Journal Scan
Journal scan: A review of 10 recent papers of immediate clinical significance, harvested from major international journals
From the desk of the Editor-in-Chief
(1). Grant RW, et al. Updated USPSTF screening recommendations for diabetes, identification of abnormal glucose metabolism in younger adults. JAMA Intern Med. 2021;181(10):1284-6.
The diabetes epidemic in the US continues unabated hand in hand with the concurrent epidemics of obesity and physical inactivity.
At present, there are about 34 million US adults living with type 2 diabetes (10.2% of the US adult population). Another 88 million US adults have abnormal glucose levels that fall short of a diabetes diagnosis (an additional 34.5% of the adult US population). These numbers reflect the fact that nearly 75% of US adults have a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) in the overweight or obese range, and 45% engage in no moderate- or vigorous-intensity physical activity in a typical week.
Despite convincing evidence supporting guidelines for lifestyle change and medical therapy, progress in the control of diabetes-related risk factors (i.e., hypertension, dyslipidemia, hyperglycemia) has plateaued or, in some cases, may have worsened. As a result, millions of individuals remain at risk for the microvascular and macrovascular complications of diabetes, disability, and early mortality.
The gaps in receipt of recommended care are greater for younger adults (aged 18-44 years) and members of at-risk racial and ethnic groups (American Indian/Alaska Native, Asian American, Black, Hispanic/Latinx, and Native Hawaiian/Pacific Islander adults) than for other adults.
In its 2021 recommendation statement, the United States Preventive Services Task Force (USPSTF) has lowered the starting age of screening for prediabetes and type 2 diabetes from 40 to 35 years for adults with overweight or obesity, while maintaining the upper age of screening at 70 years (B recommendation).
The USPSTF recommends that clinicians offer or refer patients with abnormal blood glucose levels to intensive behavioural counselling interventions to promote a healthful diet and physical activity.
To date, however, no high-quality clinical studies have directly shown clinical benefit from screening adults starting at age 35 years for abnormal glucose metabolism. This recommendation is therefore driven by an updated evidence report and systematic review that demonstrates that screening does little direct harm, that individuals can prevent progression to diabetes with intensive lifestyle changes, and that interventions for newly diagnosed diabetes have a moderate benefit in reducing all-cause mortality, diabetes-related mortality, and risk of myocardial infarction after 10 to 20 years of intervention. Indeed, long-term follow-up of the UK Prospective Diabetes Study from the 1980s of tighter glycemic control (for that era, hemoglobin A1c <7%) suggested that earlier rather than later glycemic control among newly diagnosed patients can lead to long-term clinical benefits. An important caveat is that the clinical evidence supporting the recommendation to lower the starting age of screening was derived from studies whose participants were mostly 45 years or older, not 35 years or older.
The updated USPSTF recommendations are similar to the 2021 American Diabetes Association (ADA) B-level recommendation to screen all adults 45 years and older (regardless of BMI) for diabetes and to include adults younger than 45 years with BMI values 25 and higher (or >=23 for Asian Americans) who have at least 1 additional risk factor (e.g., physical inactivity, first-degree relative with diabetes, or at-risk race or ethnicity). Compared with the ADA recommendations, the USPSTF recommendation is broader because it sets a minimum age of 35 years for screening and does not require any additional risk factors other than elevated BMI.
Both the USPSTF9 and ADA13 recommendations highlight the increasing prevalence of abnormal glucose metabolism and diabetes in younger adults, especially among at-risk racial and ethnic groups. A recent study using pooled National Health and Nutrition Examination Survey data from 2005 through 2016 found that 1 in 4 young adults (aged 19-34 years) had abnormal glucose metabolism (defined as fasting plasma glucose levels 100-125 mg/dL, 2-hour plasma glucose levels 140-199 mg/dL, or haemoglobin A1c levels 5.7-6.3%), with higher prevalence in Black and Hispanic/Latinx adults compared with non-Hispanic White adults.
Diabetes in the US is clearly no longer a disease limited to middle-aged and older adults. Lowering the age for screening may facilitate earlier recognition of diabetes, including in the racial and ethnic groups at highest risk, and holds out the promise of reducing long-term disparities in outcomes through weight loss, other lifestyle modification, and the timely initiation of medical treatment.
The rationale for screening asymptomatic individuals is that earlier identification of disease can lead to interventions that reduce the frequency of disease-related adverse outcomes, as compared with asymptomatic individuals who were not screened. This consideration raises 2 questions in the context of increasing the identification of asymptomatic patients with abnormal blood glucose levels, up to and including diabetes: (1) Does earlier recognition and treatment reduce the risk of disease-related adverse outcomes? and (2) Do individuals outside of clinical trials experience benefit from earlier diagnosis? Although the answer to the first question is a qualified yes per the USPSTF evidence report, the answer to the second question is less certain.
Adopting and sustaining healthy lifestyle changes is the foundation of diabetes self-management. Evidence from clinical trials has shown that successfully altering eating and exercise behaviours can reduce progression to diabetes among patients with abnormal glucose levels and, once diabetes is diagnosed, helps to slow the progression of disease. The USPSTF recommendation to lower the starting age for screening is therefore paired with the recommendation that these patients receive intensive behavioural counselling interventions. However, these evidence-based strategies have been challenging to implement in clinical practice owing to barriers such as the intense resources required, limitations on reimbursement, and out-of-pocket costs to patients. If young adults newly identified with abnormal glucose metabolism do not receive the needed intensive behavioural change support, screening may provide no benefit.
Care recommendations for a disease as prevalent as diabetes have implications for both individuals and society. Given the role of our obesogenic and physically inactive society in the shift toward earlier onset of diabetes, efforts to increase screening and recognition of abnormal glucose metabolism must be coupled with robust public health measures to address the underlying contributors. To date, such public health efforts have had limited success in blunting these social factors (e.g., environments with limited access to healthy diet options and safe and convenient physical exercise activities). As one example of the challenges to implementing societal-level changes, laudable efforts by cities to tax sugar-sweetened beverages have been countered by aggressive industry lobbying to increase the adoption of state laws that preempt such local initiatives.
Despite the shortcomings in diabetes prevention and management efforts, the recommendation to actively identify abnormal glucose levels in younger adults presents an opportunity to move the needle on reducing long-term complications. The USPSTF recommendation is thus a call to action for changes in public health programs and health care systems. Younger adults are more likely to have young children and/or full-time jobs than older “traditional” patients with diabetes. Evidence suggests that younger adults face challenges in adapting to the demands of chronic-disease management. Management strategies for younger and ethnically diverse adults will require innovations such as more effective virtual care, after hours and weekend office hours, and culturally tailored care.
An influx of newly diagnosed Black and Hispanic/Latinx young adults with impaired glucose tolerance or diabetes also has the potential to exacerbate disparities in diabetes treatment and outcomes. Given the limited access and high cost of effective treatments, such as behaviour-change support programs, bariatric surgery, and novel pharmacologic therapies (i.e., glucagon-like peptide-1 receptor agonists), there is an urgent responsibility to design and implement successful strategies.
The revised USPSTF recommendations both reflect and underscore the changing demographics of the diabetes epidemic. To what extent will this new USPSTF recommendation change day-to-day practice? In the current environment where less than half of eligible individuals were screened for abnormal glucose under prior USPSTF guidelines, merely expanding the eligible population by reducing the recommended age of screening is unlikely to be an effective strategy for decreasing the burden of diabetes and related adverse clinical outcomes.
To turn this recommendation into action-that is, to translate screening activities into improved clinical outcomes-change is needed at the patient-clinician level (recognizing and encouraging eligible individuals to be screened), health care system level (reducing screening barriers and ensuring access to robust lifestyle programs), and societal level (applying effective public health interventions to reduce obesity and increase exercise). Implementing effective and affordable behavioural change programs that meet the needs and schedules of younger adults from diverse backgrounds is an important step and an achievable goal. Addressing the factors that contribute to unequal access to healthy foods and opportunities for physical activity is a much greater challenge and will require a higher public health priority and increased funding.
(2). Newell LF, et al. Advances in acute myeloid leukemia. BMJ 2021;375:n2026.
Acute myeloid leukemia (AML) is an uncommon but potentially catastrophic diagnosis with historically high mortality rates. The standard of care treatment remained unchanged for decades; however, recent discoveries of molecular drivers of leukemogenesis and disease progression have led to novel therapies for AML.
Ongoing research and clinical trials are actively seeking to personalize therapy by identifying molecular targets, discovering patient specific and disease specific risk factors, and identifying effective combinations of modalities and drugs. This review focuses on important updates in diagnostic and disease classifications that reflect new understanding of the biology of AML, its mutational heterogeneity, some important genetic and environmental risk factors, and new treatment options including cytotoxic chemotherapy, novel targeted agents, and cellular therapies
(3). Sue Pavord, et al. Vaccine induced immunethrombocytopenia andthrombosis: summary of NICE guidance. BMJ 2021;375:n2195.
What you need to know
- Vaccine induced immune thrombocytopenia and thrombosis (VITT) is caused by anti-platelet factor 4 (PF4) antibodies that arise following COVID-19 vaccination and lead to intense activation of platelets and the coagulation system.
- Symptoms begin 5 to 30 days after COVID-19 vaccination and include severe or unusual headaches, new unexplained pinprick bruising or bleeding, shortness of breath, leg swelling, or persistent abdominal pain.
- Thrombosis affects the cerebral veins in 50% of cases, but any arterial or venous vascular bed may be involved and around one third of patients have thrombosis in multiple sites.
- Management includes anticoagulation with non-heparin-based anticoagulants, which should be started as soon as possible, and intravenous immunoglobulin.
- VITT is rare, but thrombotic sequelae can be life threatening and require unconventional management. Report all cases urgently and inform vaccine recipients of when to seek medical attention.
(4). Stefan D. Anker, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451-61.
Background
Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain.
Methods
In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
Results
Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P < 0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P < 0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin.
Conclusions
Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (EMPEROR-Preserved Clinical Trials)
(5). Moriah Bergwerk, et al. COVID-19 breakthrough infections in vaccinated health care workers. N Engl J Med. 2021;385:1474-84.
Background
Despite the high efficacy of the BNT162b2 messenger RNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rare breakthrough infections have been reported, including infections among health care workers. Data are needed to characterize these infections and define correlates of breakthrough and infectivity.
Methods
At the largest medical center in Israel, we identified breakthrough infections by performing extensive evaluations of health care workers who were symptomatic (including mild symptoms) or had known infection exposure. These evaluations included epidemiologic investigations, repeat reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays, antigen-detecting rapid diagnostic testing (Ag-RDT), serologic assays, and genomic sequencing. Correlates of breakthrough infection were assessed in a case-control analysis. We matched patients with breakthrough infection who had antibody titers obtained within a week before SARS-CoV-2 detection (peri-infection period) with four to five uninfected controls and used generalized estimating equations to predict the geometric mean titers among cases and controls and the ratio between the titers in the two groups. We also assessed the correlation between neutralizing antibody titers and N gene cycle threshold (Ct) values with respect to infectivity.
Results
Among 1497 fully vaccinated health care workers for whom RT-PCR data were available, 39 SARS-CoV-2 breakthrough infections were documented. Neutralizing antibody titers in case patients during the peri-infection period were lower than those in matched uninfected controls (case-to-control ratio, 0.361; 95% confidence interval, 0.165 to 0.787). Higher peri-infection neutralizing antibody titers were associated with lower infectivity (higher Ct values). Most breakthrough cases were mild or asymptomatic, although 19% had persistent symptoms (>6 weeks). The B.1.1.7 (alpha) variant was found in 85% of samples tested. A total of 74% of case patients had a high viral load (Ct value, <30) at some point during their infection; however, of these patients, only 17 (59%) had a positive result on concurrent Ag-RDT. No secondary infections were documented.
Conclusions
Among fully vaccinated health care workers, the occurrence of breakthrough infections with SARS-CoV-2 was correlated with neutralizing antibody titers during the peri-infection period. Most breakthrough infections were mild or asymptomatic, although persistent symptoms did occur.
(6). Allyah et al. COVID-19 treatments and vaccines must be evaluated in pregnancy. BMJ 2021;375:n2377.
Pregnant women should be included in drug and vaccine development from the outset.
The numbers of pregnant and postpartum women in the UK admitted to hospital or intensive care because of COVID-19 peaked over the summer. Maternal mortality has reached concerning levels in 2021, with case fatality rates rising in the US, doubling in Brazil, and almost tripling in India since the beginning of the pandemic. In Brazil, health officials even suggested avoiding pregnancy to reduce risk during the pandemic.
Inconsistent messaging from authorities, driven by lack of trial data, has increased COVID-19 vaccine hesitancy among pregnant women. This, coupled with the increased transmissibility of new variants and relaxing of social distancing restrictions, contributed to the surge in hospital admissions seen in successive waves. Concerns around the longer-term effect of COVID-19 post-partum, including long COVID, cardiovascular complications of COVID-19, and widening socioeconomic disparities are also mounting. Despite a desperate need for treatments, pregnant women continue to be left behind.
In the long shadow of the thalidomide and diethylstilboestrol tragedies, only one drug designed for use in pregnancy, atosiban, has been licensed in four decades and only five prescription medicines (amoxicillin, labetalol, diazoxidine injection, doxylamine with pyridoxine, sodium feredetate) are licensed for non-obstetric use in pregnancy in the UK. A sobering 98% of all marketed drugs have insufficient or no safety data to guide dosing during pregnancy and lactation. This includes all COVID-19 vaccines.
Vaccination in pregnancy is not a new concept; nor are the struggles with uptake. Concerns about COVID-19 vaccination, like previous vaccines, have centred around fears of side effects for the fetus, doubts regarding efficacy, and even doubts around the need for immunisation. These concerns have been further compounded by misinformation regarding fertility, suspicion of the swift rollout of vaccines, and the exclusion of pregnant women from preapproval trials, with levels of vaccine hesitancy highest in deprived communities and among those from ethnic minority groups.
Vaccination is currently recommended in pregnancy based on developmental and reproductive toxicology studies in animals, a positive risk-benefit profile in women of childbearing age, and post-marketing data from vaccinated pregnant women and their infants, rather than clinical trials. Despite cumulative data from over 200,000 pregnant women showing the effectiveness of vaccination, low public confidence remains. Decisions around booster programmes are still evolving, but it is likely some pregnant women will fall into the prioritised eligible groups. The effect of vaccine hesitancy may, worryingly, cross over to other vaccinations such as influenza. It is essential to eradicate endemic off-label prescribing in pregnancy, which excludes women and their babies from the protections afforded by the rigours of the licensing process and creates unacceptable ethical and legal dilemmas for clinicians.
Routes to change
There are clear routes to improvement. Medicines regulators in Europe, the US, and the UK have recently taken a positive step by supporting “maternity investigation plans,” which build on the successes of paediatric investigation plans (PIPs) and orphan products. The introduction of PIPs through European legislation in 2007, mandated that medicines developers evaluate the needs of children for all new products. Orphan designation revitalised medicines development for rare diseases, and the US approved 31 products (58% of all approvals) for rare diseases in 2020.
Regulators effectively enlivened research into these areas by offering incentives alongside obligations. Creative measures included a centralised procedure for the designation of orphan medicinal products, fee waivers, and scientific support from early development through to market authorisation. Both PIPs and orphan designation offer market exclusivity extensions after authorisation, with PIPs extending market protection to drugs no longer covered by patents, if they are then exclusively developed for use in children. A similar premise could be used to repurpose marketed drugs with a known safety profile for indications in pregnancy.
Additional strategies that can be readily implemented to invigorate development of drugs for pregnancy include prioritisation of developmental and reproductive toxicology studies at the start of drug development, consideration of physiologically based pharmacokinetic modelling, and ensuring pregnancy experts are involved in clinical trial development and in trial steering and monitoring committees. Consulting women and organisations representing their interests and those of their babies is key to ensuring pregnancy is not routinely used to exclude people from trials without clear scientific grounds.
These measures would encourage medicine developers in expanding fields, such as biological medicines, to include pregnant women from the start of the process. Monoclonal antibodies, for example, are likely to be strong therapeutic candidates for use during pregnancy among people with target conditions, potentially including COVID-19. The strong antigen affinity of monoclonal antibodies makes them highly effective with minimal off-target activity, and placental transfer is likely to be limited, particularly during organogenesis.
The COVID-19 pandemic is radically changing the clinical trials landscape, catalysing collaborative drug development between academics, industry, and regulators, and accelerating implementation of research findings. Equity and inclusion are essential to scientific advancement, and the benefits of innovation and drug discovery should safely reach everyone. We urge regulators and governments to implement these strategies for pregnant women and their babies, who for so long have been left behind in medicines and vaccines development. An urgent shift in policy and investment is required to ensure that inclusion becomes the norm for pregnancy in development plans, unless otherwise fully justified. This will help counter vaccine hesitancy and improve confidence in the use of new treatments, leading to better health outcomes for women and their babies.
(7). Rachel Horton, et al. Care of men with cancer-predisposing BRCA variants. BMJ 2021;375:n2376.
What you need to know?
Men and women are equally likely to inherit or pass on a cancer-predisposing BRCA variant-family history of cancers needs to encompass both sides of the family.
Men with cancer-predisposing BRCA variants have an increased risk of developing breast cancer and are advised to be breast aware.
Men with cancer-predisposing BRCA2 variants have an increased risk of developing aggressive prostate cancer (men with cancer-predisposing BRCA1 variants may also have an increased risk); it is not yet known whether prostate specific antigen screening reduces mortality in men with cancer-predisposing BRCA variants.
The European Association of Urology recommends that PSA screening is offered to men with cancer-predisposing BRCA2 variants from 40 years of age after discussion of the risks and benefits.
Around one in 260 men (~0.4%) inherits a cancer-predisposing BRCA variant that increases their risk of developing prostate, pancreatic, and breast cancer and may affect the health of their family. Most of these men are currently unaware that they have a cancer-predisposing BRCA variant, but as genetic testing becomes more common, more men will need medical advice about what having such a variant means for them and their families.
Men are just as likely as women to have a cancer-predisposing BRCA variant, but many people perceive these variants as only being relevant to women. Paradoxically, this could lead to women at very high risk of breast and ovarian cancer missing out on screening and risk-lowering treatment despite a concerning paternal family history. Clinicians might also be less attuned to paternal family history of cancer in assessing women’s breast cancer risk. This practice pointer covers what cancer-predisposing BRCA variants are, who might be tested; and what health issues men and their clinicians need to know about.
(8). Michelle Sholzberg, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with COVID-19 admitted to hospital: RAPID randomised clinical trial. BMJ 2021;375:n2400.
Abstract
Objective: To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with COVID-19 admitted to hospital wards.
Design: Randomised controlled, adaptive, open label clinical trial.
Setting: 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US.
Participants: 465 adults admitted to hospital wards with COVID-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n = 228) or prophylactic dose heparin (n = 237).
Interventions: Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death.
Main outcome measures: The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated.
Results: The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m2. At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P = 0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P = 0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P = 0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P = 0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P = 0.69).
Conclusions: In moderately ill patients with COVID-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial
(9). Sina Naghshi, et al. Current evidence on dietary intakes of fatty acids and mortality. BMJ 2021;375:n2379.
Findings from the associations between dietary intakes of different fatty acids and longevity are of particular interest to researchers, healthcare providers, and patients. Based on our meta-analysis of 41 articles from cohort studies, dietary intake of alpha linolenic acid (ALA) was associated with a reduced risk of mortality from all causes, cardiovascular disease, and coronary heart disease, and a slightly higher risk of cancer mortality. In a mixed diet, however, ALA is consumed with other fatty acids with different effects. Therefore, finding the effects of other fatty acids might help us to determine the overall effect of a diet that includes fats.
Why fatty acids matter in healthy diets
Adherence to healthy diets can delay the onset of cardiovascular disease (CVD) and cancer and improve longevity. Fatty acids are the major components of these diets. Findings on the associations between different types of fatty acids and mortality are, however, inconsistent. In this Fast Facts article, we summarize the available findings.
Saturated fatty acids
Saturated fatty acids contain carbon-to-carbon single bonds only. Palmitic acid, stearic acid, and myristic acid are the most common saturated fatty acids found in animal products, including dairy, red meat, egg, coconut and palm oils, and chocolate. A meta-analysis of cohort studies revealed no evidence of a positive association between intake of saturated fatty acids and deaths from CVD and coronary heart disease. Disregarding intakes of other types of fats might be a reason for the statistically non-significant associations found in the meta-analysis. This claim was further confirmed when a review study concluded that a lower intake of saturated fatty acids, coupled with a higher intake of polyunsaturated and monounsaturated fatty acids, was associated with a lower risk of CVD and other major causes of death. For cancer related mortality, findings are inconclusive. Future studies should therefore determine the link between intake of saturated fatty acids and cancer risk or cancer mortality.
Trans fatty acids
Trans fatty acids are produced by industry through partial hydrogenation of liquid plant oils or are naturally available in meat and dairy products. Vaccenic acid (natural) and elaidic acid (industrial) are the most common trans fatty acids in diet. A meta-analysis of six cohort studies showed positive associations between intake of trans fatty acids and risks of all cause and coronary heart disease mortality. Also, evidence suggests a positive association between intake of dietary trans fatty acids and cancer. In line with these findings, randomised controlled trials have shown that replacement of calories from other types of fats with those from trans fatty acids raises levels of low density lipoprotein cholesterol, apolipoprotein B, triglycerides, and Lp(a) lipoprotein and lowers levels of high density lipoprotein cholesterol and apolipoprotein A1. Overall, the suggestion to restrict trans fatty acids from the diet might be an optimal strategy for reducing the risk of cancer and cardiometabolic disease and increasing longevity. Recent evidence, however, suggests that the adverse effects of trans fatty acids are related to industrial trans fatty acids and that natural trans fatty acids are safe.
Omega 6 fatty acids
Polyunsaturated fatty acids contain more than one double bond in their carbon chain. Biologically relevant families are omega 6 and omega 3 fatty acids. These two classes of fatty acids are not converted to each other. The most abundant type of omega 6 fatty acid is linoleic acid, which is metabolised to arachidonic acid and subsequently to some prostaglandins, leukotrienes, and thromboxanes that are involved in inflammatory responses. The main sources of linoleic acid are plant oils, whole grains, nuts, and seeds. Based on a meta-analysis of 44 prospective cohort studies, a high intake of linoleic acid was associated with a modestly lower risk of mortality from all causes, CVD, and cancer. A review study considered all fatty acids and reported that dietary intake of linoleic acid, in replacement of saturated fatty acids or carbohydrates, had moderate benefits for preventing CVD. However, because linoleic acid is a precursor for producing compounds involved in inflammatory responses, more studies are needed to confirm the health benefits of this fatty acid.
Omega 3 fatty acids
In the family of omega 3 fatty acids, much attention has been paid to ALA, eicosapentaenoic acid, and docosahexaenoic acid. ALA is readily available in soybean, nuts, canola oils, flaxseed, and other plant food sources and is metabolised to eicosapentaenoic acid and docosahexaenoic acid, both of which have anti-inflammatory properties. Eicosapentaenoic acid and docosahexaenoic acid are long chain polyunsaturated fatty acids available in seafoods. In our meta-analysis, we found that dietary intake of ALA was associated with a reduced risk of mortality from all causes, CVD, and coronary heart disease, and a slightly higher risk of cancer mortality. Also, a meta-analysis on marine sources of omega 3 fatty acids indicated an inverse association with all cause mortality. In line with the meta-analyses of cohort studies, a meta-analysis of 45 clinical trials showed that supplementation with omega 3 fatty acids was associated with improved lipid profile, inflammation, and glycaemia in people with diabetes. Despite the beneficial effects of omega 3 fatty acids, recommendations for intakes should be made cautiously because ALA intake might slightly increase the risk of cancer mortality. Further studies are, however, needed to confirm the increased risk.
Omega 9 fatty acids
Omega 9 fatty acids often have one double bond and therefore are considered as monounsaturated fatty acids. The major omega 9 fatty acid in the food supply is oleic acid, which is available in nuts and vegetable oils, particularly olive oil. A meta-analysis of 17 cohort studies showed that intake of monounsaturated fatty acids was associated with a reduced risk of all-cause mortality, with no statistically significant association with CVD and cancer mortality. In a meta-analysis of 32 cohort studies, however, dietary intakes of monounsaturated fatty acids, olive oil, and oleic acid were associated with an overall risk reduction of mortality from all causes, CVD, and stroke. It seems that the link between intake of monounsaturated fatty acids and cancer is unclear and further studies are needed.
Conclusion
Evidence suggests that a diet with a high amount of omega fatty acids, a low amount of saturated fatty acids, and zero to a low amount of trans fatty acids might improve health outcomes and increase longevity. Further studies are still needed to assess the association between ALA and cancer and between omega 6 fatty acids and inflammatory based diseases. Future studies should also determine the effects of a diet high in fatty acids and low in saturated and trans fatty acids on health outcomes.
(10). Orla O’Carroll. Treatments for poorly controlled asthma. BMJ 2021;375:n2355.
What you need to know
In a patient with worsening symptoms of asthma, confirm the diagnosis and address possible causes of worsening, including treatment adherence, comorbidities, and environmental factors.
Combined inhaled corticosteroids with long acting β agonists (LABA) as single maintenance and reliever therapies are associated with reduced exacerbations and improved asthma related quality of life compared with traditional dual maintenance and reliever therapies.
LABA monotherapy is not recommended owing to increased risk of exacerbations and asthma related death.
Written asthma plans given to patients as part of a supported self-management strategy help reduce hospitalisation and emergency department attendances.
Treatments for poorly controlled asthma.
A 35-year-old man with a prior diagnosis of mild asthma presents to his general practitioner with a three-month history of intermittently waking at night with cough and shortness of breath. He works as a chef and has found it difficult to complete a full shift during this time. He has been prescribed beclometasone 200 μg twice a day for a long time and asks if there is a need to change his treatment in light of his new persistent symptoms.
Poorly controlled or moderate asthma occurs when patients experience either daily symptoms of asthma, nocturnal awakenings, more than two exacerbations per year, or some limitation of their daily activities. With frequent alterations of guidelines, and continual development of new medications and delivery devices, choosing a suitable treatment strategy can pose a challenge in clinical practice. In this article, we present the latest guidance on drugs used in primary care for poorly controlled asthma in adults.
What treatments are available for poorly controlled asthma?
ICS/LABA combination
Inhaled corticosteroids (ICS, e.g., beclometasone dipropionate, budesonide, fluticasone furoate, etc) and long acting β agonists (LABA, e.g., formoterol, salmeterol, vilanterol, etc) are the mainstay of treatment for poorly controlled or moderate asthma. ICS suppress airway inflammation leading to reduced bronchial hyperresponsiveness. LABAs act on bronchial smooth muscle β adrenoceptors and cause bronchodilation. ICS and LABA are typically prescribed as a single fixed dose combination inhaler rather than in separate inhalers for better efficacy, safety, adherence, and convenience.
National and international guidelines-Global Initiative for Asthma, National Institute for Health and Care Excellence (NICE), British Thoracic Society/Scottish Intercollegiate Guidelines Network, and the National Asthma Education and Prevention Program (American)-suggest two options for commencing ICS and LABA treatments in moderate persistent asthma. The Single Maintenance and Reliever Therapy (SMART or MART) protocol recommends ICS and a fast acting LABA as both maintenance and rescue treatment for relief from symptoms (for example, low dose budesonide-formoterol or beclomethasone-formoterol). Alternatively, ICS plus LABA (ICS/LABA) can be combined with a short acting β agonist (SABA) as needed as reliever treatment.
Montelukast
The guidelines recommend montelukast in patients whose symptoms are not well controlled despite adequate dosing of ICS/LABA treatments and good adherence. Montelukast is a leukotriene receptor antagonist (LTRA). It blocks the production of cysteinyl leukotrienes which are potent broncho-constricting and proinflammatory mediators. This results in enhanced bronchodilation and reduced airway mucus production.
Newer treatments
Patients whose asthma is severe and poorly controlled with the above drugs can be considered for newer add-on treatments. These include long acting muscarinic antagonists (LAMAs), azithromycin, and biological therapies. They are usually prescribed in specialist settings after careful evaluation of a patient’s symptoms, and consideration of risks and benefits.
How well do they work?
Two Cochrane reviews published in 2013 compared budesonide and formoterol as maintenance and reliever therapy (MART) with inhaled corticosteroids alone or as combination therapy for maintenance with any reliever treatment for chronic asthma. SMART was associated with reduced exacerbation rates requiring hospitalisation or emergency department visits (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57 to 0.90; I2 = 0%, P = 0.66), oral corticosteroids (OR 0.75, 95% CI 0.65 to 0.87; I2 = 0%, P = 0.82) and lower overall ICS total daily dose. The strength of evidence that SMART reduces hospitalisations or emergency department visits is weak (one fewer per 100 treated than in the control group, 95% CI, 0 to 2 fewer). Two fewer people needed a course of oral steroids per 100 treated (95% CI 1 to 3 fewer) with SMART compared with alternative regimens. Two randomised controlled trials (RCTs) published in 2013 showed similar results with use of the SMART regimen. Most studies are industry sponsored, and do not include children and adolescents. A post-hoc analysis of industry sponsored trials reported similar efficacy and safety for SMART regimens in adolescents (12-17 years). Few studies have directly compared the efficacy of various ICS preparations and have shown comparable effects.
Very limited evidence is available for montelukast in patients with poorly controlled asthma. An open label industry sponsored trial (1681 participants) reported that addition of oral montelukast to ICS or ICS + LABA improved asthma control and asthma related quality of life over six months in adults with insufficiently controlled asthma. LTRAs have been shown to decrease sputum eosinophilia,fraction of exhaled nitric oxide, airway inflammation, and bronchial hyperresponsiveness, but the clinical relevance of these outcomes is not established. LTRAs may have a role in managing exercise induced asthma, aspirin exacerbated respiratory disease (which includes non-steroidal anti-inflammatory drug intolerance), and in patients with asthma and elevated body mass index, but this evidence comes from small single studies.
What are the harms?
Few studies assess the risk of systemic adverse effects associated with the use of ICS in asthma. A Cochrane review found that the rate of serious adverse events (e.g., hospitalisation, intensive care admission, intubation) was 23 per 1000 patients in a pooled analysis of patients taking ICS plus salmeterol compared with 21 per 1000 patients taking ICS alone. ICS is generally considered safe at low to medium doses (<1000 µg beclomethasone dipropionate equivalent per day). Local side effects include dysphonia and oral candidiasis. These can be mitigated with careful attention to oral or throat hygiene, good inhaler technique, and the preferential use of spacer devices or valved holding chambers to reduce oropharyngeal deposition.
Higher doses of ICS are associated with systemic side effects; in particular, adrenal insufficiency. About 6.8% of patients on ICS experience adrenal insufficiency, according to a systematic review. These doses are not routinely used for treatment of mild to moderate asthma but some patients may be on higher cumulative doses before treatment is escalated in response to persistent symptoms. NICE recommends that patients on high dose ICS (>1000 µg/day beclomethasone dipropionate or 1600 µg/day for budesonide or equivalent) carry a steroid warning card.
LABA monotherapy is associated with an increased risk of severe asthma attacks leading to hospitalisation and asthma related death, 282930 and is discouraged by all major asthma guidelines. LABAs are combined with ICS in all fixed dose combination inhalers to prevent substitution of ICS maintenance therapy with LABA monotherapy.
Montelukast can have neuropsychiatric adverse effects including nightmares, aggression, and depression. A case series reported development of eosinophilic granulomatosis with polyangiitis with use of LTRAs, sometimes linked to weaning of corticosteroids, but causation has not been established.
How are they given and monitored?
Confirm the diagnosis of asthma in any patient with worsening symptoms, ideally by observing for reversible airflow limitation. Table 2 lists aspects to cover on initial assessment and potential causes of reduced asthma control to address before considering a change in medication.
If a change in medication is indicated, prescribe ICS/LABA combinations at the lowest dose of ICS possible to achieve symptomatic control. The aims of treatment are to minimise disruptive symptoms, improve the patient’s asthma related quality of life, and prevent exacerbations and worsening. Most inhaled corticosteroids are prescribed for use twice daily. Ciclesonide is a once daily preparation associated with lower incidence of oral candidiasis compared with fluticasone at equivalent doses. Fluticasone furoate is a once daily preparation available in some countries, including the US and Japan, as a standalone ICS and is more widely available as a combination ICS/LABA (vilanterol) inhaler preparation. Arrange a regular review to assess symptom control.
Choosing the appropriate inhaler device for a patient is important to optimise dosing schedule, adherence to therapy, and avoidance of critical errors in inhaler technique. When switching from single to combination inhalers, ensure that the equivalent ICS dosing is not lower than the patient’s current treatment.
With SMART regimens daily dosing varies in response to symptoms. Guidelines recommend a maximum safe daily dose. Dosing is capped at 72 μg metered dose for budesonide-formoterol and 48 μg metered dose for beclomethasone-formoterol. Provide patients with a written action plan tailored to the specific ICS prescribed, outlining how to change their dosing schedule in response to symptom triggers including exacerbation. Self-management involves patient education reinforced by an asthma action plan and supported by regular review. A meta-review (27 systematic reviews and 13 RCTs) showed that supported self-management for asthma can reduce hospitalisations, emergency department attendances, and unscheduled consultations in specialist and primary care.
Given the uncertain benefits of montelukast and potential adverse reactions, discuss the risks and benefits with your patient before commencing this medication.
How cost effective are they?
Few studies have compared cost effectiveness of individual ICS. A review article suggested that fluticasone propionate was associated with a marginal cost benefit over budesonide, but this effect was not seen at higher doses of ICS. An analysis of cost effectiveness in the UK and other European countries in 2006 found that SMART is more cost effective compared with the alternative dosing strategy of LABA/ICS plus SABA reliever. The current availability of generic preparations suitable for use in SMART protocols will have reduced the costs further.
The cost of inhaler devices can differ and can sometimes be a barrier to compliance. Discuss with your patient the expected costs when choosing a suitable inhaler device. Sustainability is another factor in inhaler choice. Metered dose inhalers (MDIs) contain hydrofluorocarbons, which are potent greenhouse gases that contribute significantly to the carbon footprint. A simple switch from MDI to equivalent dry powder inhaler (DPI) could reduce the yearly carbon footprint of an asthmatic patient by a similar amount as would be achieved by switching to a plant-based diet (approximately 455 CO2 equivalent).
Tips for patients
Always take your asthma medication as prescribed.
Your doctor may provide written advice (asthma action plan) on how to change how often you take your inhaler if you develop symptoms or feel an asthma attack coming on. It’s important to recognise changes in your symptoms so that you can follow this asthma plan correctly.
Peak flow meters can be useful when changing your inhaler frequency according to your asthma plan.
Inhalers can sometimes be difficult to use. If you have any doubt about how to take your inhaler, contact your pharmacist or GP.
Some inhalers can cause fungal infections in the mouth (white coating of your mouth or tongue) and this may require medication to treat. Report this to your doctor.
Rinse your mouth after taking your inhaler if it contains an inhaled steroid. This can prevent fungal mouth infections from developing.
