Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, affecting an estimated 537 million adults globally and projected to impact 784 million by 2045.1 While type 2 diabetes accounts for the majority of cases, type 1 diabetes remains a significant concern, especially in younger populations.1 Unlike type 1 diabetes, which results from the autoimmune destruction of insulin-producing pancreatic beta cells and leads to absolute insulin deficiency, type 2 diabetes is characterized by a progressive loss of beta-cell function and relative insulin deficiency.2 Both forms of diabetes pose considerable challenges, contributing to complications such as cardiovascular disease, kidney failure, neuropathy, and retinopathy.2, 3, 4 Moreover, the socioeconomic burden of diabetes care is substantial, demanding continuous medical intervention and monitoring to prevent acute and long-term complications.5 Consequently, achieving and maintaining optimal glycemic control is paramount in reducing diabetes-related morbidity and mortality.

The management of both type 1 and type 2 diabetes requires a comprehensive approach that combines lifestyle changes with pharmacological interventions.6,7 While oral hypoglycemic agents are effective in managing early-stage type 2 diabetes, many patients with both types of diabetes eventually need insulin therapy.6,7 For individuals with type 1 diabetes, the challenges of managing treatment, remain a significant barrier to achieving optimal care and improving quality of life.7 While technological advancements, such as automated insulin delivery systems, are helping to improve glucose control and reduce the daily treatment challenges for some patients, these solutions are still out of reach for the majority of people with type 1 diabetes globally, who continue to depend on multiple daily injections, including long-acting basal insulin.7,8 In this context, innovations in ultra-long-acting insulins—such as the once-weekly formulations represent a promising new frontier in diabetes management.9

Among the available options, long-acting basal insulins like insulin degludec have gained prominence for their ability to maintain stable glucose levels and reduce the risk of nocturnal hypoglycemia.8,10 Insulin degludec, with its ultra-long duration of action, has demonstrated benefits in decreasing glycemic variability and enhancing adherence.10 However, ongoing advancements in insulin formulations have introduced newer analogs, such as insulin efsitora, which aim to offer similar or improved pharmacokinetic properties.11

Insulin efsitora is a novel basal insulin analog, engineered as a fusion protein that combines a single-chain insulin variant with the human IgG2 Fc domain.11,12 This structural modification allows for a prolonged half-life, enabling once-weekly dosing without significant daily or weekly fluctuations.11,12 Early pharmacokinetic and pharmacodynamic studies indicate that efsitora provides stable glycemic control with a low peak-to-trough ratio, reducing glycemic variability over a week.12 Additionally, the once-weekly administration of efsitora addresses common adherence barriers in diabetes management, such as the frequency and discomfort associated with daily injections, potentially improving patient adherence.11,12

While efsitora shows promise in clinical settings, direct comparisons with established long-acting insulins like degludec remain limited. Previous studies have reported its potential benefits; however, a comprehensive analysis comparing the efficacy and safety profiles of efsitora and degludec is limited. Given this gap, our meta-analysis seeks to evaluate the relative safety and efficacy of efsitora and degludec in treating type 1 and type 2 diabetes, aiming to provide clinicians with a robust evidence base to inform therapeutic decisions.