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7th March 2023
A randomised, placebo-controlled trial found that among adolescents recently diagnosed with type 1 diabetes (T1D), use of verapamil tablets preserved beta cell function to a greater extent than placebo after 52 weeks.
Type 1 diabetes is an autoimmune disorder resulting in the destruction of insulin-producing beta cells in the pancreas. Among patients with T1D, measurement of connecting peptide (C-peptide) which is co-secreted with insulin from the islets of Langerhans cells, allows for an evaluation of the amount of remaining beta cell secretion of insulin. One recently identified therapeutic target is thioredoxin-interacting protein which is elevated in diabetes and over-expression of the protein leads to beta-cell apoptosis. Moreover, it has been found that verapamil can inhibit thioredoxin-interacting protein, thereby enhancing beta cell function and could serve as a means of preventing diabetes. In fact, a 2018 study with 26 T1D patients, observed that use of verapamil improved the area under the curve (AUC) for C-peptide after 3 and 12 months.
In the current study, researchers randomised adolescents recently diagnosed (within 24 days) with T1D, 1:1 to either 60 or 120 mg/day (depending on the participant’s weight) of verapamil or placebo as part of study in which subjects also received either intensive diabetes management or standard care. The primary outcome was set as the AUC values for C-peptide stimulated by a mixed-meal tolerance test, 52 weeks from their date of diabetes diagnosis.
Verapamil and changes in C-peptide area under the curve
A total of 88 participants with a mean age of 12.7 years (41% female) were randomised to either verapamil (47) or placebo.
The mean baseline C-peptide AUC for the verapamil group was 0.66 pmol/mL and 0.65 pmol/mL at 52 weeks. In contrast, in the placebo group C-peptide AUC reduced from 0.60 pmol/mL to 0.44 pmol/mL (adjusted between-group difference = 0.14, 95% CI 0.01 – 0.27, p = 0.04), which equated to a 30% higher C-peptide level at 12 months in the verapamil group.
The authors concluded that use of verapamil was able to partly preserve stimulated C-peptide secretion at 52 weeks and called for further longitudinal studies to confirm the durability of this response and the optimal length of treatment.
Citation
Forlenza GP et al. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA 2023
The use of an essential oil nasal spray led to a 40% reduction in total sino-nasal symptoms according to data presented in an abstract presented at the American Academy of Allergy and Immunology (AAAAI) at San Antonio and published in a supplement to the Journal of Allergy and Clinical Immunology.
Allergic rhinitis gives rise to symptoms which commonly include nasal congestion, nasal itch, rhinorrhoea and sneezing and is estimated to affect 18.1% of the global population, leading to impairment of both sleep and quality of life. Typically, treatment involves the use of antihistamines and or intranasal corticosteroids, although a recent randomised trial demonstrated how aromatherapy oils provided symptomatic relief in patients with perennial allergic rhinitis. Furthermore, the use of a lavender oil inhalation was also found to be of benefit in bronchial asthma.
Given the potential value of essential oils for perennial allergic rhinitis, in the current study presented at AAAAI, the role of an essential oil nasal spray, which contained menthol, eucalyptol, thymol, camphor, birch oil, pine oil, cinnamon and mint, was evaluated over a period of 7 days by patients with seasonal allergic rhinitis. Symptom severity was assessed using the Sino-Nasal Outcome Test (SNOT-22), a patient-reported outcome measure which assesses 22 symptoms, each of which were assessed at baseline and after one week, using a 0 to 5 scale, where 0 = no problem and 5 = ‘problem as bad as can be’
Essential oil nasal spray and SNOT-22 score
A total of 18 subjects (14 women) aged between 16 and 80 were included. The baseline SNOT-22 score was 37.1 and this was significantly reduced to 20.1 (p = 0.003) after one week. In fact, improvements were seen for 20 of the 22 self-reported symptoms, of which statistically significant improvements were documented for 12, with the greatest impact seen for runny nose, cough, postnasal discharge and quality of life features.
The author concluded that the essential oil spray alleviated physical and functional impairment in those with allergic seasonal related diseases.
Citation
Bielory L. Essential oil (EO) nasal spray use in seasonal allergic rhinitis. J Allergy Clin Immunol 2023
6th March 2023
The manufacturer Reata has announced that its drug omaveloxolone (brand name SKYCLARYS) has become the first treatment to be approved for the treatment of Friedreich’s ataxia, an ultra-rare, genetic, progressive neurological disorder.
Friedreich’s ataxia represents an inherited autosomal recessive disease, that affects the nervous system, producing a progressive ataxia, weakness and sensory deficits. The disease has a median onset age of 10 to 15 years and affects approximately 1 in 50,000 people worldwide. Friedreich’s ataxia is due to a lack of function in a gene responsible for the production of frataxin, a protein involved in mitochondrial iron homeostasis.
During conditions of cellular oxidative stress, there is activation of the transcription factor, NF-E2-related factor and which triggers a cellular antioxidant response, through induction of antioxidant response element driven genes. However, it appears that a lack of frataxin impairs NF-E2 signalling and this is though a contributory factor for the neuro-degeneration seen in Friedreich’s ataxia. Omaveloxolone has been shown to induce NF-E2 and thus protect cells from oxidative stress.
Omaveloxolone clinical efficacy
An initial dosing ranging study identified that a dose of 160 mg/day appeared to improve neurological function. Following on from this, a phase 2 randomised, placebo-controlled trial with 103 patients, demonstrated that omaveloxolone 150 mg daily, significantly improved the modified Friedreich’s Ataxia Rating Scale (mFARS) score after 48 weeks compared to placebo (p = 0.014). In an open label extension trial, after 72 weeks, the response to omaveloxolone compared to placebo was maintained.
Following the FDA approval, the company has created the Reata Education, Access, and Care Helpline (REACH), an integrated specialty pharmacy and patient services program, designed to help eligible patients access prescribed Reata medicines.
While yet to be approved, omaveloxolone has been granted Orphan Drug designation in Europe for the treatment of Friedreich’s ataxia and is currently under review by the European Medicine Agency.
3rd March 2023
The introduction of an antimicrobial stewardship intervention to older adult care facilities, significantly reduced the level of antibiotic prescribing for frail older adults with a suspected urinary tract infection according to the findings of a cluster, randomised trial by European researchers.
Antimicrobial resistance poses a global, major threat to human health and is recognised as a leading cause of deaths around the world. Older and frail adults are often prescribed antibiotics for a urinary tract infection (UTI) and often in the presence of non-specific symptoms such as confusion. Moreover, the presence of asymptomatic bacteriuria is a common finding which has become recognised as an important contributor to inappropriate antimicrobial use that ultimately promotes emergence of antimicrobial resistance. To date antibiotic stewardship interventions in long-term care facilities suggest that such programs collectively suggest potential to reduce antimicrobial use though the available interventions vary considerably with respect to design and intensity.
In the current study, researchers made use of a multifaceted antibiotic stewardship intervention that included a decision tool for appropriate use of antibiotics for a UTI and which was previously developed by an international expert team. The researchers wanted to find out if the intervention was effective in reducing antibiotic prescribing for suspected urinary tract infections in various older adult care settings, in comparison to usual care, in several European countries. The team used a pragmatic, parallel, cluster randomised controlled trial, with a 5 month baseline data collection period and a 7 month follow-up. They set the primary outcome as the number of antibiotic prescriptions for a suspected UTI per person-year, whereas secondary outcomes focused on the level of complications, hospital admissions and all-cause mortality.
Antimicrobial stewardship and treatment of suspected urinary tract infections
A total of 1,041 participants with a mean age of 86.3 years (70.9% female) were included and of whom, 502 were randomised to the antibiotic stewardship intervention.
During the baseline period, there was no difference in the level of antibiotic prescribing for a suspected UTI in the two groups (0.50 per person year vs 0.44 per person year, intervention vs usual care). However, during the follow-up period, the corresponding rates were 0.27 per person-year (intervention ) and 0.58 per person-year (usual care). This equated to an adjusted rate ratio of 0.42 (95% CI 0.26 – 0.68, p < 0.001).
Furthermore, there were no differences between groups with respect to either complications, hospital admissions or all-cause mortality.
The authors concluded that their antimicrobial stewardship intervention safely reduced antibiotic prescribing for a suspected UTI in frail older adults.
Citation
Hartman EAR et al. Effect of a multifaceted antibiotic stewardship intervention to improve antibiotic prescribing for suspected urinary tract infections in frail older adults (ImpresU): pragmatic cluster randomised controlled trial in four European countries. BMJ 2023
An intranasal epinephrine device provides comparable pharmacokinetic and pharmacodynamic outcomes to those of an auto-injector and manual syringe, according to the findings of a study presented at the American Academy of Allergy Asthma and Immunology (AAAAI) in San Antonio, US and which was published as a supplement to the Journal of Allergy and Clinical immunology.
Anaphylaxis is a serious allergic reaction which has a rapid onset and can lead to death, thereby warranting the need for emergency preparedness with epinephrine (adrenaline) autoinjectors, together with knowledge of how these devices should be used. However, some evidence suggests significant differences in patients’ carrying time, confidence in use and training experiences with auto-injectors, particularly EpiPens. The use of an intranasal device has already been explored as an anaphylactic treatment and found to have significant absorption via the this route. Moreover, evidence from 4 studies including 175 patients, also showed that intranasal epinephrine increased systolic blood pressure more efficiently than both manual and auto-injectors, despite achieving lower maximum plasma concentrations.
In the data presented at AAAAI, researchers undertook an open-label, 3-period, cross-over study, in 100 healthy adults to assess the relative bioavailability of a single intranasal dose of epinephrine, 13.2mg and which consisted of two consecutive sprays as opposite and single nostril dosing. These were then compared to an intramuscular 0.3 mg auto-injector and a 0.5 mg manual syringe.
Intranasal epinephrine outcomes
The pharmacokinetic parameters for the 13.2 mg intranasal device was higher than that from the 0.3 mg auto-injector (Cmax, intranasal = 429.4, auto-injector = 328.6). However, the peak epinephrine concentrations were similar for the auto-injector (14 minutes) and the intranasal device (20 minutes) when compared to the manual syringe (45 minutes).
There were also similar pharmacodynamic effects based on changes in systolic blood pressure and heart rate between the auto-injector and intranasal device as well as no safety differences.
The authors concluded that the intranasal form offers a needle-free, convenient and effective dose delivery system for self-administration of epinephrine and which could serve as an alternative to an intramuscular auto-injector for acute anaphylaxis management.
Citation
Dworaczyk D, Hunt A. 13.2mg Intranasal Epinephrine Spray Demonstrates Comparable PK/PD and Safety to 0.3mg Epinephrine Autoinjector. J Clin Allergy Immunol 2023
US and UK researchers have found that increased physical activity reduces the risk of hospitalisation for a wide range of health conditions, highlighting the potential value of this non-pharmacological intervention.
It has become widely recognised that increased physical activity (PA) is associated with a reduced risk of many different types of cancer as well as cardiovascular-related conditions such as diabetes and ischaemic stroke events. However, whether greater levels of PA impact on other less severe health conditions is less clear. Although assessment of PA levels in previous prospective studies has been largely self-reported, this introduces both measurement error and bias. One means of overcoming such limitations is through the use of accelerometers, which can measure the frequency, duration and intensity of any PA.
In the present study, researchers investigated the link between an accelerometer measured change in physical activity and the subsequent risk of hospitalisation for 25 different conditions and which included gallbladder disease, urinary tract infections, pneumonia and iron deficiency anaemia. In addition, the team also estimated the proportion of these hospitalisations which could have been avoided by swapping 20 minutes of sedentary behaviour for 20 minutes of moderate to vigorous physical activity. Researchers used participant data held in the UK Biobank, focusing on those who wore an accelerometer for one week.
Increased physical activity and hospitalisations
Data were available for 81,717 participants with a mean age of 61.5 years (56.4% female) and who were followed for a median of 6.8 years.
Increased levels of accelerometer measured physical activity were associated with a statistically significantly lower risk of hospitalisation for 9 conditions. These included gallbladder disease (Hazard Ratio, HR per 1 standard deviation increase = 0.74, 95% CI 0.69 – 079, p < 0.001), urinary tract infections (HR = 0.76, p < 0.001), pneumonia (HR = 0.83, p < 0.001) and iron deficiency anaemia (HR = 0.91, p = 0.02).
In addition, researchers calculated that replacing 20 minutes of sedentary time with moderate to vigorous activity, also significantly reduced the risk of hospitalisation for many of the conditions, e.g. gall bladder disease (HR = 0.80), pneumonia (HR = 0.86) and iron deficiency anaemia (HR = 0.91).
The authors concluded that increased physical activity was significantly associated with a reduced risk of hospitalisation for a broad range of health conditions and that increasing activity by 20 minutes per day could serve as a useful intervention to improve quality of life.
Citation
Watts EL et al. Association of Accelerometer-Measured Physical Activity Level With Risks of Hospitalization for 25 Common Health Conditions in UK Adults. JAMA Netw Open 2023
Ethnic patients and those from different geographical regions benefit from lipid-lowering therapy despite being under-represented in clinical trials, according to a systematic review by UK and Australian researchers
The benefits of LDL cholesterol-lowering treatment as a preventative strategy against atherosclerotic cardiovascular disease is now well established. Despite this recognition, some evidence points to differences in response between Caucasian and other ethnic patients. For example, one comparative study revealed how the dose of statins and the extent to which LDL-cholesterol is reduced, varied between White and Asian patients. Other work has shown that plasma levels of rosuvastatin and its metabolites are significantly higher in Chinese, Malay, and Asian-Indians compared to White patients. However, while there are apparent ethnic differences in response to lipid lowering therapy, what is less clear, is if this impacts on the incidence of adverse cardiovascular outcomes.
In the current study, researchers undertook a systemic review and meta-analysis of randomised clinical trials, to assess the reductions in cardiovascular events associated with lipid-lowering therapy in not only ethnic patients but different geographic regions. They included statins, ezetimibe and PCSK 9 inhibitors and set the outcome of interest as major adverse cardiovascular events (MACE) which was a composite of cardiovascular mortality, myocardial infarction, stroke and revascularisation.
Ethnic patients and MACE
A total of 53 trials including 329,897 participants with a mean age of 61.8 years (73% male) were included in the analysis. In the trials which reported ethnicities, 60.3% were White, 20.2% Japanese, 9.4% Asian, 5.5% Black and 4.7% Latin American.
When looking across regions, there were reductions in statistically significant reductions in MACE in Australasia (Risk Ratio, RR = 0.75), North America (RR = 0.75), Europe (RR = 0.78) and Japan (RR = 0.73).
When considering ethnicities, there were significant reductions among Black patients (RR = 0.55, 95% CI 0.37 – 0.82) and Japanese (RR = 0.73, 95% CI 0.63 – 0.85) but a non-significant reduction among Asians (RR = 0.76, 95% CI 0.54 – 1.08). In head to head comparisons between regions and different ethnicities, there were no significant differences in the extent of MACE reduction.
The authors concluded that while there was under-representation in clinical trials, ethnic patients and those from different regions appeared to derive at least as much cardiovascular benefit from lipid-lowering therapy as majority groups.
Citation
Sawant S, Wang N. Underrepresentation of ethnic and regional minorities in lipid-lowering randomized clinical trials: a systematic review and meta-analysis. Eur J Prevent Cardiol 2023
2nd March 2023
In an abstract presented at the American Academy of Allergy Asthma and Immunology (AAAAI) 2023 in San Antonio, US and published as a supplement in the Journal of Clinical Allergy and Immunology, dupilumab treatment for 24 weeks, in patients with chronic spontaneous urticaria, already taking H1-antihistamines, led to significant reductions in urticarial activity and improvements in quality of life.
Chronic spontaneous urticaria is an endogenous disorder that is strongly associated with autoimmunity, particularly with immunoglobulin G antibody to the alpha subunit of the IgE receptor. The term ‘chronic urticaria’ relates to urticaria lasting for more than six weeks and has two forms: chronic inducible urticaria and chronic spontaneous urticaria, with the latter giving rise to symptoms independent of an exogenous stimulus. Treatment guidelines published in 2022 recommend the use of second-generation H1-anti-histamines, at a dose of up to four times the usual dose. However, in 2019, a case report described use of dupilumab treatment at an initial dose of 600 mg then 300 mg every two weeks in a patient with therapy resistant chronic spontaneous urticaria. Within three months, the patient’s urticaria duration and severity resolved. Furthermore, in 2022, a randomised, placebo-controlled, phase 3 trial, of dupilumab treatment as an ‘add-on’ to therapy with either standard of < 4-fold antihistamine dosing or matching placebo, showed that after 24 weeks, the least squares mean change in the itch severity score over 7 days and the urticaria activity score over 7 days (UAS7) were both significantly reduced in those given dupilumab treatment.
Dupilumab treatment and urticarial activity
Data presented at the AAAI conference relates to the impact of dupilumab on urticarial activity score over 7 days (UAS7) and quality of life based on the dermatology quality of life index (DLQI). Patients taking an H1-antihistamine (up to fourfold approved dose) were randomised to add-on dupilumab 300 mg (or 200 mg for body weights < 60 kg but > 30 kg) or matching placebo every 2 weeks for 24 weeks.
The results showed that dupilumab treatment produced a significant improvement in the UAS7 score at week 24 (p = 0.0003) as well an improvement in the DLQI (p = 0.0026) compared to placebo.
Citation
Maurer M et al. Dupilumab Improves Urticaria Activity And Quality Of Life In Patients With Chronic Spontaneous Urticaria (CSU). J Allergy Clin Immunol 2023
Use of bimekizumab in patients with both radiographic and non-radiographic axial spondyloarthritis produced significant and rapid improvements in disease outcomes in two parallel randomised trials by a European research group.
Axial spondyloarthritis (axSpA) represents a chronic inflammatory disease involving the axial skeleton that gives rise to chronic back pain and spinal stiffness but which may also include peripheral and extra-musculoskeletal manifestations. The term includes two forms of the condition, those with either radiographic and non-radiographic disease, with patients in this latter group representing those who are symptomatic but no evidence of definitive damage seen on pelvic radiographs.
It has become recognised that the interleukin-17A (IL-17A) pathway is implicated in the pathogenesis of axial spondyloarthritis although IL-17F has also been shown to induce similar inflammatory changes to IL-17 in joints. In fact, use of bimekizumab, which is a dual IL-17A and IL-17F blocker, is effective in psoriatic arthritis, which can also present with axial involvement in up to 50% of patients.
With data from a phase 2IIb trial in active ankylosing spondylitis, proving that bimekizumab was effective, in the current study, researchers undertook two parallel randomised, double-blind, placebo-controlled phase 3 trials of the drug in patients with both forms, i.e., non-radiographic (nr-disease) and radiographic (r-disease) axial spondyloarthritis. Participants with active nr-disease were randomised 1:1 and 2:1 (r-disease) to bimekizumab 160 mg every 4 weeks and from week 16 through to 52, all patients received bimekizumab 160 mg every 4 weeks. The primary endpoint was based on the Assessment of SpondyloArthritis international Society ≥40% improvement (ASAS40), i.e., a 40% improvement is disease severity.
Bimekizumab and disease improvement
At baseline virtually all patients (> 97.6%) had high or very high disease activity. In total, 254 patients with nr-disease and a mean age of 39.4 years (54.3% male) and 332 with r-disease and a mean age 40.1 years (72.2% male) with were included in the analysis.
At week 16, there was a significantly higher proportion of participants achieving an ASAS40 in both trials (nr-disease 47.7% vs 21.4% and r-disease 44.8% vs 22.5%, p<0.001 in both cases). Moreover, improvements became apparent within one to two weeks after starting bimekizumab in both trials.
The most frequent treatment emergent adverse events (i.e. occurring in > 3% of patients) with bimekizumab included nasopharyngitis, upper respiratory tract infection, pharyngitis, diarrhoea, headache and oral candidiasis.
The authors concluded that the use of the dual IL-17A and IL-17F inhibitor bimekizumab gave rise to significant and rapid improvements in patients with both radiographic and non-radiographic axial spondyloarthritis and was well tolerated.
Citation
van de Heijde D et al. Efficacy and safety of bimekizumab in axial spondyloarthritis: results of two parallel phase 3 randomised controlled trials. Ann Rheum Dis 2023
Changing coffee intake from low (< 3 cups/month) to moderate (1 – 7 cups/week) levels in patients with metabolic syndrome over a three year period, reduces total body fat levels and may help as part of a weight management strategy according to an analysis by US and Spanish researchers.
Coffee intake appears to be associated with a wide range of health benefits, so much so that coffee can be considered part of a healthful diet. Moreover, a 2019 meta-analysis concluded that caffeine intake might promote weight, body mass index and body fat reduction which is all the more important given how obesity is a global concern with a 2016 estimate that 1.9 billion adults were overweight and of whom, 650 million were obese. However, rather than total body fat, the distribution of that fat is often more relevant to health risks. For example, visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalised adiposity. Furthermore, in recent years, techniques such as dual-energy x-ray absorptiometry (DXA) have been developed and provide a more accurate means of determining regional adiposity and thus cardiometabolic risk assessment.
In the current study, researchers used data collected from the ongoing PREMED-PLUS trial to assess the association between changes in caffeinated and decaffeinated coffee intake with concurrent changes in DXA-derived adiposity measures. The researchers assessed coffee intake as either low (< 3 cups/month), moderate (1- 7 cups/week) or high (> 1 cup/day) and this data was collected, together with DXA measurements, at baseline, after 6 and 12 months and then after 3 years.
Changes in Coffee intake and adiposity
A total of 1,483 participants with a a mean age of 65.3 years (47.5% women) were included in the study.
After adjustment for potential confounders, those whose coffee consumption increased from low to moderate (1 – 7 cups/week) were found to have a significantly lower total body fat level (Δ z-score of -0.06, p = 0.006) compared to those who maintained a low intake. In addition, trunk fat (-0.07, p = 0.009) and visceral adiposity tissue (-0.07, p = 0.029) were also significantly lowered. In contrast, increasing coffee intake to a higher level (> 1 cup/day) or any change with decaffeinated intake was not associated with changes in DXA measures.
The authors concluded that a small increase in coffee intake appeared to result in a significant reduction in measures of adiposity and may form part of a weight management strategy.
Citation
Henn M et al. Increase from low to moderate, but not high, caffeinated coffee consumption is associated with favorable changes in body fat. Clin Nutr 2023
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