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

Sex Differences in the Effectiveness of Angiotensin‐Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Sacubitril–Valsartan for the Treatment of Heart Failure

Background PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) suggested a potential benefit of sacubitril–valsartan in women with preserved ejection fraction. Among patients with heart failure previously treated with angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), we studied whether effectiveness of treatment with sacubitril–valsartan compared with ACEI/ARB monotherapy differed between men and women for both preserved and reduced ejection fraction. Methods and Results Data were derived from the Truven Health MarketScan Databases between January 1, 2011, and December 31, 2018. We included patients with a primary diagnosis of heart failure on treatment with ACEIs, ARBs, or sacubitril–valsartan on the basis of the first prescription after diagnosis. A total of 7181 patients treated with sacubitril–valsartan, 25 408 patients using an ACEI, and 16 177 patients treated with ARBs were included. A total of 790 readmissions or deaths occurred among 7181 patients in the sacubitril–valsartan group and 11 901 events in 41 585 patients treated with an ACEI/ARB. Adjusted for covariates, the hazard ratio (HR) for treatment with sacubitril–valsartan compared with an ACEI or ARB was 0.74 (95% CI, 0.68–0.80). The protective effect of sacubitril–valsartan was evident for men and women (women: HR, 0.75 [95% CI, 0.66–0.86]; P<0.01; men: HR, 0.71 [95% CI, 0.64–0.79]; P<0.01; P interaction 0.03). A protective effect for both sexes was seen only among those with systolic dysfunction. Conclusions Treatment with sacubitril–valsartan is more effective at reducing death and admission to the hospital for heart failure compared with ACEIs/ARBs similarly among men and women with systolic dysfunction; sex differences in the effectiveness of sacubitril–valsartan in diastolic dysfunction requires further investigation

Should We Have Blind Faith in Bioinformatics Software? Illustrations from the SNAP Web-Based Tool

<div><p>Bioinformatics tools have gained popularity in biology but little is known about their validity. We aimed to assess the early contribution of 415 single nucleotide polymorphisms (SNPs) associated with eight cardio-metabolic traits at the genome-wide significance level in adults in the Family Atherosclerosis Monitoring In earLY Life (FAMILY) birth cohort. We used the popular web-based tool SNAP to assess the availability of the 415 SNPs in the Illumina Cardio-Metabochip genotyped in the FAMILY study participants. We then compared the SNAP output with the Cardio-Metabochip file provided by Illumina using chromosome and chromosomal positions of SNPs from NCBI Human Genome Browser (Genome Reference Consortium Human Build 37). With the HapMap 3 release 2 reference, 201 out of 415 SNPs were reported as missing in the Cardio-Metabochip by the SNAP output. However, the Cardio-Metabochip file revealed that 152 of these 201 SNPs were in fact present in the Cardio-Metabochip array (false negative rate of 36.6%). With the more recent 1000 Genomes Project release, we found a false-negative rate of 17.6% by comparing the outputs of SNAP and the Illumina product file. We did not find any ‘false positive’ SNPs (SNPs specified as available in the Cardio-Metabochip by SNAP, but not by the Cardio-Metabochip Illumina file). The Cohen’s Kappa coefficient, which calculates the percentage of agreement between both methods, indicated that the validity of SNAP was fair to moderate depending on the reference used (the HapMap 3 or 1000 Genomes). In conclusion, we demonstrate that the SNAP outputs for the Cardio-Metabochip are invalid. This study illustrates the importance of systematically assessing the validity of bioinformatics tools in an independent manner. We propose a series of guidelines to improve practices in the fast-moving field of bioinformatics software implementation.</p></div

Summary of discordances between outputs from SNAP (the HapMap 3 reference) and the Illumina Cardio-Metabochip file.

<p>Summary of discordances between outputs from SNAP (the HapMap 3 reference) and the Illumina Cardio-Metabochip file.</p

Summary of discordances between outputs from SNAP (the 1000 Genomes reference) and the Illumina Cardio-Metabochip file.

<p>Summary of discordances between outputs from SNAP (the 1000 Genomes reference) and the Illumina Cardio-Metabochip file.</p

Phenotype characteristics at baseline of the participants involved in the present study.

<p>Phenotype characteristics at baseline of the participants involved in the present study.</p

Risk Alleles in/near <i>ADCY5</i>, <i>ADRA2A</i>, <i>CDKAL1</i>, <i>CDKN2A/B</i>, <i>GRB10</i>, and <i>TCF7L2</i> Elevate Plasma Glucose Levels at Birth and in Early Childhood: Results from the FAMILY Study

<div><p>Background</p><p>Metabolic abnormalities that lead to type 2 diabetes mellitus begin in early childhood.</p><p>Objectives</p><p>We investigate whether common genetic variants identified in adults have an effect on glucose in early life.</p><p>Methods</p><p>610 newborns, 463 mothers, and 366 fathers were included in the present study. Plasma glucose and anthropometric characteristics were collected at birth, 3, and 5 years. After quality assessment, 37 SNPs, which have demonstrated an association with fasting plasma glucose at the genome-wide threshold in adults, were studied. Quantitative trait disequilibrium tests and mixed-effects regressions were conducted to estimate an effect of the SNPs on glucose.</p><p>Results</p><p>Risk alleles for 6 loci increased glucose levels from birth to 5 years of age (<i>ADCY5</i>, <i>ADRA2A</i>, <i>CDKAL1</i>, <i>CDKN2A/B</i>, <i>GRB10</i>, and <i>TCF7L2</i>, 4.85x10^-3 ≤ <i>P</i> ≤ 4.60x10^-2). Together, these 6 SNPs increase glucose by 0.05 mmol/L for each risk allele in a genotype score (<i>P</i> = 6.33x10^-5). None of the associations described in the present study have been reported previously in early childhood.</p><p>Conclusion</p><p>Our data support the notion that a subset of loci contributing to plasma glucose variation in adults has an effect at birth and in early life.</p></div

SNPs associated with plasma glucose in children using mixed-effects regression.

<p>SNPs associated with plasma glucose in children using mixed-effects regression.</p

Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies

Background: The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. We therefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure or hospitalization for heart failure in patients with type 2 diabetes. Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addressed the effect of GLP-1 receptor agonists in adults with type 2 diabetes, and explicitly reported heart failure or hospitalization for heart failure. Two paired reviewers screened reports, collected data, and assessed the risk of bias. We pooled data from RCTs and observational studies separately, and used the GRADE approach to rate the quality of evidence. Results: We identified 25 studies that were eligible for our review; 21 RCTs (n = 18,270) and 4 observational studies (n = 111,029). Low quality evidence from 20 RCTs suggested, if anything, a lower incidence of heart failure between GLP-1 agonists versus control (17/7,441 vs. 19/4,317; odds ratio (OR) 0.62, 95 % confidence interval (CI) 0.31 to 1.22; risk difference (RD) 19 fewer, 95 % CI 34 fewer to 11 more per 1000 over 5 years). Three cohort studies comparing GLP-1 agonists to alternative agents provided very low quality evidence that GLP-1 agonists do not increase the incidence of heart failure. One RCT provided moderate quality evidence that GLP-1 agonists were not associated with hospitalization for heart failure (lixisenatide vs placebo: 122/3,034 vs. 127/3,034; adjusted hazard ratio 0.96, 95 % CI 0.75 to 1.23; RD 4 fewer, 95 % CI 25 fewer to 23 more per 1000 over 5 years) and a case–control study provided very low quality evidence also suggesting no association (GLP-1 agonists vs. other anti-hyperglycemic drugs: 1118 cases and 17,626 controls, adjusted OR 0.67, 95 % CI 0.32 to 1.42). Conclusions: The current evidence suggests that GLP-1 agonists do not increase the risk of heart failure or hospitalization for heart failure among patients with type 2 diabetes.Medicine, Faculty ofNon UBCMedicine, Department ofReviewedFacult

Glucagon-like peptide-1 receptor agonists and heart failure in type 2 diabetes: systematic review and meta-analysis of randomized and observational studies

Abstract Background The effect of glucagon-like peptide-1(GLP-1) receptor agonists on heart failure remains uncertain. We therefore conducted a systematic review to assess the possible impact of GLP-1 agonists on heart failure or hospitalization for heart failure in patients with type 2 diabetes. Methods We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov to identify randomized controlled trials (RCTs) and observational studies that addressed the effect of GLP-1 receptor agonists in adults with type 2 diabetes, and explicitly reported heart failure or hospitalization for heart failure. Two paired reviewers screened reports, collected data, and assessed the risk of bias. We pooled data from RCTs and observational studies separately, and used the GRADE approach to rate the quality of evidence. Results We identified 25 studies that were eligible for our review; 21 RCTs (n = 18,270) and 4 observational studies (n = 111,029). Low quality evidence from 20 RCTs suggested, if anything, a lower incidence of heart failure between GLP-1 agonists versus control (17/7,441 vs. 19/4,317; odds ratio (OR) 0.62, 95 % confidence interval (CI) 0.31 to 1.22; risk difference (RD) 19 fewer, 95 % CI 34 fewer to 11 more per 1000 over 5 years). Three cohort studies comparing GLP-1 agonists to alternative agents provided very low quality evidence that GLP-1 agonists do not increase the incidence of heart failure. One RCT provided moderate quality evidence that GLP-1 agonists were not associated with hospitalization for heart failure (lixisenatide vs placebo: 122/3,034 vs. 127/3,034; adjusted hazard ratio 0.96, 95 % CI 0.75 to 1.23; RD 4 fewer, 95 % CI 25 fewer to 23 more per 1000 over 5 years) and a case–control study provided very low quality evidence also suggesting no association (GLP-1 agonists vs. other anti-hyperglycemic drugs: 1118 cases and 17,626 controls, adjusted OR 0.67, 95 % CI 0.32 to 1.42). Conclusions The current evidence suggests that GLP-1 agonists do not increase the risk of heart failure or hospitalization for heart failure among patients with type 2 diabetes