Effects of Semaglutide on Albuminuria and Kidney Function in People With Overweight or Obesity With or Without Type 2 Diabetes: Exploratory Analysis From the STEP 1, 2, and 3 Trials.

OBJECTIVE: These post hoc analyses of the Semaglutide Treatment Effect in People with obesity (STEP) 1-3 trials (NCT03548935, NCT03552757, and NCT03611582) explored the effects of semaglutide (up to 2.4 mg) on kidney function. RESEARCH DESIGN AND METHODS: STEP 1-3 included adults with overweight/obesity; STEP 2 patients also had type 2 diabetes. Participants received once-weekly subcutaneous semaglutide 1.0 mg (STEP 2 only), 2.4 mg, or placebo for 68 weeks, plus lifestyle intervention (STEP 1 and 2) or intensive behavioral therapy (STEP 3). Changes in urine albumin-to-creatinine ratio (UACR) and UACR status from baseline to week 68 were assessed for STEP 2. Changes in estimated glomerular filtration rate (eGFR) were assessed from pooled STEP 1-3 data. RESULTS: In STEP 2, 1,205 (99.6% total cohort) patients had UACR data; geometric mean baseline UACR was 13.7, 12.5, and 13.2 mg/g with semaglutide 1.0 mg, 2.4 mg, and placebo, respectively. At week 68, UACR changes were -14.8% and -20.6% with semaglutide 1.0 mg and 2.4 mg, respectively, and +18.3% with placebo (between-group differences [95% CI] vs. placebo: -28.0% [-37.3, -17.3], P < 0.0001 for semaglutide 1.0 mg; -32.9% [-41.6, -23.0], P = 0.003 for semaglutide 2.4 mg). UACR status improved in greater proportions of patients with semaglutide 1.0 mg and 2.4 mg versus placebo (P = 0.0004 and P = 0.0014, respectively). In the pooled STEP 1-3 analyses, 3,379 participants had eGFR data; there was no difference between semaglutide 2.4 mg and placebo in eGFR trajectories at week 68. CONCLUSIONS: Semaglutide improved UACR in adults with overweight/obesity and type 2 diabetes. In participants with normal kidney function, semaglutide did not have an effect on eGFR decline.

Two-year effect of semaglutide 2.4 mg on control of eating in adults with overweight/obesity: STEP 5.

OBJECTIVE: This study evaluated the effect of once-weekly semaglutide 2.4 mg on 2-year control of eating. METHODS: In STEP 5, adults with overweight/obesity were randomized 1:1 to semaglutide 2.4 mg or placebo, plus lifestyle modification, for 104 weeks. A 19-item Control of Eating Questionnaire was administered at weeks 0, 20, 52, and 104 in a subgroup of participants. P values were not controlled for multiplicity. RESULTS: In participants completing the Control of Eating Questionnaire (semaglutide, n = 88; placebo, n = 86), mean body weight changes were -14.8% (semaglutide) and -2.4% (placebo). Scores significantly improved with semaglutide versus placebo for Craving Control and Craving for Savory domains at weeks 20, 52, and 104 (p < 0.01); for Positive Mood and Craving for Sweet domains at weeks 20 and 52 (p < 0.05); and for hunger and fullness at week 20 (p < 0.001). Improvements in craving domain scores were positively correlated with reductions in body weight from baseline to week 104 with semaglutide. At 104 weeks, scores for desire to eat salty and spicy food, cravings for dairy and starchy foods, difficulty in resisting cravings, and control of eating were significantly reduced with semaglutide versus placebo (all p < 0.05). CONCLUSIONS: In adults with overweight/obesity, semaglutide 2.4 mg improved short- and longer-term control of eating associated with substantial weight loss.

Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): Exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials.

Background: Inflammation is a key driver of atherosclerotic cardiovascular disease. C-reactive protein (CRP), an established biomarker of inflammation, is commonly elevated in people with overweight/obesity. Methods: STEP 1, 2, and 3 were 68-week, placebo-controlled trials of semaglutide for weight management in participants with overweight/obesity, with (STEP 2) or without (STEP 1 and 3) type 2 diabetes. Change in serum CRP from baseline to week 68 was assessed as a prespecified secondary endpoint for semaglutide 2.4 mg versus placebo (STEP 1, 2, and 3) and versus semaglutide 1.0 mg (STEP 2). Post hoc assessments included change in CRP by baseline characteristics (bodyweight, body mass index [BMI], glycaemic status, CRP concentration); change in CRP-defined cardiovascular risk category (<1 [low], 1-3 [intermediate], and >3 mg/L [high]); and correlation between change in CRP and change in bodyweight, waist circumference, fasting serum insulin (STEP 1 and 3), fasting plasma glucose, and homeostatic model assessment of insulin resistance (HOMA-IR). Findings: The trials took place from June through November 2018 (STEP 1 and 2) and from August 2018 to April 2020 (STEP 3). In all trials, semaglutide 2.4 mg reduced CRP at week 68 versus placebo (estimated treatment difference [ETD; 95% CI] -44% [-49 to -39] in STEP 1, -39% [-46 to -30] in STEP 2, and -48% [-55 to -39] in STEP 3; all p < 0.05). In STEP 2, CRP reductions were greater with semaglutide 2.4 mg (-49%) than with 1.0 mg (-42%) but the difference did not reach statistical significance (ETD [95% CI] -12% [-23 to 1]; p = 0.06). Reductions in CRP occurred in parallel with bodyweight loss and were consistent regardless of baseline BMI/bodyweight/glycaemic status. More semaglutide-treated participants had reductions in CRP-defined cardiovascular risk versus those on placebo. Reductions in CRP were positively correlated with reductions in bodyweight, waist circumference, fasting plasma glucose, fasting serum insulin, and HOMA-IR (data not shown). Interpretation: In people with overweight/obesity, once-weekly semaglutide 2.4 mg and 1.0 mg reduced CRP concentration irrespective of baseline BMI/bodyweight/glycaemic status compared with placebo. These data suggest a potential anti-inflammatory role of semaglutide in obesity. Funding: Novo Nordisk.

Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial.

The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m-2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was -15.2% in the semaglutide group (n = 152) versus -2.6% with placebo (n = 152), for an estimated treatment difference of -12.6 %-points (95% confidence interval, -15.3 to -9.8; P < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P < 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430.

Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.

AIM: To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension. MATERIALS AND METHODS: STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory. RESULTS: Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables. CONCLUSIONS: One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.

Efficacy of a glucagon-like peptide-1 agonist and restrictive versus liberal oxygen supply in patients undergoing coronary artery bypass grafting or aortic valve replacement: study protocol for a 2-by-2 factorial designed, randomised clinical trial.

INTRODUCTION: Coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) are associated with risk of death, as well as brain, heart and kidney injury. Glucagon-like peptide-1 (GLP-1) analogues are approved for treatment of type 2 diabetes, and GLP-1 analogues have been suggested to have potential organ-protective and anti-inflammatory effects. During cardiopulmonary bypass (CPB), consensus on the optimal fraction of oxygen is lacking. The objective of this study is to determine the efficacy of the GLP-1-analogue exenatide versus placebo and restrictive oxygenation (50% fractional inspired oxygen, FiO2) versus liberal oxygenation (100% FiO2) in patients undergoing open heart surgery. METHODS AND ANALYSIS: A randomised, placebo-controlled, double blind (for the exenatide intervention)/single blind (for the oxygenation strategy), 2×2 factorial designed single-centre trial on adult patients undergoing elective or subacute CABG and/or surgical AVR. Patients will be randomised in a 1:1 and 1:1 ratio to a 6-hour and 15 min infusion of 17.4 µg of exenatide or placebo during CPB and to a FiO2 of 50% or 100% during and after weaning from CPB. Patients will be followed until 12 months after inclusion of the last participant. The primary composite endpoint consists of time to first event of death, renal failure requiring renal replacement therapy, hospitalisation for stroke or heart failure. In addition, the trial will include predefined sub-studies applying more advanced measures of cardiac- and pulmonary dysfunction, renal dysfunction and cerebral dysfunction. The trial is event driven and aims at 323 primary endpoints with a projected inclusion of 1400 patients. ETHICS AND DISSEMINATION: Eligible patients will provide informed, written consent prior to randomisation. The trial is approved by the local ethics committee and is conducted in accordance with Danish legislation and the Declaration of Helsinki. The results will be presented in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02673931.

Reoperation for bleeding in an elective cardiac surgical population - Does it affect survival?

Introduction: Earlier studies have shown that re-operation for bleeding after cardiac surgery is associated with increased mortality and morbidity in both acute and elective patients. The aim of the study was to assess the effect of re-operation for bleeding on short- and long-term survival and the causes of re-operation on an exclusively elective population. Methods: This was a single-center, retrospective study conducted at the Department of Cardiothoracic Surgery at Copenhagen University Hospital. Rigshospitalet, Denmark. We included all elective patients undergoing first-time coronary bypass, valve surgery or combinations hereof between January 1998 and February 2014. Data was obtained from the electronic patient records on demographics, cardiological risk profile, blood transfusion and surgical record. Results: A total of 11813 patients were included in the analysis of whom 626 (5.3%) patients underwent re-operation for bleeding. Patients were divided into two groups; non re-operated (NRO) and re-operated(RO). Baseline characteristics were comparable. Median survival was lover in the RO group (142 vs 160months (P = 0.001)). Morbidity and 30 day mortality was significantly higher in the RO group. Cox-regression analysis showed a significantly increased age-adjusted risk of death in the RO group (HR 1.21(1.07-1.37). P = 0.003). In 85% of the patients the site of bleeding was found during the re-operation. Conclusion: We found both short and long-term survival to be lower in the RO group. A surgical cause for re-operation was found in the majority of cases. The study shows the importance of meticulous hemostasis during cardiac surgery.

Association between transfusion of blood products and acute kidney injury following cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is a serious complication following cardiac surgery associated with increased mortality. Red blood cell transfusion enhances the risk of developing AKI. However, the impact of other blood products on AKI is virtually unexplored. The aim of this study was to explore if transfusion of red blood cells, fresh frozen plasma and platelets alone or in combination were associated with postoperative AKI. METHODS: Patients undergoing elective on-pump cardiac surgery were included (n = 1960) between 2012 to 2014. Transfusion data were collected intraoperatively and until the first postoperative day. AKI was classified according to the KDIGO criteria. Data were analysed using univariate and stepwise multiple logistic regression with adjustment for clinical risk factors and complementary blood products. RESULTS: AKI was observed in 542 patients (27.7%). In univariate analysis and following adjustment for clinical risk factors, administration of red blood cells, freshfrozen plasma and platelets were all independently associated with KDIGO stage 2-3. Following additional adjustment for complementary blood products, only red blood cell transfusion remained significantly associated with AKI. A dose-dependent association between volume of red blood cells and degree of AKI severity was observed. CONCLUSION: Transfusion of all blood products in a dose-dependent manner increased the risk for AKI. However, in multivariate analysis combining all blood products, only red blood cell transfusion remained significantly associated with AKI development.

Duration of critically low oxygen delivery is associated with acute kidney injury after cardiac surgery.

BACKGROUND: Acute kidney injury is a serious complication following cardiac surgery associated with mortality. Restricted oxygen delivery is a potential risk factor for acute kidney injury. The aim of this study was to investigate the impact of the duration of low oxygen delivery (<272 mL  min-1  m-2 ), during cardiopulmonary bypass on kidney function. METHODS: Patients undergoing coronary artery bypass graft surgery ± valve repair were included n = 1968. Oxygen delivery was monitored during cardiopulmonary bypass. Data were explored using multiple regression analyses regarding association between low oxygen delivery and renal replacement therapy (RRT), acute kidney injury (AKI) and post-operative peak serum creatinine (PPSC). RESULTS: Post-operative peak serum creatinine, incidence of acute kidney injury, and need for dialysis increased in a dose-dependent manner in relation to duration of a mean oxygen delivery <272 mL  min-1  m-2 . Using multiple regression analyses, only exposure for at least 30 minutes was independently associated with increased PPSC and AKI. In contrast, both short (1-5 min, OR: 2.58 [1.20, 5.54]; P = .015) and at least 30-minute (OR: 2.85 [1.27-6.41]; P = .011) exposure to low DO2 were both independently associated with the need for RRT. CONCLUSION: A low oxygen delivery during cardiopulmonary bypass was in a dose-dependent manner associated with an increased risk of renal injury.

Higher arterial pressure during cardiopulmonary bypass may not reduce the risk of acute kidney injury.

BACKGROUND: Acute kidney injury after cardiac surgery is common and associated with increased mortality. It is unknown whether an intended higher arterial pressure during cardiopulmonary bypass reduces the incidence of acute and chronic kidney injury. METHODS: Patients were randomised either to a control group or a high pressure group (arterial pressure > 60 mmHg). The inclusion criteria were age > 70 years, combined cardiac surgery and serum creatinine < 200 µmol/L. Glomerular filtration rate using the Cr-EDTA clearance method was measured the day before surgery and 4 months postoperatively. The RIFLE criteria were used to define the presence of acute kidney injury. In addition, the ratio between urinary Neutrophil Gelatinase-Associated Lipocalin (NGAL) and creatinine was measured. RESULTS: Ninety patients were included. Mean age was 76 ± 4 years and 76% were male. Mean arterial pressure was 47 ± 5 mmHg in the control group and 61 ± 4 mmHg in the high pressure group (p < 0.0001). The change in glomerular filtration rate at follow-up was - 9 ± 12 ml/min in the control group and - 5 ± 16 ml/min in the high pressure group (p = 0.288, 95% CI - 13 to 4). According to the RIFLE criteria 38% in the control group and 46% in the high pressure group developed acute kidney injury (p = 0.447). The postoperative urinary NGAL/creatinine ratio was comparable between the groups. CONCLUSIONS: An intended increase in arterial pressure during cardiopulmonary bypass to > 60 mmHg did not decrease the incidence of acute or chronic kidney injury after cardiac surgery. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01408420 . Registered 3rd of August 2011.

Acute kidney injury is independently associated with higher mortality after cardiac surgery.

OBJECTIVES: To investigate the incidence of acute kidney injury after cardiac surgery and its association with mortality in a patient population receiving ibuprofen and gentamicin perioperatively. DESIGN: Retrospective study with Cox regression analysis to control for possible preoperative, intraoperative and postoperative confounders. SETTING: University hospital-based single-center study. PARTICIPANTS: All patients who underwent coronary artery bypass grafting ± valve surgery during 2012. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Acute surgery within 24 hours of coronary angiography, previous nephrectomy, preoperative sCr >2.26 mg/dL and selective cerebral perfusion during cardiopulmonary bypass were used as exclusion criteria. Acute kidney injury was defined, using the Acute Kidney Injury Network (AKIN) criteria. Six hundred eight patients were included in the study. Mean age was 68.2 ± 9.7 years, and 81% were males. Acute kidney injury was seen in 28.1% of the patients. Overall mortality at one year was 7% and 3% in the no-AKI group. At one year, mortality was 15% in patients with AKIN stage 1 and AKIN stage 2 compared to 70% in AKIN stage 3. A hazard ratio of 2.34 (95% CI: 1.21-4.51, p = 0.011) and 5.62 (95% CI: 2.42-13.06), p<0.0001) were found for AKIN stage 1 and 2/3 combined, respectively. CONCLUSIONS: More than 28% of the patients undergoing elective or subacute cardiac surgery developed AKI in this contemporary cohort. Furthermore, acute kidney injury was an independent predictor of increased mortality irrespective of the perioperative risk factors.

Renal replacement therapy after cardiac surgery; renal function recovers.

OBJECTIVES: To assess renal outcome in patients discharged from hospital following cardiac surgery-associated acute kidney injury (CSA-AKI) with need for renal replacement therapy. DESIGN: In April 2012 we conducted a cross-sectional study of patients treated with renal replacement therapy following cardiac surgery during 2008-2010. We included all adult patients with a pre-operative serum creatinine (sCr) < 200 µM, surviving to discharge. Primary endpoint was use of renal replacement therapy after hospital discharge; secondary endpoint was a sCr > 200 µM at the time of follow-up. RESULTS: We reviewed the records of 3828 patients receiving cardiac surgery in the defined period. A total of 107 adult patients with sCr concentrations < 200 µM were treated with post-operative renal replacement therapy of whom 70 survived to discharge. Fifty-six patients were alive at follow-up and none had required renal replacement therapy after initial discharge. Median sCr concentration at follow-up was 111 [56-257] µM and two patients had sCr above 200 µM. CONCLUSIONS: In this study, renal function recovered in patients discharged from hospital following renal replacement therapy after CSA-AKI. No patients needed further renal replacement therapy and only two (4%) had a sCr > 200 µM at follow-up.

Patient-prosthesis mismatch and reduction in left ventricular mass after aortic valve replacement.

BACKGROUND: The presence of patient-prosthesis mismatch (PPM) after aortic valve replacement may influence patient survival. We examined the relationship between PPM and changes in left ventricular mass index at 3 months follow-up and also overall survival. METHODS: From patients included in the Mosaic trial, we studied data from 266 patients who underwent aortic valve replacement with the Medtronic Mosaic porcine bioprosthesis and had an echocardiography performed 3 months postoperatively. Complete echocardiographic data, to calculate left ventricular mass index, was available in 78% of the patients. The primary outcome for this substudy was prevalence and severity of PPM. Secondary outcomes were reduction in left ventricular mass index at 3 months follow-up and medium-term survival. Patients without PPM were defined as having an indexed effective orifice area greater than 0.85 cm(2)/m(2), and those with moderate and severe PPM as having an indexed effective orifice area between 0.65 cm(2)/m(2) and 0.85 cm(2)/m(2) or below 0.65 cm(2)/m(2), respectively. RESULTS: PPM was found in 217 (82%) patients. No difference in overall survival was found between patients with PPM and those without PPM. The change in left ventricular mass index was significantly different between groups (no PPM -31.4 ± 28.0 g/m(2), moderate PPM 1.1 ± 34.4 g/m(2), and severe PPM -5.9 ± 29.7 g/m(2), respectively (p = 0.01). CONCLUSIONS: The presence of PPM did not influence medium-term survival. However, patients without PPM showed a marked reduction in left ventricular mass index as soon as 3 months postoperatively.