Dimitris Rucks Varvaki Rados

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

Genetics of diabetic nephropathy

The increasing prevalence of diabetes mellitus has led to a growing number of chronic complications including diabetic nephropathy (DN). In addition to its high prevalence, DN is associated with high morbidity and mortality especially due to cardiovascular diseases. It is well established that genetic factors play a role in the pathogenesis of DN and genetically susceptible individuals can develop it after being exposed to environmental factors. DN is probably a complex, polygenic disease. Two main strategies have been used to identify genes associated to DN: analysis of candidate genes, and more recently genome-wide scan. Great efforts have been made to identify these main genes, but results are still inconsistent with different genes associated to a small effect in specific populations. The identification of the main genes would allow the detection of those individuals at high risk for DN and better understanding of its pathophysiology as well.

Cardiovascular autonomic neuropathy in type 2 diabetes mellitus patients with peripheral artery disease

ObjectiveTo evaluate possible associations between cardiovascular autonomic dysfunction and peripheral artery disease (PAD) in patients with type 2 diabetes mellitus.Research design and methodsIn this cross-sectional study, 67 patients with type 2 diabetes were included. PAD was identified by Doppler ultrasonography: systolic ankle-brachial pressure index <0.9. Cardiovascular autonomic function, besides five conventional cardiovascular autonomic function tests, was assessed by heart rate variability (HRV; 24-h ambulatory ECG recording) in time and frequency domains (spectral analyses) and three dimensional return maps. Power spectral analyses (PSA) were quantified in low frequency (LF), high frequency (HF), and very low frequency.ResultsPatients with PAD (n = 30) had longer diabetes duration, higher systolic blood pressure (BP), waist-to-hip ratio, HbA1C test, and urinary albumin excretion (UAE) than patients without PAD. Most HRV indices in time domain were lower in patients with than without PAD. These patients also had lower PSA indices (LF=0.19±0.07 vs. 0.29±0.11 n.u.; LF/HF ratio=1.98±0.9 vs. 3.35±1.83; P<0.001) and indices of sympathetic (three-dimensional return map: P1-night 61.7±9.4 vs. 66.8±9.7; P=0.04) and vagal (24-h P2 54.5±15.2 vs. 62.7±2.9; P< 0.02) activities (arbitrary units) than patients without PAD. Multivariate logistic regression analyses, adjusted for systolic BP, DM duration, HbA1C test, and UAE, confirmed the associations between impaired autonomic modulation and PAD, except for P1 index.ConclusionIn conclusion, patients with type 2 diabetes with PAD had lower HRV indices than patients without PAD, reflecting a dysfunction of cardiovascular autonomic modulation.

Efficacy of SGLT2 inhibitors in glycemic control, weight loss and blood pressure reduction: a systematic review and meta-analysis

Background Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a novel antidiabetic class that inhibits glucose reabsorption and produce glycosuria. These medications are being increasingly used as dual therapy with metformin for type 2 diabetes (T2D) treatment, due to their beneficial effect on weight and blood pressure. Three agents are approved for clinical use and they may differ on potency due to inhibition of only renal or both renal and bowel glucose transportation.

Clinical features of patients with type 2 diabetes mellitus and hepatitis C infection.

The objective of the present cross-sectional study was to assess the prevalence and the clinical and laboratory features of hepatitis C virus (HCV)-positive patients with type 2 diabetes mellitus (DM) attending either an outpatient clinic or hemodialysis units. Serologic-HCV testing was performed in 489 type 2 DM patients (303 outpatients and 186 on dialysis). A structured assessment of clinical, laboratory and DM-related complications was performed and the patients were then compared according to HCV infection status. Mean patient age was 60 years; HCV positivity (HCV+) was observed in 39 of 303 (12.9%) outpatients and in 34 of 186 (18.7%) dialysis patients. Among HCV+ patients, 32 were men (43.8%). HCV+ patients had higher serum levels of aspartate aminotransferase (0.90 ± 0.83 vs 0.35 ± 0.13 μKat/L), alanine aminotransferase (0.88 ± 0.93 vs 0.38 ± 0.19 μKat/L), gamma-glutamyl transferase (1.57 ± 2.52 vs 0.62 ± 0.87 μKat/L; P < 0.001), and serum iron (17.65 ± 6.68 vs 14.96 ± 4.72 μM; P = 0.011), and lower leukocyte and platelet counts (P = 0.010 and P < 0.001, respectively) than HCV-negative (HCV-) patients. HCV+ dialysis patients had higher diastolic blood pressure than HCV- patients (87.5 ± 6.7 vs 81.5 ± 6.0 mmHg; P = 0.005) and a lower prevalence of diabetic retinopathy (75 vs 92.7%; P = 0.007). In conclusion, our study showed that HCV is common among subjects with type 2 DM but is not associated with a higher prevalence of chronic diabetic complications.

Screening for coronary artery disease in patients with type 2 diabetes: a meta-analysis and trial sequential analysis.

Objective To evaluate the efficacy of coronary artery disease screening in asymptomatic patients with type 2 diabetes and assess the statistical reliability of the findings. Methods Electronic databases (MEDLINE, EMBASE, Cochrane Library and clinicaltrials.org) were reviewed up to July 2016. Randomised controlled trials evaluating coronary artery disease screening in asymptomatic patients with type 2 diabetes and reporting cardiovascular events and/or mortality were included. Data were summarised with Mantel-Haenszel relative risk. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 40% reduction in outcomes. Main outcomes were all-cause mortality and cardiac events (non-fatal myocardial infarction and cardiovascular death); secondary outcomes were non-fatal myocardial infarction, myocardial revascularisations and heart failure. Results One hundred thirty-five references were identified and 5 studies fulfilled the inclusion criteria and totalised 3315 patients, 117 all-cause deaths and 100 cardiac events. Screening for coronary artery disease was not associated with decrease in risk for all-cause deaths (RR 0.95(95% CI 0.66 to 1.35)) or cardiac events (RR 0.72(95% CI 0.49 to 1.06)). TSA shows that futility boundaries were reached for all-cause mortality and a relative risk reduction of 40% between treatments could be discarded. However, there is not enough information for firm conclusions for cardiac events. For secondary outcomes no benefit or harm was identified; optimal sample sizes were not reached. Conclusion Current available data do not support screening for coronary artery disease in patients with type 2 diabetes for preventing fatal events. Further studies are needed to assess the effects on cardiac events. PROSPERO CRD42015026627.

The prevalence of chronic diabetic complications and metabolic syndrome is not associated with maternal type 2 diabetes

The maternal history of type 2 diabetes mellitus (DM) has been reported more frequently in patients with type 2 DM than paternal history. The aim of the present study was to determine if there was an association between maternal history of DM and the presence of chronic complications or metabolic syndrome (MetS) in patients with type 2 DM. A cross-sectional study was conducted with 1455 patients with type 2 DM. All outpatients with type 2 diabetes attending the endocrine clinics who fulfilled the eligibility criteria were included. Familial history of DM was determined with a questionnaire. Diabetic complications were assessed using standard procedures. The definition of MetS used was that of the World Health Organization and the National Cholesterol Education Programs Adult Treatment Panel III report criteria. Maternal history of DM was present in 469 (32.3%), absent in 713 (49.1%) and unknown in 273 patients (18.7%). Paternal history of DM was positive in 255 (17.6%), negative in 927 (63.8%) and unknown in 235 patients (16.1%). The frequency of microvascular chronic complications in patients with and without a positive maternal history of DM was similar: diabetic nephropathy (51.5 vs 52.5%), diabetic retinopathy (46.0 vs 41.7%), and diabetic sensory neuropathy (31.0 vs 37.1%). The prevalence of macrovascular chronic complications and MetS was also similar. Patients with type 2 DM were more likely to have a maternal than a paternal history of DM, although maternal history of DM was not associated with an increased prevalence of chronic complications or MetS.

Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis

The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with pancreatic cancer and acute pancreatitis. Recent meta-analyses have reported conflicting findings. Therefore, we performed a meta-analysis to assess the risk of both pancreatic cancer and acute pancreatitis associated with the use of DPP-4 inhibitors. We also used trial sequential analysis to evaluate whether the number of patients included was enough to reach conclusions. We included randomised controlled trials lasting 24 weeks or more that compared DPP-4 inhibitors with placebo or other antihyperglycaemic agents. A total of 59,404 patients were included. There was no relationship between the use of DPP-4 inhibitors and pancreatic cancer (Peto odds ratio 0.65; 95% CI 0.35–1.21), and the optimal sample size was reached to determine a number needed to harm (NNH) of 1000 patients. DPP-4 inhibitors were associated with increased risk for acute pancreatitis (Peto odds ratio 1.72; 95% CI 1.18–2.53), with an NNH of 1066 patients, but the optimal sample size for this outcome was not reached. In conclusion, there is no association between DPP-4 inhibitors and pancreatic cancer, and a small risk for acute pancreatitis was observed with DPP-4 inhibitor use, although the latter finding is not definitive.

Self-monitoring blood glucose improves glycemic control in type 2 diabetes without intensive treatment: A systematic review and meta-analysis

AIMS Systematic review and meta-analysis to evaluate the effect of Self-Monitoring of Blood Glucose (SMBG) on glycemic control in patients with type 2 Diabetes (T2D). METHODS We searched the Medline, Embase, Cochrane Central, and ClinicalTrials.gov databases up to 20 July 2017. We also performed a manual search of abstracts from recent meetings of the American Diabetes Association and the European Association for the Study of Diabetes. STUDY SELECTION randomized controlled trials (RCTs) conducted in patients with T2D comparing any kind of SMBG to a control group. Two independent reviewers assessed the eligibility of references. Influence of SMBG in glycated hemoglobin (HbA1c) was aggregated as weighted mean difference accessed by direct random effect meta-analyses at 12, 24 weeks and 1 year. Sub-analyses were made to assess the effects of previous glycemic control and number of tests performed. RESULTS SMBG was associated with a reduction of HbA1c at 12 weeks (-0.31%; 95% CI: -0.57 to -0.05) and 24 weeks (-0.34%; 95%CI: -0.52 to -0.17), but no difference was found for 1 year. Subgroup analysis including studies with baseline HbA1c greater than 8% showed a higher reduction of HbA1c: -0.83% (95% CI: -1.55 to -0.11) at 12 weeks, and -0.48% (95% CI: -0.77 to -0.19) at 24 weeks, with no difference for 1 year nor for the stratification for number the tests. CONCLUSION SMBG seems to lead to a slightly better glycemic control in the short term in patients with T2D. Patients decompensated at baseline appear to have the greatest benefit. PROSPERO register: CRD42016033558.

Effects of nurse telesupport on transition between specialized and primary care in diabetic patients : study protocol for a randomized controlled trial

BackgroundAccording to the Global Diabetes Plan, a unified health system with preventive and educational strategies is essential to proper diabetes care and primary settings should be the main site of care. In Brazil, there is limited access to outpatient hospital diabetes services, while primary-care diabetes support is underutilized. Telemedicine can be a useful adjunct to support discharge of stable patients with type 2 diabetes to the primary care setting. In this paper, we present a randomized controlled trial (RCT) protocol designed to evaluate the effects of telehealth support for stable type 2 diabetes patients discharged from hospital outpatient diabetes clinics.MethodsWe designed a RCT. Patients with stable type 2 diabetes (glycated hemoglobin < 8%) considered eligible for discharge from specialized to primary care will be included. Those with uncontrolled ischemic heart disease, severe neuropathy, and stage IV/V nephropathy will be excluded. Enrolled patients will be randomized into two groups: follow-up supported by periodic phone calls by a nurse (intervention group) plus primary care or routine primary care only (control group). The intervention group will receive regular telephone calls (every three months for one year) and will have a toll-free number to call in case of questions about disease management. The main outcome measure is a comparison of glycemic control between groups (assessed by glycated hemoglobin) at one-year follow-up.DiscussionWe plan to evaluate the effectiveness of a telephone-based intervention on glycemic control in patients with type 2 diabetes followed by primary care teams. Telemedicine can be an important adjunct in type 2 diabetes management, improving patient education and knowledge about the disease. Furthermore, it can help the healthcare system by alleviating overload in specialized care settings and supporting the stewardship role of primary care.Trial registrationClinical Trials, NCT02768480. Registered on 29 April 2016.