42: Diabetes

Diabetes mellitus (DM) is a common condition in older adults and is associated with increased risk of morbidity and mortality. The prevalence of DM (diagnosed and undiagnosed) in the U.S. population of older adults has been estimated at 10.9 million, or 27% of people older than age 65 years. If current trends continue, 16.8 million adults older than age 65 will have diabetes by 2050. There are many reasons for the increasing prevalence of diabetes in older adults, including declining beta cell function, relative insulinopenia, and insulin resistance. Furthermore, the risk of developing DM type 2 increases with obesity, lack of physical activity, and loss of muscle mass, all of which commonly occur with aging. Compared to younger people with diabetes, people older than age 65 years tend to have longer duration of diabetes, with a median duration of 10 years, higher rates of diabetic complications and comorbid disease, and more functional dependence.

The population of older adults with diabetes is incredibly diverse. Some older adults have had type 1 diabetes for many decades and reach old age with significant end-organ complications. Others develop insulin resistance and diabetes in their 70s or 80s, and have no clear evidence of related complications. Some are able to effectively self-manage their disease, whereas others cannot because of cognitive, visual, or functional impairments. Thus, the management of an older patient with diabetes must account for this tremendous heterogeneity and decision making should be individualized, focusing on patient factors such as the duration of diabetes, presence of complications, comorbid conditions, life expectancy, patient goals and preferences, and functional abilities.

Most patients older than 65 years with diagnosed DM have type 2 DM and a small minority has type 1 DM. Type 1 DM is an autoimmune disease in which pancreatic beta cells are destroyed, resulting in absolute insulinopenia, subsequent hyperglycemia, and risk for ketoacidosis. Exogenous insulin is required for survival and glucose control.

In contrast, type 2 DM results from insulin resistance, increased insulin requirements to maintain euglycemia and ultimately, relative insulin deficiency when the pancreatic beta cells are unable to meet the higher insulin requirements. In older patients, decreased insulin production (rather than insulin resistance) can be the predominant factor in the pathogenesis of type 2 DM. Treatment for type 2 DM includes exercise, carbohydrate control, and oral glucose-lowering agents with or without insulin.

Numerous studies show that, for obese adults with impaired glucose tolerance who are at high risk for developing type 2 DM, lifestyle modification that focuses on diet, exercise, and weight loss can delay or prevent progression to diabetes. The largest of these trials was the Diabetes Prevention Program (DPP), a nationwide multicenter trial that examined whether metformin or lifestyle modification decreases progression to diabetes in high-risk adults. In older adults (>60 years), lifestyle modification was especially powerful, decreasing the incidence of diabetes 71% compared to usual care in the 2.8 years of follow-up. Metformin, however, decreased the incidence of diabetes by only 11% in older adults, compared with 44% in younger adults (age 25–44 years). Thus, for obese older adults at high risk for diabetes, the focus of diabetes prevention should be on lifestyle modification (diet, exercise, and weight loss) rather than metformin.

Acute Complications

Acute complications of DM are primarily metabolic and infectious.

Diabetic ketoacidosis (DKA) is characteristic of type 1 DM, but can also occur in type 2 DM, particularly among Hispanic and African American individuals. Insulin deficiency, most commonly a result of inadequate insulin therapy in type 1 DM, leads to decreased glucose metabolism, resulting in increased lipolysis, free fatty acid metabolism, and subsequent ketoacidosis. Common precipitating factors for DKA include pneumonia, myocardial infarction, and stroke, and are thought to lead to DKA by invoking a systemic stress response with increased cortisol, glucagon, and catecholamines that counteracts some of the effects of insulin. Typically, patients present with symptoms of dyspnea, acidosis, dehydration, abdominal pain, nausea, and vomiting. Mental status alteration and coma may be present. Effective management focuses on identifying and treating the precipitating factors as well as treating the metabolic derangements with insulin and volume repletion.

Hyperglycemic hyperosmolar state occurs predominantly in older patients with type 2 DM and results in marked hyperglycemia (often glucose >600 mg/dL), hyperosmolarity, severe volume depletion, and associated acute kidney injury. Patients typically have a several-week history of hyperglycemia and osmotic diuresis, leading to dehydration and altered mental status. As with DKA, precipitating factors include serious infection, stroke, and myocardial infarction. Besides identifying and treating the precipitating condition, volume resuscitation with fluids can lead to rapid, dramatic improvements in hyperglycemia and hyperosmolarity. Mental status alterations often take longer to normalize.

Older patients with diabetes are at increased risk of infections. Hyperglycemia is associated with worse outcomes in common infections such as pneumonia, and diabetes is a potent risk factor for unusual infections such as malignant otitis externa that are uncommon in patients without diabetes. A number of causes for increased infection risk have been proposed, including impaired immune function caused by decreased neutrophil chemotaxis, phagocytosis, and opsonization. Lower-extremity soft tissue and bone infections are common, because of vascular insufficiency and repeated trauma that is unrecognized by the patient as a result of neuropathy. Urinary tract infections are more common in patients with diabetes because of glucosuria and urinary retention from autonomic neuropathy.

Chronic Complications

Older adults are at high risk for all of the chronic complications of diabetes seen in younger adults including microvascular (retinopathy, neuropathy and nephropathy) and macrovascular disease (coronary artery disease, stroke and peripheral vascular disease). Because vascular pathology plays a central role in diabetes-related complications, prevention and treatment should focus on vascular risk factors, such as smoking cessation, and blood pressure, lipid, and glycemic control.

Macrovascular complications (myocardial infarction, stroke and peripheral vascular disease)—

Cardiovascular disease (CVD) is the major cause of morbidity and mortality for older adults with diabetes. Diabetes imparts a 2-fold risk in coronary heart disease and stroke, and increases the risk of amputation 10-fold. Diabetes often co-occurs with other CVD risk factors, such as hypertension and hyperlipidemia, and studies suggest a multifaceted approach addressing multiple risk factors is most effective in decreasing cardiovascular risk. Currently, the American Diabetes Association (ADA) recommends aspirin for patients with diabetes and known CVD. Furthermore, the ADA also recommends blood pressure control to 130/80 mm Hg and lipid control to low-density lipoprotein <100 mg/dL. For frail older adults at higher risk for complications of treatment such as orthostatic hypotension, less-aggressive goals may be more appropriate.

Microvascular complications: retinopathy—

Diabetes is a leading cause of blindness in the United States. Early detection and treatment of proliferative retinopathy with laser photocoagulation has been shown to decrease the risk of visual loss by more than 50% at 6 years. Further, because visual compromise is insidious, most patients do not recognize declining visual acuity, increasing the importance of regular screening to detect retinopathy at an early, treatable stage. The ADA currently recommends a dilated eye exam by an ophthalmologist at diagnosis, with regular follow-up exams every 1–3 years, depending on the individual patients’ risk factors and initial exam results. In addition to retinopathy, older patients with diabetes also have a 2-fold risk of cataracts and a 3-fold risk of glaucoma compared to older patients without diabetes.

Microvascular complications: neuropathy—

Diabetic neuropathy is generally classified by the types of nerves that are affected. The most common type of neuropathy is the sensory distal symmetric polyneuropathy, or “glove-and-stocking” neuropathy. Common symptoms include numbness and burning pain of the hands and feet. Because sensory neuropathy predisposes patients to unrecognized lower-extremity trauma, which can ultimately progress to infection and amputation, annual screening with a 10-g monofilament at the plantar aspect of the hallux and metatarsal joint is recommended. Autonomic diabetic neuropathies include diabetic gastroparesis, which can cause nausea and vomiting after eating as a result of impaired gastric emptying, as well as erectile dysfunction and neurogenic bladder. Unlike many other microvascular complications, diabetic gastroparesis can improve quickly and dramatically with improved glycemic control.

Microvascular complications: nephropathy—

Diabetic nephropathy is the most common cause of end-stage renal disease and is strongly associated with cardiovascular mortality. Diabetic nephropathy is also more common in older diabetic patients than younger patients; however, the association between severity of nephropathy and mortality appears to be weaker in older adults. Compared to other common causes of kidney disease, diabetic nephropathy leads to more albuminuria and less early declines in glomerular filtration rate. This is reflected in the diagnostic criteria for diabetic nephropathy, which is albuminuria >300 g/day in a patient with known diabetes without other potential causes of albuminuria. Many studies have shown that treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers slow the progression of diabetic nephropathy and decrease the risk of cardiovascular events. Thus, the ADA recommends annual screening for microalbuminuria, which can be accomplished by measuring the urinary albumin-to-creatinine ratio on a spot urine specimen.

Geriatric Syndromes

Geriatric syndromes are common, serious conditions in older adults that often present similarly in different patients despite disparate causes. For example, delirium may present as an acute confusional state with a fluctuating level of consciousness in patients with urinary tract infections as well as a myocardial infarction. DM appears to increase the risk of many geriatric syndromes, including cognitive impairment, depression, urinary incontinence, falls, and functional decline.

Cognitive impairment—

In epidemiologic studies, DM appears to increase the subsequent risk of Alzheimer dementia by 50% to 100% and vascular dementia by 100% to 200%. Although some studies suggest that poor glycemic control and hyperglycemia may lead to elevated risk of dementia, there is also evidence that hypoglycemia may increase the risk of subsequent dementia.

Cognitive impairment is an especially important comorbidity in patients with diabetes, because patient activation and self-management is a cornerstone of effective diabetes treatment. Patients with even mild cognitive impairment may be less able to manage their diet, exercise, and medication regimen, and less able to identify symptoms of early hypoglycemia. Thus, the American Geriatrics Society recommends screening for cognitive impairment during the initial evaluation of the older adult with diabetes, and repeating the screening if increased difficulty with self-care or self-management is suspected.

Depression—

Depression is a common condition in older adults and is associated with adverse outcomes, including poor health-related quality of life, functional decline, and death. Diabetes and depression commonly co-occur, with 30% of older adults with diabetes reporting depressive symptoms and 5% to 10% of older adults with diabetes meeting criteria for major depressive disorder. Like cognitive impairment, depression may interfere with an older adult’s ability to self-manage their diabetes care, leading to worse diabetes control. Thus, the American Geriatrics Society (AGS) recommends screening for depressive symptoms with a validated instrument. Repeat screening may be warranted if an older patient with diabetes has new difficulty with self-management.

Urinary incontinence—

Urinary incontinence is very common in older women with diabetes, with studies reporting a prevalence of >50%. Studies suggest a strong relationship between DM and urinary incontinence, with diabetes associated with a 3-fold increased prevalence of urge incontinence and a 2-fold increased prevalence of stress incontinence. Body mass index appears to be an important risk factor for incontinence, and weight loss reduces the incidence of new incontinence. Although many have suggested poor glycemic control may lead to worse incontinence through glycosuria, studies to date have not confirmed this hypothesis. Very little data exists for incontinence in older men with diabetes.

Falls and fractures—

Falls are common in older adults and associated with increased morbidity and mortality. Overweight patients are more likely to have a higher bone mass and diabetes, leading some to initially hypothesize that patients with diabetes may be less susceptible to injurious falls. However, subsequent studies have shown nearly a 2-fold increased risk of injurious falls in older adults with diabetes compared to older adults without diabetes. Insulin use, poor vision, and peripheral neuropathy appear to further increase the risk of falls. The AGS recommends screening for falls risk in older adults with diabetes to identify potentially modifiable risk factors for falls and fractures.

Functional decline—

Functional limitations are strongly associated with quality of life, as well as mortality and nursing home admission. Diabetes increases the risk of functional limitations, with increased rates of difficulty with activities of daily living (bathing, transferring, toileting, dressing and eating), as well as walking and shopping. The association between diabetes and functional limitations persisted even after accounting for other chronic conditions (such as coronary artery disease, peripheral vascular disease, and depression) as well as age, gender, and duration of diabetes. One observational study in frail, nursing home-eligible, older adults suggests that a hemoglobin A1c level between 8% and 9% is associated with best functional outcomes over 2 years.

Glycemic Treatment

Hyperglycemia is the core pathologic finding in DM and control of hyperglycemia is a cornerstone of diabetes treatment. However, it is important to recognize that blood pressure control and lipid control appear to be as important (if not more important) in preventing and minimizing most end-organ complications of diabetes. Thus, when prioritizing interventions in medically complex older adults with diabetes, focusing first on blood pressure is a reasonable approach in most patients.

Glycemic control targets—

Hemoglobin A1c (HbA1c) has been shown to correlate closely with average glucose levels and are strongly predictive of microvascular complications. A reasonable rule of thumb is that each 1% increase or decrease in HbA1c is equivalent to a corresponding approximately 30 mg/dL change in average glucose levels, as shown in Table 42–1.

The goals of glycemic treatment differ in healthy and frail older patients, resulting in different recommended glycemic targets. Studies suggest that tight glycemic control to HbA1c ≤7% decreases the rates of microvascular complications over 8 years. Thus, the ADA recommends HbA1c <7% for healthy older adults with an extended life expectancy.

However, tighter glycemic control has also been associated with increased rates of hypoglycemia and mortality. For older patients with limited life expectancy, tight glycemic control exposes them to a higher risk of adverse events with little chance that they would survive to benefit from decreases in microvascular complications. Because very poor glycemic control can lead to immediate symptoms such as fatigue, older patients with limited life expectancy should receive glycemic treatment that is aimed at avoiding symptomatic hyperglycemia while minimizing the risk of hypoglycemia. A recent guideline from the AGS suggests an HbA1c target of 8% for older adults. For older adults who are healthy, with few comorbidities, few functional limitations and extended life expectancy, HbA1c target of 7% to 8% is appropriate. Conversely, for older adults with extensive comorbidities, functional limitations and limited life expectancy, HbA1c target of 8% to 9% is appropriate (Table 42–2).

Glycemic control targets in hospitalized patients—

Many older patients with diabetes are admitted to the hospital, most often for conditions other than diabetes. The goals for glycemic control in older hospitalized patients are to maintain euglycemia, avoid adverse events, and return to a stable outpatient regimen as soon as feasible. However, the stress of acute illness and frequent preprocedural fasting can make maintaining euglycemia challenging in hospitalized patients. In noncritically ill patients, the ADA recommends a fasting (premeal) glucose target of 90–140 mg/dL and a random glucose target of <180 mg/dL. The mainstays of glycemic treatment in hospitalized older adults are insulin and volume repletion.

Although initial studies suggested improved outcomes in critically ill surgical patients with tight glycemic control (glucose levels of 80–110 mg/dL), subsequent studies have not shown similar benefits. The ADA recommends glucose levels between 140 and 180 mg/dL in both medical and surgical ICU patients.

Nonpharmacologic Treatments

Diet—

Dietary intervention is an integral component of diabetes treatment. For patients with diabetes and a body mass index >30 kg/m², caloric restriction with the goal of weight loss is recommended. There is no role for caloric restriction in patients who are not overweight or obese. A wide variety of diets with varying macronutrient (carbohydrates, proteins, fats) proportions have been studied, but there is little data to suggest one diet is superior to another. Current ADA dietary recommendations mirror the American Heart Association recommendations and suggest (a) limiting saturated fat (<7% of total calories), (b) minimizing trans fats, and (c) limiting cholesterol intake (<200 mg/day). Medical nutritional therapy provided by a registered dietician is a covered Medicare benefit.

It is important to recognize that for some older adults with diabetes, caloric or dietary restriction may be especially difficult or even harmful. First, changes in diet may be especially challenging for older patients who have established dietary habits over a lifetime. Second, older adults with functional difficulties who have difficulty shopping for groceries and preparing food are at risk for undernutrition; recommending a restricted range of foods may lead to weight loss or micronutrient deficiencies. Third, older adults with diabetes are at higher risk for periodontal disease and xerostomia, which may limit their ability to adapt to a new diet. Thus, dietary modifications should be approached with caution in nonobese older patients with diabetes.

Exercise—

Regular exercise has been shown in improve glycemic control, blood pressure, lipids and contribute to weight loss. The ADA recommends that older adults with diabetes should strive to achieve 150 minutes per week of moderate-intensity exercise. For older patients with functional impairments who are unable to accomplish this, the ADA recommends maximizing their physical activity to reap some of the benefits of exercise. Because older patients with diabetes are at high risk for CVD, exercise regimens should start with low-intensity physical activity and gradually increase in intensity and duration.

Pharmacologic Therapy (Table 42–3)

Biguanides—

Most guidelines recommend metformin as first-line oral therapy for type 2 DM because it is efficacious (decreasing HbA1c approximately 1.5%), is not associated with weight gain or hypoglycemia, and appears to be associated with decreased cardiovascular complications compared to sulfonylureas. Large registry-based observational data suggests that patients taking metformin were at 15% to 21% decreased hazard of cardiovascular complications compared to patients taking glyburide or glipizide. Furthermore a 5-year randomized trial showed 46% decreased risk of cardiovascular outcomes in patients treated with metformin versus glipizide.

Mild renal insufficiency (serum creatinine >1.5 mg/dL or creatinine clearance <30 mL/min) has been a relative contraindication to metformin because of the concern for lactic acidosis. However, lactic acidosis appears to be exceedingly rare with metformin, with an incidence of less than 1 per 10,000 person-years of treatment. A recent Cochrane review of 347 studies representing 126,000 patients found that metformin was not associated with an increased risk of lactic acidosis compared to other anti-hyperglycemic medications.

Sulfonylureas—

The sulfonylureas in common use include glipizide and glyburide. Because sulfonylureas act predominantly by increasing pancreatic insulin secretion, weight gain is common and hypoglycemia may occur. Studies suggest that the risk of hypoglycemia is 1.5–2 times higher with glyburide than glipizide, possibly as a result of active metabolites; thus, glyburide should be avoided in older adults. Generally, most of the therapeutic effect occurs with half of the maximum recommended dose, and a decrease in HbA1c of 1% to 2% can be expected. Starting doses should be low, perhaps half that used for younger patients, and education regarding hypoglycemia provided. Sulfonylureas should be used with caution in patients with kidney disease since active metabolites are excreted slowly.

α-Glucosidase inhibitors—

The α-glucosidase inhibitors acarbose (Precose) and miglitol (Glyset) inhibit the absorption of carbohydrates in the gut and decrease postprandial hyperglycemia. Consequently, they do not cause hypoglycemia or weight gain. Because α-glucosidase inhibitors are not systemically absorbed at usual doses (especially acarbose), they generally can be safely used in older adults and with either renal or hepatic insufficiency. The primary drawbacks of α-glucosidase inhibitors are gastrointestinal discomfort including flatulence and diarrhea, and low potency with HbA1c decreasing by approximately 0.5%.

Thiazolidinediones—

The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) act as insulin sensitizers. Thiazolidinediones have fallen out of favor as mounting evidence suggests increased cardiovascular risk, heart failure, and hepatotoxicity, especially with rosiglitazone.

Meglitinides—

Meglitinides are short-acting insulin secretagogues that can decrease postprandial hyperglycemia. Repaglinide and nateglinide are the meglitinides available in the United States. Nateglinide appears to have a faster onset and shorter duration of action than repaglinide. There is limited experience with either drug in older adults, but they may be effective for patients with fasting euglycemia and postprandial hyperglycemia. Both medications should be taken before each meal, which may make medication adherence more difficult.

Incretin modulators: glucagon-like peptide-1 (GLP-1) analog and dipeptidyl peptidase-4 (DPP-4) inhibitors—

Incretins, such as GLP-1 and DPP-4, are gastrointestinal hormones that modulate postprandial glucose homeostasis. Incretin modulators can decrease postprandial hyperglycemia by increasing glucose-dependent insulin secretion and slowing gastric emptying. Although these medications do not cause hypoglycemia when used alone, they may aggravate hypoglycemia when used with insulin or sulfonylureas.

Exenatide and liraglutide are the GLP-1 analogs available in the United States. Exenatide is a synthetic analog of exendin-4, a component of Gila Monster saliva. Exendin-4 is structurally similar to GLP-1 (which decreases postprandial hyperglycemia) but is resistant to DPP-4 degradation, leading to more prolonged action. Both GLP-1 analogs appear to decrease HbA1c by approximately 1%. Because of delayed gastric emptying, nausea and weight loss are common. Acute pancreatitis is a rare but serious complication.

Sitagliptin, saxagliptin, and linagliptin are the DPP-4 inhibitors available in the United States. They lead to HbA1c decreases of approximately 0.5%. They are generally well tolerated with less nausea and weight loss than GLP-1 analogs. As with GLP-1 analogs, acute pancreatitis has also been observed with DPP-4 inhibitors.

There is little clinical experience with these medications in older adults. Given their cost and uncertainty regarding long-term safety, they should not be considered first-line agents for older adults.

Insulin—

Insulin is required in all patients with type 1 diabetes, and in many patients with moderate or severe type 2 diabetes. There is more than 75 years of clinical experience with insulin. With proper dosing, it can be used safely in cases of renal or hepatic insufficiency, as well as in the hospital, nursing home, or as an outpatient. Disadvantages of insulin include the risk of hypoglycemia, weight gain, and patient psychological barriers to injection.

Many different types of insulin have been developed to provide flexible treatment options for different patterns of hyperglycemia (Table 42–4). Commonly used longer-acting insulins include glargine and neutral protamine Hagedorn (NPH), which are used once or twice daily, respectively, to provide basal insulin for control of fasting glucose levels. Commonly used shorter-acting insulins include lispro and regular before meals to provide bolus insulin to control postprandial glucose levels. Insulin mixtures such as 70/30 (70% NPH and 30% regular) may help simplify insulin regimens for many patients. For many older patients with type 2 diabetes, once-daily long-acting insulin at nighttime, often in addition to metformin, may be a reasonable starting regimen.

Amylin mimetic—

Amylin is a peptide that is cosecreted with insulin and modulates glucose homeostasis by delaying gastric emptying, promoting satiety, and decreasing postprandial glucagon secretion. Pramlintide is the only amylin mimetic available in the United States; it is approved for subcutaneous use for patients with type 1 or 2 diabetes taking insulin. Although generally well-tolerated, its effect is modest, decreasing HbA1c approximately 0.5%. Pramlintide must be injected separately from insulin, complicating medication adherence.