Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium-glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n 5 412) or empagliflozin 25 mg (n 5 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA 1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA 1c versus empagliflozin at week 26 (treatment policy-1.3% vs.-0.9% [-14 vs.-9 mmol/mol], estimated treatment difference [ETD]-0.4% [95% CI-0.6,-0.3] [-5 mmol/mol (-6,-3)]; P < 0.0001). The treatment difference in HbA 1c significantly favored oral semaglutide at week 26 for the trial product estimand (-1.4% vs.-0.9% [-15 vs.-9 mmol/mol], ETD-0.5% [95% CI-0.7,-0.4] [-6 mmol/mol (-7,-5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product 24.7 vs. 23.8 kg; P 5 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS Oral semaglutide was superior to empagliflozin in reducing HbA 1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA 1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.

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Objective— Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein stored in granules of neutrophil leukocytes participating in inflammatory and atherosclerotic processes and possibly plaque rupture. Despite the putative role of NGAL in atherosclerosis and acute myocardial infarction, human studies of plasma NGAL are still limited. Approach and Results— We prospectively followed 5599 randomly selected men and women from the community in the fourth Copenhagen Heart Study. Plasma NGAL was measured at study entry. Participants were followed for 10 years. During follow-up, 20% died (n=1120) and 15% (n=884) developed a major adverse cardiovascular event. Plasma NGAL associated strongly with all inflammatory markers (high-sensitivity C-reactive protein, total leukocyte count, neutrophil count) and inversely with estimated glomerular filtration rate (all, P <0.001). Multivariate analysis identified neutrophil leukocyte count as the main determinant of plasma NGAL. During follow-up, participants with increasing NGAL had increased risk of all-cause mortality and major adverse cardiovascular event (both, P <0.001). Even after adjustment for confounding risk factors by Cox regression analysis, NGAL remained an independent predictor of both all-cause mortality and major adverse cardiovascular event. When added to the Framingham risk score, NGAL improved c -statistics and correctly reclassified ≈15% into more appropriate risk groups. In comparison with high-sensitivity C-reactive protein, when both markers were added to the Framingham risk score, NGAL conferred 3× to 4× the risk. Conclusions— Plasma NGAL is strongly associated with inflammation in the general population. NGAL independently associated with 10-year outcome, and when added to the Framingham risk score, NGAL both improves c -statistics and correctly reclassifies participants into more accurate risk categories.