Japan initiates market authorization of weight‐loss drug semaglutide under universal health coverage, but with stringent prescription restrictions

Abstract

In November 2023, semaglutide (brand name Wegovy), a glucagon-like peptide-1 (GLP-1) receptor agonist, was granted regulatory approval for chronic weight management in Japan for the first time in Asian countries. Other Asian countries, such as China, are expected to introduce the drug shortly, and how authorities regulate weight-loss drugs is an internationally recognized concern. The drug has been covered by Japan's national universal health insurance since 22 February 2024 onwards under specific circumstances. The drug expense in Japan is less expensive compared with those in the United States or Europe; its monthly cost per patient without any reimbursement is about 1350 USD in the United States, 338 USD in Germany, and 290 USD in Japan (87 USD with national health insurance reimbursement). However, there is a concern about extremely limited patient access to the drug. In Japan, the drug is indicated for adult patients with either hypertension, hyperlipidaemia or type 2 diabetes mellitus who cannot achieve sufficient effect through dietary therapy and physical activity with an initial body mass index (BMI) of ≥35 kg/m2 or ≥27 kg/m2 in the presence of at least two weight-related comorbidities (Table 1).1 Although the prevalence of obesity in Japanese adults is low,2, 3 Japan's BMI criterion of ≥35 kg/m2 is more stringent and complicated compared with the United States or Europe. These countries allow an unconditional prescription for patients with a BMI of ≥30 kg/m2 (Table 1). Under this condition, Novo Nordisk, a manufacturer of Wegovy, estimates a 216 million USD (32.8 billion JPY) market in Japan, with 100 000 people being administered this drug at its peak. Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial BMI of for example, dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease Marketing authorization indication Semaglutide (Wegovy; Novo Nordisk) is indicated as an adjunct to a reduced calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial BMI of ≥30 kg/m2 (obesity), or ≥27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity NICE recommendation Semaglutide is recommended as an option for weight management, including weight loss and weight maintenance, alongside a reduced-calorie diet and increased physical activity in adults, only if: they have at least 1 weight-related comorbidity and: In line with the drug's market authorization, the Japanese government issued a guideline to prevent inappropriate prescription of the drug,4 restricting the number of physicians who can prescribe the drug. In the background, the authorities are afraid of issues related to overuse, which have already been reported regarding out-of-pocket diet-purposed use where patients subscribe to semaglutide online outside of universal health coverage.5 Nonetheless, the guideline shows further concern for patient access to the drug. First, the guideline constrains institutions to be qualified educational training institutions that employ full-time medical doctors qualified by either of three obesity-related academic societies: Japan Diabetes Society, Japan Endocrine Society or Japan Circulation Society.4 This presumably indicates that only large, leading medical institutions, such as university hospitals, could be qualified for the guidelines. Therefore, patients cannot rely on their general practitioners in their nearby clinics. Second, for the first year on the market, physicians are only allowed to prescribe the drug for up to 2 weeks at a time, forcing patients to visit their doctors frequently.4 This would probably discourage patient compliance to see their doctors regularly (and frequently) because of the long waiting time in large hospitals in Japan. Third, unlike other countries, Japan imposes a maximum administration duration limit of 68 weeks for the drug,4 requiring physicians to carefully consider its prescription initiation. This duration restriction was simply set because no clinical trials have been reported to administer the drug over 68 weeks to Japanese individuals. Fourth, Japan's guidelines mandate that patients, in advance of the Wegovy administration, undergo dietary therapy and physical activity for a minimum of 6 months at the healthcare facility where the drug will be administered. This prerequisite underscores the importance of comprehensive obesity management and well-organized preparation. On the other hand, the restriction can become a barrier for patients, such as those with severe obesity who need immediate drug treatment or who have been receiving diet and physical therapy from their primary care physicians (who cannot prescribe Wegovy in most cases). Unlike Japan, the drug is available from family doctors in most European countries. However, similar restrictive attitudes towards the prescription of the drug are also observed among most European governments because of swelling health care budgets. Within Europe, the drug is available in Norway, Denmark, Germany, Switzerland, Iceland and the United Kingdom as of February 2024. Most of these countries do not reimburse the drug with national health insurance. Germany is one of the most stringent, prohibiting health insurance systems from paying out for weight-loss drugs under their legal system. It is reasonable for authorities to restrict the prescription to a certain extent, given the drug's high cost and international shortages of these injections because of the high demand, particularly in the United States.6-8 On the other hand, the United Kingdom will initiate a government pilot study from April 2024 to widen access to the drug, allowing general practitioners to prescribe the weight-loss drug to patients with obesity,9 despite concerns about shortages, particularly for patients with type 2 diabetes.10 This drug can currently be accessed only through specialist weight management services providing multidisciplinary management of overweight or obesity, which are largely hospital-based and prescribed for free.9 In the United States, general practitioners and nurse practitioners are generally allowed to prescribe the drug, and not a few private insurance companies cover it despite the high cost of the drug before the coverage. Such easy access has led to the drug being placed on the shortage list by the Food and Drug Administration (FDA). The shortage is expected to be addressed by Novo Nordisk's extended effort to boost supply, as well as the FDA's approval of tirzepatide (brand name Mounjaro), another GLP-1 receptor agonist developed by Eli Lily. There remains a discrepancy regarding the prescribing of this weight-loss drug, which necessitates further discussion. Nonetheless, Japan's stringent criteria contrast starkly in comparison with those of the United Kingdom and the United States, where individuals have the option of reimbursement. Japan should strike a balance between health care expenditures and ensuring access to newly introduced drugs to address the therapeutic needs of patients. Indeed, the drug has provided a benefit in reducing the incidence of heart attacks, strokes, or the risk of death from cardiovascular events for patients with pre-existing cardiovascular disease and overweight or obesity.11 In response to this evidence, the European Medical Agency and the US FDA started to consider a label expansion. Deregulation by Japan's regulatory body may be warranted to ensure the delivery of the drug to patients with indispensable needs, with balanced regulatory intervention for safeguarding equitable distribution and adequate pricing. H.H. is supported by the Toyobo Biotechnology Foundation Fellowship, outside the submitted work. Open Access funding enabled and organized by Projekt DEAL. TT receives personal fees from MNES Inc. and Bionics Inc., outside the submitted work. MO has no conflicts of interest to declare. HH is supported by the Toyobo Biotechnology Foundation Fellowship, outside the submitted work. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15638. The data that support the findings of this study are openly available in reference numbers 1, 4, and 12-15.

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