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1.5 and 2.1 yr for EXAMINE and SAVOR-TIMI 53]) found almost identical rates of hospital admission for heart failure in the sitagliptin and placebo groups.8 The potential safety issue that arose from SAVOR-TIMI 53 and EXAMINE led to the Food and Drug Administration’s (FDA) recommendation9 to consider discontinuing saxagliptin and alogliptin for patients if heart failure evolves. and required hospital admission. Pooled results suggested a 13% increase in heart failure (relative risk [RR] 1.13, 95% confidence interval [CI] 1.01-1.26, = 54?640, 1244 events). When including only the 3 large RCTs, the increase was similar, but not significant (RR 1.14, 95% CI 0.97-1.32; 3 RCTs, = 36?543, 1169 adjudicated events; number needed to harm 246) owing to heterogeneity (= 16?492 patients with a history of, or at risk for, cardiovascular events) unexpectedly found a significantly higher rate Mouse monoclonal to CD54.CT12 reacts withCD54, the 90 kDa intercellular adhesion molecule-1 (ICAM-1). CD54 is expressed at high levels on activated endothelial cells and at moderate levels on activated T lymphocytes, activated B lymphocytes and monocytes. ATL, and some solid tumor cells, also express CD54 rather strongly. CD54 is inducible on epithelial, fibroblastic and endothelial cells and is enhanced by cytokines such as TNF, IL-1 and IFN-g. CD54 acts as a receptor for Rhinovirus or RBCs infected with malarial parasite. CD11a/CD18 or CD11b/CD18 bind to CD54, resulting in an immune reaction and subsequent inflammation of heart Zinc Protoporphyrin failure requiring admission to hospital.4,5 The second was the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) (= 5380 patients post-acute coronary syndrome), which found a numerical but nonsignificantly higher rate of heart failure requiring hospital admission.6,7 In contrast, Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS) (= 14?735 patients with cardiovascular disease and longer follow-up [median 3. 0 yr v. 1.5 and 2.1 yr for EXAMINE and SAVOR-TIMI 53]) found almost identical rates of hospital admission for heart failure in the sitagliptin and placebo groups.8 The potential safety issue that arose from SAVOR-TIMI 53 and EXAMINE led to the Food and Drug Administration’s (FDA) recommendation9 to consider discontinuing saxagliptin and alogliptin for patients if heart failure develops. Given the apparent discrepant results from TECOS,3,10,11 we felt it Zinc Protoporphyrin was important to inform clinicians who are concerned about the potential increased heart failure signal by providing them with the totality of the available RCT evidence in the field. In addition, the publication of the Empagliflozin, Cardiovascular Outcomes, and Mortality in type 2 Diabetes [EMPA-REG OUTCOMES] trial,12 which shows that hopspital admission for heart failure was significantly reduced with the use of an oral antihyperglycemic agent of a different class, empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has increased the importance of quantifying the risk of increased heart failure for DPP-4 inhibitors. The 2 2 specific Zinc Protoporphyrin questions resolved by this systematic review and meta-analysis are whether DPP-4 inhibitors, as a class, compared with placebo or no therapy, increases heart failure in patients with type 2 diabetes, and whether you will find significant within-class differences. Methods Data sources and study selection We systematically searched MEDLINE and Embase (inception to August 2016) and ClinicalTrials.gov in duplicate for RCTs that compared treatment with any DPP-4 inhibitor with either placebo or no therapy (active comparator RCTs were excluded) and that enrolled adult patients with type 2 diabetes for at least 24 weeks. For multiple treatment group RCTs, we included only randomized groups in which treatments differed by DPP-4 inhibitor treatment. Groups with different DPP-4 inhibitor doses were combined within the same trial. Trials in which placebo groups were subsequently switched to open-label active therapy were only included if this switch occurred after 24 weeks of therapy. Data extraction and risk of bias assessment For each RCT, baseline patient characteristics, intervention, outcome definitions and events were collected in duplicate (discrepancies resolved by consensus). Risk of bias (individual, caregiver and end result assessor blinding; allocation concealment; intention-to-treat analysis; early stopping for benefit;13 loss to follow-up) were also assessed in duplicate.14 Data analysis In the primary analysis, we included all heart failure outcomes when listed either as a serious adverse event or adverse event. In 2 individual secondary analyses, we included only RCTs in which (1) cardiovascular outcomes were the primary end result, and (2) hospital admission for heart failure was an adjudicated main or secondary Zinc Protoporphyrin end result. Additional data analysis details, including sensitivity analysis, are provided in the online appendix (Appendix 1, available at www.cmajopen.ca/content/5/1/E152/suppl/DC1). We did not register or publish a review protocol. Results Search results We recognized 121 RCTs in which treatment between randomized groups differed only by DPP-4 inhibitor treatment. Of these, 11 RCTs outlined only on ClinicalTrials.gov provided no results (“type”:”clinical-trial”,”attrs”:”text”:”NCT00683735″,”term_id”:”NCT00683735″NCT00683735, “type”:”clinical-trial”,”attrs”:”text”:”NCT01356381″,”term_id”:”NCT01356381″NCT01356381, “type”:”clinical-trial”,”attrs”:”text”:”NCT01582230″,”term_id”:”NCT01582230″NCT01582230, “type”:”clinical-trial”,”attrs”:”text”:”NCT01697592″,”term_id”:”NCT01697592″NCT01697592, “type”:”clinical-trial”,”attrs”:”text”:”NCT01704261″,”term_id”:”NCT01704261″NCT01704261, “type”:”clinical-trial”,”attrs”:”text”:”NCT01792518″,”term_id”:”NCT01792518″NCT01792518, “type”:”clinical-trial”,”attrs”:”text”:”NCT01890122″,”term_id”:”NCT01890122″NCT01890122, “type”:”clinical-trial”,”attrs”:”text”:”NCT01990469″,”term_id”:”NCT01990469″NCT01990469, “type”:”clinical-trial”,”attrs”:”text”:”NCT02015299″,”term_id”:”NCT02015299″NCT02015299, “type”:”clinical-trial”,”attrs”:”text”:”NCT02099110″,”term_id”:”NCT02099110″NCT02099110, “type”:”clinical-trial”,”attrs”:”text”:”NCT02104804″,”term_id”:”NCT02104804″NCT02104804) and 10 RCT publications did not provide heart failure data,15-24 leaving 100 RCTs that reported the number of patients with heart failure (Appendix 1, Physique 1), which enrolled 79 867 patients into.

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