Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes.

IMPORTANCE Early-stage chronic kidney disease (CKD) characterized by microalbuminuria is associated with future cardiovascular events, progression toward end-stage renal disease, and early mortality in patients with type 2 diabetes.OBJECTIVE To compare the albuminuria-lowering effects of Roux-en-Y gastric bypass (RYGB) surgery vs best medical treatment in patients with early-stage CKD, type 2 diabetes, and obesity.DESIGN, SETTING, AND PARTICIPANTS For this randomized clinical trial, patients with established type 2 diabetes and microalbuminuria were recruited from a single center from April 1, 2013, through March 31, 2016, with a 5-year follow-up, including prespecified intermediate analysis at 24-month follow-up.INTERVENTION A total of 100 patients with type 2 diabetes, obesity (body mass indexes of 30 to 35 [calculated as weight in kilograms divided by height in meters squared]), and stage G1 to G3 and A2 to A3 CKD (urinary albumin-creatinine ratio [uACR] >30 mg/g and estimated glomerular filtration rate >30 mL/min) were randomized 1:1 to receive best medical treatment (n = 49) or RYGB (n = 51). MAIN OUTCOMES AND MEASURESThe primary outcome was remission of albuminuria (uACR <30 mg/g). Secondary outcomes were CKD remission rate, absolute change in uACR, metabolic control, other microvascular complications, quality of life, and safety.RESULTS A total of 100 patients (mean [SD] age, 51.4 [7.6] years; 55 [55%] male) were randomized: 51 to RYGB and 49 to best medical care. Remission of albuminuria occurred in 55% of patients (95% CI, 39%-70%) after best medical treatment and 82% of patients (95% CI, 72%-93%) after RYGB (P = .006), resulting in CKD remission rates of 48% (95% CI, 32%-64%) after best medical treatment and 82% (95% CI, 72%-92%) after RYGB (P = .002). The geometric mean uACRs were 55% lower after RYGB (10.7 mg/g of creatinine) than after best medical treatment (23.6 mg/g of creatinine) (P < .001). No difference in the rate of serious adverse events was observed. CONCLUSIONS AND RELEVANCEAfter 24 months, RYGB was more effective than best medical treatment for achieving remission of albuminuria and stage G1 to G3 and A2 to A3 CKD in patients with type 2 diabetes and obesity.

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Objective To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose. Design Systematic review and network meta-analysis of randomised trials. Data sources Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021. Eligibility criteria for selecting studies Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis. Outcomes and measures The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed. Review methods Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo. Results 192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%). Conclusions Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis. Systematic review registration PROSPERO number CRD42020213656