Points of View The Latest Trends in Flail

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

1. Introduction

One of the important goals of next-generation health care is "extension of healthy life expectancy. To realize this goal, the focus of healthcare should shift from "diagnosis and treatment," which focuses on curing diseases, to "prevention" and "symbiosis," in which people live their lives with as few restrictions as possible even if they suffer from a disease. When considering "prevention" from the perspective of "extending healthy life expectancy," one of the main players is the elderly.

In the previous issue of the ISS News (No. 65) ^{1) , the} author examined the health status of the elderly over time and by age group based on long-term care data, and examined the main causative diseases that impair health. The results showed that dementia accounted for 22.2% of the total number of major causes of the need for long-term care among the elderly aged 75 years and older (in 2019). However, weakness due to old age (16.5%) and fractures/falls (15.6%) followed, accounting for a greater proportion of the total than dementia. In other words, it is important to address (prevent) these two causes in order to extend the healthy life expectancy of the elderly. The purpose of this issue of the Journal is to understand the latest trends in the field of frailty, a concept that is closely related to these two causes.

What is frailty?

The term "frail" means "frailty. However, due to the academic background that "frail" gives the impression of irreversible old age and decline and does not express the multifaceted nature of frailty, the Japanese Geriatrics Society agreed to use "frail" as the translation, and in May 2014, issued the "Statement from the Japanese Geriatrics Society on Frailty2) . Statement ²⁾ " was issued in May 2014. In the Statement, frail is indicated as "a condition in which vulnerability to stress is increased due to a decline in physiological reserve in old age, making people vulnerable to turning points such as impairment of daily functioning, need for nursing care, and death. It is also considered to be "an intermediate stage between the healthy state and the state of needing care" (Figure 1). (Figure 1)

It is important to note that frail includes the reversibility of returning to a healthy state through appropriate intervention. Early detection of frail elderly people and appropriate intervention can be expected to maintain and improve their life functions.

Frail is a multifaceted concept that has three manifestations: physical frailty, in which physical abilities necessary for daily living (walking, eating, etc.) decline; social frailty, in which social ties become weak due to decreased outings and living alone; and psychiatric frailty, in which cognitive functions decline and depression ^{occurs4) (} Figure 2).

The concepts "locomo" and "sarcopenia" are related to physical frailty. Locomo" stands for "locomotive syndrome," a condition in which mobility is impaired due to musculoskeletal disorders. Sarcopenia" is a condition in which physical function declines due to a decrease in skeletal muscle mass with age. Oral frailty, which focuses on oral function as a risk factor for inducing physical frailty, has also been proposed, and research has shown that the risk of developing physical frailty is 2.41 times greater in those aged 65 years or older with oral frailty. ⁵⁾

The Japanese version of the CHS criteria (J-CHS criteria) ^6, a modified version of the CHS criteria (Cardiovascular Health Study criteria), is regarded as the representative method for diagnosis of frailty in Japan. The diagnosis of frailty is based on five criteria: (1) weight loss, (2) muscle weakness, (3) fatigue, (4) walking speed, and (5) physical activity, with three or more of the five criteria being applicable. (Figure 3)

3. Declaration of the Medical Association for Overcoming Frailty and Locomotion

In a major move related to frailty, on April 1, 2022, the Japanese Federation of Medical Societies, together with 57 member organizations of the Japanese Federation of Medical Societies and 23 non-member organizations, released the "Medical Association Declaration for Overcoming Frailty and ^Locomotion4). Table 1 shows the main text of the Declaration.

The Declaration consists of four sections. The first section explains the concept of frailty and locomotion, and notes that people with frailty and locomotion have approximately four times the risk of requiring long-term care compared to those without frailty and locomotion. The second point refers to the importance of prevention and early response, the fact that appropriate measures can reduce the risk level and return people to a healthy state, and the need for measures that are tailored to their life course. The third item is a statement of determination to achieve healthy longevity for the nation, and the vision/goals and activity plans of the individual participating societies and organizations that jointly issued the Declaration of the Japan Medical Association are shown in an attached table. The fourth item states the development of the "80GO (Hachimaru Go)" movement as an activity goal for the public, with the goal of walking (or operating a wheelchair by oneself) at the age of 80, and the target walking speed of 11 meters in 10 seconds (1.1 meters per second, 4 km/h) as an example. .

Frail is not yet well recognized in the general public. In a ^survey7) conducted by the Tokyo Metropolitan Institute of Gerontology and Geriatric Medicine (TGHM) (about 10,000 men and women aged 65-84 living in Ota Ward, Tokyo were analyzed; the survey was conducted in July 2018), awareness of frailty was only 20.1% (15.5% for men and 24.3% for women), indicating that awareness is low among those who need to take measures against frailty This is the reality of the situation.

In connection with the Ministry of Health, Labor and Welfare's "Integrated Implementation of Health Services and Care Prevention for the Elderly" newly enforced from April 2020, a new questionnaire for the elderly in the later stages of life has been developed and the so-called "Frail Health Examination" has been ^started8). 8) It is hoped that the start of the Frail Health Examination and the declaration of the Medical Association for Overcoming Frail and Locomotion will be an opportunity to raise awareness of frail to a sufficient level.

4. prevention and intervention of frailty (non-drug related) 5. prevention and intervention of frailty (non-drug related)

Non-drug interventions such as "exercise," "nutrition," and "social environment (connections with others)" are the main prevention and intervention strategies for frailty. We would like to take a longitudinal look at the impact of the new coronavirus infection as well.

4-1Prevention and intervention from the viewpoint of exercise

The usefulness of exercise in improving physical function in the elderly has been demonstrated in a systematic ^review9) of exercise programs for the elderly aged 65 years and older. The exercise program was found to be effective in improving muscle strength, exercise function, depression, ADL, and fall prevention. It was also shown that these effects were more likely to be obtained with resistance exercise (exercise in which movements are repeatedly performed to load the muscles) and multi-component exercise that includes two or more types of exercise (exercise that combines aerobic exercise, resistance exercise, balance exercise, etc.). In addition, the longer the total duration of exercise, the more effective the exercise was. In other words, the results indicate that the implementation of exercise programs aimed at improving exercise function and preventing falls for the elderly aged 65 years and older is generally useful, and that it is important to combine multiple exercise programs centered on resistance exercise and to implement them over a relatively long period of time.

Despite the benefits of exercise, there is growing concern about the deterioration of frailty, which is based on inactivity due to the self-restraint in living following the devastation caused by the new coronavirus infection. Some surveys have reported that about 40% of the elderly showed a marked decrease in the frequency of going out, and others reported a decrease of about 30% in physical activity time per week, indicating the multifaceted progression of frailty, especially sarcopenia. Recently, the infection situation is calming down, and it is important to increase opportunities to go out and improve the amount of physical activity while taking infection prevention into consideration. ^{10) 11)}

4-2Prevention and intervention from the viewpoint of nutrition

According to the National Institute for Longevity Sciences' "Guide to Long-Term Care Prevention: Practice and Evidence, " ¹²⁾ it is reported that the intake of nutrients such as total energy, protein, and fat decreases with age among the elderly living in the community in Japan, and that approximately 40% of them are undernourished or at risk of undernutrition. It has been reported that about 40% of the elderly are undernourished or at risk of becoming undernourished. Many of the undernourished elderly are complicated by frailty and sarcopenia. Appropriate nutritional intervention for these elderly people has been shown to increase weight gain, improve physical function (skeletal muscle mass, muscle strength, walking ability, and ADL), and improve quality of life. In particular, regarding protein intake in the elderly, it has been suggested that effective protein synthesis in skeletal muscle may not be maintained throughout the day unless at least 25-30 g of protein is consumed at each meal (75 g or more per day). ¹²⁾ In addition, for elderly patients with sarcopenia, combined intervention of exercise and nutrition is more effective than single intervention ¹³⁾

Regarding the effects of the novel coronavirus disaster on nutrition, the results showed that the elderly who were originally overnourished gained more weight, while the elderly who were undernourished experienced a further deterioration in their nutritional status, with a marked polarization between the two, especially among the elderly who lived alone. On the other hand, 67% of the elderly in nursing homes showed weight loss, with 23% showing a loss of more than 5%, according to the study. The importance of regular nutritional assessment has been suggested, and it is important to proceed with nutritional intervention as soon as unintentional weight loss is observed. ¹⁴⁾

4-3Prevention and intervention from the perspective of social environment

Social isolation and seclusion are one phenomenon of social frailty. While there is still no consensus on the definition of social frailty, there is general agreement that social frailty has a negative impact on the future health of the elderly. Social frailty precedes physical and psycho-psychological frailty, and it is believed that social frailty causes physical frailty. However, compared to physical frailty, social frailty is more difficult for the elderly to recognize. ¹⁵⁾

It has been reported that the more social interactions such as work, neighborhood, participation in community events, environmental beautification activities, hobbies and recreational activities, senior citizen clubs, and volunteer activities, the higher the sense of health and life satisfaction, and the less the tendency toward mental depression. Therefore, it is recommended that measures be taken to maintain interaction with the local community, and to prevent and support seclusion. ¹⁶⁾

Although the decrease in frequency of going out due to the new coronavirus infection disaster has been mentioned above, people should be aware not only of the prevention of infection, but also of the prevention of lifestyle inactivity and the prevention of decreased connection with others. In recent years, there has been a movement to construct a hybrid type of frailty prevention system that combines face-to-face and online services by utilizing online technology. We look forward to the realization of a community where people can be physically apart but emotionally close. ¹⁰⁾

Prevention and Intervention of Frailty (Drug-Related) 6.

When looking at the relationship between frailty and medication, the issues of polypharmacy and chronic disease management are important.

5-1Polypharmacy and frailty

It is not uncommon for the elderly to suffer from multiple diseases, and it is quite possible that they may be forced to take a large number of medications. According to the Ministry of Health, Labour and Welfare's Summary of Statistics by Social Medical Practice for ^202017), the percentage of out-of-hospital prescriptions for five or more drugs was 27.2% for those aged 65-74 and 40.7% for those aged 75 and older. (Figure 4)

Although there is no strict definition of how many types of drugs constitute polypharmacy, it is often considered to be five or more. A cross-sectional study of community residents showed that the number of medications was significantly higher among the elderly diagnosed with frailty, and a cross-sectional study of frail elderly showed that the frequency of polypharmacy (5 or more medications) was significantly higher among those with frailty, suggesting that polypharmacy is likely to be a risk for frailty. ⁽¹⁵⁾

Polypharmacy is often considered to be the state of taking many different drugs, but in the "Guidelines for the Appropriate Use of Medicines for the Elderly (General Comments) ¹⁸⁾ issued by the MHLW in May 2018, it is not simply the number of drugs taken, but the associated increased risk of adverse drug reactions, medication errors, and decreased medication adherence, which can lead to problems such as increased risk of medication-related adverse drug reactions, medication errors, and decreased medication adherence. The "Guidelines for the Appropriate Use of Medications in Elderly Patients" (General Comment 18) defines a high number of medications as a condition that leads to increased risk of adverse drug events, medication errors, and poor adherence.

A report analyzing the relationship between the number of medications and the frequency of adverse drug events in elderly hospitalized patients showed that the risk of adverse drug events is particularly increased with six or more medications. (Figure 5.) ¹⁹⁾ In frail elderly patients, adverse drug events may exacerbate medical conditions and worsen frailty. Although it is desirable to have fewer drugs when adverse drug events are taken into account, the elderly have multiple diseases and require many drugs. In order to prevent polypharmacy, the need for drugs should be carefully reviewed for each individual patient. In particular, it is important to discontinue or change high-risk drugs that are likely to cause adverse drug events or have the potential to cause serious adverse drug events. ¹⁵⁾ In the "Guidelines for Safe Pharmacotherapy of the Elderly 201519 ⁾ " by the Japanese Geriatrics Society, it is particularly important to review the drug needs of the elderly aged 75 years or older, who are at high risk of adverse drug events, and those aged under 75 years. (15) The Japanese Geriatrics Society's "Guidelines for Safe Medication Therapy in the Elderly" (201519) provides a "list of drugs requiring particularly careful administration" with the main objective of avoiding adverse drug events, especially for the elderly aged 75 years and older, who are at high risk of adverse drug events, and for those aged less than 75 years but frail or requiring care.

On the other hand, frailty is also a risk factor for falls: a longitudinal observational study of outpatients aged 65 years and older showed a significant increase in the frequency of falls with 5 or more types of medication. (Figure 6) ¹⁹⁾

Although it is difficult to provide a single explanation for why polypharmacy increases susceptibility to falls, it has been suggested that it may be because some medications, such as sedative, antihypertensive, and anticholinergic medications, have a high probability of inhibiting brain function. When an elderly patient is prone to falls, there is a need to review medications to see if polypharmacy can be eliminated, and to consider reducing or discontinuing medications. ¹⁵⁾

5-2Chronic disease management and frailty

In chronic diseases such as diabetes and hypertension, it has been noted that adverse events associated with strict disease management may have adverse effects, and special consideration should be considered for frail elderly patients. The problem with diabetes in the elderly is that they are prone to severe hypoglycemia. Severe hypoglycemia can impair cognitive function and increase the risk of cardiovascular events such as myocardial infarction and stroke. Against this backdrop, the Japan Diabetes Society and the Japan Geriatrics Society established a joint committee to improve treatment of diabetes in the elderly and created "Glycemic Control Goals for Diabetes in the Elderly" in May 2016. (Figure 7)

The basic ideas behind the preparation are as follows. (1) Blood glucose control targets are set individually, taking into consideration the patient's age, cognitive function, physical function (basic ADLs and instrumental ADLs), etc., (2) If severe hypoglycemia is feared, a lower target limit is set to provide safer treatment, and (3) For elderly patients, the target can be flexibly set below or above the target value. In other words, the target value is devised to be loosened according to the patient's activity level of daily living (ADL) and degree of dementia, and special consideration is shown for frail elderly patients. ²⁰⁾

Regarding hypertension in the elderly, some have pointed out that overhypertension may increase the risk of falls. In the "Guidelines for the Treatment of Hypertension 2014, " ²¹⁾ a description of frail elderly patients was added. The guideline focused on walking as an indicator of frailty in the elderly, and recommended that the criteria for starting antihypertensive medication for frail elderly who are unable to complete a 6-meter walk be determined on an individual basis. The latest version of the guideline also states that the criteria for initiation of drug therapy and antihypertensive targets for frail elderly patients should be determined on an individual basis.

Trends in the Development of Drugs for Frail and Other Conditions

Since there are no drugs approved for the treatment of frailty at this time, we conducted a survey on global trends in the development of drugs for frailty and other diseases. 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 stage was Active (pre-clinical to filed). The indications were "frailty," "sarcopenia," and "locomotive syndrome," but "sarcopenia" was searched as "muscle loss. The results are shown in Table 2. As a result, there were 1 hit for "flail," 2 hits for "muscular depletion," and 0 Active search results for "locomotive syndrome." （Considering the situation in Japan, where frailty and other conditions are the main cause of health problems among the elderly aged 75 and over, we must say that this is an unfortunate development trend. Further investigation into the publicly available information on the three hit products revealed that the National Institute on Longevity announced in January 2022 that it had entered into a support agreement with Longeveron for a domestic Phase II clinical trial (investigator-initiated clinical trial) for patients with age-related frailty (22). ^It was mentioned that the product is a regenerative medicine product made from human (allogeneic) mesenchymal stem cells and that a Phase IIb clinical trial conducted by Longeveron in the U.S. for frail elderly patients showed a statistically significant improvement in walking distance at 270 days after administration in frail elderly patients with low mobility. The study showed a statistically significant improvement in walking distance at 270 days post-treatment in frail elderly subjects with low mobility. This is one of the few drugs available for the treatment of frailty, and we look forward to future developments.

As for other trends in therapeutic drug development based on public information, the Japan Agency for Medical Research and Development (AMED) announced that Teijin Limited's "Research and Development of Drugs for the Prevention and Treatment of Frail" was selected in the FY 2008 "Creation of Innovative Infrastructure for Medical Research and Development (CiCLE): 3rd Open Call" by the AMED. ^23)The research period is from FY2018 to FY2027, and we will keep an eye on this trend. The research period will be from FY2018 to FY2027, and we would like to pay attention to this trend as well.

Administrative Trends Related to Frailty

A recent topic in administrative trends related to frailty seems to be the "integrated implementation of health services and care prevention for the elderly" (hereinafter referred to as "integrated implementation"). In Japan's medical insurance system, when a person reaches the age of 75, he or she is transferred from the national health insurance system to the late-stage medical care system for the elderly. As a result, the implementation entity of health services is also transferred from municipalities, etc. to the wide-area federation for late-stage medical care for the elderly, and it has been pointed out that health services under the national health insurance system up to age 74 and those under the late-stage medical care for the elderly after age 75 are not properly continued. It was also pointed out that in many cases, wide-area federations only provide health checkups. In addition to multiple chronic diseases, the elderly are prone to frailty, a state in which cognitive functions and social connections deteriorate, and have needs for both disease prevention and maintenance of lifestyle functions. However, since the wide-area federations were responsible for implementing health services for the elderly and the municipalities were responsible for implementing long-term care prevention initiatives, the health status and lifestyle function issues could not be addressed in an integrated ^manner25) (Figure 8).

In response to these issues, municipalities are able to provide detailed resident services from a position close to the citizens and have expertise in health services and long-term care prevention since they are the insurers of long-term care insurance and national health insurance, so in order to promote health services that meet the physical and mental characteristics of the elderly, individual projects As shown in Figure 9, a law was established to allow municipalities to implement individual projects, and efforts to implement them in an integrated manner began in April 2020. As of February 2022, 793 municipalities, or approximately 50% of the total, had applied for implementation plans, and efforts are underway with the goal of having all municipalities implement integrated implementation by fiscal 2024. ²⁷⁾

The following is an image of the integrated implementation, with a particular focus on frailness. First, medical professionals in charge of coordinating the project in the community will analyze medical and nursing care data, including the aforementioned "frail health checkups (checking the state of frailness)," to understand the health issues in the community. Care prevention will be integrated with disease prevention and prevention of serious illnesses, which have been conducted by the health service, and support for the elderly will be provided with an eye to preventing frailty. Implement measures to prevent frailty, including social participation, and aim for the participation of the elderly in health promotion. In addition, elderly people in a frail state will be connected to appropriate medical and long-term care services. ²⁵⁾

Regarding the integrated implementation, many examples of efforts according to the current situation in each municipality are ^{introduced28)}, showing the creativity and ingenuity of each municipality. It is hoped that the provision of appropriate medical and nursing care services will promote the prevention of frailty, disease, and serious illness, thereby contributing to the extension of healthy life expectancy.

8. summary

There is no doubt that addressing frailty is important when considering extending the healthy life expectancy of the elderly. Non-drug measures, such as exercise and nutrition, are the main preventive and intervention measures for frailty, but the impact of the new coronavirus disaster should be closely monitored. On the other hand, the "Declaration of the Medical Association for Overcoming Frail and Locomotion" and the "Integrated Implementation of Health Services and Care Prevention for the Elderly" are gospels for dealing with frail, and future developments are to be expected.

In consideration of the pharmaceutical industry's contribution to frailty, further promotion of appropriate drug use, including measures against polypharmacy, is desirable. The development of therapeutic drugs is also expected, but as mentioned above, the development status is far from satisfactory. In the case of novel coronavirus infection, drug repositioning has shown a certain level of success, and attempts have been made to utilize data. Currently, medical and nursing care data analysis is used only for understanding local health issues, but we would like to propose its use for drug repositioning with an emphasis on treating frailty. Medical and nursing care data analysis may also contribute to the appropriate use of drugs, including measures against polypharmacy. The promotion of data utilization in frailty control is worth considering.

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