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14th March 2023
MK-0616 is an investigative oral, once-daily, PCSK9 inhibitor and its manufacturer Merck has reported that it gave rise to significant reductions in LDL cholesterol in adult patients with hypercholesterolaemia.
Increased levels of PCSK9 elevate plasma LDL cholesterol and conversely, lowering PCSK9 reduces LDL cholesterol.
As a result, inhibition of PCSK9 represents a therapeutic target and drugs such as evolocumab have been recommended in the treatment of primary hypercholesterolaemia or mixed dyslipidaemia and in patients with a high or very high risk of cardiovascular disease, where LDL cholesterol levels remain above 3.5 mmol/l.
However, to date, all PCSK9 inhibitors are only available as an injectable form, whereas MK-0616 is an oral PCSK9 inhibitor.
In a study of healthy patients with hypercholesterolaemia, the use of once daily MK-0616 (dose 10 to 300 mg), exhibited a dose dependent increase in plasma exposure and a >90% mean maximum reduction of free plasma PCSK9 levels from baseline at all dose levels studied.
The recent findings are from a phase 2b clinical trial in which MK-0616 was given at varying doses (6, 12, 18 and 30 mg) to adult patients with hypercholesterolaemia and who were divided into one of three categories, in which fasting LDL cholesterol levels ranged from > 1.81 to < 6.48 mmol/l.
In addition, participants were either stable on one or more lipid lowering therapies or who had not received any such treatments for more than 30 days before screening.
Individuals were then randomised 1:1:1:1:1 (i.e. each dose and placebo) and the treatment continued for 16 weeks and the primary objective of the study was to evaluate the percent change in LDL cholesterol from baseline to Week 8.
A total of 380 participants with a median age of 62 years (49% female) with hypercholesterolaemia and a moderate to high risk of atherosclerotic cardiovascular disease were included.
At Week 8, all four doses of MK-0616 significantly reduced LDL-C compared to placebo and the placebo-adjusted reduction from baseline ranged from 41.2% with the 6 mg dose to 60.9% with the 30 mg dose (p < 0.001 for each dose).
The drug was well tolerated and the proportion of participants experiencing greater than one adverse event was similar (ranging from 39.5% to 44.2%) between the different doses and placebo (44%).
The findings of the phase 2b study have been published in the Journal of the American College of Cardiology.
13th March 2023
Bempedoic acid (BPA) use in patients at high risk for cardiovascular disease or who are statin intolerant, significantly reduced the incidence of major adverse cardiovascular events compared to placebo according to the findings of a large, randomised, double-blind, placebo-controlled trial by an international research group.
Treatment with statin drugs is a recommended as part of the therapeutic strategy for the management of patients with atherosclerotic cardiovascular disease or in those at a high risk of such disease. Nevertheless, not all patients can tolerate a statin and it is estimated that between 7 and 29% of patients complain of statin-associated muscle symptoms. One alternative treatment to reduce LDL cholesterol for statin-intolerant patients is BPA which, like statins, reduces hepatic cholesterol synthesis and raises LDL receptor expression. The drug is an ATP citrate lyase inhibitor and targets cholesterol synthesis upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is the enzyme targeted by statins and has a lower incidence of muscle-related adverse effects. Currently studies have revealed that bempedoic acid is able to significantly reduce LDL cholesterol levels although whether this also translates into a reduction of adverse cardiovascular outcomes is unknown.
In the current study, researchers randomised patients who were either unwilling or unable to take statins, (i.e., were statin intolerant) and/or were at a high risk of cardiovascular disease, to oral bempedoic acid, 180 mg daily or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, i.e., death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or coronary revascularisation.
Bempedoic acid and adverse cardiovascular events
A total of 13,970 patients with a mean age of 65.5 years (48.3 % female) were randomised to bempedoic acid (6,992) or placebo and followed for a median of 40.6 months.
The primary outcome occurred in 11.7% of those assigned to BPA and 13.3% of placebo patients and this difference was statistically significant (Hazard ratio, HR = 0.87, 95% CI 0.79 – 0.96, p = 0.004).
Significant differences favouring bempedoic acid were also found for fatal or non-fatal myocardial infarction (HR = 0.77, p = 0.002) and coronary revascularisation (HR = 0.81, p = 0.001) but not for fatal and non-fatal strokes.
The authors concluded that for statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events.
Citation
Nissen SE et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Eng J Med 2023
Elevated plasma levels of the artificial sweetener erythritol, in patients undergoing cardiac risk assessment is associated with an increased 3-year risk of a major cardiovascular event according to the findings of an analysis by an international research group.
Low calorie artificial sweeteners are widely found in food and drinks and some of the most thoroughly tested and evaluated of all food additives. However, there is some evidence to suggest a significant association between intake of artificially sweetened soda consumption and obesity and to an increased risk of all-cause mortality. Nevertheless, a 2017 scoping review was unable to offer conclusive evidence for either beneficial or harmful effects of artificial sweeteners on several adverse health outcomes.
Erythritol is a sugar alcohol and commonly used as a sugar substitute and there is actually data indicating how acute consumption improves small vessel endothelial function whereas chronic use reduces central aortic stiffness. In contrast, other work suggests an association between erythritol and incident diabetes. Despite these findings, little is known about the relationship between erythritol and both cardiovascular disease and atherothrombotic complications and this was the purpose of the current study. Researchers initially measured plasma levels of the artificial sweetener among US patients undergoing elective diagnostic cardiac evaluation (which they referred to as the ‘discovery cohort’) and then compared the findings with results obtained from a second US and European cohort also undergoing cardiac evaluation.
Erythritol levels and incident MACE
In the discovery cohort with 1,157 patients, circulating levels of erythritol, were associated with incident (3-year) risk for major adverse cardiovascular events, including death or nonfatal myocardial infarction or stroke (adjusted hazard ratio, aHR = 2.95, 95% CI 1.70 – 5.12, p < 0.001) when comparing the highest vs lowest plasma erythritol levels. Subsequent analysis in the US cohort also confirmed an increased risk of MACE (aHR = 1.80, 95% CI 1.18 – 2.77, p = 0.007) as well as the European cohort (aHR = 2.21, 95% CI 1.20 – 4.07, p = 0.010). In fact, for every 1 μM increase in plasma erythritol levels, there was a 21% and 16% increase in the adjusted HR for MACE in the US and European validation cohorts respectively (p < 0.001 and p = 0.005).
In trying to better understand the potential mechanisms behind these effects, the researchers also found that erythritol heightened platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a small study with 8 healthy subjects, ingestion of the sweetener produced elevated plasma levels which remained high for hours after ingestion and remained substantially elevated for over two days.
Although recognising a limitation of the study in that the data were obtained from patients with a high prevalence of cardiovascular disease and with traditional risk factors, the authors concluded that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis.
Citation
Witkowski M et al. The artificial sweetener erythritol and cardiovascular event risk. Nat Med 2023
10th March 2023
Antioxidant and anti-inflammatory treatment for those who survived sepsis resulted in lower cognitive and psychological scores compared to placebo after 6 months according to a randomised trial by the VICTAS investigators.
Evidence suggests that patients with sepsis exhibit long-term neurological sequelae, particularly substantial declines in cognitive function. In fact, according to the Sepsis Alliance, the presence of Post-traumatic stress disorder, depression and anxiety are not unusual among sepsis survivors.
It is thought that the presence of oxidative damage is an important factor in post-sepsis cognitive impairment. Additionally, in animal models, deficiency of the vitamin thiamine, also enhances oxidative stress and inflammatory response changes and some preliminary data indicates a synergistic effect of vitamin C and hydrocortisone on endothelial barrier protection in patients with sepsis.
Given these findings, could a triple combination of vitamin C, hydrocortisone and thiamine, have a positive impact on cognitive, psychological and functional outcomes in those who survive sepsis?
The VICTAS trial attempted to answer this question and randomised 1:1, sepsis survivors to either triple combination therapy, consisting of intravenous vitamin C, thiamine and hydrocortisone or placebo. The combination was administered within 4 hours of randomisation and every 6 hours thereafter for up to 96 hours. The outcomes of interest were cognitive performance, risk of posttraumatic stress disorder and functional status, all of which were assessed 6 months after randomisation.
Antioxidant, anti-inflammatory treatment outcomes
A total of 213 participants with a median age of 57 years (52.6% male) were included and randomised to the triple therapy (108) or placebo.
At 6 months, the triple therapy group had significantly lower immediate memory (i.e., cognitive) scores than placebo participants (adjusted odds ratio, aOR = 0.49, 95% CI 0.26 – 0.89, p = 0.02) and a higher odds of posttraumatic stress disorder (aOR = 3.51, 95% CI 1.18 – 10.40, p = 0.02). In contrast, there was a lower odds among triple group participants, of receiving formal psychiatric, psychological, or mental health care during the 6 months after discharge. However, there were no significant differences in measures of functional support.
The authors concluded that in sepsis survivors, treatment with vitamin C, thiamine, and hydrocortisone made worse, cognitive and psychological outcomes and made no difference to functional outcomes at 6 months compared to placebo.
Citation
Roberson SW et al. Association of Vitamin C, Thiamine, and Hydrocortisone Infusion With Long-term Cognitive, Psychological, and Functional Outcomes in Sepsis Survivors: A Secondary Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis Randomized Clinical Trial. JAMA Netw Open 2023
A prospective study by researchers at the Karolinska University Hospital, Stockholm, Sweden, has revealed that elevated plasma calprotectin levels was superior to other biomarkers for the identification of emergency department (ED) patients with sepsis who required urgent transfer to either an intensive care (ICU) or high dependency unit (HDU).
In data for 2017, it was reported that globally, there were an estimated 48.9 million incident cases of sepsis and which led to 11 million deaths. Moreover, it is also recognised that the early detection of sepsis results in greater patient survival. Calprotectin is a protein present in the cytoplasm of neutrophils and levels have been found to increase early in response to a bacterial challenge and in fact, other work demonstrates how serum calprotectin levels are a reliable biomarker in patients with bacterial sepsis. Nevertheless, while measurement of serum calprotectin levels is of value in sepsis, whether the biomarker serves to identify ED sepsis patients who required direct transfer to an ICU or HDU is less clear.
In the current study, the Swedish team turned to patients ED patients identified as likely to have sepsis based on an alert system used within the department, i.e., those with signs of organ dysfunction and symptoms of infection. Among such patients, blood samples were analysed for several biomarkers including C-reactive protein, procalcitonin, neutrophils, lymphocytes and calprotectin which was analysed from frozen plasma samples. The researchers set the primary outcome as direct transfer to an ICU or HDU from the ED, based on the decision of the multidisciplinary team.
Calprotectin levels and ED to ICU transfer
Among a total of 319 patients with a median age of between 71 and 73 (37.5% female) identified with an infection, 26% were immediately transferred to either ICU or HDU and the remainder to a hospital ward.
The overall median calprotectin level was 2.2 mg/L (IQR 1.2 – 3.9 mg/L) for all infected patients but was significantly higher (3.3 vs 2.1, p = 0.0001) among those transferred to either an ICU or HDU compared to a ward.
Using the receiver operating characteristic curve analysis, calprotectin had the highest area under the curve (AUC) at 0.65 compared to C-reactive protein (AUC = 0.55), procalcitonin (AUC = 0.46) and the neutrophil-lymphocyte ratio (AUC = 0.47).
A cut-off value for calprotectin of 4.0 mg/L, gave the best combination of sensitivity (42.5%) and specificity (83%) for the transfer to the ICU/HDU among patients with infection.
The authors concluded that among sepsis alert patients, plasma calprotectin was significantly elevated in patients requiring immediate transfer to ICU or HDU and proved to be superior to other biomarkers for the prediction of such transfers.
Citation
Parke A et al. Plasma calprotectin as an indicator of need of transfer to intensive care in patients with suspected sepsis at the emergency department BMC Emerg Med 2023
Work by researchers from San Diego, La Jolla in the US, has shown that an increased exposure to particulate matter 2.5 μm or less in diameter (PM2.5), increases the risk for all-cause and infection-related visits to an emergency department among infants during their first year of life.
It has been recognised for several years that particulate matter comprising particles with a diameter of less than 2.5 micrometres, can penetrate deeply into the lungs, causing irritation and corrosion of the alveolar wall and therefore impairing lung function. PM2.5 comes from a wide range of sources including natural (i.e., dust, sea salt), anthropogenic emissions, e.g., vehicles, as well as household wood burning and from industry. The composition of PM2.5 is a complex mix of inorganic components such as heavy metals, organics (polycyclic aromatic hydrocarbons) and biologicals e.g., bacteria, viruses and fungi. Prior studies have shown that exposure to PM2.5 during pregnancy can increase adverse outcomes and stillbirth and early childhood exposure to air pollutants may play a role in the development of asthma. However, research to data on the impact of early PM2.5 exposure and the risk of hospitalisation during infancy is conflicting, indicating either an increased risk of bronchiolitis or no noticeable effect compared to older children.
In the current study, researchers examined all live births in California between 2014 and 2018 and estimated weekly exposure to particular matter based on the postal (zip) codes using a machine learning model. They set the outcomes of interest as both the first all-cause emergency department (ED) visit and the first infection-related visit based on birth status (pre or full-term).
Particulate matter and ED visits
A total of 983,700 infants, (49.4% female) were included in the analysis.
During the first year of life, the odds of an ED visit for any cause was higher for both pre-term (odds ratio, OR = 1.05, 95% CI 1.04 – 1.06) and full-term infants (OR = 1.05, 95% CI 1.04 – 1.05) for each 5-μg/m3 increase in exposure to PM2.5.
Similarly, there were elevated odds for a respiratory infection-related ED visit, pre-term (OR = 1.03) and full-term (OR = 1.05). In fact, the highest risks for an ED in both types of infant occurred between 18 to 23 weeks.
The authors concluded these elevated risks associated with exposure to particulate matter, may have implications for minimising exposure to air pollution.
Citation
Teyton A et al. Exposure to Air Pollution and Emergency Department Visits During the First Year of Life Among Preterm and Full-term Infants. JAMA Netw Open 2023
9th March 2023
In a meta-analysis by Canadian and European researchers it was shown that the risk of extubation failure (EF) in acute brain injury is elevated in older patients and following a longer duration of mechanical ventilation.
Patients with acute brain injury admitted to the intensive care unit (ICU) frequently require mechanical ventilation or other forms of respiratory support, as a consequence of respiratory failure due to loss of airway protective reflexes or decreased respiratory drive. In fact, delaying extubation has been shown to increase the incidence of pneumonia and prolong the length of stay in ICU. However, guidelines designed to support the extubation decision-making process have found limited evidence to support clinicians. Identification of prognostic factors of extubation failure are therefore clearly needed but most evidence on such factors has been derived from non-brain injury patient cohorts.
In the current study, researchers undertook a systematic review and meta-analysis in an effort to identify possible prognostic factors that were associated with EF in acute brain-injured adult patients receiving invasive ventilation in an ICU. The team defined extubation failure as unplanned re-intubation within 72 hours of extubation.
Extubation failure prognostic factors
A total of 21 studies with 3,274 patients and a median age of 53 years were included in the analysis and median incidence of EF was 25%.
The researchers found moderate certainty evidence demonstrating that the risk of EF was associated with increased age (adjusted Odds ratio, aOR = 3, 95% CI 1.78 – 5.07, upper vs lower tertile) as well as a longer duration of mechanical ventilation (aOR = 3.47, 95% CI 1.68 – 7.19, upper vs lower tertile).
In contrast, there was moderate certainty evidence that risk of EF was reduced in the presence of intact cough on the day of extubation (aOR = 0.40, 95% CI 0.28 – 0.57) as well as intact swallow (aOR = 0.34, 95% CI 0.21 – 0.54). However, the certainty of evidence for association with any other factors was either low or very low.
The authors concluded that among adult patients with acute brain injury receiving mechanical ventilation for at least 24 hours, there was moderate certainty evidence to suggest that both older age, a longer duration mechanical ventilation and a lack of intact cough or swallow, were associated with increased risk of extubation failure.
Citation
Taran S et al. Prognostic Factors Associated With Extubation Failure in Acutely Brain-Injured Patients: A Systematic Review and Meta-Analysis. Crit Care Med 2023
The potential for long-term cognitive impairment (CP) among mechanically ventilated patients within an intensive care unit can be significantly reduced through early mobilisation according to the findings of a randomised trial by researchers at the University of Chicago, Chicago, USA.
Patients in both medical and surgical intensive care units are at a high risk of long-term cognitive impairment. In fact, after only two days of documented delirium, at 12 months, 71% of survivors had cognitive impairment and of whom, 36% had severe impairment. While delirium commonly occurs in critical illness, whether this causes longer-term cognitive impairment is less clear. Delirium can be reduced through early mobilisation, i.e., whole-body rehabilitation with interruption of sedation and physical and occupational therapy in the earliest days of critical illness. However, no studies have examined whether early mobilisation also positively impacts on the longer-term development of CP.
In the current study, the US team performed a randomised trial of early mobilisation among functionally independent and mechanically ventilated patients admitted to the ICU versus usual care to determine if this reduced cognitive impairment, 12 months after the critical illness. Adult patients admitted to the ICU intensive-care unit (ICU), were randomised 1:1 to either early physical and occupational therapy (i.e., early mobilisation) or usual care. The primary outcome, cognitive impairment 1 year after hospital discharge, was assessed using the Montreal Cognitive Assessment (MoCA) scale and on which, CP is deemed to be present if the score is < 26.
Cognitive impairment and early mobilisation
A total of 198 patients with mean age of 56.2 years (42.5% female) were equally randomised to early mobilisation or usual care.
When assessed after 12 months, the rate of CP among those assigned to early mobilisation was 24% (mean MoCA score = 26) compared with 43% (mean MoCA score = 23) with usual care and this difference was statistically significant (p = 0.0043). In fact, CP was also significantly lower upon hospital discharge, (54% vs 69%, p = 0.029). The early mobilisation group also had significantly fewer ICU-acquired weaknesses (p = 0.0001) and higher physical component quality-of-life scores (p < 0.0001). However, there were no significant differences in the rates of functional independence or mental component scores between groups after 12 months.
The authors concluded that early mobilisation could be the first known intervention to improve long-term cognitive impairment among ICU patients following mechanical ventilation.
Citation
Patel BK et al. Effect of early mobilisation on long-term cognitive impairment in critical illness in the USA: a randomised controlled trial. Lancet Respir Med 2023
Neoadjuvant pembrolizumab therapy given to patients with stage III or IV resectable melanoma provides superior 2-year event-free survival in comparison to using only adjuvant therapy according to the findings of randomised, Phase II trial by US researchers.
Cutaneous melanoma is the most serious form of skin cancer worldwide with an estimated 325,000 new cases and 57,000 deaths in 2020. In a randomised, placebo-controlled trial of patients with completely resected stage III melanoma, adjuvant treatment with the programmed death 1 (PD-1) inhibitor, pembrolizumab, significantly improved recurrence-free survival compared to placebo. Neoadjuvant therapy involves the provision of systemic treatment before surgery and is designed to improve surgical outcomes for such patients. In fact, work in animal models indicates that there is a significantly greater therapeutic efficacy from using neoadjuvant, compared with adjuvant, immunotherapy to eradicate distant metastases following primary tumour resection. However, the added value of using neoadjuvant pembrolizumab therapy in patients with either stage III or IV resectable melanoma compared to adjuvant treatment alone has not been tested.
In the current study, the US researchers undertook a randomised, Phase II, open-label trial, in patients with measurable stage IIIB to IVC melanoma that was amenable to surgical resection. Participants were randomised 1:1 to either three doses of neoadjuvant pembrolizumab, surgery followed by 15 doses of adjuvant pembrolizumab or to surgery followed by pembrolizumab for approximately 1 year (adjuvant-only group). The primary end point was set as event-free survival in the intention-to-treat population.
Neoadjuvant pembrolizumab and event-free survival
In total, 313 patients with a median age of 63 years (35% female) were randomised to either neoadjuvant (154) or adjuvant only therapy.
After a median follow-up of 14.7 months, event-free survival was significantly longer in the neoadjuvant group (p = 0.004).
After 2 years, event-free survival occurred in 72% (95% CI 64 – 80) of those given neoadjuvant pembrolizumab compared to 49% (95% CI 41 – 59) in the adjuvant only group. In addition, the incidence of treatment-related adverse events of grades 3 or higher was similar between the two groups (12 vs 14%, neoadjuvant vs adjuvant).
The authors concluded that giving pembrolizumab both before and after surgery resulted in significantly longer event-free survival compared to adjuvant therapy alone.
Citation
Patel SP et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 2023
A technology appraisal guidance document from NICE has recommended the use of semaglutide for the management of overweight and obesity.
Obesity is a global health problem and the World Obesity Atlas 2023 report has estimated based on current trends, that overweight and obesity will affect over 4 billion people by 2035, reflecting an increase from 38% of the global population in 2020 to more than 50% in 2035. Semaglutide (brand name Wegovy) has a current marketing authorisation ‘as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of ≥30 kg/m2 (obesity), or ≥27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity.’
In its guidance, NICE has recommended use of the drug based on the licensed use, only if it is used ‘for a maximum of 2 years, and within a specialist weight management service providing multidisciplinary management of overweight or obesity.’ Adding that semaglutide should be stopped if an individual fails to achieve less than 5% of the initial weight after 6 months of treatment.
Semaglutide clinical efficacy
In an associated press release from NICE, it was stated that evidence for the effectiveness of the drug in weight loss was derived from the STEP 1 trial. This randomised, double-blind, placebo-controlled trial included nearly 2,000 adults with a body mass index (BMI) of 30 or more and individuals with a BMI of 27 but with ≥1 weight-related coexisting condition and who were not diabetic. Participants received once weekly semaglutide 2.4 mg or placebo. After 68 weeks of treatment, participants receiving semaglutide saw 14.9% mean decrease in their body weight compared to baseline compared to only 2.4% among placebo participants and this difference was statistically significant (p < 0.001).
In the press release, Helen Knight, Director of Medicines Evaluation at NICE, said that ‘it (semaglutide) won’t be available to everyone. Our committee has made specific recommendations to ensure it remains value for money for the taxpayer, and it can only be used for a maximum of two years.’
The release also cites data from a 2019 Health Survey for England, which estimated that 28% of adults in England were obese and a further 36% were overweight and that the government estimated that the current NHS costs of obesity in the UK were £6.1 billion and £27 billion to wider society.
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