Volume 2 - Issue 11

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). Evans E, et al. Epinephrine before defibrillation in patients with shockable in-hospital cardiac arrest: propensity matched analysis. BMJ 2021;375:e066534.

Objective: To determine the use of epinephrine (adrenaline) before defibrillation for treatment of in-hospital cardiac arrest due to a ventricular arrhythmia and examine its association with patient survival.

Design: Propensity matched analysis.

Setting: 2000-18 data from 497 hospitals participating in the American Heart Association's Get With The Guidelines-Resuscitation registry.

Participants: Adults aged 18 and older with an index in-hospital cardiac arrest due to an initial shockable rhythm treated with defibrillation.

Interventions: Administration of epinephrine before first defibrillation.

Main outcome measures: Survival to discharge; favorable neurological survival, defined as survival to discharge with none, mild, or moderate neurological disability measured using cerebral performance category scores; and survival after acute resuscitation (that is, return of spontaneous circulation for > 20 min). A time dependent, propensity matched analysis was performed to adjust for confounding due to indication and evaluate the independent association of epinephrine before defibrillation with study outcomes.

Among 34820 patients with an initial shockable rhythm, 9630 (27.6%) were treated with epinephrine before defibrillation, contrary to current guidelines. In comparison with participants treated with defibrillation first, participants receiving epinephrine first were less likely to have a history of myocardial infarction or heart failure, but more likely to have renal failure, sepsis, pneumonia, and receive mechanical ventilation before in-hospital cardiac arrest (P < 0.0001 for all). Treatment with epinephrine before defibrillation was strongly associated with delayed defibrillation (median 3 min v 0 min). In propensity matched analysis (9011 matched pairs), epinephrine before defibrillation was associated with lower odds of survival to discharge (25.2% v 29.9%; adjusted odds ratio 0.81, 95% confidence interval 0.74 to 0.88; P < 0.001), favorable neurological survival (18.6% v 21.4%; 0.85, 0.76 to 0.92; P < 0.001), and survival after acute resuscitation (64.4% v 69.4%; 0.76, 0.70 to 0.83; P < 0.001). The above findings were consistent in a range of sensitivity analyses, including matching according to defibrillation time.

Conclusions: Contrary to current guidelines that prioritize immediate defibrillation for in-hospital cardiac arrest due to a shockable rhythm, more than one in four patients are treated with epinephrine before defibrillation, which is associated with worse survival.

(2). Schon KR, et al. Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders:cohort study. BMJ 2021;375:e066288.

Objective: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.

Design: Cohort study.

Setting: National Health Service, England, including secondary and tertiary care.

Participants: 345 patients with suspected mitochondrial disorders recruited to the 100000 Genomes Project in England between 2015 and 2018.

Intervention: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.

Main outcome measure: Definite or probable genetic diagnosis.

Results: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis.

Conclusion: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

(3). Rajesh S, et al. Practice Guidelines: Obstructive sleep apnoea/hypopnoea syndrome and obesity hyperventilation syndrome in over 16s: summary of NICE guidance. BMJ 2021;375:n2360.

What you need to know:

Not all people with obstructive sleep apnoea/hypopnoea syndrome (OSAHS) are sleepy (some are tired, fatigued, or have insomnia), so do not rely exclusively on sleepiness scores for referral.

Continuous positive airway pressure (CPAP) therapy can reduce symptom burden in people with symptomatic mild OSAHS.

CPAP therapy remains the first choice of treatment for moderate and severe OSAHS.

Mandibular advancement splints have a role in symptomatic mild OSAHS and in those with moderate or severe OSAHS who do not tolerate CPAP or decline to try CPAP.

Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) affects around 5% of adults in the UK, while obesity hypoventilation syndrome (OHS) is estimated to affect 0.3-0.4% of the general population. In addition to sleepiness, OSAHS may present with a range of symptoms including insomnia and difficulties concentrating, and it can lead to hypertension and exacerbate pre-existing cardiovascular disease. People with OHS are at higher risk of cardiovascular complications and have higher mortality compared with non-obese people.

This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE) guideline for obstructive sleep apnoea/hypopnoea syndrome and obesity hypoventilation syndrome in adults (over 16 years old). The guideline, published in August 2021, covers diagnosis and management of OSAHS, OHS, and COPD-OSAHS overlap syndrome. This guideline summary discusses only selected recommendations on OSAHS and OHS, focusing on those most relevant to primary care.

(4). Ledingham JM, et al. COVID-19: surging demand for some arthritis drugs. BMJ 2021;375:n2700.

The importance of systemic inflammation in covid-19 morbidity and mortality drove interest in other immunomodulatory medications. Tocilizumab is a monoclonal antibody that inhibits interleukin-6 (IL-6) and is used to reduce symptoms and prevent disease progression in moderate-to-severe rheumatoid arthritis. In 2018, tocilizumab became the first targeted therapy licensed for giant cell arteritis, providing a much-needed treatment option for patients with steroid refractory disease. It is also licensed to treat systemic and polyarticular juvenile idiopathic arthritis and cytokine release syndrome after chimeric antigen receptor T cell (CAR-T) therapy. The NHS in England spent an estimated £55m on tocilizumab in 2017–18.

In November 2020, NHS England and the devolved administrations issued an interim statement permitting use of tocilizumab for patients with severe covid-19 pneumonia who require respiratory support or intensive care. This followed publication of data showing improvements in survival and other outcomes after treatment with IL-6 inhibitors.1213 The US FDA granted emergency use authorisation for tocilizumab for severe covid-19 in June 2021, and in July the World Health Organization added tocilizumab for severely or critically ill patients to its covid-19 patient care guidelines.

Demand for tocilizumab has subsequently increased substantially worldwide. Roche, the manufacturer, issued a statement in August 2021 highlighting a global surge in demand, which had increased by over 400% in the US alone since the start of the pandemic.

The manufacturing processes for biological drugs such as tocilizumab are complex, and the capacity to rapidly scale up production is more limited than for other drugs. The unprecedented increase in demand for tocilizumab has resulted in global supply shortages. In September, the Australian Therapeutic Goods Administration warned that intravenous tocilizumab stocks would run out unless usage was reduced by 75%. And shortages in the subcutaneous formulation of tocilizumab mean that patients in the UK are now restricted to no more than four weeks' supply at a time.

Global shortages raise important questions around how to prioritise and conserve the use of potentially lifesaving medications such as tocilizumab. Patients with some rheumatic diseases have few other treatment options (for example, those with giant cell arteritis or systemic juvenile idiopathic arthritis), and some countries have prioritised these patients for treatment with IL-6 inhibitors. Patients with other diseases such as rheumatoid arthritis have alternative options, including tumour necrosis factor-α inhibitors, Janus kinase inhibitors, B cell depletion therapy, and T cell co-stimulatory blockade. However, not all options are available or effective for everyone. Furthermore, changes to treatment increase the risk of disease flares, which in turn increase the risk of covid-19. Reducing the dose of IL-6 inhibitors may be another option for patients who are in remission, but again this increases the risk of disease flares.

(5). Banerjee A. Long covid: new wine in need of new bottles. BMJ 2021;375:n2736.

William Osler famously said, "Listen to the patient, he is telling you the diagnosis." For long covid, patients have not only told us the diagnosis since April 2020, but also gave a clear steer as to how we should proceed with this new disease: "recognition, research, and rehabilitation." We have made mixed progress across these areas.

It is not hard to see why we have not always been successful in responding to long covid. From HIV/AIDS to Ebola, emerging disease threats with coordinated international responses are usually acute and infectious. A new chronic condition, albeit as a post-acute complication of SARS-CoV-2 infection, requires new ways of thinking across clinical, public health, policy, and academic disciplines. Whether it be the World Health Organisation (WHO), governments, or research funders, emergency preparedness has tended to exclude chronic and post-infectious disease management, but long covid must change that.

Recognition of a new disease requires it to be classifiable and recordable, facilitating monitoring, research, and treatment. SNOMED CT codes for long covid were developed and released in the UK in November 2020, followed by ICD-10 codes and a WHO case definition in June and October of 2021. However, the uptake of these codes is still low in the UK2 and worldwide, leading to a systematic underestimation of the disease burden of long covid in routine care, despite high estimated prevalence from self-reported surveys (e.g. 1.7% of the UK population as of 5 September 2021).

As the UK enters a second winter of the pandemic, long covid is still Cinderella at the ball of covid-19 discourse. The vast majority of policy documents, political discussions, research, and public health interventions over the past two years have tackled the acute impact of SARS-CoV-2, with limited consideration of its long term sequelae. Even when we've faced Groundhog Day moments of rising cases and hospitalisations, the argument for avoiding and managing long covid has been neglected by policy makers-whether it be as a reason to suppress infection, increase vaccination rates, protect the NHS, or avoid economic downturn. We know the inevitability of countries worst affected by the pandemic experiencing a chronic burden of morbidity, yet there is still no policy recognition of the scale of threat from long covid.

The good news is that research is now being funded at scale. The National Institute for Health Research (NIHR) has so far funded two rounds of research focused on long covid, awarding £18.6 million for four studies in February 2021, and £19.6 million for 15 studies in July 2021.7 For example, in the STIMULATE-ICP study (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways), in which I am a lead investigator, we will be conducting the largest trial on long covid to date. We will be recruiting more than 4500 people to test the effectiveness of existing drugs by measuring the effect of three months' treatment on symptoms, mental health, and other outcomes such as returning to work. We will also assess the use of MRI scans to help diagnose potential organ damage, as well as digitally enhanced rehabilitation to track patients' symptoms and recovery.

In the US, the National Institutes of Health announced in September 2021 that US$470 million would be dedicated to long covid research projects.8 Across countries, and even across the NIHR portfolio of projects, from epidemiology and health economics to treatment interventions and core outcome datasets, clinically relevant research is happening at pace.

Rehabilitation for a new chronic disease such as long covid relies on the right health system responses and the right research. Yet some commentators have raised concerns that not enough research is being done as services are implemented. The ITU management of acute covid occurred simultaneously with platform trials such as RECOVERY-an approach that worked well. Similarly, long covid research, including trials, must happen at the same time as dedicated services are rolled out across countries, to support integrated care for the hundreds of thousands of affected individuals already seeking investigation and treatment.

Health professionals and academics may see boundaries between clinical service versus research, or between primary and secondary care, but patients do not, and our solutions shouldn't either. The acknowledgment of the limitations of our current knowledge needs to be combined with a willingness to move in a changing landscape, whether that means shifting definitions of hospitalised versus non-hospitalised long covid, using rapidly emerging preclinical data to understand and test underlying mechanisms, or testing treatments in general patient populations in order to establish disease subtypes. Where academic expertise is not yet developed or established, funding and advisory panels need to incorporate greater frontline clinical and lived experience.

When it comes to long covid, traditional models of care and research need to move pragmatically, adaptively, iteratively, and rapidly, considering dissemination and implementation in parallel-otherwise, we risk finding the answers after the train has left the station.

(6). Male V. Menstrual changes after covid-19 vaccination. BMJ 2021;374:n2211.

Common side effects of covid-19 vaccination listed by the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) include a sore arm, fever, fatigue, and myalgia. Changes to periods and unexpected vaginal bleeding are not listed, but primary care clinicians and those working in reproductive health are increasingly approached by people who h6.ave experienced these events shortly after vaccination. More than 30000 reports of these events had been made to MHRA's yellow card surveillance scheme for adverse drug reactions by 2 September 2021, across all covid-19 vaccines currently offered

Most people who report a change to their period after vaccination find that it returns to normal the following cycle and, importantly, there is no evidence that covid-19 vaccination adversely affects fertility. In clinical trials, unintended pregnancies occurred at similar rates in vaccinated and unvaccinated groups. In assisted reproduction clinics, fertility measures and pregnancy rates are similar in vaccinated and unvaccinated patients.

MHRA states that evaluation of yellow card reports does not support a link between changes to menstrual periods and covid-19 vaccines since the number of reports is low relative to both the number of people vaccinated and the prevalence of menstrual disorders generally. However, the way in which yellow card data are collected makes firm conclusions difficult. Approaches better equipped to compare rates of menstrual variation in vaccinated versus unvaccinated populations are needed, and the US National Institutes of Health has made $1.67m (£1.2m; €1.4m) available to encourage this important research.

Menstrual changes have been reported after both mRNA and adenovirus vectored covid-19 vaccines,1 suggesting that, if there is a connection, it is likely to be a result of the immune response to vaccination rather than a specific vaccine component. Vaccination against human papillomavirus (HPV) has also been associated with menstrual changes. Indeed, the menstrual cycle can be affected by immune activation in response to various stimuli, including viral infection: in one study of menstruating women, around a quarter of those infected with SARS-CoV-2 experienced menstrual disruption.

Biologically plausible mechanisms linking immune stimulation with menstrual changes include immunological influences on the hormones driving the menstrual cycle or effects mediated by immune cells in the lining of the uterus, which are involved in the cyclical build-up and breakdown of this tissue. Research exploring a possible association between covid-19 vaccines and menstrual changes may also help understand the mechanism.

Although reported changes to the menstrual cycle after vaccination are short lived, robust research into this possible adverse reaction remains critical to the overall success of the vaccination programme. Vaccine hesitancy among young women is largely driven by false claims that covid-19 vaccines could harm their chances of future pregnancy. Failing to thoroughly investigate reports of menstrual changes after vaccination is likely to fuel these fears. If a link between vaccination and menstrual changes is confirmed, this information will allow people to plan for potentially altered cycles. Clear and trusted information is particularly important for those who rely on being able to predict their menstrual cycles to either achieve or avoid pregnancy.

We are still awaiting definitive evidence, but in the interim how should clinicias counsel those who have experienced these effects? Initially, they should be encouraged to report any changes to periods or unexpected vaginal bleeding to the MHRA's yellow card scheme. This will provide more complete data to facilitate research into any link and signal to patients that their concerns about vaccine safety are taken seriously, building trust. In terms of management, the Royal College of Obstetricians and Gynaecologists and the MHRA recommend that anyone reporting a change in periods persisting over several cycles, or new vaginal bleeding after the menopause, should be managed according to the usual clinical guidelines for these conditions.

One important lesson is that the effects of medical interventions on menstruation should not be an afterthought in future research. Clinical trials provide the ideal setting in which to differentiate between menstrual changes caused by interventions from those that occur anyway, but participants are unlikely to report changes to periods unless specifically asked. Information about menstrual cycles and other vaginal bleeding should be actively solicited in future clinical trials, including trials of covid-19 vaccines.

(7). 100 years of insulin: a technical success but an access failure. Lancet 2021;398(10313):P1777.

The isolation of insulin in 1921 and its subsequent delivery to a 14-year-old boy in a diabetic coma in Toronto in 1922 was a ground-breaking scientific and clinical achievement that has transformed diabetes care and is celebrated in this themed issue of The Lancet. But despite the altruistic sentiments of the discoverers—Banting, Best, Collip, and Macleod-that "insulin belongs to the world", the lack of access to insulin over the past 100 years reflects an appalling policy and implementation failure.

A Review describes the scale of the problem when it comes to insulin access in low-income and middle-income countries. There is a paucity of data-fewer than half of countries in central and east Asia and western sub-Saharan Africa have the necessary policies and registries to account accurately for the numbers and needs of patients with diabetes. Globally, an estimated 76% of children with type 1 diabetes are unable to stay within the recommended glycaemic ranges, putting them at risk of life-threatening short-term and long-term complications. More than 50% of patients with type 2 diabetes are unable to receive the insulin they need. A lack of data makes knowing how these failures affect life expectancy hard to quantify. But in one longitudinal study with 20-year follow-up from Soweto, South Africa, the mortality rate for people with type 1 diabetes was 43%. Early deaths from type 1 and type 2 diabetes globally have increased by 5% since 2000, in stark contrast to premature deaths from other non-communicable diseases, which have been decreasing.

When it comes to insulin access, cost is a major barrier. Global production and supply of insulin are dominated by three companies—Novo Nordisk, Eli Lilly, and Sanofi. Despite efforts such as the WHO prequalification of insulin, which aimed to encourage more insulin manufacturers and lower costs, together with the inclusion of long-acting insulin analogues and their biosimilars on the WHO Essential Medicines List (human insulin has been on the list since 1977), insulin remains unaffordable for many people. A move this year from the WHO Essential Medicines List expert committee to create a working group on highly priced essential medicines is welcome.

In the USA, a quarter of the 7 million patients taking insulin have reported difficulties in affordability. A Perspectives piece documents how a century of controversial pricing practices, including price fixing, has led to repeated market failures and continued unnecessary deaths in the USA. Insulin pricing has been subject to the worst type of regulatory capture, where policy and regulatory processes work to the benefit of a few greedy drug companies rather than serving the needs of people who require insulin. A Comment highlights the need to focus on the structural racism that complicates insulin access pricing for racially marginalised Americans, who are both more likely to be prescribed insulin and more likely to be from low-income, uninsured, or underinsured populations that are unable to pay for it.

Research and development have focused on incrementally newer insulin analogues-some of which have unclear evidence of increased effectiveness despite higher costs-and continuous glucose monitoring apparatus that are out of reach to most patients globally. The result is that little has changed in how patients with type 1 diabetes are treated in much of the world over the past 100 years. Along with difficulty in getting insulin, many patients do not have access to basic blood glucose monitoring, diagnosis continues to be a problem, and access to patient education is limited.

A hopeful step is the creation of the WHO Global Diabetes Compact, which brings together private and public sectors to work on three main areas: improving access to insulin and accompanying diabetes treatment products, building resilient health systems, and involving those living with diabetes in the conversation. There is also a focus on improving the prevention of type 2 diabetes. The Compact's success in improving insulin access will rest on whether public–private partnerships are sufficiently meaningful to catalyse change and transparency.

Globally, around 80% of patients living with diabetes live in low-income and middle-income countries, yet most interested parties continue to pursue a research agenda driven by high-income needs. A focus on bridging the information gap with better data, frugal innovation, and concentrating on advances for low-resource settings will help. But for the next 100 years to atone for the past, the market for insulin and the companies that drive it must be made to serve those most in need.

(8). Matthew A, et al. Blood pressure lowering in the prevention of type 2 diabetes. 2021;398(10313):P1778-1779.

Hypertension increases the risk for many conditions, including ischaemic heart disease, heart failure, stroke, and kidney disease. Hypertension frequently coexists with diabetes as obesity increases the risk of developing both conditions. In patients with diabetes, two-thirds also have hypertension. In the USA, four of the top ten causes of death are associated with hypertension (i.e., heart disease, stroke, diabetes, and renal disease). Thus, strategies that reduce comorbidities associated with hypertension are important.

In the Lancet, Milad Nazarzadeh and colleagues present an individual participant data meta-analysis of 145939 patients (57439 [39 4%] women) from 19 randomised trials. The authors explored the relationship between blood pressure reduction, therapies used, and the subsequent risk of developing diabetes. For every 5 mm Hg reduction in systolic blood pressure, the risk of diabetes fell by 11% (hazard ratio [HR] 0·89 [95% CI 0·84–0·95]). Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, in particular, were associated with a lower risk of developing diabetes, whereas β blockers and thiazides increased the risk of developing diabetes. Calcium channel blockers had neutral effects.

To further test their hypothesis, the authors also performed a supplementary mendelian randomisation study using genetic variants that affect blood pressure via the known targets of the same anti-hypertensive drugs. Within the International Consortium for Blood Pressure genome-wide association study and the UK Biobank, genetic variants affecting the renin–angiotensin system (RAS) pathway that were associated with lower blood pressure were also associated with a reduced risk of diabetes. Blood pressure lowering variants within the β adrenergic pathway were associated with increased risk. The effects of calcium channel blocker variants were neutral, and sodium–chloride cotransporter (thiazide) variants were inconclusive. The fact that these complementary approaches are largely concordant substantially bolsters the findings from the meta-analysis and are largely consistent with previous studies.

It is important to highlight some aspects that could affect the interpretation of the meta-analysis and previous trials. Retrospective ascertainment of new-onset diabetes can be difficult as this condition was not necessarily a prespecified endpoint in these trials. In fact, of the 51 trials included in the Blood Pressure Lowering Treatment Trialists’ Collaboration dataset, the majority (n = 29) did not have sufficient data to be included in the meta-analysis. Each trial also differed with regards to how type 2 diabetes was defined and ascertained (e.g., adverse event coding, administrative [International Classification of Diseases-ninth revision] codes, or laboratory testing specifically for type 2 diabetes). However, in sensitivity analyses, the association between blood pressure reduction and the development of diabetes was strongest in the studies that used laboratory testing (the most specific assessment) to ascertain diabetes.

Measures to reduce the incidence and prevalence of type 2 diabetes are urgently needed. In the USA, it is estimated that 13% of all Americans have diabetes and a staggering 34·5% have prediabetes. Lifestyle modifications are effective and reduce other risk factors associated with cardiovascular disease (e.g., blood pressure and lipids) in addition to reducing the risk of diabetes. Previous studies have found that metformin can reduce the risk of progression to diabetes and is the drug used most commonly to reduce this risk in clinical practice.

Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes. This strategy is supported by a previous randomised clinical trial, which found that valsartan reduced the proportion of patients developing diabetes by 14% compared with placebo (a coprimary endpoint of the overall trial). The mean difference in systolic blood pressure between the valsartan and the placebo group was 2·8 mm Hg. Furthermore, in the DREAM trial, patients given a RAS inhibitor (ramipril) had lower plasma glucose concentrations 2 h post-glucose load, although there was no significant difference in the risk of progression to diabetes (HR 0·91 [95% CI 0·81–1·03]; p = 0·15). Whether other therapies that lower blood pressure and have effects on the kidney (e.g., SGLT2 inhibitors and mineralocorticoid recepto antagonists) have similar or additive effects in the prevention of diabetes remains unknown.

RAS inhibitors are the cornerstone of therapy for patients with hypertension. Current guidelines of the European Society of Cardiology for the treatment of hypertension give a class I recommendation to the initiation of a RAS blocker (in combination with either a calcium channel blocker or thiazide diuretic). Similar recommendations are given by both diabetes and cardiology professional societies in the USA; however, the preference for a RAS inhibitor over other agents (e.g., calcium channel blockers or thiazide diuretics) is limited to those patients with concomitant albuminuria.

The absolute risk reduction found in this meta-analysis is modest; however, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension. It remains unknown to what extent the reduction in diabetes risk is due to blood pressure reduction per se versus RAS inhibition specifically. Despite its limitations, this meta-analysis provides additional evidence supporting the hypothesis that blood pressure control with specific medications can reduce the risk of diabetes. This study supports the possibility that earlier, more aggressive lowering of blood pressure, with an emphasis on RAS inhibitors, can decrease the incidence of diabetes. Perhaps these data are enough to encourage the writers of the hypertension guidelines in the USA to follow the lead of the European Society of Cardiology to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria.

(9). Bernard et al. Surpassing insulin glargine in type 2 diabetes with tirzepatide. 2021;398(10313):P1779-1781.

In this centennial year of the isolation and purification of insulin by Banting and colleagues, insulin remains a mainstay of treatment for diabetes, being efficacious and cost-effective in controlling glycaemia in people with type 2 diabetes who are poorly controlled on maximal or near-maximal doses of oral hypoglycaemics. The basal analogue insulin glargine is often used as the first-choice injectable for this group, using the algorithm pioneered in the 2003 Treat-to-Target Trial (TTT), with progressive titration of insulin doses dependent on measurements of fasting glucose. However, insulin glargine has shortcomings, including significant risks of hypoglycaemia, especially during the night, and a tendency for people to gain weight with treatment. GLP-1-based treatments, particularly the weekly analogues such as dulaglutide and semaglutide, are beginning to supplant insulin glargine for this indication. Based on the AWARD-2 3 and SUSTAIN-4 4 trials, dulaglutide and semaglutide are considered superior in lowering glucose, with fewer hypoglycaemic events, and reductions in bodyweight are seen in contrast to small weight gains with insulin glargine.

(9). Simon R Heller et al. Insulin, the patient, and the health professional. 2021;398(10313):P1785-1786.

Before 1921 the diagnosis of diabetes was a death sentence, with an average life expectancy of less than 2 years in young people, who were only kept alive by a starvation regimen that reduced them to walking skeletons. The discovery of insulin in 1921 was transformative and many patients with diabetes went on to live full and productive lives.

Yet the optimism that the ready availability of insulin would result in a cure for a previously fatal disease was gradually replaced by a realisation that insulin is not a panacea. Over the years that followed, many of those taking insulin to treat type 1 diabetes began to develop microvascular complications that resulted in blindness and renal failure. Embarking on a pregnancy with diabetes was perilous for the mother as well as her unborn child—an editorial in the BMJ in 1949 reported a perinatal mortality of 50%. It gradually became clear that keeping glucose concentrations close to normal was key. But since blood glucose measurement was confined to hospital laboratories, doctors relied on a single glucose measurement at hospital visits with unreliable urinary glucose records measured at home in between. For patients, the challenges of meeting glucose targets were immense. Episodes of severe hypoglycaemia were common and some authorities considered the risk of hypoglycaemia too hazardous to attempt rigid control of glucose at near normal concentrations.

With the advent of glucose monitoring during the late 1970s, pioneers such as Berger, Mühlhauser, and their colleagues, working in Düsseldorf, Germany, realised that this revolutionary technology could be used by the patient at home to enable them to manage diabetes themselves. They advocated what they called an insulin treatment and training programme, recognising the need for structured education to teach self-management.

Surprisingly, the positive trial results from Germany were largely ignored by many health-care professionals, including those in the UK. This slow uptake of self-management perhaps reflected the approach to management of type 1 diabetes at the time: the doctor was in charge and both chose and adjusted the insulin dose while the patient was expected to fit their life around their insulin dose. Whatever the reason, it took more than 30 years for the UK diabetes establishment to adopt this approach as standard of care after translation of the German programme into English and a positive controlled trial. Even today, although about 40% of adults with type 1 diabetes are offered structured education programmes in the UK, only around 10% participate.

Flexible intensive insulin therapy as a treatment of a chronic disease places demands on the patient and their family as opposed to the health-care professional. The tools of insulin therapy are fairly crude substitutes for the physiology of carbohydrate metabolism and contrast with the relative simplicity of hormone replacement in other conditions of endocrine deficiency, such as hypothyroidism or Addison's disease. People who live with type 1 diabetes are asked to learn and implement complex skills, calculating insulin dose according to current blood glucose and anticipated carbohydrate intake at each meal, every day of their lives. They also must anticipate the impacts of other activities such as exercise, driving, or alcohol consumption. Too much insulin can lead to hypoglycaemia, which can result in confusion and coma, while raised blood glucose over the long term leads to major complications. Effective self-management requires considerable time and effort and interferes with many everyday activities. These pressures take their toll and diabetes distress, defined by some as the emotional stress resulting from living with diabetes, and the burden of relentless management are among the negative impacts of self-management on quality of life.12 Other mental health conditions that are more common in people with diabetes include depression, anxiety, and eating disorders.

In high-income countries advanced technologies, such as insulin analogues, insulin pumps, continuous glucose monitoring, and hybrid closed-loop devices, have become firmly established for diabetes management and treatment. Many believe that closed-loop devices, which adjust insulin infusion largely automatically according to changing glucose values, will soon enable people with type 1 diabetes to lead lives without the continual demands of self-management; the research evidence is encouraging, showing improved time in normoglycaemic range (4-10 mmol/L) with reduced rates of hypoglycaemia.However, these approaches demand much input from the person themselves and those who find it challenging to engage in their own self-management benefit less from expensive technologies. In one registry study, about 40% of patients with type 1 diabetes who were prescribed glucose sensors returned them or did not use them effectively.

Furthermore, these technological advances have highlighted the differences between the rich and poor. In many low-income and middle-income countries (LMICs), few patients can afford modern insulin analogues let alone devices to record glucose continuously or adjust insulin automatically. But there are other gaps in implementing diabetes management programmes in LMICs, including insufficient knowledge, inadequate motivation, time constraints, social stigma, excessive patient burden for health-care professionals, and scarcity of a systematic multidisciplinary team approach. The provision of free medicines and glucose monitoring would make a major difference. Two multinational surveys involving participants with type 1 diabetes from the Middle East and Latin America showed that those who received diabetes education were more likely to practise self-management and attain glycaemic targets than those who did not. These data highlight how strategies that encourage self-management through diabetes education can help to reach glycaemic targets at low cost in all countries.

Globally, patients continue to strive to manage their diabetes with a treatment that although life-saving remains far from perfect. The evolution of treatment programmes from diagnosis, technology, and modern structured education have had a crucial role in enabling patients to live with type 1 diabetes. But perhaps the most important advance has been the recognition by health-care professionals that it is the patient who treats their condition hour by hour. The quality of the partnership between the patient and the professional will remain the cornerstone of future type 1 diabetes treatment, irrespective of technological advances.

(10). LeCouffe NE. A randomized trial of intravenous alteplase before endovascular treatment for stroke. N Engl J Med. 2021;385:1833-1844.

Background

The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations.

Methods

We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points.

Results

The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81).

Conclusions

In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups.


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