Management of older adults with diabetes mellitus: Perspective from geriatric medicine

ABSTRACT

Advances in diabetes medication and population aging are lengthening the lifespans of people with diabetes mellitus (DM). Older patients with diabetes mellitus often have multimorbidity and tend to have polypharmacy. In addition, diabetes mellitus is associated with frailty, functional decline, cognitive impairment, and geriatric syndrome. Although the numbers of patients with frailty, dementia, disability, and/or multimorbidity are increasing worldwide, the accumulated evidence on the safe and effective treatment of these populations remains insufficient. Older patients, especially those older than 75 years old, are often underrepresented in randomized controlled trials of various treatment effects, resulting in limited clinical evidence for this population. Therefore, a deeper understanding of the characteristics of older patients is essential to tailor management strategies to their needs. The clinical guidelines of several academic societies have begun to recognize the importance of relaxing glycemic control targets to prevent severe hypoglycemia and to maintain quality of life. However, glycemic control levels are thus far based on expert consensus rather than on robust clinical evidence. There is an urgent need for the personalized management of older adults with diabetes mellitus that considers their multimorbidity and function and strives to maintain a high quality of life through safe and effective medical treatment. Older adults with diabetes mellitus accompanied by frailty, functional decline, cognitive impairment, and multimorbidity require special management considerations and liaison with both carers and social resources.

Frailty, dementia, and multimorbidity are associated with each other and lead to a high risk of hypoglycemia.

INTRODUCTION

The prevalence of diabetes mellitus (DM) is increasing worldwide, especially in the older population. In particular, type 2 diabetes mellitus is more common than type 1 in older adults. This specific type of diabetes mellitus manifests as hyperglycemia due to a deterioration of insulin secretion and elevated insulin resistance of varying degrees. These two conditions tend to progress with aging, increasing the number of older adults living with diabetes mellitus ¹ . One study estimated that the prevalence of diabetes mellitus peaks in individuals in their late 70s in high‐income countries ² . Advances in the treatment and management of diabetes mellitus, particularly type 2, have led to the longer survival of individuals with diabetes mellitus. Consequently, the population of older adults with diabetes mellitus and other long‐term conditions is growing. While diabetes management primarily focuses on avoiding diabetes‐related complications through glycemic control, the approach becomes more complex in frail older adults with multimorbidity, cognitive impairment, and functional decline. In this population, the merits of lowered glycemic levels often decrease while the risks of severe hypoglycemia increase. The clinical guidelines of several academic societies have begun to recognize the importance of setting lower limits for glycemic control to prevent severe hypoglycemia and to maintain quality of life (QOL) ³ . However, glycemic control targets are still based on expert consensus rather than on robust clinical evidence.

Given the global increase in the older population, it is imperative to understand the characteristics of older patients with diabetes mellitus and to develop effective management strategies for this population. However, older patients, especially those older than 75 years old, are often underrepresented in the randomized controlled trials conducted to test treatments, resulting in limited clinical evidence for this population. Therefore, a deeper understanding of the characteristics of older patients is essential for their personalized management. For older adults with diabetes mellitus, a geriatric perspective is often practical, useful, and, above all, helpful for patients. A geriatric perspective in diabetes mellitus management does not overly focus on single diseases but instead considers the overall management of multimorbidity while taking into account patients’ functional status and social circumstances.

MULTIMORBIDITY AND POLYPHARMACY

Multimorbidity is usually defined as the coexistence of two or more chronic diseases ⁴ . It is associated with an elevated risk of death and disability, reduced QOL, and high utilization of health care services and increased costs ⁵ . One study reported that more than 90% of patients with type 2 diabetes mellitus exhibit multimorbidity ⁶ , which has been associated with a significantly higher risk of hypoglycemia and adverse drug reactions ⁷ . In multimorbid individuals, polypharmacy and reduced organ function are at least partly associated with the increased risk of hypoglycemia. Indeed, a study in Europe showed that older people with type 2 diabetes mellitus and multimorbidity experience more adverse drug reactions and higher mortality, mainly due to medication‐associated acute kidney injury (AKI) ⁸ .

Polypharmacy, often defined as the use of more than five prescription medications, is prevalent among older patients with type 2 diabetes mellitus due to multimorbidity. Multimorbid type 2 diabetes mellitus patients are often taking multiple antidiabetic agents for glycemia control and also require several additional medications to manage comorbidities such as hypertension, hyperlipidemia, and cardiovascular disease. Polypharmacy is found at high frequencies in older patients ⁹ . A recent systematic review found a 64% prevalence of polypharmacy in older patients with diabetes ¹⁰ , which was associated with poor glycemic control, increased risk of hypoglycemia, and other adverse health outcomes such as falls, syncope, hospitalization, and death ¹¹ . Furthermore, the presence of diabetes–multimorbidity combinations is associated with disability in middle‐aged and older adults ¹² .

It is not very practical and sometimes even harmful to implement the combined treatment of single diseases in multimorbid older adults. The management of older adults with multimorbidity exhibits increased complexity. Clinicians require a personalized approach for this population, and clinical guidelines have suggested considering multimorbidity when setting glycemic control targets for older patients with type 2 diabetes mellitus ¹³ , ¹⁴ , because older multimorbid patients are likely to develop organ damage due to reduced renal function and to have adverse drug reactions due to drug interactions. However, in reality, a study reported that older and multimorbid patients achieved even lower glycated hemoglobin (HbA1c) levels than the non‐multimorbid population, possibly due to treatment ¹⁵ , which could increase the risk of severe hypoglycemic events.

Potentially inappropriate medications (PIMs) are medications that should be avoided due to their high risk of adverse drug reactions. Polypharmacy is often associated with the prescription of PIMs, which have been linked to adverse health outcomes such as all‐cause hospital admissions, emergency room visits, and fractures in older adults with diabetes ¹⁶ . Studies have reported a prevalence of PIM prescriptions ranging from 24.9% to 39.6% in older patients with diabetes ¹⁷ , ¹⁸ (Figure 1).

Figure 1.

Polypharmacy and adverse drug reactions.

While several clinical practice guidelines advocate for the deprescription of glucose‐lowering agents in older patients with complex backgrounds, such as frailty, multimorbidity, or dementia, particularly those residing in institutional settings, recommendations supported by high‐level clinical evidence have not yet been provided ¹⁹ . Further accumulation of data is warranted.

COGNITIVE DYSFUNCTION AND DEMENTIA

Diabetes mellitus has been identified as one of the modifiable risk factors for dementia ²⁰ . The relative risk has been reported to be 1.5 (95% confidence interval: 1.3–1.8). Although the mechanism underlying the relationship between diabetes mellitus and dementia is still unclear ²¹ , ²² , several hypotheses have been proposed ²³ . One is the possibility that hyperglycemic conditions and insulin resistance both affect amyloid‐β metabolism and tau phosphorylation, thereby exacerbating Alzheimer's disease brain pathology. Furthermore, it has been pointed out that diabetes mellitus increases chronic inflammation and oxidative stress, which may lead to neurodegeneration. Diabetes mellitus also worsens vascular lesions due to arteriosclerosis, which may lead to cognitive decline associated with cerebrovascular disorders ²² .

The association between glycemic control levels and dementia incidence also remains to be elucidated. Randomized control studies have not shown the ability of lower glycemic levels to reduce dementia risk ²⁴ . However, several observational studies support a U‐ or J‐shaped association between HbA1c levels and dementia incidence ²⁵ , ²⁶ , ²⁷ . These studies suggest that an HbA1c level of around 7% seems to be associated with a low dementia risk, although the results regarding the appropriate levels of HbA1c are not entirely consistent.

The reasons for the U‐ or J‐shaped associations between dementia risk and glycemic levels are not clearly understood. Intensive glycemic control via medication may induce hypoglycemia, which is a risk factor for dementia, potentially offsetting the protective effects of therapy. Further research is warranted.

Cognitive impairment is associated with poor adherence to therapy, leading to difficulties in performing self‐care, which often make the therapeutic management more challenging. Therefore, some guidelines, including those of the American Diabetes Association and Endocrine Society, recommend relaxing the glycemic targets for older patients with dementia ²⁸ , ²⁹ . Once dementia is diagnosed, formal and informal care should be considered, and specific medication indications may be explored, including cholinesterase inhibitors or memantine.

FUNCTIONAL DECLINE

A systematic review concluded that diabetes mellitus was a risk factor for mobility disability and disability of both instrumental and basic activities of daily living (ADLs) ³⁰ . The consequences of a decline in ADL in older adults with diabetes mellitus can be significant and multifaceted. Functional decline may lead to poor self‐care and predispose the patients to poor disease control or hypoglycemia. A greater level of dependency was identified as a risk factor for hypoglycemia ³¹ . Some clinical guidelines recommend that overtreatment be avoided in older adults with a functional decline ³ . An ADL decline is also a risk factor for falls ³² , which could cause further functional declines. Difficulty in performing ADL restricts social activities, which may lead to social isolation. Moreover, functional decline restricts patients’ ability to perform essential tasks of daily life, which may lead to reduced QOL ³³ .

FRAILTY AND GERIATRIC SYNDROME

Frailty and sarcopenia are age‐related conditions. Frailty is characterized by a reduced physiological reserve ³⁴ , whereas sarcopenia is defined as age‐associated loss of muscle mass and power ³⁵ . Type 2 diabetes mellitus has been linked to both conditions ³⁶ . A recent meta‐analysis reported prevalences of prefrailty and frailty in older adults (aged 60 years and above) with diabetes of 20.1% and 49.1%, respectively ³⁷ . Frailty in older people with diabetes has been associated with adverse clinical outcomes, including death, hospitalization, emergency department visits, and disability ³⁸ . Older adults with diabetes mellitus reportedly have a higher risk of fractures, with sarcopenia cited as a contributing factor to falls that lead to fractures ³⁹ .

There are several possible reasons why frailty and sarcopenia may predispose diabetes ³⁶ . Insulin resistance is increased in diabetes. It is often thought that, under insulin resistance conditions, protein anabolism may be reduced, leading to a fall in muscle synthesis. Furthermore, mitochondrial function is impaired in diabetic patients, resulting in decreased muscle performance. Moreover, chronic inflammation and oxidative stress associated with diabetes promote the development of sarcopenic frailty.

Frailty in older people with diabetes has been associated with adverse clinical outcomes, including death, hospitalization, emergency department visits, and disability ⁴⁰ , ⁴¹ .

While some reports suggest that the incidence of frailty is associated with poor blood glucose control ⁴² , ⁴³ , a low glycemic state may also pose a risk for frailty ⁴⁴ , and hypoglycemic episodes are another risk factor ⁴⁵ .

The evidence regarding the optimal glycemic levels in frail older adults with diabetes is limited ⁴⁶ . In a subanalysis of the Action to Control Cardiovascular Risk in Diabetes (ACOORD) study, intensive glycemic control was found to be ineffective in preventing diabetic complications and death among frail subjects ⁴⁷ . This finding may support the relaxing of glycemic control levels in frail older adults. Furthermore, deintensification of glycemic control in a nursing home population did not lead to increased emergency department visits, hospitalizations, or mortality ⁴⁸ . This suggests that deintensification of glycemic control to avoid overtreatment may be considered in institutionalized frail older adults with diabetes mellitus.

However, a study from the UK Biobank demonstrated that higher HbA1c levels were associated with higher mortality in frail individuals, which may contradict the possible recommendation of relaxed glycemic control levels in this population ⁴⁹ . This study also indicated that HbA1c levels lower than 40 mmol/mol (~5.9%) were associated with higher mortality in frail older individuals, suggesting the importance of avoiding overtreatment in this population.

Geriatric syndrome encompasses a group of multifactorial health conditions rooted in biological aging and multimorbidity, although its specific contributors have not been strictly defined ⁵⁰ . The conditions considered part of geriatric syndrome typically include falls, cognitive impairment, urinary incontinence, and dizziness. Polypharmacy is often associated with geriatric syndrome because medications are frequently prescribed to manage its symptoms ⁵¹ , and it has been linked to a diminished QOL ⁵² . Geriatric syndrome typically involves multiple organ systems. Because frailty is often associated with functional decline and cognitive impairment, there is significant overlap between frailty and geriatric syndrome, despite their distinctions, and they mutually interact in complex ways, leading to adverse health outcomes.

COMPREHENSIVE GERIATRIC ASSESSMENTS

Comprehensive geriatric assessment (CGA) is a thorough, multidimensional process involving various disciplines aimed at identifying the medical, social, and functional needs of older adults. It facilitates the development of integrated care plans tailored to meet those needs ⁵³ . CGA has shown positive outcomes in terms of survival among acutely unwell hospitalized older individuals, irrespective of the presence of diabetes mellitus ⁵⁴ . Additionally, evidence suggests a reduction in unplanned admissions among frail, community‐dwelling older adults ⁵⁵ . The CGA process helps to provide holistic and patient‐centered care by understanding social support networks, identifying caregiver strain, addressing family dynamics, assessing social determinants of health, and promoting social engagement and it aims to optimize outcomes and to enhance the overall well‐being of older adults.

As noted previously, older patients with diabetes mellitus often present with multimorbidity, reduced ADLs, and cognitive decline ⁵⁶ . They may also have geriatric syndrome and frailty. CGA is expected to be effective in addressing the needs of this population ⁵⁷ . However, while promising, the evidence supporting the effectiveness of CGA specifically in older individuals with diabetes mellitus is not yet sufficient, warranting further research.

HYPOGLYCEMIA

Cognitive impairment, dementia, renal impairment, and sulfonylurea use ⁵⁸ , as well as multimorbidity, are all risk factors for hypoglycemia, with an increased number of comorbidities associated with higher risk ⁷ . Hypoglycemia, in turn, increases the risk of dementia incidence ⁵⁹ and frailty ⁴⁵ (Figure 2). More importantly, severe glycemic events have been associated with greater fear and lower QOL in patients with diabetes mellitus ⁶⁰ .

Figure 2.

Association of hypoglycemia with frailty, dementia, and multimorbidity.

Older adults tend to have less awareness of ⁶¹ and worse recovery from ⁶² hypoglycemia due to age‐associated physiological changes, which may increase harms. Several studies reported that hypoglycemia in older adults was associated with severe clinical consequences and increased risk of death ⁶³ , ⁶⁴ .

Recent clinical guidelines recommend avoiding diabetes overtreatment to prevent hypoglycemia by setting lower limits for glycemia levels in older patients with complex backgrounds, although discrepancies exist regarding individualized HbA1c targets ³ . The Endocrine Society recommends HbA1c targets between 8.0% and 8.5% for individuals with declined ADLs in two or more domains, moderate‐to‐severe dementia, end‐stage illness, or residence in long‐term care facilities ²⁹ . A study of multimorbid older patients with diabetes reported that overtreatment (lower HbA1c values than guideline recommendations) was associated with higher mortality ⁶⁵ . Although further studies are warranted, glycemic control levels in multimorbid frail older subjects, particularly those in long‐term care facilities, should be carefully considered, balancing the benefits of pharmacotherapy with the risks of severe hypoglycemia.

PHARMACOTHERAPY

Adequate glycemic control is required to prevent diabetes mellitus‐related complications at all ages. However, intensive treatment may be less beneficial in frail older patients with complex backgrounds and predispose vulnerable patients to hypoglycemia.

Several guidelines recommend individualized glycemic control levels based on patients’ health backgrounds ³ . However, the definitions of patient background categories and the recommended HbA1c levels are not entirely consistent. Moreover, these recommendations are currently primarily based on expert opinions, and additional clinical evidence is required to support them.

Metformin is a first‐line medication at any age. Because sufficient renal function is needed to clear this drug, dose titration is required in older subjects with reduced renal function ⁶⁶ . An unrecognized renal functional decline may induce lactic acidosis, which is a rare but severe adverse event. Regular monitoring of kidney function is required.

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are recommended for the treatment of frail older adults with diabetes mellitus at high risk of hypoglycemia ⁶⁷ due to the low risk of these agents inducing hypoglycemia. DPP‐4 inhibitors are weight‐neutral, which may also be advantageous for populations with a low body weight. However, the clinical guidelines of the American College of Physicians recently recommended against the use of DPP‐4 inhibitors due to a lack of evidence for reducing all‐cause mortality and cardiovascular events ⁶⁸ . This recommendation applied to the general long‐standing type 2 diabetes mellitus population with an HbA1c level around 8% despite usual care with metformin and lifestyle modification. Further consideration of metformin use is warranted in frail older adults with renal functional decline whose condition complicates the use of metformin.

Sodium‐glucose transporter‐2 (SGLT‐2) inhibitors have beneficial effects on cardiometabolic and renal outcomes in patients with type 2 diabetes. Recent studies suggest that SGLT‐2 inhibitors may be tolerated by frail older adults with type 2 diabetes mellitus who have obesity‐based frailty ⁶⁹ , ⁷⁰ . However, there is limited evidence for anorexic, malnourished older adults with frailty. Frailty is a heterogeneous condition, ranging from sarcopenic obesity‐based phenotypes to anorexic, malnourished phenotypes with less muscle mass and lower body weight. Weight‐neutral hypoglycemic agents may be more suitable for those with the anorexic, malnourished phenotype ⁷¹ .

Glucagon‐like peptide 1 (GLP‐1) receptor agonists also have several beneficial effects in the general population with diabetes mellitus, and several lines of evidence have indicated their efficacy and tolerance in the older population ⁷² , ⁷³ . However, the evidence is currently very limited in frail older adults ⁷⁰ . This drug category sometimes causes initial nausea and other gastrointestinal symptoms, which may necessitate caution in anorexic, malnourished patients with frailty.

Long‐acting sulfonylureas are defined as PIMs by several screening tools, including the STOPP/START ⁷⁴ and Beers ⁷⁵ criteria, because of a high risk of hypoglycemia. Prescribers should balance the merits of glycemia lowering with the risk of hypoglycemia by contemplating each patient's background and also consider alternatives to these medications.

Insulin therapy for frail multimorbid older patients with cognitive impairment requires particular caution because it is associated with hypoglycemia. On the other hand, the weight gain observed with insulin therapy, while often considered unfavorable, might be useful in undernourished frail patients. Complex therapeutic regimens with multiple daily injections could be considered after trying simpler combinations including basal insulin plus oral agents. Complex regimens may lead to poor adherence, not only because injections are missed, but also because excessive insulin doses might be administered. Education of caregivers as well as patients themselves would also be required.

Complex pharmacotherapy sometimes leads to a large burden in frail older adults with multimorbidity and cognitive impairment, which may reduce these patients’ QOL ⁷⁶ . The aim of the treatment should be carefully reviewed with assessment of patients’ capacity and consideration of their opinions.

NONPHARMACOTHERAPY

Frailty, as discussed previously, can manifest as a spectrum from undernutrition to overnutrition. Therefore, dietary therapy should be tailored to individual needs ⁷⁷ . Adequate protein intake is recommended to prevent sarcopenia in older individuals with diabetes, as well as in the general population ⁷⁸ . Too stringent a diet may accelerate muscle loss and malnutrition.

Exercise is crucial for glycemic management in diabetes and also promotes muscle hypertrophy. Resistance training typically enhances muscle mass, strength, and performance in older individuals with diabetes ⁷⁸ . Although the effects of aerobic training on body composition have been less studied in older patients with diabetes, one study did report positive outcomes ⁷⁹ while a systematic review reported effects on glucose metabolism ⁸⁰ .

Combining nutritional therapy with exercise is more effective for increasing muscle strength and improving physical function. Such multifactorial interventions have been reported to improve physical function in elderly patients with diabetes ⁸¹ , ⁸² .

COORDINATION OF CARE AND USE OF SOCIAL RESOURCES

Public long‐term care insurance systems have been established in some countries, including Japan, and care services are provided according to the level of care needs of the individual ⁸³ . Coordination of care has been associated with positive outcomes, including a reduced risk of hospitalization and emergency room visits for DM ⁸⁴ . A Korean study showed that good continuity of care reduced avoidable hospitalizations and diabetes‐related complications ⁸⁵ . In addition, social and economic situations often affect the management of diabetes mellitus. For example, living alone is sometimes associated with poor nutrition and medication adherence, necessitating comprehensive assessments. It is important to establish an individualized care delivery with the collaboration of official and unofficial care providers. The appropriate use of social resources in older frail patients with functional decline should be based on multidisciplinary and collaborative assessments.

CONCLUSION

Improvements in diabetes medications and aging of the population are leading to the longer survival of people with diabetes mellitus. Although the worldwide population with frailty, dementia, disability, and/or multimorbidity is increasing, the evidence supporting the safe and effective treatment of these populations is still lacking. QOL is also one of the top priorities in the treatment of these people but the associated evidence remains poor.

The personalized management of older adults with diabetes mellitus is urgently required to maintain a high QOL and to ensure safe and effective medical treatment. Older adults with diabetes mellitus and frailty, functional decline, cognitive impairment, and multimorbidity require special management considerations and liaison with both carers and social resources.

DISCLOSURE

The author declares no conflict of interest.