Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes. METHODS: This randomised, double-blind, placebo-controlled, phase 3, superiority trial enrolled adults with a BMI of at least 30 kg/m2, or at least 27 kg/m2 with bodyweight-related complications and comorbidities, without type 2 diabetes. The trial was done at 50 outpatient clinics in nine countries across Asia, Europe, and North America. Participants were randomly allocated (1:1) via an interactive web-response system to oral semaglutide escalated to 50 mg, or visually matching placebo, once per day for 68 weeks, plus lifestyle intervention. Group assignment was masked for participants, investigators, and those assessing outcomes. Coprimary endpoints were the percentage change in bodyweight and whether participants reached a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg versus placebo, assessed regardless of treatment discontinuation or use of other bodyweight-lowering therapies (an intention-to-treat analysis). Safety was assessed in participants who received at least one dose of trial drug. This trial, registered with ClinicalTrials.gov (NCT05035095), is now complete. FINDINGS: From Sept 13 to Nov 22, 2021, 709 participants were screened, of whom 667 were randomly assigned to oral semaglutide 50 mg (n=334) or placebo (n=333). The estimated mean bodyweight change from baseline to week 68 was -15·1% (SE 0·5) with oral semaglutide 50 mg versus -2·4% (0·5) with placebo (estimated treatment difference -12·7 percentage points, 95% CI -14·2 to -11·3; p<0·0001). More participants reached bodyweight reductions of at least 5% (269 [85%] of 317 vs 76 [26%] of 295; odds ratio [OR] 12·6, 95% CI 8·5 to 18·7; p<0·0001), 10% (220 [69%] vs 35 [12%]; OR 14·7, 9·6 to 22·6), 15% (170 [54%] vs 17 [6%]; OR 17·9, 10·4 to 30·7), and 20% (107 [34%] vs 8 [3%]; OR 18·5, 8·8 to 38·9) at week 68 with oral semaglutide 50 mg versus placebo. Adverse events were more frequent with oral semaglutide 50 mg (307 [92%] of 334) than with placebo (285 [86%] of 333). Gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo. INTERPRETATION: In adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo. FUNDING: Novo Nordisk.

Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity.

OBJECTIVE: In the Semaglutide Treatment Effect in People with obesity (STEP) trials, once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention reduced body weight and improved cardiometabolic parameters in adults with obesity (or overweight with weight-related comorbidities). Effects on the risk of developing type 2 diabetes (T2D) require investigation. METHODS: STEP 1 (68 weeks) and 5 (104 weeks) randomized participants to semaglutide 2.4 mg or placebo. STEP 4 included a 20-week semaglutide run-in followed by randomization to 48 weeks of continued semaglutide or withdrawal (placebo). Ten-year T2D risk scores were calculated post hoc using Cardiometabolic Disease Staging. RESULTS: In STEP 1 (N = 1583), relative risk score reductions were greater with semaglutide versus placebo (semaglutide: -61.1%; placebo: -12.9%; p < 0.0001). These reductions were maintained to week 104 in STEP 5 (N = 295; semaglutide: -60.0%; placebo: 3.5%; p < 0.0001). Risk scores during the STEP 4 run-in period (N = 776) were reduced from 20.6% to 11.1% and further to 7.7% at week 68 with continued semaglutide, increasing to 15.4% with withdrawal (relative risk score change: semaglutide: -32.1%; placebo: +40.6%; p < 0.0001). Risk score reductions mirrored weight loss. CONCLUSIONS: Cardiometabolic Disease Staging risk assessment suggests that once-weekly semaglutide 2.4 mg may substantially lower 10-year T2D risk in people with overweight or obesity.

Importance of elevated heart rate in the very early phase of ST-segment elevation myocardial infarction: Results from the DANAMI-3 trial.

BACKGROUND: Elevated heart rate is associated with poor clinical outcome in patients with acute myocardial infarction. However, in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention the importance of elevated heart rate in the very early phase remains unknown. We evaluated the impact of elevated heart rate in the very early pre-hospital phase of ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention on cardiovascular magnetic resonance markers of reperfusion success and clinical outcome. METHODS: In this DANAMI-3 substudy, 1560 ST-segment elevation myocardial infarction patients in sinus rhythm without cardiogenic shock were included in the analyses of clinical outcome and 796 patients underwent cardiovascular magnetic resonance to evaluate area at risk, infarct size and left ventricular ejection fraction. Heart rate was assessed on the first electrocardiogram with ST-elevation (time of diagnosis). RESULTS: Despite equal area at risk (33%±11 versus 36%±16, p=0.174) patients with a pre-hospital heart rate ⩾100 beats per minute developed larger infarcts (19% (interquartile range, 9-17) versus 11% (interquartile range, 10-28), p=0.001) and a lower left ventricular ejection fraction (54%±12 versus 58%±9, p=0.047). Pre-hospital heart rate ⩾100 beats per minute was independently associated with an increased risk of all-cause mortality and heart failure (hazard ratio 2.39 (95% confidence interval 1.58-3.62), p<0.001). CONCLUSIONS: Very early heart rate ⩾100 beats per minute in ST-segment elevation myocardial infarction was independently associated with larger infarct size, reduced left ventricular ejection fraction and an increased risk of all-cause mortality and heart failure, and thus serves as an easily obtainable and powerful tool to identify ST-segment elevation myocardial infarction patients at high risk.

The role of fibrinogen: a new paradigm in the treatment of coagulopathic bleeding.

Fibrinogen is involved in both primary and secondary hemostasis, playing an important role in platelet aggregation and the establishment of a fibrin network. Recent evidence suggests that very high levels of fibrinogen act as antithrombin and can reduce endogenous thrombin potential and compromise clot stability, particularly following a low tissue factor stimulus. Several laboratory methods for measuring plasma fibrinogen concentrations are available, but results vary depending on the type of method and the use of artificial colloid plasma expanders. Adopting only the Clauss method can provide erroneously high levels when used in patients who have received colloid plasma expanders. This may contribute to a hazardous delay or complete lack of treatment. Multiple in vitro experiments, animal studies, and proof-of-principle randomized, clinical studies have recently suggested that hemostatic intervention with a fibrinogen concentrate may be efficient and safe in controling perioperative bleeding. In particular, fibrinogen concentrate has a key role in improving clotting function and reducing blood loss in settings such as trauma and cardiothoracic surgery. However, prospective studies are needed to determine the clinical efficacy and safety of fibrinogen concentrate when used as a hemostatic intervention for patients with massive bleeding due to trauma or surgery.