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5th October 2022
The mortality benefit of high-flow nasal cannula (HFNC) oxygen therapy in those with COVID-19 and respiratory failure remains uncertain and was examined in a recent randomised trial by the SOHO-COVID Study Group.
According to a 2019 meta-analysis, in patients with acute hypoxaemic respiratory failure, high-flow nasal cannula oxygen flow, while not affecting mortality, was found to decrease the risk of requiring intubation or escalation of oxygen therapy. Moreover, a further study in critically ill patients with COVID-19 found that HFNC significantly reduced intubation and subsequent invasive mechanical ventilation but did not affect mortality. Other work among those with severe COVID-19 has also shown that HFNC significantly decreased need for mechanical ventilation support and the time to clinical recovery compared with conventional low-flow oxygen therapy. In contrast, data from the RECOVERY group found that the requirement for tracheal intubation or mortality within 30 days was not significantly different between an initial strategy of HFNO compared with conventional oxygen therapy. Prior to the pandemic, there has been conflicting data on the mortality benefits of HFNO in patients with acute respiratory failure. Some evidence indicates that there is a mortality benefit whereas other data suggests that in critically ill immunocompromised patients with acute respiratory failure, high-flow oxygen therapy did not significantly decrease day-28 mortality compared with standard oxygen therapy.
For the present study, researchers set out to establish if HFNO compared to standard oxygen impacted on 28-day mortality in patients with COVID-19 admitted to an intensive care unit (ICU). Individuals were randomised to HFNO or standard oxygen which was delivered through a non-rebreathing mask. The primary outcome was set as 28-day mortality and there were 13 secondary outcomes including, for example, the proportion of patients who required intubation.
High-flow nasal oxygen and 28-day mortality
A total of 711 patients with respiratory failure and a mean age of 61 years (30% female) were randomised to HFNO (357) or standard oxygen.
For the primary outcome, 28-day mortality occurred in 10% of those receiving HFNO and 11% of patients given standard oxygen and this difference was not significant (adjusted odds ratio, aOR = 0.78, 95% CI 0,48 – 1.28, p = 0.32).
Out of all the secondary outcomes, only the need for intubation at day 28 was significantly different between the two groups, favouring the use of HFNO (aOR = 0.65, 95% CI 0.48 – 0.89, p = 0.007).
The authors concluded that in patients with respiratory failure due to COVID-19, the use of high-flow nasal oxygen was no better than standard oxygen with respect to 28-day mortality.
Frat JP et al. Effect of High-Flow Nasal Cannula Oxygen vs Standard Oxygen Therapy on Mortality in Patients With Respiratory Failure Due to COVID-19: The SOHO-COVID Randomized Clinical Trial JAMA 2022
3rd October 2022
Combining glargine or liraglutide with metformin is significantly, albeit modestly, more effective at maintaining a glycated haemoglobin target than either glimepiride or sitagliptin according to the findings of a 5-year study by the GRADE Study Research Group.
Data from 2017 suggest that approximately 462 million individuals were affected by type 2 diabetes (6.28% of the world’s population) and with over 1 million annual deaths attributable to the condition, making it the ninth leading cause of mortality. The fact that improved blood-glucose control decreases the progression of diabetic microvascular disease as been known for many years and can be assessed using the level of glycated haemoglobin (HbA1c). In a recent meta-analysis it was concluded that the optimal HbA1c range for type 2 diabetes is 7.1-7.7% regardless of diabetes duration. Moreover, the European Society of Cardiology Guidelines have suggested that glucose control to target a near-normal HbA1c (<7.0% or <53 mmol/mol) will decrease the frequency and severity of microvascular complications in patients with diabetes. Metformin is a recommended by the guidelines as a first-choice treatment in overweight patients with type 2 diabetes and without cardiovascular disease and in those at moderate cardiovascular risk. However, if this fails to provide adequate diabetic control, there is a lack of clarity over which second treatment should be added to achieve control. This was the purpose of the GRADE study and designed to inform decisions about the clinical effectiveness of addition of four classes of diabetes medications to metformin.
Patients with type 2 diabetes were given metformin and during a 6 to 14 week run-in period, the dose of the drug was increased to at least 1000 mg daily but with a target dose of 2000 mg daily. Four medications could be added to metformin to maintain disease control: insulin glargine; glimepiride; liraglutide or sitagliptin and participants were randomised to one of these four treatments in addition to metformin. The primary metabolic outcome was a metabolic failure, defined as a glycated haemoglobin of 7% or higher.
Glargine and diabetic control
A total of 5047 participants with a mean age of 57.2 years (63.6% male) and a mean body mass index of 34.3 were included in the study. Across the whole cohort, the mean duration of diabetes was 4.2 years and participants were followed for 5 years.
Over the 5-year follow-up period, 71% of the cohort had a primary metabolic outcome event, i.e., did not achieve the target glycated haemoglobin level of less than 7%. This was highest for those taking sitagliptin (77.4%), followed by glimepiride (72.4%), liraglutide (68.2%) and lowest for glargine (67.4%). Using a global test of differences across groups, this finding was significant (p < 0.001). However, when comparing the rate/100 participant-years, the values for each of the drugs were broadly similar, ranging from 26.5% (glargine) to 38.1% (sitagliptin).
In pairwise comparisons, the risk of the primary outcome was significantly lower with glargine than with sitagliptin (hazard ratio, HR = 0.71, 95% CI 0.64 – 0.78, p < 0.001). It was also lower for liraglutide compared with sitagliptin (HR = 0.69, 95% CI 0.63 – 0.76, p < 0.001).
The authors concluded that while all four treatments when added to metformin improved glycated haemoglobin, glargine and liraglutide were significantly, though modestly, more effective at achieving and maintaining target levels.
The GRADE Study Research Group. Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes N Engl J Med 2022
30th September 2022
A study presented at the European Association for the Study of Diabetes (EASD) annual meeting by Norwegian researchers suggests that the risk of developing new-onset type 1 diabetes is significantly elevated among children and adolescents, more than 30 days after an infection with COVID-19.
Type 1 diabetes (TID) is a chronic, autoimmune disease that is influenced by both genetic and environmental factors and characterised by the destruction of insulin-producing cells. It also appears to be on the increase with a 2019 study finding that the pooled estimate across European centres continued to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. There is some data to suggest that the onset of type 1 diabetes can be initiated after respiratory infections that give rise to the common cold, influenza-like illness, sinusitis, and laryngitis/tracheitis. Moreover, while some evidence suggests that COVID-19 can trigger severe diabetic keto-acidosis in those with new-onset diabetes, there is no hard evidence that the virus can induce T1D.
As a result, for the study presented at EASD, the Norwegian team undertook nationwide register-based study to test whether infection with COVID-19 was associated with an increased risk of developing TID in children and adolescents. Using the Norwegian preparedness register that is updated daily with individual-level data on PCR-confirmed COVID-19 infections, vaccinations and disease diagnoses from primary and secondary health care, the team linked individual level data for children and adolescents. Individuals were then followed from the start of the pandemic (March 1st 2020) until diagnosis of type 1 diabetes, age 18 years, death, until March 2022 (whichever came first). The researchers used both a test-negative design and a full population cohort to examine the relationship between the first type 1 diabetes diagnosis within or after 30 days post-COVID-19 infection. The results were expressed as hazard ratios which were adjusted for age, sex, non-Nordic country of origin, geographical area and socio-economic factors.
Type 1 diabetes and COVID-19 infection
A total of 424,354 children with COVID-19 infection (of 1,202,174 children included at study start) and 990 incident cases of T1D were identified .
Using the test negative design, the adjusted HR for type 1 diabetes at least 31 days after COVID-19 infection was 1.63 (95% CI 1.08 – 2.47, p = 0.02). However, less than 30 days post-infection, the adjusted hazard ratio was not significant (HR = 1.25, 95% CI 0.72 – 2.17, p = 0.42).
For the whole population cohort, the adjusted hazard ratio was 1.57 (95% CI 1.06 – 2.33, p = 0.03) and again was not significant for less than 30 days post-infection.
Based on these findings, the authors concluded that COVID-19 infection is associated with increased risk of subsequent T1M.
Gulseth HL et al. SARS-CoV-2 infection and subsequent risk of type 1 diabetes in 1.2 million children
29th September 2022
Neoadjuvant therapy (NAT) prior to surgery in patients with DNA mismatch repair deficient (dMMR) colon cancer gave rise to a major pathologic response of 95% according to the findings by Dutch researchers presented at the recent European Society of Medical Oncology Congress.
The World Health Organisation estimated that in 20202, there were 1.93 million cases of colorectal cancers and which gave rise to 916 000 deaths. Moreover, defective DNA mismatch repair (dMMR) occurs in approximately 15% of sporadic colorectal cancers and evidence indicates that patients with dMMR colon cancers do not benefit from treatment with adjuvant 5-fluorouracil chemotherapy. In the Nivolumab, Ipilimumab and COX2-inhibition in Early Stage Colon Cancer: an Unbiased Approach for Signals of Sensitivity (NICHE) trial, patients with stage 1-3 adenocarcinoma of the colon and with no signs of distant metastases, were treated with short-term immunotherapy (nivolumab and ipilimumab) and COX2-inhibitors prior to surgical resection of the tumour. The results showed that a pathological response was observed in 20/20 dMMR tumours, with 19 major pathological responses (i.e., ≤10% residual viable tumour, RVT) and 12 pathological complete responses.
Based on these findings, researchers instigated NICHE-2 in which patients with non-metastatic dMMR colon cancer received NAT with 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab in the first cycle, then only nivolumab in the second cycle 2 weeks later, followed by surgery within 6 weeks of enrolling on the trial. They set the primary end points as 3-year disease-free survival (DFS) and safety with secondary end points including major pathological response (MPR) and complete response. For the purposes of the study, a pathologic response (PR) was defined as ≤ 50% residual viable tumour (RVT) and MPR as ≤ 10% RVT.
Neoadjuvant therapy treatment outcomes
A total of 112 patients with a median age of 60 years (58% female) were enrolled. For 107 patients included in the efficacy analysis, baseline radiologic assessment revealed 89% to be at stage III, 77% high-risk stage III and 64% T4 tumours. The median time between the first dose of neoadjuvant therapy and surgery was 5 weeks.
A pathologic response was observed in 106/107 (99%) patients with 95% achieving a MPR and a complete response was observed in 67% of patients with 4% achieving a partial response. After a median follow-up of 13 months none of the patients had disease recurrence.
Grade 3-4 immune-related adverse events were observed in 3% of patients and only 3 experienced delay in surgery, meeting the safety primary endpoint.
The authors concluded by stating that ‘the first survival data suggest a strong potential for neoadjuvant immunotherapy to become standard of care and allow further exploration of organ-sparing approaches.’
Chalabi M et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study LBA7
RP2 oncolytic mono-therapy has been shown in a phase 1 study to provide an objective response in a small number of patients as well as in combination with nivolumab according to findings presented at the recent European Society for Medical Oncology congress.
RP2 oncolytic therapy involves genetically engineered viruses designed to target and kill cancer cells while sparing normal cells and activating the host immunity to recognise and attack the tumour. The current RP2 therapy makes use of the herpes simplex virus (HSV) and which acts as a multifaceted gene therapy vector, carrying genes encoding immunostimulatory molecules in its genome. The oncolytic effect of HSV and the inflammatory response that the virus stimulates provide a one-two punch at attacking tumours. The first oncolytic virus therapy to be approved by the FDA in 2015 was T-VEC for the treatment of patients with metastatic melanoma that cannot be surgically removed. T-VEC was also approved by the EMA in 2016. As well as killing tumour cells, RP2 oncolytic therapy induces production of human granulocyte-macrophage colony-stimulating factor (GM-CSF) which has been shown to promote anti-tumour immunity in mice and humans. It also leads to the production of anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule since CTLA-4 indirectly facilitates tumour progression by restraining host anti-tumoral immunity. Consequently, blockage of CTLA-4 function promotes immune-mediated tumour regression.
In the phase 1 open-label trial discussed at the congress, PR2 was used as both mono-therapy and combined with nivolumab in a cohort of 30 patients with nivolumab given at a dose of 240 mg twice weekly for 4 months from the second RP2 dose, then 480 mg every four weeks for 20 months. Patient’s response to treatment were assessed using the modified RECIST v1.1.
RP2 oncolytic therapy outcomes
All patients involved in the trial had advanced cancers which had failed to respond to, or were not eligible for, standard of care options.
An objective response with RP2 mono-therapy was seen in 3 of 9 patients and which included 1 complete response for longer than 15 months in a patient with mucoepidermoid carcinoma, one partial response for over 18 months in oesophageal cancer with liver metastases and a partial response in uveal melanoma with liver metastases that progressed at 15 months. Objective responses with RP2 and nivolumab were seen in 44.4% of those with cutaneous melanoma, 25% in uveal melanoma and 33% in squamous cell carcinoma of the head and neck.
Immuno-histochemistry analysis of the tumour site revealed a robust increase in CD8 T cell influx, PD-L1 expression, and an increase in the CD8/foxp3+ cell ratio. Clinical responses were independent of baseline CD8 T cell infiltration, PD-L1 expression levels, and prior anti-PD-1 therapy status.
In a statement on the Institute for Cancer Research site, study leader Professor Kevin Harrington said ‘our study shows that a genetically engineered, cancer-killing virus can deliver a one-two punch against tumours – directly destroying cancer cells from within while also calling in the immune system against them.’ He added that ‘our initial trial findings suggest that a genetically engineered form of the herpes virus could potentially become a new treatment option for some patients with advanced cancers – including those who haven’t responded to other forms of immunotherapy. I am keen to see if we continue to see benefits as we treat increased numbers of patients.’
Inspiratory muscle strength training (IMST) for a period of six weeks results in a significant reduction in both systolic and diastolic blood pressure compared to sham strength training according to a review of studies by US researchers.
Elevated systolic blood pressure is a leading cause of global deaths, accounting for 10·4 million deaths and 218 million disability-adjusted life-years. Lifestyle interventions to lower blood pressure include increased physical activity, weight loss and adoption of a healthy (lower salt) diet. Another intervention which has gained interest in recent years is inspiratory muscle strength training which has been previously used to help wean patients off mechanical ventilation in hospital. Moreover, IMST has also been shown to be of some value by increasing peak power in recreational cyclists. Nevertheless, IMST has also been shown to reduce blood pressure and autonomic cardiovascular control in hypertensive patients. In recent years, high-resistance low volume inspiratory muscle strength training which involves 30 daily inspiratory efforts against a resistance equal to 75% of an individual’s maximal inspiratory pressure, has emerged as a time-efficient lifestyle intervention (requiring only 5 minutes) to lower blood pressure. The technique has already been shown to lower blood pressure and may potentially improves vascular endothelial function. Nevertheless, to date, most blood pressure lowering studies have only included a small number of participants. Consequently, for the present study, the US researchers pooled data from 5 randomised trials to provide a better estimate of the blood pressure lowering effect of IMST. The trials included young adults, some of whom were taking blood pressure lowering medication but who overall had a low-to-moderate cardiovascular disease risk. Individuals were randomised to either high-resistance IMST or low-resistance (or sham) IMST and each of the trials lasted 6 weeks. Participants performed 30 inspiratory efforts every day as a single bout, comprising 5 sets of 6 inspiratory efforts.
Inspiratory muscle strength training and blood pressure changes
Data from 128 adults were included of whom 67 with a mean age of 50 years (43.2% female) were assigned to high-resistance IMST and the remainder a sham procedure.
After 6 weeks, systolic blood pressure remained unchanged in the sham group but decreased from a mean of 127 mmHg to 118 mmHg in the high resistance IMST group and this difference was statistically significant (p < 0.01). In addition, systolic blood pressure was observed to decline by an average of 1.5 mmHg per week.
After 6 weeks, the mean diastolic pressure was also significantly lower in the high resistance IMST group (72 vs 76 mmHg, p < 0.01) and significantly lower than for the sham procedure which also reduced by a mean of 1 mmHg (p = 0.03).
The maximal inspiratory pressure (which is a measure of the strength of the inspiratory muscles, in particular the diaphragm) improved in both groups, but to a significantly higher level for the high resistance group (20 cmH2O vs 6 cmH2O, p < 0.01).
The authors noted that reductions in both systolic and diastolic pressures also occurred for those taking antihypertensive medication but that the effect was smaller.
They concluded that high resistance IMST induced clinically meaningful reductions in blood pressure and provide support for this technique as a time-efficient lifestyle intervention to lower blood pressure.
Craighead DH et al. A multi-trial, retrospective analysis of the antihypertensive effects of high-resistance, low-volume inspiratory muscle strength training J Appl Physiol (1985) 2022
Tumour-infiltrating lymphocyte therapy (TILT) provided superior progression-free survival to immune checkpoint inhibitor therapy with ipilimumab in a phase 3 trial of patients with advanced melanoma according to the findings of a study presented at the European Society for medical Oncology (ESMO) Congress by Dutch researchers.
Tumour-infiltrating lymphocyte therapy is a type of adoptive cellular therapy in which infiltrated lymphocytes are removed from a patient’s tumour and grown in large numbers in a laboratory. These cells are then infused back into the patient to help the immune system kill the cancer cells. In fact, studies have already suggested that TILT can mediate a durable complete responses in patients with metastatic melanoma with similar efficacy irrespective of prior treatment. In a phase 2 open-label trial, Lifileucel, which is an autologous, centrally manufactured tumour-infiltrating lymphocyte product, demonstrated durable responses, addressing a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy. However, to date, there have been no phase 3 trials examining the value of tumour-infiltrating lymphocyte therapy in patients with advanced melanoma.
The current study was a multicentre, open-label phase 3 trial of patients with unresectable stage IIIC-IV melanoma, aged between 18 and 75 and who were randomised 1:1 to TILT or ipilimumab (3mg/kg q3wks, max 4 doses). Individuals were stratified for BRAFV600 mutation status, treatment line and centre. Those receiving TILT underwent resection of a melanoma lesion (2-3cm) for the ex vivo outgrowth and expansion of tumour resident T cells. The researchers set the primary endpoint as progression-free survival (PFS) per RECIST 1.1 whereas secondary endpoints were (overall and complete) response rate, overall survival (OS) and safety.
Tumour-infiltrating lymphocyte therapy and progression-free survival
A total of 168 patients, the majority (86%) of whom were refractory to anti-programmed cell death-1 ligand treatment, received TILT (84) or ipilimumab.
After a median follow-up of 33 months, the median PFS was 7.2 months for TILT (95% CI 4.2 – 13.1) compared to 3.1 months (95% CI 3.0 – 4.3) for ipilimumab, giving a hazard ratio, HR of 0.50 (95%CI 0.35 – 0.72, p < 0.001).
The overall response rate was 49% for TILT but only 21% for ipilimumab and 20% of those receiving TILT achieved a complete response compared to 7% for ipilimumab. The median OS for TILT was 25.8 months and 18.9 months for ipilimumab. Moreover, grade ≥3 treatment-related adverse events occurred in all TILT patients but only and 57% of those assigned to ipilimumab.
The authors concluded that TILT therapy significantly improved PFS compared to ipilimumab, adding that since the vast majority of those included in the trial were anti-PD-1 refractory, TILT was a potential new treatment option in this patient population.
A caffeine genotype is associated with a longer prostate cancer specific survival among men who drink higher amounts of coffee in comparison to other genotypes, according the findings of a study by an international team of researchers.
Prostate cancer the 2nd most common cancer in men worldwide and there were more than 1.4 million new cases in 2020. One possible lifestyle factor that may have a protective role against the development of prostate cancer is intake of coffee. In fact, a 2015 meta-analysis of 13 cohort studies including 539,577 participants concluded that coffee consumption may be associated with a reduced risk of prostate cancer and it that there was also has an inverse association with non-advanced prostate cancer.
Caffeine is metabolised by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme although single nucleotide polymorphisms (SNPs) have been identified which impact on the speed with which caffeine is metabolised giving rise to differences in caffeine genotype. For example, rs762551 (also known as -164A>C or -163C>A) is a SNP encoding the CYP1A2*1F allele of the CYP1A2 gene (which metabolises caffeine). Furthermore, rs762551 SNP can affect CYP1A2 enzyme activity and has been used to categorise individuals as either ‘fast’ (AA genotype) or ‘slow’ (AC or CC genotype) caffeine metabolisers. Moreover, there is some data to suggest that individuals with a ‘fast’ caffeine genotype with localised prostate cancer and a low to moderate coffee intake, are less likely to experience grade progression than non-consumers. Based on this earlier work, suggesting that a caffeine genotype may affect prostate cancer survival, for the present study, researchers examined the association between coffee intake, rs762551 genotype and survival among men with prostate cancer. Using data from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium, researchers included individuals with the caffeine genotype of interest (i.e., -163C>A rs762551). Coffee consumption before their diagnosis of prostate cancer was categorised as none/very low (0 to 3 or more cups/week); low’ (3 or more cups/week) or high (2 or more cups/day). The low consumption level was used as the reference point for statistical analysis.
Caffeine genotype and prostate cancer survival
The whole cohort comprised 5,727 men with a median age of 63 years and who consumed a median of 2.5 cups of coffee/day. Individuals were followed for a median of 5.1 years. In the overall cohort there were 906 deaths including 481 due to prostate cancer.
A high intake of coffee was associated with a 15% lower (but non-significant) reduction in prostate cancer-specific survival in the overall cohort (Hazard ratio, HR = 0.86, 95% CI 0.68 – 1.08, p = 0.19). A similar, non-significant reduction was also observed for overall survival (HR = 0.90, 95% CI 0.77 – 1.07, p = 0.24).
For men in the group with localised disease, a higher intake of coffee was associated with a significantly longer prostate cancer-specific survival (HR = 0.66, 95% CI 0.44 – 0.98, p =0.04). However, among those with more advanced disease (e.g., node positive, distant metastases), higher coffee intake was not associated with better survival (HR = 0.92, 95% CI 0.69 – 1.27, p = 0.60).
When researchers considered survival among those with different caffeine genotypes, those with the AA genotype (i.e., the fast metabolisers), there was a significantly longer prostate cancer specific survival (HR = 0.67, 95% CI 0.49 – 0.93, p = 0.017) for the highest level of coffee intake. In contrast, this relationship was non-significant for the other genotype (AA/CC) examined (HR = 1.04, 95% CI 0.74 – 1.47, p = 0.8).
The authors concluded that coffee intake was associated with longer prostate cancer specific survival among men with a CYP1A2 -163AA genotype and suggested that this finding would require further replication.
Gregg JR et al. Coffee Intake, Caffeine Metabolism Genotype, and Survival Among Men with Prostate Cancer. Eur Urol Oncol 2022
28th September 2022
Semaglutide 2.4 mg given as a weekly subcutaneous injection to patients with obesity but without type 2 diabetes in combination with diet and exercise, led to a significant reduction in their 10-year risk of developing type 2 diabetes compared to placebo according to the findings of a study by US researchers presented at the 58th European Association for the Study of Diabetes (EASD) 2022.
Obesity is a major public health challenge and several lines of evidence from both observational and clinical studies over the past 30 years have clearly demonstrated a strong link between visceral and ectopic fat and the development of a clinical syndrome characterised by atherogenic dyslipidaemia, hyper-insulinaemia/glucose intolerance, hypertension, atherosclerosis and adverse cardiac remodelling and heart failure. Although diet and exercise are recommended as a first step to reduce obesity, some evidence shows that among obese individuals who have lost weight, multiple compensatory mechanisms encouraging weight gain, can persist for at least 12 months after weight loss. Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved as an adjunct to diet and exercise in adults with insufficiently controlled type 2 diabetes mellitus. However, the STEP 1 trial showed that semaglutide at a dose of 2.4 mg weekly in combination with a lifestyle intervention could also result in sustained, clinically relevant reductions in body weight among patients with a body mass index (BMI) > 30. Moreover, in a further trial (STEP 4), researchers examined the effect of continuing vs withdrawing treatment with semaglutide on weight loss maintenance and showed that after a 20-week run-in period, maintaining treatment with semaglutide 2.4 mg once weekly, compared with switching to placebo resulted in continued weight loss over the following 48 weeks.
With clear evidence that semaglutide could lead to weight loss, whether this also reduced an individual’s risk of developing type 2 diabetes was unclear and was the objective of the study presented at the EASD meeting. Researchers used data from both STEP 1 and 4, to assess an individual’s 10-year risk of developing type 2 diabetes. The team used the cardiometabolic disease staging tool which uses three unmodifiable factors (age, sex, and race) and five modifiable factors (BMI, blood pressure, glucose level, high-density lipoprotein (HDL) cholesterol, and triglycerides) to predict an individual’s percentage risk of developing the disease over the next 10 years.
Semaglutide and 10-year diabetes risk
For the STEP 1 trial, the 10-year risk scores of developing T2D after 68 weeks of treatment decreased from 18.2% to 7.1% with semaglutide 2.4 mg, and 17.8% to 15.6% with placebo (p < 0.01). In STEP 4, most of the risk score reduction with semaglutide 2.4 mg occurred during weeks 0-20, from 20.6% to 11.4% but the risk score decreased further to 7.7% with continued semaglutide 2.4 mg during weeks 20-68 but increased to 15.4% after a switch to placebo (p < 0.01). In addition, data from STEP 4 showed that weight loss was 11% for weeks 0 – 20 and a further 9% with continued semaglutide 2.4 mg vs a 6%
regain with switch to placebo for weeks 20 – 68.
The authors concluded that treatment with semaglutide 2.4 mg reduces the 10-year risk of T2D by
~60% adding that sustained treatment was required to maintain this benefit but suggested that semaglutide 2.4 mg could help prevent type 2 diabetes in people with obesity.
Use of tofersen in patients with amyotrophic lateral sclerosis (ALS) with mutations in the gene encoding for superoxide dimutase 1 (SOD1), reduced cerebrospinal fluid levels of the SOD1 protein and neurofilament light chain (a marker of axonal damage) but failed to improve clinical endpoints. This was the interim conclusion of an on-going study by researchers from the VALOR and OLE working groups.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord and has a prevalence of approximately 6 cases per 100 000. ALS is both relentless and incurable and begins with a progressive paralysis and usually leads to death within 3 to 5 years of diagnosis. However, in the majority of cases, the intellect appears to remain intact while the motor system degenerates. While the cause remains uncertain, superoxide dismutase 1 (SOD1), which is an antioxidant enzyme that protects cells from reactive oxygen species toxicity, was the first gene in which mutations were found to be causative for ALS. Moreover, around 2.3% of ALS cases are due to SOD1 mutations.
Tofersen is an antisense oligonucleotide that bind to the SOD1 mRNA and in doing so, prevents it from being read, thereby stopping SOD1 protein production and potentially slowing disease progression. The present study is part of the VALOR trial which is divided into three parts, A, B and C. The first two parts evaluated the safety, tolerability, and pharmacokinetics of ascending doses of tofersen in adults with ALS and a SOD1 mutation, whereas the primary objective of Part C was to evaluate the clinical efficacy of tofersen. VALOR was a phase 3, double-blind, randomised trial that included 24 weeks of treatment and a follow-up period of 4 – 8 weeks and then an on-going open-label extension phase. Eligible patients were randomised 2:1 to intrathecal tofersen (100 mg) or placebo administered as three doses once every two weeks, then five doses once every 4 weeks for a total of 24 weeks. Upon completion of VALOR, participants could opt to continue in the open-label phase, lasting up to 236 weeks. In the present analysis, researchers reported data at week 52. In their analysis, participants were classed as an ‘early-start’ cohort, i.e., where they had been randomised to tofersen from the start of the trial and ‘delayed-start’ where individuals randomised to placebo, switched to active treatment for the open-label phase. In addition, the trial included a group of patients estimated to have either faster or slower disease progression. The primary efficacy endpoint in VALOR was a change from baseline to week 28 in the Amyotrophic lateral sclerosis Functional Rating scale-Revised (ALSFRS-R score) which is a measure of functional capacity (ranging from 0 to 48, with higher scores indicating better function). Secondary outcomes included cerebrospinal fluid concentrations of SOD1 protein, plasma neurofilament light chains, the percent of the predicted slow vital capacity and the handheld dynamometry megascore, which provided a measure of strength and again, with higher scores meaning greater strength.
Tofersen and ALS outcomes
A total of 108 participants with 42 unique SOD1 mutations were enrolled, 72 given tofersen, of which 39, were deemed to be in the faster progression group. The mean ALSRFS-R score among the tofersen group was 36.9. In addition, 62% of those in the tofersen group were also prescribed riluzole and 8% edaravone.
For the primary outcome, the adjusted mean change in ALSFRS-R score was -8.14 in the placebo group and -6.98 in the tofersen group which was not significantly different (mean difference = -1.2, p = 0.97). There were also no significant differences for the secondary outcomes although in the faster progressing group SOD1 proteins were reduced by 29% in those receiving tofersen compared to an increase of 16% in the placebo group. Similarly, there was a 60% reduction in neurofilament light chains in the tofersen-treated faster progression group compared to a 20% increase in the placebo group.
For the open-label extension group, at 52 weeks, the change in ALSFRS-R score from the VALOR baseline was -6.0 points for early-start participants compared to -9.5 points for the delayed-start group. In other words, patients who started tofersen earliest, irrespective of whether they were fast or slower progressing, had a small decline in ALSFRS-R score. Other differences indicative of improvements between early and delayed starters compared to the VALOR baseline were also seen with predicted slow vital capacity (-9.4% vs -18.6%, early vs delayed) and for handheld dynamometry megascore (-0.17 vs -0.45, early vs delayed)
The authors concluded that while there was no significant difference in the decline in a composite measure of ALS progression for patients given tofersen compared to placebo, the potential effects of early vs later use of the drug is being further investigated in the open-label extension study.
Miller TM et al. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS New Eng J Med 2022