Points of View Diabetes Mellitus

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Minoru Ito, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

1. Introduction

In the New Economic and Fiscal Revitalization Plan Reform Process Chart 20221 presented at the 16th Meeting of the Council on Economic and Fiscal Policy held on December 22, 2022, "extension of healthy life expectancy for the promotion of prevention and health promotion, and employment and social participation of the elderly" was indicated as one of the policy goals in the social medical security field, The importance of extending healthy life expectancy is unquestionable. One of the important goals of next-generation health care is "extension of healthy life expectancy. In order to realize this goal, the focus of healthcare should shift from "diagnosis and treatment," which focuses on curing illness, to "prevention" before illness occurs and "coexistence," in which people can live their lives with as few restrictions as possible even if they are afflicted with illness. When considering "extension of healthy life expectancy," diabetes has a significant impact on healthy life expectancy because of the large number of patients and pre-patients with diabetes. Therefore, in this report, we have conducted a survey and research on diabetes in order to understand the status of diabetes and its countermeasures, as well as to understand the development status of therapeutic drugs to which the pharmaceutical industry can contribute, and the status of related medical DX.

What is diabetes?

Diabetes mellitus is "a disease in which high blood glucose levels persist for a chronic period of time due to a deficiency or reduced action of insulin, which results in a decreased ability to control the rise in blood glucose levels (glucose tolerance)" and is classified into type 1 and type 2 diabetes. type 1 is also called insulin-dependent diabetes and occurs when insulin-secreting cells are destroyed due to autoimmune diseases, etc. Type 1 is also called insulin-dependent diabetes mellitus. Type 2, on the other hand, is called insulin-independent and is caused by a combination of genetic factors and lifestyle habits such as overeating and lack of exercise. The fear of diabetes is the development of serious complications without subjective symptoms. In addition to the three major complications of retinopathy, nephropathy, and neuropathy, which are microvascular disorders (microvascular disorders), the risk of heart disease and stroke also increases due to the progression of atherosclerosis in larger blood vessels (macrovascular disorders). It is believed that atherosclerosis progression begins at the level of impaired glucose tolerance (pre-diabetes). Therefore, prevention is particularly important for diabetes. Primary prevention is to prevent the onset of diabetes before it occurs by improving lifestyle, secondary prevention is to control blood glucose levels and lead a healthy life even if diabetes develops, and tertiary prevention is to prevent the onset of complications. 2)

Status of Diabetes

Fig. 1 Annual change in the estimated number of

The National Health and Nutrition Examination Survey conducted by the Ministry of Health, Labour and Welfare based on the Health Promotion Law indicates the estimated number of "persons with strong suspicion of diabetes" and "persons whose possibility of diabetes cannot be denied" at regular intervals (Figure 1) 3). The former can be read as "diabetes" and the latter as "impaired glucose tolerance (prediabetes).

The number of "strongly suspected diabetics" exceeded 10 million for the first time in 2016 and is likely to continue to increase in 2019 (independently calculated by the National Institute of Biomedical Innovation Policy using the same method as in other years). This is believed to be due to the increase in the number of elderly people with diabetes, who have a higher incidence of diabetes. On the other hand, the number of people with pre-diabetes, which peaked at 13.2 million in 2007 and declined to 10 million in 2016, is likely to remain almost unchanged in 2019. This is thought to be due to the increased interest in diabetes resulting from the government's "Healthy Japan 21 (2nd stage)," a national policy discussed below, and the preventive effect of the specific health checkups and specific health guidance that began in 2008. 5)

Fig. 2 Status of treatment among persons strongly suspected to have diabetes mellitus

The National Health and Nutrition Examination Survey also examines the percentage of "persons with diabetes strongly suspected (diabetes)" who are currently receiving treatment; in the 2019 survey, the percentage was 76.9% (78.5% for men and 74.8% for women). By sex and age group, the proportion of men and women in their 40s was low, which is considered a hotbed for the development of diabetic complications (Figure 2). (Figure 2)

The reasons for untreated diabetes are assumed to be that many people have no symptoms in the early stages and are unaware of their diabetes even when their blood glucose levels are in the diabetic range, that many people do not receive medical checkups even if they are suspected of having diabetes, and that even if they do receive medical checkups, their visits are discontinued after only initial treatment. 5) (The interruption rate of medical checkups is estimated to be about 8% annually.6 )6)

Fig. 3 Annual change in national health care expenditure for diabetes (age 0 and above)

The national medical expenditure on diabetes has been increasing steadily, perhaps reflecting the increasing trend of "persons strongly suspected to have diabetes" (Figure 3). (Figure 3) In 2019, it reached 1,215.4 billion yen, accounting for 3.8% of the total, and occupying 7th place in the disease ranking.

In Policy Research Institute News No. 658 ), the author investigated the main causes of the need for long-term care among persons aged 40 and over, using data on long-term care systems, which are considered the most valid complementary indicator of healthy life expectancy. The results showed that diabetes accounted for 2.9% of all causes in 2019 and ranked ninth in terms of causal disease ranking.

As described above, diabetes has a significant impact on national healthcare costs and national healthy life expectancy due to its large number of patients, and effective measures are expected to be implemented.

Measures against diabetes

4-1. Healthy Japan 21 (2nd stage)

An important national effort to combat diabetes is the Healthy Japan 21 initiative. Healthy Japan 21 was launched in 2000 as a basic policy to comprehensively promote the health of the nation. The first phase of Healthy Japan 21 (FY2000-FY2012) focused on "emphasis on primary prevention" as its basic policy, while the second phase of Healthy Japan 21 (initially started in FY 2013-FY2022, then extended by one year to FY2023) promoted the health of the nation with the ultimate goal of "extending healthy life expectancy and reducing health inequalities. The second phase of Healthy Japan 21 (the second phase) is based on the basic principles of the Health Japan 21 (the second phase). The basic directions of Healthy Japan 21 (the second phase) are: 1) Extension of healthy life expectancy and reduction of health disparities, 2) Thorough prevention of the onset and severity of lifestyle-related diseases (prevention of NCDs (noncommunicable diseases)), 3) Maintenance and improvement of functions necessary for social life, 4) Development of social environment to support and protect health, and 5) Promotion of nutrition, dietary habit, physical activity (5) Improvement of lifestyle related to nutrition, diet, physical activity, rest, drinking, smoking, dental and oral health, and improvement of social environment. As goals related to thorough prevention of the onset and severity of lifestyle-related diseases, "cancer, cardiovascular disease, diabetes, and COPD" were identified as specific diseases, and the final evaluation report of Healthy Japan 21 (2nd stage) was released in October 2022. 9)

Fig. 4 Approach to setting goals for diabetes and evaluation of goal items
Table 1 Evaluation of target items for diabetes

As measures against diabetes, it is important to review lifestyle, correct obesity, early detection through health checkups and health guidance, and appropriate medical care, etc. without interruption, and these measures need to be strengthened and coordinated at each stage of creating a healthy environment, community and workplace health programs, health checkups and health guidance, and medical care. The following measures were required: (1) reduction of the number of new dialysis patients annually due to diabetic nephropathy), appropriate control of diabetes (2) increase in the proportion of patients who continue treatment, (3) reduction in the proportion of patients with poor control in glycemic control index), prevention of diabetes onset (4) control of the increase in the prevalence of diabetes, (5) reduction in the number of patients with metabolic syndrome and those with pre-diabetes), and countermeasures (6) reduction in the number of patients with metabolic syndrome and those with pre-diabetes). The final evaluation report presents an assessment of the goals (Figure 4, Table 1). (Figure 4, Table 1)

The number of patients newly introduced to dialysis for diabetic nephropathy was rated C. However, the number of newly introduced patients under 75 years old decreased, suggesting that efforts to prevent severe disease and advances in diabetes care may have contributed to the decrease. It was pointed out that the number of patients who continued treatment remained unchanged, and that the way of recommending medical examinations should be examined. The number of diabetics with diabetes mellitus was estimated by an alternative method, and it was considered that the increase was suppressed to a certain degree, although the target was not achieved. Target (6): The implementation rate of specific health checkups and specific health guidance increased significantly, but the target was not achieved. Goal 5) Metabolic syndrome tended to worsen after the interim evaluation, suggesting the need to use more effective strategies in the future specified health checkups and specified health guidance. (6) Measures for those with metabolic syndrome who are taking medication are insufficient (because those on medication are not subject to specific health guidance), and it was evaluated that measures for those on medication are also important in the future.

Based on these evaluations, the final evaluation report mentions future issues related to diabetes countermeasures. The report states that it is important to take measures to prevent the onset and severity of diabetes, maintain an appropriate body weight, and improve the rate of health checkups by promoting "moderate exercise, proper diet, smoking cessation, and health checkups". It was also mentioned that health promotion projects should continue to be implemented and that research on lifestyle habits such as nutrition, diet, physical activity, and exercise should be promoted. It was pointed out that it is necessary to inform local governments of the measures against diabetes in the elderly due to the aging of diabetics, and that the impact of sarcopenia and physical inactivity is significant, and that the way of support for diabetics with dementia needs to be revised. Promotion of research and measures related to cancer, dementia, and diabetes was also mentioned. It was also noted that the stigma against diabetes (discrimination due to social prejudice) must be corrected. Since diabetes is often associated with depression, the need for measures that take into consideration the psychological aspects of the disease was also pointed out.

4-2. Next National Health Promotion Campaign Plan

Figure 5 Promotion of the next plan (draft)

In anticipation of the expiration of the second phase of Healthy Japan 21 in FY2023, a special committee for the formulation of the next National Health Promotion Campaign Plan was established in September 2022 and has started to discuss the next plan for the start of FY2024.11) (Figure 5)

At the time of writing (January 2023), the committee has met five times to discuss the basic policy framework and draft goals of the next plan. The draft framework12) summarizes that since the launch of Healthy Japan 21 in 2000, basic legal systems and mechanisms have been developed and various entities, including local governments, insurers, businesses, educational institutions, and private organizations, have been engaged in prevention and health promotion, resulting in a steady increase in healthy life expectancy. On the other hand, the report also points out that some indicators (especially in primary prevention) have worsened, that some indicators by sex and age group have deteriorated even though the overall situation has improved, that visualization and utilization of health promotion-related data is insufficient, and that the PDCA cycle is not sufficiently promoted by both the national and local governments.

The following four basic directions are indicated. (1) Extension of healthy life expectancy and reduction of health disparities, (2) improvement of individual behavior and health status, (3) improvement of the quality of the social environment, and (4) life course (health promotion based on a chronological view of a person's life from the fetal period to old age). With regard to the improvement of individual behavior and health (Direction 2), it is stated that efforts will continue to be made to prevent the onset of lifestyle-related diseases such as cancer, cardiovascular diseases, diabetes, and COPD, as well as to prevent the onset of complications and the progression of symptoms and other serious illnesses. The next plan includes a reference to diabetes as a specific disease name.

Table 2 Goals in the Next Plan (Draft) Diabetes-related

Table 2 shows the proposed goals13) related to diabetes in the next plan.

The next plan has seven targets, compared to six targets in the second phase of Healthy Japan 21. Regarding complications, the target has been changed from "decrease the number of new patients introduced to dialysis due to diabetic nephropathy per year" to "decrease the number of complications (diabetic nephropathy)" and the focus is now on a less severely ill population. Regarding blood glucose control, "decrease the proportion of patients with poor control" was revised to "decrease the number of patients with poor control. In addition, "specific health checkups and specific health guidance," which were previously combined into one item, have been separated into two items. Although there is no change in the major flow of the plan, the final evaluation of the Health Japan 21 (second round) was not favorable, so we expect that the next plan will address this issue.

4-3. Healthy People 2030 (U.S.)

Table 3 Diabetes-related targets in Healthy People 2030

As a reference for Japan's measures, we surveyed measures in the United States. Healthy People 2030 (HP2030) 14) plays a major role in diabetes control in the U.S. HP2030 is an initiative launched in 1979 by the U.S. Department of Health and Human Services (HHS: UnitedStates Department of Health and Human Services). HP2030 is an initiative launched in 1979 by the UnitedStates Department of Health and Human Services (HHS), a national agenda designed to identify health concerns facing the public, set measurable (2020-2030) goals for health promotion and disease prevention, and take action across multiple sectors. Diabetes is one of them. 15)

More than 30 million people in the U.S. have diabetes, making it the seventh leading cause of death, and HP2030 focuses on reducing diabetes cases, complications, and death. Specific diabetes goals are shown in Table 3. As can be seen at first glance, while the second phase of Healthy Japan 21 and the next National Health Promotion Plan focus on prevention (primary, secondary, and tertiary), HP2030 emphasizes disease control including prevention (reducing diabetes cases, complications, and deaths), and this difference This difference was clear. Another difference is that HP2030 has more detailed targets (14 items) compared to Japan's targets (6 to 7 items). For example, with regard to complications, only nephropathy is specifically targeted in Japan, while HP2030 covers all three major complications (retinopathy, nephropathy, and neuropathy (lower limb amputation)) and sets specific targets16) for each complication. HP2030 also includes mortality as a target. While specific health checkups and specific health guidance are emphasized as effective measures in Japan, the emphasis on education in HP2030 seems to reflect the difference in the diabetes care environment.

Development of therapeutic drugs (contribution of the pharmaceutical industry)

When considering the contribution of the pharmaceutical industry to diabetes, it can be inferred that expectations for therapeutic drug development rank first and foremost. In this report, we surveyed global trends in therapeutic drug development. The survey was conducted using the global search function of "Tomorrow's New Drugs (Technomic Co., Ltd.). The fields were pharmaceuticals and regenerative medicine, and the stages were categorized as active: pre-clinical, clinical preparation, phase 1-3, filed, approved, and already on the market. The "approved and launched" category is limited to items approved in 2016 or later because it includes older items, and the actual launch status may be unclear, so the total is shown. Biosimilars were excluded. The indications were "type 1 diabetes, type 2 diabetes, and diabetes (type unknown)," and diabetic complications were listed as "diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic neuropathy, diabetic neuropathic pain, diabetic foot ulcer, diabetic foot infection, diabetic macrovascular disease, diabetic cardiomyopathy, diabetic gastric insufficiency palsy, Diabetic ketoacidosis" was also included in the search.

Table 4 Number of development items related to diabetes

As a result, the current (December 28, 2022) number of diabetes mellitus (including complications) products in global development (meaning the number of all hits in the global search) is 203. The number of products in global development (meaning the number of hits in the global search) for diabetes (including complications) as of December 28, 2022 was 203. By country, 143 items were from the U.S., 70 items from Europe, and 48 items from Japan, in that order. The global 203 items consisted of 155 pharmaceuticals (84 small molecule compounds and 71 biopharmaceuticals), 21 regenerative medicine items (9 gene therapy items and 12 cell therapy items), and 27 other/unknown items. 17) As for regenerative medicine (gene therapy and cell therapy), which is a new modality, the U.S. was the largest market with 9 items, followed by Europe with 70 items, and Japan with 48 items. (17) As for regenerative medicine (gene therapy and cell therapy), which is a new modality, development was active in the U.S. with 9 items and 5 items, followed by Europe with 1 item and 4 items. On the other hand, Japan had 0 and 2 products. Compared to Europe and the U.S., development in Japan tends to be concentrated on low molecular weight compounds. (Table 4)

Table 5 Number of development projects related to diabetes

We continued our review of the current development status. In cases where the same drug is being developed for multiple indications, the development progress may differ depending on the indication, so the data were tabulated separately for each indication. In addition, when a product is being developed for the same indication in multiple countries, the development progress may differ, so the data are tabulated separately for each indication. In other words, the data were tabulated for each development project. As a result, 397 development projects are in progress globally. By country, the United States had the largest number of projects (158), followed by Europe (82) and Japan (56). While the majority of projects were in Phase II and Phase III development, the U.S. tended to have a relatively large number of projects in the younger phases of development, such as preclinical to Phase I, indicating that new development is active. Japan, with 12 preclinical and 5 phase 1 projects, occupied the second position after the U.S., along with Europe. (Table 5)

Table 6 Diabetes-related indications (by development project)

Furthermore, we examined which indications for diabetes (including complications) were being developed. Aggregation was performed for each development project. 18) (Table 6)

As a result, 152 of the 397 projects were being developed for type 2 diabetes, followed by diabetic retinopathy in 78 projects, type 1 diabetes in 63 projects, and diabetic nephropathy in 43 projects. Not a small number of projects were also being undertaken for complications, indicating the importance of measures against complications in diabetes mellitus.

Table 7 Indications related to diabetes by modality

A separate study was conducted to examine the relationship between indication and modality in detail. This study only represents the global situation. (Table 7) When the same drug is being developed for multiple indications, the data are tabulated by indication, but it should be noted that the number of data is different from that in Table 6 because the data are not broken down by country. As a general result, it can be seen that small molecule compounds are being developed for a wide range of indications, including complications. Proteins and peptides were also in development for the second widest range of indications after small molecule compounds.

Looking at modalities by indication, the recent news that the FDA approved teplizumab, the world's first antibody drug to delay the onset of type 1 diabetes, in November 2022 caught the public's attention19), but the development of cell therapy for type 1 diabetes was also a feature. In type 2 diabetes, low molecular weight compounds and proteins/peptides have been the focus of development. In the case of type 2 diabetes, low molecular weight compounds and proteins/peptides have been the main focus of development. VEGF (vascular endothelial growth factor) is the most important molecule in the molecular cascade that regulates angiogenesis and vascular permeability in retinopathy. VEGF (vascular endothelial growth factor) is one of the most important cytokines in the molecular cascade that regulates angiogenesis and vascular permeability in retinopathy, and its expression is known to be upregulated in diabetic retinopathy. 21)

As described above, many small molecule compounds and biopharmaceuticals (proteins, peptides, antibodies, nucleic acid drugs, etc.) are under development for diabetes and diabetic complications, and it was confirmed that the development of regenerative medicine such as gene therapy and cell therapy is also progressing. There were also some items for which development information was confirmed in Japan, confirming the contribution of the pharmaceutical industry in this area. We hope that these products will be launched as soon as possible and contribute to the treatment of diabetes, including its complications.

Medical DX related to diabetes

As mentioned earlier, prevention is particularly important in diabetes. Primary prevention is to prevent the onset of diabetes before it occurs by improving lifestyle, secondary prevention is to control blood glucose levels appropriately after the onset of diabetes and to live a healthy life, and tertiary prevention is to prevent the onset of complications. However, the goal of Healthy Japan 21 (the second phase) to "reduce the number of people with metabolic syndrome and those with pre-diabetes" has been deteriorating, and "increase the percentage of people who continue treatment" has been evaluated as unchanged. 9) This means that support for self-management, including diet, exercise, and medication, and motivation to continue treatment for diabetes without subjective symptoms, are important. 9) In other words, the key issue is to support self-management such as diet, exercise, and medication, and to maintain motivation to continue treatment for diabetes without subjective symptoms. One of the promising measures to address this issue is to support self-management using IoT devices. In the next National Health Promotion Campaign Plan12), it is expected that health promotion efforts will be promoted more effectively and efficiently by actively utilizing digital technology, and the need to consider health promotion using services based on ICT, online applications, and apps is mentioned.

Table 8 Trend of medical DX related to diabetes mellitus

In the course of the study, we investigated the events of medical DX that may be related to diabetes. Unfortunately, there are no databases or other tools available to fully investigate medical DX, so we collected and categorized information related to medical DX from various media22) for the past two years both domestically and internationally (Table 8). (Table 8)

As a result, 49 events were identified. As a general trend of medical DX related to diabetes, "device-based monitoring" and "AI-based risk management" seemed to be the main directions. The "device-based monitoring" includes health management and exercise support in the primary prevention phase before the onset of diabetes, and diet and exercise therapy management, insulin administration management, blood glucose level measurement, etc. in the secondary prevention phase after the onset of diabetes. On the other hand, "AI-based risk management" includes prediction of the onset of type 2 diabetes at the primary prevention stage and AI screening for diabetic retinopathy at the tertiary prevention stage (complication prevention). Typical information is exemplified below.

  1. (1)
    As of December 2021, the number of users of "Asmile," a free health management application provided by Osaka Prefecture to its residents, exceeded 270,000. It has an excellent system in which points are awarded based on actions useful for health, and for national health insurance subscribers, specific health checkup data is automatically transferred. Using the accumulated health checkup data, an AI has also been developed to almost accurately predict the probability of developing three major lifestyle-related diseases, including diabetes. The team is also developing functions as a companion AI, aiming to quantitatively indicate the extent to which exercise and diet can reduce the risk of developing lifestyle-related diseases. 23)
  2. (2)
    As part of a larger project to build an "artificial pancreas system for diabetics," an Illinois Institute of Technology research team has received a $1.2 million grant from the National Institutes of Health (NIH) to develop a machine learning tool for automatic insulin administration. The system is a total system that supports blood glucose management and consists of a glucose sensor, a wristband, a dedicated smartphone, and a fully automated insulin pump. The system can automatically administer optimal insulin according to metabolic changes such as diet and exercise. Patient behavior is analyzed with machine learning tools to add the ability to identify and predict behaviors that affect blood glucose control. 24)
  3. (3)
    Eyenuk, a company developing AI screening for diabetic retinopathy, announced the validation results of its AI system, EyeArt, which "achieved a detection sensitivity significantly higher than conventional mydriatic fundus examination. EyeArt is a useful adjunct to diabetic retinopathy screening, and has been used at more than 200 facilities in 18 countries, including 14 states in the U.S., and has screened more than 60,000 patients since its FDA approval in 2020. 25)

When considering medical DX efforts related to diabetes, a major topic was the July 2010 FDA approval of WellDoc's BlueStar Ⓡ, a physician-prescribed diabetes self-management application, as the world's first DTx. 26) BlueStar Ⓡ is a drug compliance, It is a mobile health system that supports patient health behaviors such as medication adherence, diet and exercise management, psychological and social health, and provides diagnostic support for physicians to help patients and healthcare professionals improve glycemic control. Recently, in June 2020 FDA approved additional features and added an insulin adjustment program that facilitates real-time adjustment of insulin. 27) In Japan, in November 2019, Astellas Pharma Inc. in collaboration with Welldoc Inc. in Japan and some other Asian regions (28) In 2018, IBM Watson Health provided estimates of the economic impact of BlueStarⓇ in type 2 diabetes in three cases, depending on the HbA1c level at the start of use (an indicator of blood glucose status over the past month or two). The Medicare case is divided into three cases. For Medicare, annual cost savings per patient were projected to be cost-beneficial in all cases: (1) all averages above 7% HbA1c: $1,392; (2) all averages above 8% HbA1c: $3,048; (3) all averages above 9% HbA1c: $3, 67229)

As a further pharmaceutical industry initiative for medical DX, in February 2022 Novo Nordisk Pharma K.K. announced the launch of an insulin pen injector that automatically records insulin administration data and works with a smartphone app to allow patients to check their administration history. It is said to enable accurate recording of data, enhance discussions with healthcare professionals, and assist with dose adjustments that lead to better treatment efficacy and improved long-term outcomes. 30)

Medical DX efforts related to diabetes are progressing in a wide range of phases, including primary, secondary, and tertiary prevention, and examples of the pharmaceutical industry's attempts to contribute in this area were also identified. The trend of new efforts to extend people's healthy life expectancy more effectively and efficiently through the active use of digital technology should continue to be closely monitored.

7. summary

The situation of diabetes is not necessarily favorable, as the number of "persons strongly suspected to have diabetes" is increasing to more than 10 million with the aging of the population, and the number of "persons with undeniable possibility of diabetes (pre-diabetic group)" has been leveling off in recent years at around 10 million. Diabetes is a disease that has a significant impact on the healthy life expectancy of the population and society as a whole. The next National Health Promotion Plan is scheduled to be implemented from 2024, and it is hoped that this situation will be turned around.

The pharmaceutical industry is expected to contribute most to the development of therapeutic drugs, and a reasonable number of items are in the development stage. However, efforts to develop new modalities such as biopharmaceuticals and regenerative medicine (gene therapy and cell medicine) in Japan tend to be a bit lower than those in Europe and the U.S. Continued research and development efforts in diabetes are expected.

The efforts of medical DX are covering a wide range of phases, including primary, secondary, and tertiary prevention, and we look forward to future development as one of the measures to turn the current situation around in terms of maintaining motivation to continue treatment for diabetes without subjective symptoms and supporting self-management in terms of diet, exercise, medication, and so on.

Diabetes is a disease for which prevention is particularly important. In the "Policy Research Institute News No. 6731, " the author mentioned that, "For cardiovascular diseases, improvement of lifestyle is important, and it is desirable for the public to actively participate in the fight against these diseases by changing their behavior. In this sense, diabetes countermeasures can be positioned as another all-out war involving the public (patients and pre-patients). 2.

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