Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

Summary Background Anti‐tumour necrosis factor (TNF) agents are effective in Crohn's disease but some patients lose response and require alternative biologic therapy. There are few data on comparative effectiveness of vedolizumab and ustekinumab in this setting. Aim To compare the effectiveness of ustekinumab and vedolizumab in anti‐TNF‐refractory Crohn's disease over 12 months. Methods Patients commencing ustekinumab or vedolizumab for anti‐TNF‐refractory Crohn's disease with minimum follow‐up of 12 months were included. The primary outcome measure was the difference in steroid‐free remission rates at end of induction (2 months) and at 12 months. We also assessed rates of clinical response and remission, treatment persistence, surgery and adverse events in both groups. We performed logistic regression analysis to assess factors associated with steroid‐free remission and clinical response and remission. Results We included 85 patients commencing vedolizumab and 45 commencing ustekinumab. In an unadjusted model, rates of steroid‐free and clinical remission were significantly higher among ustekinumab‐treated patients. After adjusting for confounders, steroid‐free remission was higher among ustekinumab‐treated patients at 2 months (odds ratio, OR 2.79, 95% confidence interval, CI 1.06‐7.39, P = 0.038) and 12 months (OR 2.01, 95% CI 0.89‐4.56, P = 0.095). More patients treated with ustekinumab remained on therapy at the end of 12 months (84.4% vs 61.5%, P = 0.007). Conclusions Ustekinumab appeared more effective in treating anti‐TNF‐refractory Crohn's disease and more patients persisted with therapy.

Vedolizumab is an effective therapy for inducing and maintaining remission of IBD, with better results for UC, and with a good safety profile.

Background Intravenous (IV) infliximab is a well-established therapy for inflammatory bowel diseases (IBD) patients. A subcutaneous (SC) formulation of infliximab (CT-P13) has recently been shown to be as effective as IV infliximab after 2 doses of IV induction in a randomised trial but there are no data to support elective switching of patients on maintenance IV infliximab therapy. We aimed to assess the effectiveness of an elective switching program to SC CT-P13 in patients treated with IV infliximab. Methods Patients on established maintenance IV infliximab who switched to SC CT-P13 were included in this retrospective multi-centre cohort study. Disease activity was monitored serially with Harvey-Bradshaw Index (HBI) for Crohn’s disease (CD) and simple clinical colitis activity index (SCCAI) for up to 12 months at months 3, 6 and 12. Faecal calprotectin (FC) and C-reactive protein (CRP) was recorded at baseline and follow-up, if available. Infliximab trough levels were measured prior to switch and at months 3, 6 and 12 following switch. The primary outcome measure was treatment persistence at last follow-up. Secondary outcome measures included infliximab pharmacokinetics (PK), safety, need for corticosteroid rescue therapy and need for surgery. Results We included 181 patients of who 115 (63.5%) had CD. The majority (72.4%) were on 8-weekly dosing of intravenous infliximab prior to switching and more than half (59.1%) were on concomitant immunomodulatory therapy. The majority of patients (CD: N=106, 92.2%, UC: N=46, 76.7% and IBD-U: N=5, 83.3%) were in clinical remission. Treatment persistence rate was high (N=167, 92.3%) and only 14 patients (7.7%) stopped treatment during the follow-up period. There was no significant difference between baseline and repeat measurements at 3, 6 or 12 months for HBI, SCCAI, CRP or FC. Of the total cohort, 25 patients (21.7%) had perianal CD. Of these, only two patients (8%) had worsening of perianal CD and required antibiotic therapy and further examination under anaesthesia (EUA). Both these patients also switched back to intravenous infliximab. Median infliximab level increased from a baseline of 8.9 µg/dl (range 0.4-16) to 16.0 µg/dl (range 2.3-16, P&lt;0.001) at 3 months. Serum levels stayed stable at 6 months (median 16 µg/dl, range 0.3-17.2) and 12 months (median 16 µg/dl, range 0.3-19.1, both P&lt;0.001 compared to baseline). Among the variables examined, only antibodies to infliximab (ATI) was associated with infliximab levels (OR -13.369, 95% CI -15.405, -11.333, P&lt;0.001). A total of 14 patients (7.7%) developed ATI of which 9 (64.3%) were on concomitant immunomodulatory therapy. Immunomodulatory therapy was not significantly associated with development of ATI (P=0.15). In a subset of patients receiving escalated IV infliximab dosing frequency prior to switch, no difference in treatment persistence was observed in patients receiving weekly versus alternate weekly SC CT-P13. Patient acceptance and satisfaction rates with SC CT-P13 were very high. Conclusions Among patients on IV infliximab maintenance therapy switched to SC CT-P13, we observed high treatment persistence rates and low rates of immunogenicity with no change in clinical disease activity indices or biomarkers. Infliximab levels increased after switch to SC CT-P13 and only ATI was associated with serum infliximab levels. Patient acceptance and satisfaction rates were high with SC CT-P13.

Background:The optimal choice of biological agents after failure of anti-tumournecrosis-factor-(TNF)α agent in Crohn's disease (CD) is yet to be defined. Aims:To assess the effectiveness and safety of ustekinumab compared to vedolizumab as second-line treatment in CD patients who failed anti-TNFα therapy.Methods: Retrospective analysis of clinical response and remission at 14 and 52 weeks to ustekinumab by physician global assessment (PGA). A propensity scorematched analysis with a cohort treated with vedolizumab was performed.Results: Of 282 patients (mean age 40 ± 15, F:M ratio 1.7:1) treated with ustekinumab, clinical response or remission was reached by 200/282 patients (70.9%) at 14 weeks, and 162/259 patients (62.5%) at 52 weeks. Overall, 74 adverse events occurred, of which 26 were labelled as serious (8.3 per 100 person-year). After exclusion of patients without prior anti-TNFα exposure and patients previously exposed to vedolizumab or ustekinumab, we analysed 275/282 patients (97.5%) on ustekinumab and 118/135 patients (87.4%) on vedolizumab. Propensity score analysis revealed that at 14 weeks, patients treated with ustekinumab were 38% (95% CI 25%-50%; P < 0.001) more likely to achieve clinical remission, while at 52 weeks, the difference of 9% (95% CI −15% to 33%; P = 0.462) was not significant. Conclusions:Ustekinumab was effective and well tolerated in this real-world cohort.While ustekinumab proved more effective at 14-weeks, we found no statistically significant differences at 52 weeks compared to vedolizumab.