A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known. METHODS: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients. RESULTS: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed. CONCLUSIONS: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is associated with increased risk of liver-related and cardiovascular morbidity and mortality. Given the complex pathophysiology of NASH, combining therapies with complementary mechanisms may be beneficial. This trial evaluated the safety and efficacy of semaglutide, a glucagon-like peptide-1 receptor agonist, alone and in combination with the farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat in patients with NASH. METHODS: This was a phase II, open-label, proof-of-concept trial in which patients with NASH (F2-F3 on biopsy, or MRI-proton density fat fraction [MRI-PDFF] ≥10% and liver stiffness by transient elastography ≥7 kPa) were randomised to 24 weeks' treatment with semaglutide 2.4 mg once weekly as monotherapy or combined with once-daily cilofexor (30 or 100 mg) and/or once-daily firsocostat 20 mg. The primary endpoint was safety. All efficacy endpoints were exploratory. RESULTS: A total of 108 patients were randomised to semaglutide (n = 21), semaglutide plus cilofexor 30 mg (n = 22), semaglutide plus cilofexor 100 mg (n = 22), semaglutide plus firsocostat (n = 22) or semaglutide, cilofexor 30 mg and firsocostat (n = 21). Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. Despite similar weight loss (7-10%), compared with semaglutide monotherapy, combinations resulted in greater improvements in liver steatosis measured by MRI-PDFF (least-squares mean of absolute changes: -9.8 to -11.0% vs. -8.0%), liver biochemistry, and non-invasive tests of fibrosis. CONCLUSIONS: In patients with mild-to-moderate fibrosis due to NASH, semaglutide with firsocostat and/or cilofexor was generally well tolerated. In exploratory efficacy analyses, treatment resulted in additional improvements in liver steatosis and biochemistry vs. semaglutide alone. Given this was a small-scale open-label trial, double-blind placebo-controlled trials with adequate patient numbers are warranted to assess the efficacy and safety of these combinations in NASH. CLINICAL TRIAL REGISTRATION NUMBER: NCT03987074. LAY SUMMARY: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis (NASH), are serious liver conditions that worsen over time if untreated. The reasons people develop NASH are complex and combining therapies that target different aspects of the disease may be more helpful than using single treatments. This trial showed that the use of 3 different types of drugs, namely semaglutide, cilofexor and firsocostat, in combination was safe and may offer additional benefits over treatment with semaglutide alone.

Fast-acting insulin aspart versus insulin aspart in the setting of insulin degludec-treated type 1 diabetes: Efficacy and safety from a randomized double-blind trial.

AIM: To evaluate the efficacy and safety of mealtime or post-meal fast-acting insulin aspart (faster aspart) vs mealtime insulin aspart (IAsp), both in combination with insulin degludec, in participants with type 1 diabetes (T1D). METHODS: This multicentre, treat-to-target trial (Clinical trial registry: NCT02500706, ClinicalTrials.gov) randomized participants to double-blind mealtime faster aspart (n = 342) or IAsp (n = 342) or open-label post-meal faster aspart (n = 341). The primary endpoint was change from baseline in HbA1c 26 weeks post randomization. All available information, regardless of treatment discontinuation, was used for evaluation of the effect. RESULTS: Non-inferiority for the change from baseline in HbA1c was confirmed for mealtime and post-meal faster aspart vs IAsp (estimated treatment difference [ETD]: 95%CI, -0.02% [-0.11; 0.07] and 0.10% [0.004; 0.19], respectively). Mealtime faster aspart was superior to IAsp for 1-hour PPG increment using a meal test (ETD, -0.90 mmol/L [-1.36; -0.45]; P < 0.001). Self-monitored 1-hour PPG increment favoured faster aspart at breakfast (ETD, -0.58 mmol/L [-0.99; -0.17]; P = 0.006) and across all meals (-0.48 mmol/L [-0.74; -0.21]; P < 0.001). Safety profiles and overall rate of severe or blood glucose-confirmed hypoglycaemia were similar between treatments, but significantly less hypoglycaemia was seen 3 to 4 hours after meals with mealtime faster aspart. CONCLUSION: Mealtime and post-meal faster aspart in conjunction with insulin degludec provided effective glycaemic control compared with IAsp, with no increased safety risk. Mealtime faster aspart provided PPG control superior to that of IAsp.

Once versus twice daily gentamicin dosing for infective endocarditis: a randomized clinical trial.

OBJECTIVES: The aim of this randomized study was to investigate the effects of once versus twice daily gentamicin dosing on renal function and measures of infectious disease in a population with infective endocarditis (IE). METHODS: Seventy-one IE patients needing gentamicin treatment according to guidelines were randomized to either once (n = 37) or twice daily (n = 34) doses of gentamicin. Kidney function (glomerular filtration rate, GFR) was measured with an isotope method ((51)Cr-EDTA) at the beginning of treatment and at discharge. Treatment efficacy was assessed by C-reactive protein (CRP) time to half-life, mean CRP and leukocytes. RESULTS: Baseline GFR was similar in the two groups. Both groups displayed a significant fall in GFR from admission to discharge. The mean decrease in GFR was as follows: with once daily gentamicin, 17.0% (95% confidence interval 7.5-26.5), and with twice daily gentamicin, 20.4% (95% confidence interval 12.0-28.8). However, there was no significant difference in the GFR decrease between the once and twice daily regimens (p = 0.573). No difference in infection parameters was demonstrated between the two dosing regimens. CONCLUSIONS: A twice daily gentamicin dosing regimen is neither less nephrotoxic nor more efficient than a once daily regimen in the treatment of IE patients. When indicated, gentamicin may therefore also be administered as a single-dose regimen in the treatment of IE patients.

Infective endocarditis: long-term reversibility of kidney function impairment. A 1-y post-discharge follow-up study.

The aim of this study was to quantify the long-term reversibility of kidney function decrease occurring during hospitalization and treatment for infective endocarditis (IE). A prospective observational cohort study was performed at a tertiary university hospital in Copenhagen from October 2002 through May 2008; 223 consecutive IE patients were included. Forty patients died in hospital and 38 within 1 y of discharge. Of the 145 patients called in for the 1-y follow-up, 111 accepted. Kidney function was assessed by estimated endogenous creatinine clearance (EECC). Statistical correlation between EECC at admission, discharge and follow-up, as well as correlations between gentamicin and EECC changes, were analyzed. In the 111 follow-up patients, the bacteriological aetiologies were: Streptococcus species (47.7%), Enterococcus (16.2%) and Staphylococcus aureus (11.7%). The mean EECC decrease from admission to discharge was 8.4% (95% confidence interval 1.6-15.2; p < 0.001). However this kidney function impairment was reversed at the 1-y follow-up. When divided into subgroups, a full kidney function restitution was seen in only 35.1% of patients with an EECC decrease of >22%. In conclusion, kidney function impairment occurring during hospitalization for IE is potentially reversible within the first y post-discharge.

Systematic Literature Review and Critical Appraisal of Health Economic Models Used in Cost-Effectiveness Analyses in Non-Alcoholic Steatohepatitis: Potential for Improvements.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a severe, typically progressive form of non-alcoholic fatty liver disease (NAFLD). The global prevalence of NASH is increasing, driven partly by the global increase in obesity and type 2 diabetes mellitus (T2DM), such that NASH is now a leading cause of cirrhosis. There is currently an unmet clinical need for efficacious and cost-effective treatments for NASH; no pharmacologic agents have an approved indication for NASH. OBJECTIVE: Our objective was to summarise and critically appraise published health economic models of NASH, to evaluate their quality and suitability for use in the assessment of novel treatments for NASH, and to identify knowledge gaps, challenges and opportunities for future modelling. METHODS: A systematic literature review was performed using the MEDLINE, Embase, Cochrane Library and EconLit databases to identify published health economic analyses in patients with NAFLD or NASH. Supplementary hand searches of grey literature were also performed. Articles published up to November 2019 were included in the review. Quality assessment of identified studies was also performed. RESULTS: A total of 19 articles comprising 16 unique models including either NAFLD as a whole or NASH alone were included in the review. Structurally, most models had a state-transition component; in terms of health states, two different approaches to early disease states were used, modelling either progression through fibrosis stages or NAFLD/NASH-specific health states. Conditions that frequently co-exist with NASH, such as obesity, T2DM and cardiovascular disease were not captured in models identified here. Late-stage complications such as cirrhosis, decompensated cirrhosis and hepatocellular carcinoma were consistently included, but input data (e.g. costs, utilities and transition probabilities) for late-stage complications were frequently sourced from other liver disease areas. The quality of included studies was heterogenous, and only a small proportion of studies reported internal and external validation processes. CONCLUSION: The health economic models identified in this review are associated with limitations primarily driven by a lack of NASH-specific data. Identified models also largely overlooked the intricate association between NASH and other conditions, including obesity and T2DM, and did not capture the increased risk of cardiovascular events associated with NASH. High-quality, transparent, validated health economic models of NASH will be required to evaluate the cost effectiveness of treatments currently in development, particularly compounds that may target other non-hepatic outcomes.

Severity of gentamicin's nephrotoxic effect on patients with infective endocarditis: a prospective observational cohort study of 373 patients.

BACKGROUND: Gentamicin is often used to treat infective endocarditis (IE). Gentamicin is highly effective, but its applicability is reduced by its nephrotoxic effect. The aim of this study was to quantify the nephrotoxic effect of gentamicin and the association between the nephrotoxic effect and mortality in patients with IE. METHODS: A prospective observational cohort study was performed at 2 tertiary university hospitals in Copenhagen from October 2002 through October 2007; 373 consecutive patients with IE were included. A total of 287 (77%) of the patients received gentamicin treatment (median duration, 14 days); dosage was adjusted according to daily serum creatinine and trough serum gentamicin levels. Kidney function was determined by estimated endogenous creatinine clearance (EECC). Statistical correlation between gentamicin and EECC change was analyzed, and the association between mortality and nephrotoxicity was investigated. RESULTS: The primary bacteriological etiologies were as follows: Streptococcus species (37.1%), Staphylococcus aureus (18.2%), and Enterococcus species (16.1%). In the gentamicin group, the mean EECC change was an 8.6% decrease, but in the no-gentamicin group, the mean change was an increase of 2.3% (P = .05). The decrease in EECC was significantly correlated with the duration of gentamicin treatment: a 0.5% EECC decrease per day of gentamicin treatment (P = .002). The decrease in EECC during hospitalization was not related to postdischarge mortality. The mean duration of follow-up was 562 days. CONCLUSIONS: The nephrotoxic effect of gentamicin is directly related to treatment duration, with a decrease in EECC of 0.5% per day of gentamicin treatment. In patients treated with gentamicin, the in-hospital decrease in EECC was not related to postdischarge mortality. Consequently, this study does not support abolishment of gentamicin in treatment of IE.

Major cerebral events in Staphylococcus aureus infective endocarditis: is anticoagulant therapy safe?

OBJECTIVES: To study the impact of anticoagulation on major cerebral events in patients with left-sided Staphylococcus aureus infective endocarditis (IE). METHODS: A prospective cohort study; the use of anticoagulation and the relation to major cerebral events was evaluated separately at onset of admission and during hospitalization. RESULTS: Overall, 70 out of 175 patients (40%; 95% CI: 33-47%) experienced major cerebral events during the course of the disease, cerebral ischaemic stroke occured in 59 patients (34%; 95% CI: 27-41%), cerebral infection in 23 patients (14%; 95% CI: 9-19%), and cerebral haemorrhage in 5 patients (3%; 95% CI: 0.5-6%). Patients receiving anticoagulation were less likely to have experienced a major cerebral event at the time of admission (15%) compared with those without anticoagulation (37%, p = 0.009; adjusted OR: 0.27; 95% CI: 0.075-0.96; p = 0.04). In-hospital mortality was 23% (95% CI: 17-29%), and there was no significant difference between those with or without anticoagulation. CONCLUSIONS: We found no increased risk of cerebral haemorrhage in S. aureus IE patients receiving anticoagulation. Anticoagulation was associated with a reduced risk of cerebral events before initiation of antibiotics. Data support the continuance of anticoagulation in S. aureus IE patients when indicated.

One-year mortality in coagulase-negative Staphylococcus and Staphylococcus aureus infective endocarditis.

The aim of this study was to investigate in-hospital mortality and 12-month mortality in patients with coagulase-negative Staphylococcus (CoNS) compared to Staphylococcus aureus (S. aureus) infective endocarditis (IE). We used a prospective cohort study of 66 consecutive CoNS and 170 S. aureus IE patients, collected at 2 tertiary university hospitals in Copenhagen (Denmark) and at 1 tertiary university hospital in Gothenburg (Sweden). Median (range) C-reactive protein at admission was higher in patients with S. aureus IE (150 mg/l (1-521) vs 94 mg/l (6-303); p<0.001), which may suggest a more serous infection. CoNS was associated with prosthetic valve IE (49% vs 24%; p<0.001) and median diagnostic delay was longer in CoNS IE patients (20 d (0-232) vs 9 d (0-132); p<0.001). In-hospital mortality was equally high in both groups but 25% of the CoNS IE patients had died after 1 y compared to 39% of patients with S. aureus IE (p =0.05). In conclusion, CoNS IE was associated with a long diagnostic delay and high in-hospital mortality, whereas post-discharge prognosis was better in this group of patients compared to patients with IE due to S. aureus.

Efficacy and Safety of Fast-Acting Insulin Aspart in People with Type 1 Diabetes Using Carbohydrate Counting: A Post Hoc Analysis of Two Randomised Controlled Trials.

INTRODUCTION: Insulin dosing based on carbohydrate counting is the gold standard for improving glycaemic control in type 1 diabetes (T1D). This post hoc analysis aimed to explore the efficacy and safety of fast-acting insulin aspart (faster aspart) according to bolus dose adjustment method in people with T1D. METHODS: Post hoc analysis of two 26-week, treat-to-target, randomised trials investigating treatment with double-blind mealtime faster aspart, insulin aspart (IAsp), or open-label post-meal faster aspart (onset 1, n = 1143; onset 8, n = 1025). Participants with previous experience continued carbohydrate counting (onset 1, n = 669 [58.5%]; onset 8, n = 428 [41.8%]), while remaining participants used a bolus algorithm. RESULTS: In onset 1, HbA1c reduction was statistically significantly in favour of mealtime faster aspart versus IAsp with carbohydrate counting (estimated treatment difference [ETD 95% CI] - 0.19% [- 0.30; - 0.09]; - 2.08 mmol/mol [- 3.23; - 0.93]). In onset 8, there was no statistically significant difference in HbA1c reduction with either dose adjustment method, although a trend towards improved HbA1c was observed for mealtime faster aspart with carbohydrate counting (ETD - 0.14% [- 0.28; 0.003]; - 1.53 mmol/mol [- 3.10; 0.04]). In both trials, bolus insulin doses and overall rates of severe or blood glucose-confirmed hypoglycaemia were similar between treatments across dose adjustment methods. CONCLUSION: For people with T1D using carbohydrate counting, mealtime faster aspart may offer improved glycaemic control versus IAsp, with similar insulin dose and weight gain and no increased risk of hypoglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01831765 (onset 1) and NCT02500706 (onset 8). FUNDING: Novo Nordisk.

In infectious endocarditis patients mortality is highly related to kidney function at time of diagnosis: a prospective observational cohort study of 231 cases.

BACKGROUND: Infective endocarditis is a serious disease with a high mortality even with optimal treatment and care. A number of complicating conditions are known to be of importance for the outcome. But only few data are available in IE patients on the independent prognostic value of kidney function at the time of admittance. METHODS: In a prospective observational cohort study data from 235 consecutive IE patients were collected at 2 tertiary heart centres in Copenhagen. Kidney function was evaluated as Estimated Endogenous Creatinine Clearance (EECC) calculated at the time of admission. Patients were divided into 4 groups according to their EECC: 1) >90 ml/min, 2) 60-90 ml/min, 3) 30-60 ml/min and 4) <30 ml/min. Mortality statistical analysis was then applied. RESULTS: >Gender: 70.2% male, mean age: 61.3+/-SD 15.0. The most common pathogens were streptococcus species (32.9%) and Staphylococcus aureus (21.8%). Mean follow-up time was 453 days (SD 350). A total number of 76 patients died (32%), with an in-hospital mortality of 14%, and a post discharge mortality of 18%. In 64.9% EECC was decreased at time of admission, and a highly significant relationship between EECC and mortality was demonstrated, P<0.001. For every decrease of 10 ml/min in EECC we found an increase in Hazard Ratio for mortality of 23.1% (CI 13.2-33.8), P<0.001. CONCLUSION: Decreased kidney function is prevalent in patients with endocarditis. Calculated EECC at the time of admission is easily obtained in all IE patients and has a high and independent predictive prognostic value for mortality.