All LAMA/LABA FDCs were found to have similar efficacy and safety. Definitive assessment of the relative efficacy of different treatments can only be performed through direct comparison in head-to-head RCTs. In the absence of such data, this indirect comparison may be of value in clinical and health economic decision-making.

This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists. Correspondence to: M Underwood m.underwood@warwick.ac.uk For personal use only: See rights and reprints

Introduction Ertugliflozin is a new sodium-glucose co-transporter-2 inhibitor (SGLT2i) for the treatment of type 2 diabetes mellitus. As there are no head-to-head trials comparing the efficacy of SGLT2is, the primary objective of this analysis was to indirectly compare ertugliflozin to other SGLT2i in patient populations with inadequately controlled glycated hemoglobin (HbA1c > 7.0%) and previously treated with either diet/exercise, metformin alone or metformin plus a dipeptidyl peptidase-4 inhibitor (DPP4i). Methods A systematic literature review (SLR) identified randomized controlled trials (RCTs) reporting outcomes at 24–26 weeks of treatment. Comparators to ertugliflozin were the SGLT2is canagliflozin, dapagliflozin and empagliflozin, with non-SGLT2i comparators also evaluated third-line [insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)]. Outcomes were change from baseline in HbA1c, weight and systolic blood pressure (SBP) as well as HbA1c < 7% and key safety events. Bayesian network meta-analysis was used to synthesize evidence. Results are presented as the median of the mean difference (MD) or as odds ratios with 95% credible intervals (CrI). Results In patients uncontrolled on diet/exercise, the efficacy of ertugliflozin 5 mg monotherapy was not significantly different from that of other low-dose SGLT2is in terms of HbA1c reduction, while ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD − 0.36%, CrI − 0.65, − 0.08) and empagliflozin 25 mg (MD − 0.31%, CrI − 0.58, − 0.04). As add-on therapy to metformin, ertugliflozin 5 mg was more effective in lowering HbA1c than dapagliflozin 5 mg (MD − 0.22%, CrI − 0.42, − 0.02), and ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD − 0.26%, CrI − 0.46, − 0.06) and empagliflozin 25 mg (MD − 0.23%, CrI − 0.44, − 0.03). Among patients uncontrolled on combination therapy metformin plus a DPP4i, no relevant RCTs with insulin were identified from the SLR. One study with a GLP-1 RA was included in a sensitivity analysis due to limited data. There were no differences between ertugliflozin 5 or 15 mg and other SGLT2is, with the exception of dapagliflozin 10 mg, which was significantly less effective when added to sitagliptin and metformin. Overall, there were no other significant differences for remaining efficacy and safety outcomes except for a lower SBP for canagliflozin 300 mg compared to ertugliflozin 15 mg in the diet/exercise population. Conclusions Indirect comparisons for HbA1c reduction found that ertugliflozin 5 mg was more effective than dapagliflozin 5 mg when added to metformin monotherapy, whereas ertugliflozin 15 mg was more effective than dapagliflozin 10 mg and empagliflozin 25 mg when added to diet/exercise and to metformin monotherapy. The HbA1c reduction associated with ertugliflozin was no different than that associated with canagliflozin across all populations. Funding Mer...

BackgroundThis was an updated network meta-analysis (NMA) of anti-vascular endothelial growth factor (VEGF) agents and laser photocoagulation in patients with diabetic macular edema (DME). Unlike previous NMA that used meta-regression to account for potential confounding by systematic variation in treatment effect modifiers across studies, this update incorporated individual patient-level data (IPD) regression to provide more robust adjustment.MethodsAn updated review was conducted to identify randomised controlled trials for inclusion in a Bayesian NMA. The network included intravitreal aflibercept (IVT-AFL) 2 mg bimonthly (2q8) after 5 initial doses, ranibizumab 0.5 mg as-needed (PRN), ranibizumab 0.5 mg treat-and-extend (T&E), and laser photocoagulation. Outcomes included in the analysis were change in best-corrected visual acuity (BCVA), measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart, and patients with ≥10 and ≥ 15 ETDRS letter gains/losses at 12 months. Analyses were performed using networks restricted to IPD-only and IPD and aggregate data with (i) no covariable adjustment, (ii) covariable adjustment for baseline BVCA assuming common interaction effects (against reference treatment), and (iii) covariable adjustments specific to each treatment comparison (restricted to IPD-only network).ResultsThirteen trials were included in the analysis. IVT-AFL 2q8 was superior to laser in all analyses. IVT-AFL 2q8 showed strong evidence of superiority (95% credible interval [CrI] did not cross null) versus ranibizumab 0.5 mg PRN for mean change in BCVA (mean difference 5.20, 95% CrI 1.90–8.52 ETDRS letters), ≥15 ETDRS letter gain (odds ratio [OR] 2.30, 95% CrI 1.12–4.20), and ≥10 ETDRS letter loss (OR 0.25, 95% CrI 0.05–0.74) (IPD and aggregate random-effects model with baseline BCVA adjustment). IVT-AFL 2q8 was not superior to ranibizumab 0.5 mg T&E for mean change in BCVA (mean difference 5.15, 95% CrI -0.26–10.61 ETDRS letters) (IPD and aggregate random-effects model).ConclusionsThis NMA, which incorporated IPD to improve analytic robustness, showed evidence of superiority of IVT-AFL 2q8 to laser and ranibizumab 0.5 mg PRN. These results were irrespective of adjustment for baseline BCVA.Electronic supplementary materialThe online version of this article (10.1186/s12886-018-1006-9) contains supplementary material, which is available to authorized users.

5051 Background: In PROfound, olaparib demonstrated improved radiological PFS (rPFS) and overall survival (OS) versus new hormonal agent (NHA) in patients with homologous recombination repair mutated (HRRm) mCRPC that had progressed on prior NHA. This efficacy was observed across prespecified subgroups including patients treated with prior taxane therapy and for whom intravenous cabazitaxel is an alternative treatment option. The relative efficacy of olaparib versus cabazitaxel has not been assessed in head-to-head studies. An indirect treatment comparison (ITC) was performed to simulate the comparative efficacy of olaparib and cabazitaxel in patients with HRRm mCRPC after prior taxane and NHA. Methods: Fixed-effects frequentist ITCs were conducted using efficacy data from the prior taxane subgroup of PROfound (NCT02987543) and published data from the Phase IV CARD study of cabazitaxel versus NHA after prior NHA and taxane treatment (NCT02485691). Baseline variables feasible for comparison across studies were assessed for effect modification. Efficacy analyses were performed on the hazard ratios (HR) of rPFS by independent central review and OS. The OS analysis was performed using the final PROfound OS results, which included switching from NHA to olaparib after progression, and using results that were adjusted for switching. In the absence of biomarker subgroup data, the efficacy results of the overall population in CARD were assumed generalizable to the HRRm biomarker population of PROfound, such that mutation status is not a modifier of relative treatment effect for cabazitaxel versus NHA. Results were presented for the comparison of olaparib with cabazitaxel in the BRCA1-/BRCA2-mutated (BRCAm) and BRCAm/ATM populations. Results: The ITC HR for rPFS was 0.36 (95% confidence interval 0.20–0.64) in BRCAm and 0.51 (0.31–0.84) for the BRCAm/ATM population. Without adjustment for switching in PROfound, the ITC HRs for OS in the BRCAm population and BRCAm/ATM population were 0.99 (0.55–1.78) and 0.88 (0.52–1.47), respectively; after switch adjustment, the OS HRs were 0.47 (0.12–1.79) and 0.44 (0.17–1.10), respectively. Conclusions: The ITC results suggest that olaparib is associated with significantly improved rPFS versus cabazitaxel in the treatment of BRCAm and BRCAm/ATM patients who have progressed on taxane and NHA therapy. After removing the effect of switching from NHA to olaparib in PROfound, olaparib appears associated with a non-significant OS improvement versus cabazitaxel in both populations. The results require confirmation in comparative studies. Analysis limitations include uncertainty over the efficacy of cabazitaxel versus NHA in HRRm mCRPC patients, and heterogeneity in prior taxane and NHA therapy. Clinical trial information: NCT02987543.