ng Li

Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies

Objective To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Eligibility criteria Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. Data collection and analysis Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. Results 60 studies (n=353 639), consisting of 55 randomised controlled trials (n=33 350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320 289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). Conclusions The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies.

Objectives To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes. Design Systematic review and meta-analysis of randomised and observational studies. Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts. Eligibility criteria Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure. Data collection and analysis Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach. Results Eligible studies included 43 trials (n=68 775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1 777 358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15 701 v 33/12 591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18 554 v 552/18 474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use. Conclusions The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.

Mobile App-Based Interventions to Support Diabetes Self-Management: A Systematic Review of Randomized Controlled Trials to Identify Functions Associated with Glycemic Efficacy

Background Mobile health apps for diabetes self-management have different functions. However, the efficacy and safety of each function are not well studied, and no classification is available for these functions. Objective The aims of this study were to (1) develop and validate a taxonomy of apps for diabetes self-management, (2) investigate the glycemic efficacy of mobile app-based interventions among adults with diabetes in a systematic review of randomized controlled trials (RCTs), and (3) explore the contribution of different function to the effectiveness of entire app-based interventions using the taxonomy. Methods We developed a 3-axis taxonomy with columns of clinical modules, rows of functional modules and cells of functions with risk assessments. This taxonomy was validated by reviewing and classifying commercially available diabetes apps. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Chinese Biomedical Literature Database, and ClinicalTrials.gov from January 2007 to May 2016. We included RCTs of adult outpatients with diabetes that compared using mobile app-based interventions with usual care alone. The mean differences (MDs) in hemoglobin A1c (HbA1c) concentrations and risk ratios of adverse events were pooled using a random-effects meta-analysis. After taxonomic classification, we performed exploratory subgroup analyses of the presence or absence of each module across the included app-based interventions. Results Across 12 included trials involving 974 participants, using app-based interventions was associated with a clinically significant reduction of HbA1c (MD 0.48%, 95% CI 0.19%-0.78%) without excess adverse events. Larger HbA1c reductions were noted among patients with type 2 diabetes than those with type 1 diabetes (MD 0.67%, 95% CI 0.30%-1.03% vs MD 0.37%, 95% CI –0.12%-0.86%). Having a complication prevention module in app-based interventions was associated with a greater HbA1c reduction (with complication prevention: MD 1.31%, 95% CI 0.66%-1.96% vs without: MD 0.38%, 95% CI 0.09%-0.67%; intersubgroup P=.01), as was having a structured display (with structured display: MD 0.69%, 95% CI 0.32%-1.06% vs without: MD 0.69%, 95% CI –0.18%-0.53%; intersubgroup P=.03). However, having a clinical decision-making function was not associated with a larger HbA1c reduction (with clinical decision making: MD 0.19%, 95% CI –0.24%-0.63% vs without: MD 0.61%, 95% CI 0.27%-0.95%; intersubgroup P=.14). Conclusions The use of mobile app-based interventions yields a clinically significant HbA1c reduction among adult outpatients with diabetes, especially among those with type 2 diabetes. Our study suggests that the clinical decision-making function needs further improvement and evaluation before being added to apps.

C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease

BACKGROUND Endothelial-myofibroblast transition (EndMT) has been implicated in the pathogenesis of diabetic renal fibrosis. In this study, the effect of the complement fragments C3a/C5a and their receptor antagonists C3aRA and C5aRA on EndMT in diabetic kidney disease (DKD) and the possible mechanisms were investigated. METHODS The coexpression of CD31 with α-smooth muscle (α-SMA), C3a receptor (C3aR) and C5a receptor (C5aR) was detected in human renal biopsy tissue obtained from patients with early and advanced DKD and in normal renal tissues from patients with renal-cell carcinoma. The effects of C3aRA and C5aRA on EndMT and the expression of C3a/C3aR, C5a/C5aR, α-SMA, CD31, TGFβ, FN and β-catenin were examined in a streptozotocin (STZ)-induced rat model of DKD and in human renal glomerular endothelial cells (HRGECs) cultured in high glucose and with C3a/C5a, and DKK1 (a Wnt/β-catenin inhibitor). RESULTS Double-labeling of α-SMA, C3aR, C5aR and CD31 was detected in the glomerulus of renal tissues obtained from biopsies of patients with DKD. Upregulated expression of α-SMA, TGF-β, FN and β-catenin and downregulated expression of CD31 were detected in the GECs of diabetic rats. The expression of these proteins was inhibited by treatment with C3aRA/C5aRA. In vitro, C3aRA/C5aRA and DKK1 ameliorated the high glucose-induced EndMT and the subsequent expression of α-SMA, TGFβ, FN and β-catenin in HRGECs. CONCLUSIONS The blockade of C3aR/C5aR and the downstream Wnt/β-catenin pathway may prevent EndMT and alleviate fibrosis in the glomeruli of individuals with DKD.

Association Between SLCO1B1 Gene T521C Polymorphism and Statin-Related Myopathy Risk: A Meta-Analysis of Case–Control Studies

Abstract Statin-related myopathy is an important adverse effect of statin which is classically unpredictable. The evidence of association between solute carrier organic anion transporter 1B1 (SLCO1B1) gene T521C polymorphism and statin-related myopathy risk remained controversial. This study aimed to investigate this genetic association. Databases of PubMed, EMBASE, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database, and Wanfang Data were searched till June 17, 2015. Case-control studies investigating the association between SLCO1B1 gene T521C polymorphism and statin-related myopathy risk were included. The Newcastle–Ottawa Scale (NOS) was used for assessing the quality of included studies. Data were pooled by odds ratios (ORs) and their 95% confidence intervals (CIs). Nine studies with 1360 cases and 3082 controls were included. Cases of statin-related myopathy were found to be significantly associated with the variant C allele (TC + CC vs TT: OR = 2.09, 95% CI = 1.27–3.43, P = 0.003; C vs T: OR = 2.10, 95% CI = 1.43–3.09, P < 0.001), especially when statin-related myopathy was defined as an elevation of creatine kinase (CK) >10 times the upper limit of normal (ULN) or rhabdomyolysis (TC + CC vs TT: OR = 3.83, 95% CI = 1.41–10.39, P = 0.008; C vs T: OR = 2.94, 95% CI = 1.47–5.89, P = 0.002). When stratified by statin type, the association was significant in individuals receiving simvastatin (TC + CC vs TT: OR = 3.09, 95% CI = 1.64–5.85, P = 0.001; C vs T: OR = 3.00, 95% CI = 1.38–6.49, P = 0.005), but not in those receiving atorvastatin (TC + CC vs TT: OR = 1.31, 95% CI = 0.74–2.30, P = 0.35; C vs T: OR = 1.33, 95% CI = 0.57–3.12, P = 0.52). The available evidence suggests that SLCO1B1 gene T521C polymorphism is associated with an increased risk of statin-related myopathy, especially in individuals receiving simvastatin. Thus, a genetic test before initiation of statins may be meaningful for personalizing the treatment.

Risk factors of earthquake inpatient death: a case control study

IntroductionAt 2:28 p.m. on 12 May, 2008, a devastating earthquake measuring 8.0 on the Richter scale hit Wenchuan County, Sichuan Province in southwest China, and resulted in the deaths of thousands of people. To date, few epidemiological studies have been conducted on the determinants of the mortality of patients hospitalised after an earthquake. This paper is aimed at identifying the contributing factors of mortality and providing a clinical reference for the management of those injured in earthquakes.MethodsA hospital-based case-control study was conducted. Cases included all deaths (n = 36) due to earthquake injuries in the West China Hospital. Controls were the quake survivors from the same hospital by at a ratio of four survivors to one death matched for sex and age. Data sources included death certificates and medical records. A conditional logistic regression was performed to assess the odds ratio (OR) of variables used in the study. A chi-squared test for trend was performed to reveal the possible relations between risk factor (variable) number and case fatality.ResultsPeople with a severe traumatic brain injury (TBI) had the greatest risk of death (adjusted OR = 253.3, 95% confidence interval (CI) = 8.9 to 7208.6), followed by patients with multiple system organ failure (MSOF; adjusted OR = 87.8, 95% CI = 3.9 to 1928.3). Prior major disease and infection significantly increased the risk of earthquake-related death (adjusted OR = 14.9, 95% CI = 1.9 to 119.0; adjusted OR = 13.7, 95% CI = 1.8 to 103.7; respectively). The number of fatal cases increased as the risk factor numbers also increased.ConclusionsSevere TBI, infection, MSOF and prior major disease are the significant determinants of earthquake-related inpatient death in the 2008 Wenchuan earthquake. Future research with a large sample size including macro- and micro-level factors is needed.

C3a Receptor Antagonist Ameliorates Inflammatory and Fibrotic Signals in Type 2 Diabetic Nephropathy by Suppressing the Activation of TGF-β/smad3 and IKBα Pathway

Objective Diabetic nephropathy (DN) is a serious complication for patients with diabetes mellitus (DM). Emerging evidence suggests that complement C3a is involved in the progression of DN. The aim of this study was to investigate the effect of C3a Receptor Agonist (C3aRA) on DN and its potential mechanism of action in rats with type 2 diabetes mellitus (T2DM). Methods T2DM was induced in SD rats by a high fat diet (HFD) plus repeated low dose streptozocin (STZ) injections. T2DM rats were treated with vehicle or C3aRA for 8 weeks. Biochemical analysis, HE and PAS stains were performed to evaluate the renal function and pathological changes. Human renal glomerular endothelial cells (HRGECs) were cultured and treated with normal glucose (NG), high glucose (HG), HG+C3a, HG+C3a+C3aRA and HG+C3a+BAY-11-7082 (p-IKBα Inhibitor) or SIS3 (Smad3 Inhibitor), respectively. Real-time PCR, immunofluorescent staining and western blot were performed to detect the mRNA and protein levels, respectively. Results T2DM rats showed worse renal morphology and impaired renal function compared with control rats, including elevated levels of serum creatinine (CREA), blood urea nitrogen (BUN) and urine albumin excretion (UACR), as well as increased levels of C3a, C3aR, IL-6, p-IKBα, collagen I, TGF-β and p-Smad3 in the kidney of T2DM rats and C3a-treated HRGECs. In contrast, C3aRA treatment improved renal function and morphology, reduced CREA, UACR and the intensity of PAS and collagen I staining in the kidney of T2DM rats, and decreased C3a, p-IKBα, IL-6, TGF-β, p-Smad3 and collagen I expressions in HRGECs and T2DM rats. Conclusion C3a mediated pro-inflammatory and pro-fibrotic responses and aggravated renal injury in T2DM rats. C3aRA ameliorated T2DN by inhibiting IKBα phosphorylation and cytokine release, and also TGF-β/Smad3 signaling and ECM deposition. Therefore, complement C3a receptor is a potential therapeutic target for DN.

Charlson comorbidity index helps predict the risk of mortality for patients with type 2 diabetic nephropathy

Our intent is to examine the predictive role of Charlson comorbidity index (CCI) on mortality of patients with type 2 diabetic nephropathy (DN). Based on the CCI score, the severity of comorbidity was categorized into three grades: mild, with CCI scores of 1–2; moderate, with CCI scores of 3–4; and severe, with CCI scores ≥5. Factors influencing mortality and differences between groups stratified by CCI were determined by logistical regression analysis and one-way analysis of variance (ANOVA). The impact of CCI on mortality was assessed by the Kaplan-Meier analysis. A total of 533 patients with type 2 DN were enrolled in this study, all of them had comorbidity (CCI score >1), and 44.7% (238/533) died. The mortality increased with CCI scores: 21.0% (50/238) patients with CCI scores of 1–2, 56.7% (135/238) patients with CCI scores of 3–4, and 22.3% (53/238) patients with CCI scores ≥5. Logistical regression analysis showed that CCI scores, hemoglobin, and serum albumin were the potential predictors of mortality (P<0.05). One-way ANOVA analysis showed that DN patients with higher CCI scores had lower levels of hemoglobulin, higher levels of serum creatinine, and higher mortality rates than those with lower CCI scores. The Kaplan-Meier curves showed that survival time decreased when the CCI scores and mortality rates went up. In conclusion, CCI provides a simple, readily applicable, and valid method for classifying comorbidities and predicting the mortality of type 2 DN. An increased awareness of the potential comorbidities in type 2 DN patients may provide insights into this complicated disease and improve the outcomes by identifying and treating patients earlier and more effectively.

The Metabolic Effects of Oats Intake in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

The present study aimed to comprehensively assess if oats intake is beneficial for diabetic patients. The literature search was conducted in PubMed database up to 23 August 2015. Fourteen controlled trials and two uncontrolled observational studies were included. Compared with the controls, oats intake significantly reduced the concentrations of glycosylated hemoglobin A1c (HbA1c) (MD, −0.42%; 95% CI, −0.61% to −0.23%), fasting blood glucose (FBG) (MD, −0.39 mmol/L; 95% CI, −0.58 to −0.19 mmol/L), total cholesterol (TC) (MD, −0.49 mmol/L; 95% CI, −0.86 to −0.12 mmol/L), low-density lipoprotein cholesterol (LDL-C) (MD, −0.29 mmol/L; 95% CI, −0.48 to −0.09 mmol/L). Oatmeal significantly reduced the acute postprandial glucose and insulin responses compared with the control meal. The present study has revealed a beneficial effect of oats intake on glucose control and lipid profiles in type 2 diabetic patients. Further investigations of oats intake in patients with type 1 diabetes and the safety of oats consumption are required.

Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective Acetyl-L-carnitine (ALC), a constructive molecule in fatty acid metabolism, is an agent potentially effective for treating peripheral neuropathic pain (PNP). Its effect, however, remains uncertain. We aimed to access the efficacy and safety of ALC for the treatment of patients with PNP. Methods We searched MEDLINE (1996–2014), EMBase (1974–2014), and CENTRAL (May 2014) up to June 27, 2014 for randomized controlled trials (RCTs) comparing ALC with placebo or other active medications in diabetic and non-diabetic PNP patients that reported the change of pain using visual analogue scale (VAS). Mean difference (MD) and 95% confidence interval (CI) were used for pooling continuous data. Results Four RCTs comparing ALC with placebo and reporting in three articles (n = 523) were included. Compared with placebo, ALC significantly reduced VAS scores of PNP patients (MD of VAS, 1.20; 95% CI, 0.68-1.72, P <0.00001). In the subgroup analysis, the effect of ALC on VAS was similar in different administration routes (intramuscular-oral sequential subgroup: MD, 1.19; 95% CI, 0.34-2.04, P = 0.006; oral only subgroup: pooled MD, 1.15; 95%CI, 0.33-1.96, P = 0.006), and ALC appeared more effective in diabetic PNP patients than non-diabetic PNP patients (diabetic subgroup: MD, 1.47; 95%CI, 1.06-1.87, P <0.00001; non-diabetic subgroup: MD, 0.71; 95% CI, -0.01-1.43, P = 0.05). No severe adverse events were reported related to ALC. The common adverse events were pain, headache, paraesthesia, hyperesthesia, retching, biliary colic, and gastrointestinal disorders. The rates of total adverse events were similar in ALC and control group. Conclusion The current evidence suggests that ALC has a moderate effect in reducing pain measured on VAS in PNP patients with acceptable safety. Larger trials with longer follow-up, however, are warranted to establish the effects.