The Pathophysiology of Hyperglycemia in Older Adults: Clinical Considerations Free

Diabetes is one of the leading chronic medical conditions among older adults, with high risk for vascular comorbidities such as coronary artery disease, physical and cognitive function impairment, and mortality. Despite decades of effort to prevent diabetes, diabetes remains an epidemic condition with particularly high morbidity affecting older adults. In fact, nearly 11 million people in the U.S. aged 65 years or older (more than 26% of adults aged 65 years or older) meet current American Diabetes Association criteria for diabetes (diagnosed and undiagnosed), accounting for more than 37% of the adult population with diabetes (1). At the same time, adults 65 years or older are developing diabetes at a rate nearly three-times higher than younger adults: 11.5 per 1,000 people compared with 3.6 per 1,000 people among adults aged 20–44 years old (1). However, increasing research in diabetes and aging has improved our understanding of the pathophysiology of diabetes and its association with aging and led to the development of a number of antihyperglycemic medications. The mechanism of diabetes complications has been previously reviewed (2). The current paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population.

Type 2 diabetes is by far the most prevalent form of diabetes in older adults and is an age-related disorder. The criteria for diagnosing diabetes are the same for all age groups because the risks of diabetes-related complications are associated with hyperglycemia over time across all age groups (3). Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. These factors contribute to hyperglycemia through effects on both β-cell insulin secretory capacity and on tissue sensitivity to insulin. The occurrence of type 2 diabetes in an older person is complicated by the comorbidities and functional impairments associated with aging.

Hyperglycemia develops in type 2 diabetes when there is an imbalance of glucose production (i.e., hepatic glucose production during fasting) and glucose intake (i.e., food ingestion) as opposed to insulin-stimulated glucose uptake in target tissues, mainly skeletal muscle. Multiple factors in an older person contribute to such an imbalance of glucose regulation, as illustrated by Fig. 1. Although resistance to peripheral insulin action contributes to altered glucose homeostasis, current evidence has found that the direct effect of aging on diabetes pathophysiology is through impairment of β-cell function, resulting in a decline in insulin secretion.

There is a strong genetic predisposition to type 2 diabetes (4). The genetic susceptibility to type 2 diabetes is polygenic, involving a number of variants, where each allele has a modest effect on the risk of disease in an individual person. Genome-wide association studies, linkage analysis, candidate gene approach, and large-scale association studies have identified ∼70 loci conferring susceptibility to type 2 diabetes (5). These genetic alleles appear to affect the risk of type 2 diabetes primarily through impaired pancreatic β-cell function, reduced insulin action, or obesity risk.

Genome-wide association studies have consistently found that p16^INK4a, a cyclin-dependent kinase inhibitor (CDKI), encoded by the Cdkn2a locus, is associated with type 2 diabetes risks (6). Expression of p16^INK4a was increased in aging mice (7), and an additional copy of p16^INK4a was associated with markedly reduced pancreatic islet cell proliferation (8). β-Cell proliferation was increased in p16^INK4a knockout mice. Therefore, p16^INK4a increases with age and appears to mediate an age-associated decline in the replicative capacity of mouse islets; p16^INK4a could be a potential link between aging, metabolic derangements, and β-cell failure in type 2 diabetes.

In the setting of genetic and lifestyle-related risk factors, aging contributes to the development of type 2 diabetes through impaired β-cell function and impaired β-cell adaptation to insulin resistance (9,10) leading to impaired insulin secretion (11,12), as illustrated in Fig. 1. Studies in rodents and humans have found that aging may exert a distinct influence on β-cell turnover as well as function.

In older patients who have developed diabetes, autoimmune destruction of β-cells is rarely observed. Limited pathologic investigation suggests that total β-cell mass may be moderately reduced, but severe loss of β-cell mass is uncommon. Pancreatic β-cell mass in adult humans exists in a dynamic state such that the cells can undergo compensatory changes to maintain euglycemia. Aging is thought to be associated with reduced capacity to regenerate β-cells, as suggested by studies involving rodents (13–15) and humans (16–18). On the one hand, for example, the β-cell toxin streptozotocin, partial pancreatectomy, or exendin-4 were more effective in stimulating β-cell proliferation in younger mice (younger than 12 months old) than in older mice (13–15,19). On the other hand, the age-associated decline in β-cell function in older rats has been shown to be reversible with glucagon-like peptide 1 (GLP-1; exendin) treatment (20), suggesting stimulation of β-cell regeneration (21). In humans, the baseline β-cell population and appropriate association with other islet cell types is established before 5 years of age (22). Other studies using C¹⁴ or Ki67 have found that human adult β-cell turnover is very low (16,17,22,23). Similarly among middle-aged and older adults, minimal β-cell regeneration was observed after a mean follow-up period of 1.8 ± 1.2 years after a 50% partial pancreatectomy: β-cell mass and new β-cell formation were not increased, and β-cell turnover was unchanged (18). The follow-up time of this study may have been too short for human β-cells to replicate, but other studies have also found evidence of slow β-cell proliferation in humans with advancing age (24,25). The decline in β-cell replication was directly associated with a decrease in the expression of a transcription factor known as the pancreatic and duodenal homeobox 1 (pdx1) (26). Thus, the overall evidence suggests that human β-cells survive for a long time and are unlikely to be replenished by replications once adulthood is reached (27). Several age-related potential molecular pathways have been found to restrict β-cell regeneration. For example, the replication refractory period, the time between cell divisions (G0 stage of cell cycle), appears to lengthen with age (28); the replicative capacity of β-cells might be reduced due to accumulation of DNA mutations with aging.

Therefore, β-cell function in human adults might be enhanced in the setting of hyperglycemia or insulin resistance to maintain euglycemia. Pancreatic β-cells appear to primarily compensate for limited replication capacity through hyperplasia and hypertrophy. However, a number of studies have demonstrated a decline in β-cell function and insulin secretion with age in rodents (26). In humans, as shown in Fig. 2, the insulin secretion rate in response to glucose was significantly and progressively decreased in older individuals, with the greatest impairment in older individuals with impaired glucose tolerance compared with older individuals with normal glucose tolerance or with younger individuals matched for degree of insulin resistance (9). In fact, a 50% reduction in β-cell secretory capacity has been observed in older men compared with younger men in response to arginine stimulation (29).

Impaired pancreatic β-cell adaptation to insulin resistance appears to be an important contributing factor to age-related glucose intolerance and risk for diabetes. Although aging per se has a minimal effect on insulin action directly (30), many older individuals develop insulin resistance as a result of diminished physical activity, obesity, and loss of lean body mass, particularly those with a disproportional loss of skeletal muscle over adipose tissue. Age had no independent effect on insulin sensitivity when controlled for obesity; age-related reductions in insulin sensitivity are likely the result of an age-related increase in adiposity rather than a consequence of advanced chronological age (31).

Insulin resistance with aging appears to reflect predominantly lifestyle factors such as poor diet and diminished physical activity. These changes lead to decreased lean body mass and increased adiposity, particularly visceral adiposity, with aging. More than 35% of U.S. adults aged 60 years or older are obese, having a BMI of 30 kg/m² or greater (3). An absolute or relative increase of body adiposity, particularly central body adiposity, often associated with advancing age, appears to account in large part for the age-related increase in insulin resistance (32,33). Even among adults without diabetes, intraabdominal fat mass correlates with insulin resistance and age after controlling for obesity (34). However, insulin resistance is more closely associated with abdominal adiposity than with age (35,36). In addition to excessive caloric intake, increased body adiposity is partly related to a sedentary lifestyle, which is common among older adults; for example, only 12% of adults aged 75 or older engage in 30 min of physical activity 5 or more days per week, and 65% report no leisure time physical activity (37). Increasing physical activity in older adults reduces insulin resistance (38), reduces the risk of developing diabetes (39), and improves glycemic control in people with diabetes (40).

Low-grade inflammation and stress-response changes associated with obesity and aging are likely to contribute to the increased risk of type 2 diabetes among older adults (41). Aging and obesity are both thought to be independently associated with the development of low-grade inflammation (42), and proinflammatory cytokines, such as C-reactive protein, interleukin 6, and tumor necrosis factor-α, have been found to inhibit insulin signaling and increase insulin resistance and risk of type 2 diabetes (41,43).

The role of mitochondrial function in aging and type 2 diabetes remains unclear. Older adults were found to have a decrease in mitochondrial function compared with younger adults (i.e., decreased ATP synthesis); however, older adults with normal glucose tolerance had similar ATP production level compared with older adults with impaired glucose tolerance (44). On the other hand, exercise reverses age-related declines in mitochondrial oxidative capacity and ATP production, which may be part of the underlying mechanism through which exercise improves insulin sensitivity (44,45).

As summarized in Fig. 1, there is a maladaptive response to insulin resistance in the setting of impaired β-cell function leading to further impairment of insulin secretion and progression to impaired glucose tolerance and type 2 diabetes. Hyperglycemia, in turn, contributes directly to insulin resistance and impairs pancreatic β-cell function, effects described as glucose toxicity (46). Such glucose toxicity sets up a vicious cycle of maladaptive mechanisms leading to further deterioration of β-cell function and more severe insulin resistance.

Coexisting illness is another factor that can affect insulin sensitivity and insulin secretion in an older person. Hypertension, for example, is common in older people and has been associated with diminished insulin sensitivity (47). Furthermore, any acute illness can precipitate hyperglycemia because of effects of stress hormones to cause insulin resistance combined with the α-adrenergic effects of catecholamines released during stressful illness to inhibit insulin secretion.

Medications used in treating chronic medical conditions may induce or increase insulin resistance or worsening hyperglycemia among patients with diabetes. Glucocorticoids, for example, promote hepatic gluconeogenesis, thus increasing hyperglycemia, and contribute to insulin resistance by increasing visceral fat and promoting proteolysis, lipolysis, free fatty acid production, and fat accumulation in the liver (48).

Impaired glucose regulation over time leads to overt diabetes, which in turn leads to microvascular or macrovascular complications. Diabetes-associated complications, along with other comorbidities prevalent among older adults, such as arthritis, cognitive impairment, and depression, may contribute to decreased physical activity and disability (49). All of these changes can further impair glucose regulation and adversely affect glycemic management.

The complexity of diabetes and its management requires a collaborative effort by a team of health care providers, which may include physicians, nurse practitioners, nurses, dietitians, pharmacists, social workers, and mental health professionals. Patients and family members must also assume an active role (50). When developing a treatment plan, in addition to targeting the various factors involved in the pathophysiologic pathways of type 2 diabetes, providers should address other relevant comorbid conditions that are common among older adults and can easily affect the ability of the patient to manage diabetes. Aging is associated with increasing risk of developing geriatric syndromes, such as visual impairment, cognitive impairment, and functional impairment, and diabetes is also associated with an increased risk of retinopathy (51) and deficits in cognitive and physical functioning (52). Geriatric syndromes will in turn affect the ability of older adults to manage their diabetes. Such limitations may affect a patient’s ability to obtain food or medications, to exercise, or to see his or her health care providers.

Because older adults with diabetes are quite heterogeneous with respect to their health status and available care support, the goal for hyperglycemia management should be individualized based on their comorbidities and physical and cognitive function status. A comprehensive geriatric assessment (53) will help the providers to assess an older patient’s ability to safely follow a complex diabetes treatment plan. Given that type 2 diabetes develops after years of metabolic abnormalities, a thorough medical evaluation in search for existing diabetes complications is warranted even when a new diagnosis is made in an older adult. The clinical assessment is used to recommend individualized glycemic, blood pressure, and lipid goals for older adults with diabetes. An interdisciplinary expert panel that included geriatricians, endocrinologists, and other diabetes health care providers was convened by the American Diabetes Association at a Consensus Development Conference on Diabetes and Older Adults in 2012. This group developed a framework to set diabetes treatment goals based on individual patients’ comorbidities and physical and cognitive function status (54,55).

Lifestyle interventions, including regular physical activity and mild-moderate weight loss, are the first-line intervention for diabetes prevention and for treatment of hyperglycemia in older people. Lifestyle interventions are particularly effective in reducing the risk of developing diabetes among older adults (39,56) and are also beneficial in improving diabetes management among older adults (57). Lifestyle interventions can reduce insulin resistance and thereby help reverse the vicious cycles in Fig. 1. However, there is no evidence that lifestyle interventions can reverse the effects of aging on β-cells; thus, such interventions may delay, but are not likely to completely prevent, the ultimate development of hyperglycemia.

Regular physical activities for older adults with diabetes, particularly activities of moderate to vigorous intensity, can improve insulin sensitivity (38). Regular physical activities are a useful adjunct to drug therapy to manage glucose levels and may well contribute to enhanced effectiveness of glucose-lowering agents. Furthermore, increasing physical activity as part of a lifestyle intervention is effective in reducing physical functioning impairment among patients with diabetes, improving glucose, lipid, and blood pressure control, and enhancing weight loss (40,56,58–60).

Traditionally, aerobic training activities have been recommended for older adults, given their benefits in cardiorespiratory fitness. Evidence also supports regular whole-body resistance training for older adults with type 2 diabetes. As previously discussed, the pathophysiology of type 2 diabetes involves insulin resistance, and the main tissues in the body that are sensitive to insulin are muscles and adipose cells. Resistance training changes body composition (e.g., increases skeletal muscle mass), improves insulin sensitivity, and reduces HbA_1c (61,62).

In fact, physical activity programs that include both aerobic and resistance training improve glycemic levels more than aerobic or resistance training alone (63,64). Thus, the American Diabetes Association recommends that all adults with diabetes should perform at least 150 min/week of moderate-intensity aerobic physical activity, spread over at least 3 days/week with no more than 2 consecutive days without exercise. As part of the exercise routine, resistance training should be performed at least twice weekly (65).

Given the high prevalence of coronary artery disease in older patients with diabetes, which may be asymptomatic or atypical in symptoms, it is important for such patients to have medically supervised stress testing before entering any challenging exercise training program. Additional issues to consider in an older person participating in an exercise program include the potential for foot and joint injury with upright exercise, such as jogging, unstable comorbidities, autonomic neuropathy, peripheral neuropathy, or foot lesions that may predispose to injures, and the ability to promptly identify and treat hypoglycemia, which can be induced by exercise if the patient is on insulin or a sulfonylurea. Therefore, each patient’s exercise prescription needs to be individualized based on his or her capability to safely participate in an exercise program.

Even a modest to moderate body weight loss (5–10% of initial body weight) increases insulin sensitivity and improves glucose tolerance in obese individuals as well as in those with impaired glucose tolerance or type 2 diabetes (66). As part of diabetes management, the American Diabetes Association recommends that overweight adults with type 2 diabetes lose 2–8 kg weight through lifestyle changes (65). Recent studies have not substantiated previous concerns about the risks of weight loss among older adults, where older adults who intentionally lost weight by combining caloric restriction and exercise had minimal reduction in lean muscle mass and actually had increased bone density and improvement in physical function compared with individuals who lost weight by caloric restriction alone or by exercise alone (67–69). Hence, weight loss programs for older adults with diabetes should incorporate caloric restriction with physical activity.

Caloric restriction is appropriate for healthier overweight and obese older diabetes patients as part of management of hyperglycemia but is not appropriate for some older patients who are at risk for undernutrition already. More pressing dietary issues for these patients are how to maintain adequate caloric intake and coordinate food intake with administration of glucose-lowering agents appropriately to avoid hypoglycemia. Older adults with mobility limitation or who lack transportation are likely to have limited access to healthy and fresh food (70). Social isolation (i.e., living alone, eating alone), poverty, and functional reliance on others to purchase food are all risk factors for decreased food intake. The presence of impaired cognitive function may make following a dietary prescription particularly difficult. Furthermore, dietary habits established for a lifetime and often with a cultural background may be particularly difficult to modify. Problems with taste and oral health, which are common in older people, may further limit adaptation to a prescribed diet (71). Oral health problems can be exacerbated by diabetes, which may increase the rate of periodontal disease. Xerostomia is also more common in older people owing to decreased salivary gland flow and is sometimes exacerbated by coexisting medication use.

Most medications to treat hyperglycemia in older adults with type 2 diabetes target one or more of the pathophysiological impairments of age-related type 2 diabetes: reducing hepatic glucose production, increasing insulin secretion, increasing insulin sensitivity, decreasing glucagon secretion, increasing incretin levels, and decreasing satiety. Unfortunately, older patients are often underrepresented in large clinical trials; therefore, data on antihyperglycemic medications are often extrapolated from younger populations (72).

Treatment of older adults with diabetes needs to account for the progression of type 2 diabetes over time (73). Because of the age-related decline of β-cell function, maintaining target levels of glycemic control may necessitate escalation of drug doses or the addition of other antihyperglycemic agents (74). Thus, medications that target the β-cells, such as sulfonylureas or GLP-1–related drugs, are likely to become less effective over time. Medications such as metformin, thiazolidinediones (TZDs), and sodium glucose transporter 2 (SGLT2) inhibitors may help to reverse some of the vicious cycles contributing to hyperglycemia but do not directly address the effects of aging on β-cells.

A review of the pharmacologic treatment for hyperglycemia is beyond the scope of this article but has been extensively discussed elsewhere (75,76). Tables 1 and 2 list most of the currently available antihyperglycemic agents (noninsulin and insulin), including a brief description of the physiological action of the medication and the advantages and disadvantages of the agent when used by older patients. Treatment choices should be tailored to the specific situation of the individual patient, as determined in part by the initial comprehensive assessment of the patient’s comorbidities, cognition, functional status, care support, and financial situation (55). Although it is common for an older adult to have multiple comorbidities, impairment in cognition or functional status, and limited financial support, a strong supportive care system may be sufficient to help the patient to safely implement a complex medical treatment plan.

The treatment plan should minimize risk for hypoglycemia, especially in frail, vulnerable older patients and when using agents with high risk for hypoglycemia such as insulin and sulfonylureas. Thus, emphasis on lifestyle interventions and classes of drugs that do not cause hypoglycemia can often result in safe achievement of lower A1C targets, especially early in the course of type 2 diabetes. As these safer interventions become less effective as a result of progressive β-cell failure with aging, insulin may be needed, and the A1C target may need to be higher to avoid hypoglycemia. Sulfonylurea drugs should be used only with extreme caution in any vulnerable older patient. Frequent follow-up should be provided to ensure that the treatment program is progressing smoothly and that hypoglycemia does not occur.

Metformin, a biguanide, is the first-line oral medication for hyperglycemia for older adults (76). Because metformin’s mechanism of action predominately involves reducing hepatic glucose production, it rarely causes hypoglycemia when used alone. Some older patients may experience intolerable gastrointestinal discomfort, decreased appetite, and modest weight loss associated with metformin.

Metformin is contraindicated in patients with renal insufficiency, and the U.S. Food and Drug Administration recommends against the use of metformin in patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m². Furthermore, metformin is recommended to be discontinued at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m², and can be restarted if the eGFR is stable 48 h after the imaging procedure.

Sulfonylureas are probably overused in older adults with type 2 diabetes. These drugs are inexpensive, and their overall safety record is good. Their primary mechanism of action is to enhance insulin secretion by β-cells of the pancreas. Hypoglycemia is a serious risk, however, and conservative use is thus recommended for older people. Glyburide is associated with a high risk for hypoglycemia in older patients due to its long half-life so is not recommended in this population (77). Other sulfonylureas may be safer to use in older patients, but all have a hypoglycemia risk. Another concern about use of sulfonylurea drugs in older adults is a higher secondary failure rate than other drugs, probably related to progressive β-cell dysfunction (78).

TZDs improve insulin sensitivity in skeletal muscle, reduce hepatic glucose production, and have the advantages of low risk for hypoglycemia. However, concerns over potential adverse effects associated with TZDs have been raised, including increased risks of bladder cancer, weight gain, fluid retention, and bone fractures (75). TZDS are usually not considered as first-line antihyperglycemic agents.

GLP-1 is an incretin, an intestinal hormone that is released as glucose levels increase with meals and cause glucose-dependent insulin secretion; therefore, GLP-1 agents are unlikely to cause hypoglycemia. Two classes of GLP-1 drugs are used clinically:

1. The injectable GLP-1 receptor agonists stimulate insulin section in a glucose-dependent fashion, suppress glucagon output, slow gastric emptying, and decrease appetite. These agents have the advantages of modest weight loss, but for some patients, the weight loss can be too much and there may be resistance against performing injections.

2. The oral dipeptidyl peptidase-4 (DPP-4) inhibitors enhance circulating concentrations of active GLP-1.

When used alone, both classes of GLP-1 agents rarely cause hypoglycemia, but high cost may be prohibitive for some older adults. Pilot studies of myocardial ischemia and animal studies suggested that GLP-1 agonists may improve cardiovascular outcomes, but the results from two recent large trials are mixed. Among patients with type 2 diabetes and high cardiovascular risk, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke was lower with liraglutide than with placebo (79), but among patients with type 2 diabetes and recent acute coronary syndrome, no significant effect on the rate of major cardiovascular events was found with lixisenatide compared with placebo (80).

SGLT-2 inhibitors allow the kidneys to reabsorb most filtered glucose. SGLT-2 is found only in the proximal tubule of the kidney and accounts for 90% of the reabsorption of glucose. SGLT-2 inhibitors are oral agents that lower glucose levels by increasing urinary excretion of glucose. They are approved for use in both type 1 and type 2 diabetes. They are used once daily, result in modest lowering of A1C similar to DPP-4 inhibitors, and rarely cause hypoglycemia. They are contraindicated in chronic kidney disease. These agents increase urine volume and sodium excretion, so usually lower blood pressure modestly but may cause volume depletion. This volume effect may contribute to increased risk for diabetic ketoacidosis in people with type 1 diabetes. There is increased risk for genital yeast infection and urinary tract infection, likely resulting from the induced glycosuria. Because of these adverse effects, relatively high cost, and limited experience with these drugs in older adults, their use is usually reserved for situations in which other classes of drugs are not tolerated.

Because β-cell dysfunction plays a major role in type 2 diabetes in older adults, insulin replacement therapy may be necessary to achieve the goal for hyperglycemia control, especially in patients with longer duration of type 2 diabetes with progressive β-cell dysfunction. The approach to use of insulin in older adults with type 2 diabetes is to start with a once-daily, long-acting insulin (basal insulin), with minimal peak or trough effect. Long-acting agents, such as insulin glargine 100 and detemir insulin, have a lower incidence of nocturnal hypoglycemia than shorter-acting insulin agents, even among older adults (81).

Premeal injections of a rapid-acting insulin analog can be added to the basal insulin, if necessary, in older patients in whom the physician has determined can safely administer insulin and monitor for hypoglycemia. Insulin aspart and insulin lispro have a very rapid onset and short duration of action and are used just before meals. They are less likely to result in postmeal hypoglycemia than human regular insulin (82). These rapid-acting insulin agents can be given within 20 min after starting a meal, and hence, are particularly useful in older patients who may not eat regularly.

Use of combination antihyperglycemic agents in older patients may be necessary with the progression of the disease. Combinations of different classes of drugs are theoretically attractive because their different modes of action address various aspects of the pathophysiology of hyperglycemia. For older patients who have persistent hyperglycemia (above their individualized A1C target) with lifestyle intervention and metformin (if not contraindicated), adding another agent would be recommended. The options include adding an oral agent such as short-acting sulfonylurea (i.e., glipizide), DPP-4 inhibitors (83), or SGLT2 inhibitors (75). Alternatively, a basal insulin, such as glargine, may be added (75). If a sulfonylurea is already being used, we would recommend tapering it to discontinue because a combination of sulfonylurea and insulin greatly increases the risk of hypoglycemia (84).

Older adults are at high risk for the development of type 2 diabetes as a result of the combined effects of genetic, lifestyle, and aging influences. Despite the advancement in understanding the pathophysiology of type 2 diabetes, more research is needed to elucidate the underlying molecular mechanisms of how aging is related to type 2 diabetes and to diabetes-related complications (45). Prevention of type 2 diabetes and treatment of hyperglycemia in older adults should emphasize lifestyle interventions based on the pathophysiology of the development of type 2 diabetes and their numerous benefits on the overall health of older adults. With the aging of β-cell function, the addition of one or more medications to achieve glycemic control targets may be needed. However, the overall management of hyperglycemia needs to be individualized for older adults based on individuals' likelihood of benefiting from tight control versus the risks associated with implementing complex management regimens, especially when insulin or a sulfonylurea drug is included. A comprehensive assessment involving the individual’s comorbidities and geriatric syndromes, including cognitive and functional status, can help tailor the treatment plan.

Funding. P.G.L. was supported by the VA Career Development Award 1IK2RX001190-01A2. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. Government.

Conflict of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. P.G.L. and J.B.H. researched the data, wrote the manuscript, and reviewed and edited the manuscript.