Early-onset type 2 diabetes (defined as type 2 diabetes diagnosed in people aged <40 years) is increasingly prevalent with substantial health and socioeconomic implications. Unlike late-onset type 2 diabetes, early-onset type 2 diabetes is a high-risk and aggressive phenotype, with accelerated pancreatic β-cell decline and greater insulin resistance due to the rising rate of obesity. People with early-onset type 2 diabetes have higher rates of macrovascular and microvascular complications with increased health-care use and premature mortality (due to cardiovascular and non-cardiovascular complications) than do people with late-onset type 2 diabetes. Emerging evidence also suggests that people with early-onset type 2 diabetes face an increased risk of complications in reproductive health (eg, during periconception and postpartum periods), metabolic-associated steatotic liver disease, mental health (eg, diabetes distress, depression, anxiety, and psychotic disorders), and some cancers, creating additional challenges in managing multiple long-term conditions. In this Series paper, we highlight the consequences of early-onset type 2 diabetes and the key driver for these risks-long duration of exposure to hyperglycaemia, with its effects amplified by younger age at type 2 diabetes diagnosis and interactions with other cardiometabolic risk factors. Recognising these adverse risks associated with early-onset type 2 diabetes is crucial for guiding the development and implementation of a more focused and integrated life-course approach to mitigate its long-term effect on individuals, communities, and health-care systems globally. However, substantial research gaps remain that must be addressed, particularly in diverse populations.

The incidence of early-onset type 2 diabetes is increasing, with a growing number of cases now occurring in children, adolescents, and young adults. This transition is primarily driven by the rising prevalence of obesity in younger populations, especially in high-income countries. However, the relationship between obesity and early-onset type 2 diabetes varies across ethnic groups, with some populations exhibiting a higher risk at lower BMI thresholds, possibly due to differences in insulin resistance and β-cell function. Socioeconomic factors further shape disease patterns, with early-onset type 2 diabetes disproportionately affecting lower-income populations in high-income settings, whereas in low-income and middle-income countries, economic development and urbanisation have contributed to increasing incidence among more affluent groups. The consequences of this transition to early-onset type 2 diabetes are severe, with accelerated disease progression, heightened risks of microvascular and macrovascular complications, and considerable societal and health-care burdens compared with later-onset disease. Given the continuing rise in childhood and adolescent obesity, the incidence of early-onset type 2 diabetes is expected to increase further, placing mounting pressure on health-care systems worldwide. In the first of three papers in this Series, we examine global trends in the incidence and prevalence of early-onset type 2 diabetes, identify key drivers of this transition to diagnosis at younger ages, and review the evidence for risk factors both at population and individual level.

Insulin efsitora alfa (efsitora), a once-weekly basal insulin, has the potential to reduce the treatment burden of people with type 2 diabetes who require insulin. We aimed to assess the efficacy and safety of once-weekly efsitora compared with insulin glargine U100 in adults with type 2 diabetes treated with basal and prandial insulin.

Once-weekly insulin efsitora alfa (efsitora) is in development for the treatment of people with diabetes. The aim of the current study was to assess the efficacy and safety of once-weekly efsitora compared with daily insulin degludec (degludec) in adults with type 2 diabetes using basal insulin.

Amycretin is a novel, unimolecular GLP-1 and amylin receptor agonist. The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and effects on bodyweight of subcutaneous amycretin administered over a treatment period of up to 36 weeks in participants with overweight or obesity.

Cerebral palsy is a lifelong physical disability affecting movement and posture. The motor impairments of cerebral palsy result from non-degenerative brain injuries, brain malformations, and genetic variations, arising from multiple risk factors and causal pathways during preconception, pregnancy, birth, or within the first 2 years of life. Over the past decade, substantial progress in diagnosing, preventing, and managing the condition has transformed treatment approaches. A key discovery is that up to 30% of individuals with CP have a genetic contribution. In high-income countries, the prevalence has decreased by as much as 40%, from 2·1 per 1000 livebirths to 1·6 per 1000 livebirths. However, the prevalence is higher in low-income and middle-income countries. Advances in early diagnosis make identification of cerebral palsy at as early as age 3 months possible, enabling timely, intensive early intervention that improves child and parent outcomes. Additionally, new medical, regenerative, and rehabilitation therapies have emerged, enhancing function and participation. Growing awareness of the health challenges and physical decline faced by adults underscores the need for a lifelong approach. This Seminar highlights the best available evidence and recent progress to help clinicians address key questions identified by individuals with lived experience.

GLP-1 receptor agonists and amylin receptor agonists have shown clinically relevant weight loss and glucose-lowering effects in people with overweight, obesity, and type 2 diabetes. Amycretin is a novel, single-molecule GLP-1 receptor and amylin receptor agonist. We aimed to investigate the safety, tolerability, pharmacokinetic properties, and pharmacodynamic effects of single ascending doses (part A) and multiple ascending doses (parts B and C/D) of amycretin in adult participants with overweight or obesity.

This Review offers an evaluation of current treatments for symptomatic uterine fibroids, including uterine artery embolisation, MRI-guided high-intensity focused ultrasound, laparoscopic radiofrequency ablation, transcervical radiofrequency ablation, ulipristal acetate, and oral gonadotropin-releasing hormone antagonists with add-back therapy. Placing these therapies within the IDEAL (Idea, Development, Exploration, Assessment, And Long-Term Follow-Up) framework and the clinical phases of drug development framework, we highlight key gaps in the evidence such as the lack of head-to-head comparisons with standard care, scarce long-term data, and inadequate consideration of real-world fibroid and patient characteristics. We provide a clear overview, assess the strength of the available evidence, and propose a practical flowchart to help clinicians navigate treatment decisions, ensuring the best care for women with symptomatic fibroids at various stages of therapy development. Insight into these matters equips both patient and clinician with essential information to support the process of shared and fully informed decision making. Importantly, this Review also identifies knowledge gaps that contribute to the specification of the fibroid research agenda.

Non-transfusion-dependent (NTD) thalassaemia is characterised by ineffective erythropoiesis and haemolytic anaemia, leading to long-term complications, poor quality of life, and early mortality. No oral disease-modifying therapies are approved for β-thalassaemia and no agents are approved for α-thalassaemia. The objective of this study was to evaluate the efficacy and safety of mitapivat, an oral activator of pyruvate kinase, in adults with NTD α-thalassaemia or NTD β-thalassaemia.

Since its inception in 2005, the US President's Malaria Initiative (PMI) has played a major role in the reductions in malaria morbidity and mortality observed across Africa. With the status of PMI funding and operations currently uncertain, we aimed to quantify the impact that a fully functioning PMI would have on malaria cases and deaths in Africa during 2025.