (n = 223). Of the patients 42% were male, mean age was 59 ± 10 years and the median known duration of DM2 was 11 (5 - 43) years. Retinopathy was identified by direct fundoscopy; CHD by WHO questionnaire and/or abnormal ECG and/or perfusion abnormalities on myocardial scintigraphy; DSN by compatible symptoms and absent sensation on 10 g monofilament and/or tune fork; PVD by the presence of claudication and absent foot pulses; stroke by presence of sequels and history; and nephropathy by the urinary albumin excretion rate (>20 µg/min). Hypertension was defined by blood pressure (>140/90 mmHg) and/or use of antihypertensive drugs. Body mass index (BMI, kg/m2) and waist-to-hip ratio (WHR) were calculated. RESULTS: CHD was present in 36% and PVD in 33% of the patients. Among the microvascular, 37% had nephropathy (12% with macroalbuminuria); 48% retinopathy (15% proliferative retinopathy). DSN was present in 36%. Seventy three percent of the patients presented arterial hypertension. Cholesterol levels were >200 mg/dl in 64% and BMI > 30 kg/m2 in 36%. Twenty two percent of patients were smokers and 21% ex-smokers. CONCLUSION: Diabetic complications are frequent among out patients referring to general hospitals. Almost all patients presented at least one risk factor for cardiovascular disease, justifying the efforts for identification and adequate control.

Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: systematic review and meta-analysis

Objective To investigate the association of coronary artery calcium score with all cause mortality and cardiovascular events in people with type 2 diabetes. Design Systematic review and meta-analysis of observational studies. Data sources Studies were identified from Embase, PubMed, and abstracts from the 2011 and 2012 annual meetings of the American Diabetes Association, European Association for the Study of Diabetes, American College of Cardiology, and American Heart Association (2011). Eligibility criteria Prospective studies that evaluated baseline coronary artery calcium score in people with type 2 diabetes and subsequent all cause mortality or cardiovascular events (fatal and non-fatal). Data extraction Two independent reviewers extracted the data. The predictive value of the coronary artery calcium score was assessed by random effects model. Results Eight studies were included (n=6521; 802 events; mean follow-up 5.18 years). The relative risk for all cause mortality or cardiovascular events, or both comparing a total coronary artery calcium score of ≥10 with a score of <10 was 5.47 (95% confidence interval 2.59 to 11.53; I2=82.4%, P<0.001). The overall sensitivity of a total coronary artery calcium score of ≥10 for this composite outcome was 94% (95% confidence interval 89% to 96%), with a specificity of 34% (24% to 44%). The positive and negative likelihood ratios were 1.41 (95% confidence interval 1.20 to 1.66) and 0.18 (0.10 to 0.30), respectively. For people with a coronary artery calcium score of <10, the post-test probability of the composite outcome was about 1.8%, representing a 6.8-fold reduction from the pretest probability. Four studies evaluated cardiovascular events as the outcome (n=1805; 351 events). The relative risk for cardiovascular events comparing a total coronary artery calcium score of ≥10 with a score of <10 was 9.22 (2.73 to 31.07; I2=76.7%, P=0.005). The positive and negative likelihood ratios were 1.67 (1.30 to 2.17) and 0.11 (0.04 to 0.29), respectively. Conclusion In people with type 2 diabetes, a coronary artery calcium score of ≥10 predicts all cause mortality or cardiovascular events, or both, and cardiovascular events alone, with high sensitivity but low specificity. Clinically, the finding of a coronary artery calcium score of <10 may facilitate risk stratification by enabling the identification of people at low risk within this high risk population.

Five-Year Prospective Study of Glomerular Filtration Rate and Albumin Excretion Rate in Normofiltering and Hyperfiltering Normoalbuminuric NIDDM Patients

OBJECTIVE To evaluate the evolution of glomerular filtration rate (GFR) and albumin excretion rate (AER) of normofiltering (NF) and hyperfiltering (HF) normoalbuminuric NIDDM patients. RESEARCH DESIGN AND METHODS A longitudinal study of 32 normoalbuminuric (AER < 20 μg/min) NIDDM patients and 20 age-, sex-, and BMI-matched normal individuals was done. Subjects had their GFR (51Cr-labeled EDTA single-injection method) measured at entry and after 40 and 60 months. At entry, 13 NIDDM patients had GFR values above the upper limit of the normal range in our laboratory (> 137 ml · min−1 x 1.73 m−2) and were considered as HF. In NIDDM patients, the 24-h AER (radioimmunoassay), HbA1c, urinary urea, and mean arterial blood pressure (MBP) were analyzed at entry and after 40 and 60 months. RESULTS There was a significant decline of GFR in NIDDM patients and normal subjects at 60 months. The decline was significantly greater in HF patients (−0.61 ml · min−1.month−1; P = 0.001) than in NF (−0, 18) and control subjects (−0, 14); the rate of change in NF and control subjects was the same (P > 0.05). In stepwise multiple regression analysis, with GFR decline as the dependent variable and GFR and AER at baseline, age and change in MBP, change in urinary urea, change in HbA1c, and change in therapy as independent variables, only baseline GFR (R2 = 0.19, P = 0.002) and age (R2 = 0.31, P = 0.048) were significantly related to the outcome. At 60 months, AER raised > 20 μg/min in three HF and in four NF patients. In logistic regression analysis, only higher initial AER (although still in the normal range; P = 0.037) and an increase in urinary urea (P = 0.021) were significantly related to the later development of microalbuminuria. CONCLUSIONS The GFR of normoalbuminuric NIDDM patients declines significantly over 60 months. This decline is associated to baseline GFR and age. HF NIDDM patients show a faster decline in GFR than NF patients, whose GFR falls at a rate that is compatible with the age-related change observed in normal control subjects. The development of microalbuminuria is related to higher baseline AER and to increases in urinary urea and is similar in NF (4 of 19) and HF (3 of 13) NIDDM patients (P > 0.05).

Efficacy and safety of topiramate on weight loss: a meta-analysis of randomized controlled trials

Topiramate was associated with weight loss in clinical trials. We summarize the evidence on the efficacy and safety of topiramate in the treatment of overweight/obesity. The databases Medline, Embase, and Cochrane were searched. Randomized controlled studies with at least 16 weeks of duration that report the effect of topiramate on weight loss and adverse events were eligible for inclusion. Ten studies were included (3320 individuals). Patients treated with topiramate lost an average of 5.34 kg (95% confidence interval [95%CI]−6.12 to −4.56) of additional weight as compared with placebo. According to meta‐regression analysis, treatment duration and dosage were associated with the efficacy of topiramate treatment. Evaluating trials using topiramate 96–200 mg day−1, the weight loss was higher in trials with >28 weeks of duration (−6.58 kg [95%CI −7.48 to −5.68]) than in trials with ≤28 weeks (−4.11 kg [95%CI −4.92 to −3.30]). Data of 6620 individuals were available for adverse events evaluation and those more frequently observed were paraesthesia, taste impairment and psychomotor disturbances. The odds ratio for adverse events leading to topiramate withdrawal was 1.94 (95%CI 1.64–2.29) compared with the control group. In conclusion, topiramate might be a useful adjunctive therapeutic tool in the treatment of obesity as long as proper warnings about side effects are considered.

The European-Specific Mitochondrial Cluster J/T Could Confer an Increased Risk of Insulin-Resistance and Type 2 Diabetes: An Analysis of the m.4216T > C and m.4917A > G Variants

The aims of this study were to investigate the contributions of the mitochondrial DNA m.4216T > C and m.4917A > G variants, and also of the European‐specific mitochondrial cluster J/T, to the development of type 2 diabetes mellitus in Caucasian‐Brazilian patients from Southern Brazil. We analyzed 347 type 2 diabetes patients and 350 control subjects. Variant frequencies in patients and control subjects were compared using χ2 tests or odds ratio. We also compared clinical and laboratory characteristics among patients with and without the variants. We found that the frequencies of the m.4216T > C and m.4917A > G variants are higher in diabetic patients than in control subjects. Moreover, haplogroups J (partially defined by the presence of the m.4216T > C variant only) and T (partially defined by the presence of both m.4216T > C and m.4917A > G variants) are more frequent in the type 2 diabetic group than in the control group. Patients belonging to the cluster J/T are more insulin resistant than patients of other haplogroups. In conclusion, our results indicate the association of the cluster J/T (as suggested by analyses of the m.4216T > C and m.4917A > G variants) with insulin resistance and type 2 diabetes.

Endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus☆

AIM To evaluate the relationship of plasma endothelin-1 (ET-1) levels, a marker of endothelial dysfunction, and urinary albumin excretion in patients with type 2 diabetes mellitus (DM). METHODS Cross-sectional study was conducted in 279 patients (132 males, mean age: 58.7+/-11.0 years, mean DM duration: 11.3+/-8.1 years). Urinary albumin excretion, ET-1, and insulin were measured. Insulin sensitivity was estimated by homeostasis model assessment (HOMA-ir) index. RESULTS ET-1 was associated with urinary albumin excretion after controlling for age, gender, body mass index, blood pressure, HbA1c test, and total cholesterol (R=0.436; adjusted R(2)=0.190, P<0.01). Furthermore, there was a progressive increase in plasma ET-1 levels from patients with normoalbuminuria (n=187, 0.92+/-0.50pg/ml), microalbuminuria (n=68, 1.13+/-0.52pg/ml) to macroalbuminuria (n=24, 1.93+/-1.10pg/ml, P<0.01). CONCLUSION There is an independent association of plasma ET-1 levels with urinary albumin excretion. In addition, plasma ET-1 levels started to increase in the normal values of urinary albumin excretion suggesting that in patients with type 2 DM endothelial dysfunction is already present, in urinary albumin excretion values considered normal.