Day: 08/28/2022

Major advances in sleep neurology: 2002–22

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Over the past 20 years, researchers and clinicians have made remarkable advances in understanding and treating a variety of sleep and circadian disorders. An improved knowledge of sleep neurobiology, coupled with therapies that target these neural circuits, is now providing much more effective medications and improving quality of life for people with sleep-related movement disorders, hypersomnia, sleep apnoea, and other problems.

One of the most dramatic advances has been in our understanding of the relationship between rapid eye movement (REM) sleep behaviour disorder (RBD) and neurodegenerative disorders. First reported by Mark Mahowald and Carlos Schenk in 1986, RBD at the time seemed to be an idiopathic disorder in which patients did not develop the typical muscle atonia during REM sleep and acted out their dreams. However, by 1996, 11 of the 29 patients in the original cohort had developed parkinsonism.

 In the early 2000s, reports from additional cohorts confirmed this finding, and by that time, approximately 80% of the patients in the original cohort had developed a synucleinopathy: Parkinson’s disease, Lewy body dementia, or multiple system atrophy.

 Kaplan-Meier analysis showed that approximately half of the patients develop a synucleinopathy within 12–15 years of the onset of idiopathic RBD symptoms, and more than 90% of the patients develop a synucleinopathy by 25 years.

 The cause of RBD is now thought to be due to degeneration of neurons in the pons that cause atonia during REM sleep early in the course of a synucleinopathy.

 If correct, this mechanism would mean that the synucleinopathy was present many years before it affected motor or cognitive circuits, which is a profound difference from the understanding of these disorders 20 years ago. RBD is often treated with clonazepam, but in patients with RBD who have an underlying movement disorder, this treatment increases the risk of falls. Hence, many movement disorder specialists now treat such patients with high-dose melatonin, despite the absence of randomised, controlled trials to support this practice.

A further area of rapid advance in movement disorders associated with sleep has been in the understanding of restless legs syndrome and periodic limb movements of sleep (PLMS). Restless legs syndrome is an uncomfortable urge to move the legs (and sometimes arms), usually in the evening when sedentary, and PLMS involves frequent kicking movements similar to a triple flexion reflex that can disrupt sleep. Although long viewed as distinct entities, about 80–90% of patients with restless legs syndrome have PLMS, and about 45% of patients with PLMS have restless legs syndrome.

 Genome-wide association studies confirmed that some genes, such as BTBD9, increase the risk for both disorders.

 The cause of these two movement disorders of the evening and night are not clear. However, the presence of low ferritin in the CSF and reduced iron stores in the brains of patients with restless legs syndrome suggests that iron transport into neurons is impaired.

 As a result, patients with restless legs syndrome or PLMS who have low iron stores (blood ferritin concentrations <75 μg/L) are now often treated with iron repletion. Treatment of restless legs syndrome in the past generally relied upon levodopa or dopamine D2 receptor agonists, until it was found that these drugs often cause augmentation of the symptoms with time. Pregabalin and gabapentin are now thought to cause less augmentation than dopamine D2 receptor agonists.

Another major development has been in the understanding of narcolepsy as one of the rare disorders caused by the loss of a single neurotransmitter. Although first described by clinicians in the 1870s, the cause of narcolepsy remained a mystery until about 20 years ago when it was discovered that narcolepsy with cataplexy (brief episodes of emotionally triggered muscle paralysis, similar to the atonia of REM sleep) is caused by a selective and severe loss of the hypothalamic neurons that produce the orexin (hypocretin) neuropeptides,

 which results in low CSF orexin concentrations.

 This discovery also spurred the recognition of two forms of narcolepsy: type 1, in which patients have cataplexy and low CSF orexin concentrations; and type 2, in which patients do not have cataplexy and have normal orexin concentrations. The orexins usually help drive wakefulness across the day and regulate REM sleep so it occurs only in the night. However, with loss of the orexin neurons, people with narcolepsy type 1 struggle to stay awake during the day and have wakefulness interrupted by REM sleep-related phenomena, such as hypnagogic hallucinations (similar to the dreams of REM sleep), and cataplexy. Mice that do not have the orexin peptides or the orexin neurons also have severe sleepiness and cataplexy, which has enabled researchers to map out the specific neural circuits through which orexins usually function. For example, orexins help promote wakefulness by activating neurons that make histamine, norepinephrine, and dopamine, and this new information has helped spur the development of drugs that increase histamine tone (eg, pitolisant) or norepinephrine and dopamine tone (eg, solriamfetol) to combat daytime sleepiness.

 Additionally, several small molecule orexin receptor agonists are being developed and are in clinical trials for treating narcolepsy type 1. These drugs might also help patients who have other causes of daytime sleepiness, such as idiopathic hypersomnia and shift work. Conversely, antagonists that block the two orexin receptors are now clinically available as treatments for insomnia.

The mechanism for the selective loss of the orexin neurons in patients with narcolepsy type 1 was unknown until the past 10 years. Some lines of evidence, such as the strong linkage of narcolepsy type 1 to an immune-modulating gene (HLA-DQB1*06:02), and the increased incidence of the disorder in adolescents after infection with influenza virus or Streptococcus, suggested that the orexin neurons might be the subject of auto-immune attack. This concept received strong support when the incidence of narcolepsy type 1 spiked in people immunised with a specific H1N1 vaccine in Scandinavia and sometimes after infection with H1N1 itself.

 T cells have now been identified in patients with narcolepsy type 1 that cross-react with H1N1 proteins and the orexins, suggesting that this type of narcolepsy is caused by an autoimmune attack on the orexin neurons through a process of molecular mimicry.

Researchers are also developing better treatments for obstructive sleep apnoea. In this disorder, relaxation of the airway dilator muscles during sleep results in airway closure, and the patient can become apnoeic or have reduced air flow (hypopnoea), despite efforts to breathe. After a period typically of 10–20 s, the patient awakens with a start, resumes breathing, and usually promptly falls back asleep. This cycle might repeat hundreds of times per night. Although continuous positive airway pressure has been the mainstay of treatment for sleep apnoea, essentially stenting the airway open during sleep, this is not tolerated by many patients.

 One advance has been the adaptation of nerve stimulation technology for use on the hypoglossal nerve, which can advance the tongue, reducing airway closure in many patients.

 Recent studies of the brain circuitry responsible for arousal from sleep apnoea have suggested a pharmacological approach to suppress the awakening response (which fragments sleep) and augment the re-establishment of airway tone.

 A small randomised clinical trial combining atomoxetine (to activate airway dilator pathways) and oxybutynin (to block forebrain arousal and potentiate brainstem airway dilator tone) showed a 75% reduction in the number of airway blockages.

An additional area of great advance has been in the understanding of circadian rhythm disorders. A molecular transcriptional–translational loop mechanism results in a 24 h cycle of clock gene expression that drives daily circadian rhythms, a profound discovery for which the Nobel Prize for Medicine and Physiology was awarded to Michael Rosbash, Jeffrey Hall, and Michael Young in 2017. Rare families have now been identified with advanced sleep phase disorder, in which affected individuals have a circadian clock cycle shorter than the standard 24 h, and so they tend to fall asleep early (eg, around 2000 h to 2100 h) and wake up very early (often at 0300 h or 0400 h). Researchers have now found that this wake–sleep pattern is due to mutations in the clock genes themselves or in associated proteins that modulate the activity of these genes.

In summary, the rapid advances in sleep medicine in the past 20 years underscore the value of a robust dialogue between clinical medicine and basic science. Clinical disorders such as narcolepsy or RBD provide us with intriguing experiments of nature, and laboratory investigations can then help us to understand their mechanisms. Those mechanisms then inform the design of rational and potent therapies.

Woman sleeping in bed

Source: Lancet

Genetics of multiple sclerosis: lessons from polygenicity

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Summary

Large-scale mapping studies have identified 236 independent genetic variants associated with an increased risk of multiple sclerosis. However, none of these variants are found exclusively in patients with multiple sclerosis. They are located throughout the genome, including 32 independent variants in the MHC and one on the X chromosome. Most variants are non-coding and seem to act through cell-specific effects on gene expression and splicing. The likely functions of these variants implicate both adaptive and innate immune cells in the pathogenesis of multiple sclerosis, provide pivotal biological insight into the causes and mechanisms of multiple sclerosis, and some of the variants implicated in multiple sclerosis also mediate risk of other autoimmune and inflammatory diseases. Genetics offers an approach to showing causality for environmental factors, through Mendelian randomisation. No single variant is necessary or sufficient to cause multiple sclerosis; instead, each increases total risk in an additive manner. This combined contribution from many genetic factors to disease risk, or polygenicity, has important consequences for how we interpret the epidemiology of multiple sclerosis and how we counsel patients on risk and prognosis. Ongoing efforts are focused on increasing cohort sizes, increasing diversity and detailed characterisation of study populations, and translating these associations into an understanding of the biology of multiple sclerosis.

Source: Lancet

Emerging therapies for Duchenne muscular dystrophy

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Summary

Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene therapies, tools that induce exon skipping, and other therapeutic approaches, including treatments targeting molecular pathways downstream of the absence of functional dystrophin. However, glucocorticoids remain the only treatment unequivocally shown to slow disease progression, despite the adverse effects associated with their long-term use. Besides glucocorticoids, which are standard care, five compounds have received regulatory approval in some but not all jurisdictions, with further efficacy results being awaited. Several compounds with promising results in early-phase clinical trials have not met their efficacy endpoints in late-phase trials, but the clinical development of many other compounds is ongoing. The current landscape is complicated by the number of compounds in various stages of development, their various mechanisms of action, and their genotype-specific applicability. The difficulties of clinical development that arise from both the rarity and variability of Duchenne muscular dystrophy might be overcome in the future by use of sensitive biomarkers, natural history data, and ameliorated trial designs.

Source: Lancet

Parkinson’s disease needs an urgent public health response

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The number of people who have Parkinson’s disease, and the resulting disability and number of deaths, are rising faster than those of any other neurological disorder. However, resources and access to care for many people with Parkinson’s disease are still insufficient. This situation, which is outlined in two new documents released by WHO, needs to change.

The prevalence, burden of disability, and number of deaths associated with Parkinson’s disease all more than doubled between 1990 and 2016. These increases are not entirely attributable to rising population age, and other potential contributing factors include greater exposure to risk factors and longer disease duration. The symptoms of Parkinson’s disease are treatable but, in many areas of the world, access to therapy remains unacceptably low. Levodopa is listed as a WHO essential medicine and is less expensive than many other treatments, but is still unavailable or unaffordable for many patients. Access to drug infusions and deep brain stimulation is scarcer, owing to costs and a shortage of facilities and expertise. Even in high-income countries, women are less likely to receive deep brain stimulation than men, and integrated care, which can help patients to manage the diverse symptoms of Parkinson’s disease, is often unavailable. Meanwhile low-income countries have a median of only 0·03 neurologists per 100 000 population. Information about Parkinson’s disease is often unavailable in local languages, and symptoms can be associated with stigmatisation or dismissed as normal ageing.

To address this appalling situation, on June 14, 2022, WHO launched a technical brief entitled Parkinson Disease: a Public Health Approach, developed in consultation with experts from around the world, including people living with Parkinson’s disease. The document is intended as a resource for policy makers, health programme managers and planners, health-care providers, researchers, people with Parkinson’s disease, carers, and other stakeholders, and is in line with the aims of the new WHO Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders 2022–2031 (IGAP). After summarising the problems faced by people with Parkinson’s disease, the technical brief lists 43 key actions in seven areas: global health policies; advocacy and awareness raising; prevention and risk reduction; availability of basic drugs and therapies; strengthening health and social systems and building capacity; carer support; and research. The specific actions include reducing exposure to air pollution and chemicals possibly implicated in Parkinson’s disease, increasing affordability of therapies, training of primary health-care providers, and establishing local initiatives to promote awareness and reduce discrimination.

The release of the technical brief was followed on July 11, 2022, by publication of Six Action Steps to Address Global Disparities in Parkinson Disease: A World Health Organization Priority, a special communication by some of the experts who were involved in preparing the technical brief. This second document covers similar ground but is aimed at clinicians and researchers, and it identifies six main avenues for action: disease burden (particularly the need for better and more representative epidemiological data); advocacy and awareness; prevention and risk reduction; diagnosis, treatment, and care (including availability of basic therapies, strengthening of health and social systems, and building capacity); caregiver support; and research.

Together, the two documents present an almost overwhelming number of action points. Adoption of IGAP at the 75th World Health Assembly means that governments have committed to tackle neurological diseases, and policy makers now need to start to make changes happen locally, for example by increasing funding for Parkinson’s disease services and research, and by better regulation of drug production and pricing. Many of the problems raised in the new documents are not specific to Parkinson’s disease, and resources and efforts might be pooled across specialties, for example in reduction of common risk factors and in dementia services. Neurologists could potentially help to bring about change through advocacy, training of primary health-care providers, and supporting local health-care professionals remotely, although virtual neurological assessments are not always ideal.

The global burden of Parkinson’s disease is rising quickly, and even access to an essential medicine is not keeping up. WHO correctly considers that “An urgent public health response is necessary to meet the health and social requirements of people with Parkinson disease”. Politicians and other people in charge of health services need to pay attention to these new documents and respond, urgently.

Source: Lancet

Polycystic ovary syndrome

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Summary

Polycystic ovary syndrome (PCOS) affects 5–18% of women, and is a reproductive, metabolic, and psychological condition with impacts across the lifespan. The cause is complex, and includes genetic and epigenetic susceptibility, hypothalamic and ovarian dysfunction, excess androgen exposure, insulin resistance, and adiposity-related mechanisms. Diagnosis is recommended based on the 2003 Rotterdam criteria and confirmed with two of three criteria: hyperandrogenism (clinical or biochemical), irregular cycles, and polycystic ovary morphology. In adolescents, both the criteria of hyperandrogenism and irregular cycles are needed, and ovarian morphology is not included due to poor specificity. The diagnostic criteria generates four phenotypes, and clinical features are heterogeneous, with manifestations typically arising in childhood and then evolving across adolescent and adult life. Treatment involves a combination of lifestyle alterations and medical management. Lifestyle optimisation includes a healthy balanced diet and regular exercise to prevent excess weight gain, limit PCOS complications and target weight reduction when needed. Medical management options include metformin to improve insulin resistance and metabolic features, combined oral contraceptive pill for menstrual cycle regulation and hyperandrogenism, and if needed, anti-androgens for refractory hyperandrogenism. In this Review, we provide an update on the pathophysiology, diagnosis, and clinical features of PCOS, and discuss the needs and priorities of thoseL with PCOS, including lifestyle, and medical and infertility treatment. Further we discuss the status of international evidence-based guidelines (EBG) and translation, to support patient self management, healthcare provision, and to set research priorities.

Source: Lancet

Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study

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Summary

Background

Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment.

Methods

In the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (≥18 years, with a BMI of less than 35 kg/m2, natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks’ gestation. Ultrasound scans were performed every 5±1 weeks until delivery to measure fetal growth and feto–placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants’ health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis.

Findings

From Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20–25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto–placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1·5 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group.

Interpretation

Early pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity.

Source: Lancet

Burden of diabetes and hyperglycaemia in adults in the Americas, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

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Summary

Background

High prevalence of diabetes has been reported in the Americas, but no comprehensive analysis of diabetes burden and related factors for the region is available. We aimed to describe the burden of type 1 and type 2 diabetes and that of hyperglycaemia in the Americas from 1990 to 2019.

Methods

We used estimates from GBD 2019 to evaluate the burden of diabetes in adults aged 20 years or older and high fasting plasma glucose in adults aged 25 years or older in the 39 countries and territories of the six regions in the Americas from 1990 to 2019. The main source to estimate the mortality attributable to diabetes and to chronic kidney disease due to diabetes was vital registration. Mortality due to overall diabetes (ie, diabetes and diabetes due to chronic kidney disease) was estimated using the Cause of Death Ensemble model. Years of life lost (YLLs) were calculated as the number of deaths multiplied by standard life expectancy at the age that the death occurred, years lived with disability (YLDs) were estimated based on the prevalence and severity of complications of diabetes. Disability-adjusted life-years (DALYs) were estimated as a sum of YLDs and YLLs. We assessed the association of diabetes burden with the level of development of a country (according to the Socio-demographic Index), health-care access and quality (estimated with the Healthcare Access and Quality Index), and diabetes prevalence. We also calculated the population attributable fraction (PAF) of diabetes burden due to each of its risk factors. We report the 95% uncertainty intervals for all estimates.

Findings

In 2019, an estimated total of 409 000 (95% uncertainty interval 373 000–443 000) adults aged 20 years or older in the Americas died from diabetes, which represented 5·9% of all deaths. Diabetes was responsible for 2266 (1930–2649) crude DALYs per 100 000 adults in the Americas, and high fasting plasma glucose for 4401 DALYs (3685–5265) per 100 000 adults, with large variation across regions. DALYs were mostly due to type 2 diabetes and distribution was heterogeneous, being highest in central Latin America and the Caribbean and lowest in high-income North America and southern Latin America. Between 1990 and 2019, age-standardised DALYs due to type 2 diabetes increased 27·4% (22·0–32·5). This increase was particularly high in Andean Latin America and high-income North America. Burden for both type 1 and type 2 diabetes across countries increased with higher diabetes prevalence and decreased with greater Socio-demographic and Healthcare Access and Quality Indices. Main risk factors for the burden were high BMI, with a PAF of 63·2% and dietary risks, with a PAF of 27·5%. The fraction of burden due to disability has increased since 1990 and now represents nearly half of the overall burden in 2019.

Interpretation

The burden of diabetes in the Americas is large, increasing, heterogeneous, and expanding. To confront the rising burden, population-based interventions aimed to reduce type 2 diabetes risk and strengthening health systems to provide effective and cost-efficient care for those affected are mandatory.

Source: Lancet

Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis

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Summary

Background

Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure.

Methods

We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists’ Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, calcium channel blockers, and thiazide diuretics, was estimated using a network meta-analysis framework. This study is registered with PROSPERO, CRD42018099283.

Findings

We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0–5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91–0·98]) compared with those without type 2 diabetes (0·89 [0·87–0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated.

Interpretation

Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted.

Source: Lancet

Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): a double-blind, multicentre, randomised, phase 3 trial

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Summary

Background

As the disease progresses, many patients with type 2 diabetes have difficulty in reaching treatment goals. We aimed to assess the efficacy and safety of tirzepatide, a novel GIP and GLP-1 receptor agonist, compared with dulaglutide in Japanese patients with type 2 diabetes.

Methods

This multicentre, randomised, double-blind, parallel, active-controlled, phase 3 trial was conducted in 46 medical research centres and hospitals in Japan. Adults aged 20 years or older with type 2 diabetes who had discontinued oral antihyperglycaemic monotherapy or were treatment-naïve were included. Participants were randomly assigned (1:1:1:1) to receive tirzepatide (5, 10, or 15 mg) or dulaglutide (0·75 mg) once per week using a computer-generated random sequence with an Interactive Web Response System. Participants were stratified based on baseline HbA1c (≤8·5% or >8·5%), baseline BMI (<25 or ≥25 kg/m2), and washout of antidiabetic medication. Participants, investigators, and the sponsor were masked to treatment assignment. The starting dose of tirzepatide was 2·5 mg once per week for 4 weeks, which was then increased to 5 mg in the tirzepatide 5 mg treatment group. For the tirzepatide 10 and 15 mg treatment groups, increases by 2·5 mg occurred once every 4 weeks until the assigned dose was reached. The primary endpoint was mean change in HbA1c from baseline at week 52 measured in the modified intention-to-treat population.

Findings

Between May 7, 2019, and March 31, 2021, 821 participants were assessed for study eligibility and 636 were randomly assigned to receive at least one dose of tirzepatide 5 mg (n=159), 10 mg (n=158), or 15 mg (n=160), or dulaglutide 0·75 mg (n=159). 615 (97%) participants completed the study and 21 (3%) discontinued. Participants had a mean age of 56·6 years (SD 10·3) and were mostly male (481 [76%]). At week 52, HbA1c decreased from baseline by a least squares mean of −2·4 (SE 0·1) for tirzepatide 5 mg, −2·6 (0·1) for tirzepatide 10 mg, −2·8 (0·1) for tirzepatide 15 mg, and −1·3 (0·1) for dulaglutide. Estimated mean treatment differences versus dulaglutide were −1·1 (95% CI −1·3 to −0·9) for tirzepatide 5 mg, −1·3 (−1·5 to −1·1) for tirzepatide 10 mg, and −1·5 (−1·71 to −1·4) for tirzepatide 15 mg (all p<0·0001). Tirzepatide was associated with dose-dependent reductions in bodyweight with a least square mean difference of −5·8 kg (SE 0·4; −7·8% reduction) for 5 mg, −8·5 kg (0·4; −11·0% reduction) for 10 mg, and −10·7 kg (0·4; −13·9% reduction) for 15 mg of tirzepatide compared with −0·5 kg (0·4; –0·7% reduction) for dulaglutide. The most common treatment-emergent adverse events were nausea (19 [12%] participants in the 5 mg group vs 31 [20%] in the 10 mg group vs 32 [20%] in the 15 mg group all receiving tirzepatide vs 12 (8%) in the group receiving dulaglutide), constipation (24 [15%] vs 28 [18%] vs 22 [14%] vs 17 [11%]), and nasopharyngitis (29 [18%] vs 25 [16%] vs 22 [14%] vs 26 [16%]). The most frequent adverse events were gastrointestinal (23 [4%] of 636).

Interpretation

Tirzepatide was superior compared with dulaglutide for glycaemic control and reduction in bodyweight. The safety profile of tirzepatide was consistent with that of GLP-1 receptor agonists, indicating a potential therapeutic use in Japanese patients with type 2 diabetes.

Source: Lancet

Safety and efficacy of tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with type 2 diabetes in Japan (SURPASS J-combo): a multicentre, randomised, open-label, parallel-group, phase 3 trial

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Summary

Background

Due to potential ethnic differences in the pathophysiology of type 2 diabetes, new therapeutics need to be evaluated in Japanese patients. We aimed to assess the safety and glycaemic efficacy of tirzepatide as an add-on treatment in Japanese patients with type 2 diabetes who had inadequate glycaemic control with stable doses of various oral antihyperglycaemic monotherapies.

Methods

This multicentre, open-label, parallel-group, randomised, phase 3 trial was conducted at 34 medical research centres and hospitals in Japan. Eligible participants were aged 20 years or older with inadequately controlled (HbA1c ≥7·0% to <11·0%) type 2 diabetes and were receiving oral antihyperglycaemic monotherapy (sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinedione, glinides, or SGLT2 inhibitors) for at least 3 months (stable dose for ≥8 weeks before screening), had a BMI of 23 kg/m2 or higher, and stable bodyweight (±5%) for at least 3 months before screening. After a 2-week screening and 2-week lead-in period, all participants were randomly assigned (1:1:1) to receive 5, 10, or 15 mg of tirzepatide, administered once per week subcutaneously for 52 weeks followed by a 4 week safety follow-up period, using a computer-generated random sequence and interactive web response system, stratified by oral antihyperglycaemic medication group. All participants started receiving 2·5 mg tirzepatide and doses were escalated by 2·5 mg every 4 weeks until the assigned dose was reached. The primary endpoint was safety and tolerability during 52 weeks of treatment, assessed as incidence of treatment-emergent adverse events in the modified intention-to-treat (mITT) population.

Findings

Between March 30, 2019, and Feb 16, 2021, with recruitment and enrolment continuing until Feb 4, 2020, 484 participants were assessed for eligibility and 443 were randomly assigned to receive at least one dose of tirzepatide (148 [33%] in the 5 mg group, 147 [33%] in the 10 mg group, and 148 [33%] in the 15 mg group). 398 (90%) participants completed the study and treatment. Most participants (343 [77%] of 443) had at least one treatment-emergent adverse event. Treatment-emergent adverse events were more frequent in the tirzepatide 15 mg group (125 [84%] of 148) than the 5 mg (109 [74%] of 148) and 10 mg groups (109 [74%] of 147). The most frequent treatment-emergent adverse events with tirzepatide were mild or moderate nasopharyngitis (75 [17%]), nausea (74 [17%]), constipation (54 [12%]), diarrhoea (51 [12%]), and decreased appetite (44 [10%]). At week 52, mean changes from baseline in bodyweight were –3·8 kg (SE 0·5; –5·1% reduction) in the 5 mg group, –7·5 kg (0·5; –10·1% reduction) in the 10 mg group, and –10·2 kg (0·5; –13·2% reduction) in the 15 mg group. Least squares mean HbA1c at baseline reduced from 8·5% (SE 0·1) to 6·0% (0·1) in the 5 mg tirzepatide group, from 8·6% (0·1) to 5·6% (0·1) in the 10 mg group, and from 8·6% (0·1) to 5·6% (0·1) in the 15 mg group at week 52. No adjudication-confirmed deaths were reported.

Interpretation

Tirzepatide was well tolerated as an add-on to oral antihyperglycaemic monotherapy in Japanese participants with type 2 diabetes and showed improvement in glycaemic control and bodyweight, irrespective of background oral antihyperglycaemic medication. Tirzepatide is a potential new treatment option for Japanese patients with type 2 diabetes that is inadequately controlled with single oral antihyperglycaemic medication.