Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is variable degrees of peripheral insulin resistance and impaired insulin secretion leading to hyperglycemia. It is common among the elderly because of age-related increases in body fat. Hyperglycemia may be mild and is usually asymptomatic; it may be present for years before it is detected. In the elderly, when hyperglycemia has been severe enough and present long enough to cause symptoms, symptoms may be nonspecific. Later complications include MI, stroke, peripheral arterial disease, retinopathy, nephropathy, peripheral neuropathy, and predisposition to infection. Diagnosis is by measuring plasma glucose. Treatment is diet, exercise, and drugs that reduce glucose levels, including oral antihyperglycemics and insulin. Prognosis varies with degree of glucose control and control of coexisting risk factors for coronary artery disease (eg, hypertension, dyslipidemia).

Geriatric Essentials

• Type 2 diabetes mellitus (DM) is far more common than type 1 DM among the elderly; prevalence increases with aging.
• Most patients with type 2 DM have both inadequate insulin secretion and increased peripheral resistance to insulin caused by age-related weight gain and increased body fat. However, there are many elderly patients with type 2 DM who are not obese; in these patients, insulin secretion is severely impaired and peripheral insulin resistance is mild or nonexistent.
• In patients > 65, risk factors include obesity; sedentary lifestyle; family history of DM; history of impaired glucose regulation; gestational DM or delivery of a baby > 4.1 kg; history of hypertension or dyslipidemia; polycystic ovary syndrome; and black, Hispanic, or American Indian ethnicity.
• Drugs are more likely to cause or exacerbate hyperglycemia in the elderly; corticosteroids, -blockers, some fluoroquinolone antibiotics (which may also cause hypoglycemia), 2nd-generation antipsychotics, high doses of thiazide diuretics, and therapeutic doses of niacin are most notable. Hyperglycemia typically resolves when the drug is stopped.
• In the elderly, hyperglycemia may manifest subtly as depression, cognitive impairment (including dementia), falls, urinary incontinence, lethargy or fatigue, chronic pain, or unexplained weight loss. Nonketotic hyperosmolar syndrome is also common.
• The prevalence of diabetic complications is highest in the elderly because of their long-term exposure to elevated glucose levels and the high prevalence of hypertension and dyslipidemia.
• Cardiovascular disorders (eg, coronary artery disease, stroke, peripheral arterial disease) are probably the most common and serious diabetic complications and mandate aggressive management of risk factors (hypertension, dyslipidemia, smoking) and preventive interventions (aspirin, ACE inhibitors, angiotensin II receptor blockers).
• Diabetic retinopathy and neuropathy increase the risk of falls, reduced mobility, social isolation, and depression.
• Most elderly patients can be treated as aggressively as younger patients, but some require modifications based on their life expectancy, functional status, cognitive abilities, and preferences. Often, education about treatment and monitoring must be directed toward the patient's spouse or caregivers. Risk of complications is high for patients taking drugs for multiple disorders.
• Hypoglycemia is a risk of treatment; autonomic neuropathy, dementia, and the use of -blockers and sedative-hypnotics make elderly patients less likely to be aware of hypoglycemia. These patients are at highest risk of CNS dysfunction with rapid deterioration into a hypoglycemic coma.

See also the American Geriatrics Society's Guidelines for Improving the Care of the Older Person With Diabetes Mellitus.

Type 2 diabetes mellitus (DM) is far more common than type 1 DM among the elderly. Relatively few elderly people develop type 1 DM, an autoimmune disorder of children and young adults in which insulin-secreting -cells are destroyed. However, an increasing number of people with type 1 DM are surviving into later life. Prevalence of type 2 DM increases with aging, from about 3 to 5% of people in their 30s and 40s to about 10 to 20% of people in their 60s and 70s. About 10% of adults age 60 to 74 have type 2 DM and do not know it.

Etiology

In type 2 DM, hyperglycemia results from insulin resistance in peripheral tissues (muscles and liver) and impaired insulin secretion.

In the elderly, insulin resistance often results from age-related weight gain and increased adipose tissue. Visceral and abdominal obesity, measured by a waist-to-hip ratio > 1, poses higher risk. Weight gain, increased adipose tissue, and obesity usually result from consumption of excess calories, lack of exercise, and genetic determinants. Increased adipose tissue leads to an increase in plasma levels of free fatty acids, which may impair insulin-stimulated glucose transport and muscle glycogen synthase activity. Adipose tissue also appears to function as an endocrine organ, releasing multiple factors (adipocytokines) that favorably (adiponectin) and adversely (tumor necrosis factor-, IL-6, leptin, resistin) influence glucose metabolism. Hyperglycemia itself may augment insulin resistance by decreasing insulin sensitivity and increasing hepatic glucose production. In the early stages of insulin resistance, insulin levels may increase; this hyperinsulinemia may be a part of the metabolic syndrome, characterized by visceral and abdominal obesity, hypertension, dyslipidemia, and atherosclerosis. The combination of DM, hypertension, dyslipidemia, and cigarette smoking is synergistic, rapidly accelerating many diabetic complications.

Impaired insulin secretion results from -cell dysfunction; evidence of dysfunction includes impaired first-phase insulin secretion in response to IV glucose infusion, loss of normally pulsatile insulin secretion, an increase in proinsulin secretion (signaling impaired insulin processing), and accumulation of islet amyloid polypeptide (a protein normally secreted with insulin). In most patients, -(insulin-secreting) and -(glucagon-secreting) cell masses and ratios appear to be preserved. Hyperglycemia itself may impair insulin secretion because high glucose levels desensitize cells, cause -cell dysfunction (glucose toxicity), or both. This impairment typically takes years to develop in patients with insulin resistance. Type 2 DM in most elderly patients develops when insulin secretion can no longer compensate for insulin resistance and when reduced insulin levels reduce tissue glucose uptake and do not inhibit hepatic glucose production. However, there are many elderly people with type 2 DM who are not obese; in these patients, insulin secretion is severely impaired and peripheral insulin resistance is mild or nonexistent.

Secondary causes of type 2 DM in the elderly include chronic pancreatitis, other endocrine disorders (eg, Cushing's disease, acromegaly, pheochromocytoma, glucagonoma, somatostatinoma), and drugs. Chronic pancreatitis can lead to loss of insulin- and glucagon-secreting islet cells. Patients tend to be mildly hyperglycemic, are not prone to diabetic ketoacidosis (DKA), and are usually sensitive to low doses of insulin. Because counterregulatory glucagons are absent, patients given exogenous insulin are at greater risk of hypoglycemia.

Drugs commonly used by the elderly can cause or exacerbate hyperglycemia; these drugs include corticosteroids, -blockers, some fluoroquinolone antibiotics (which may also cause hypoglycemia), 2nd-generation antipsychotics (eg, clozapine, olanzapine), high doses of thiazide diuretics, and therapeutic doses of niacin. Hyperglycemia usually resolves when the drug is stopped.

Type 1 DM may occur with other autoimmune disorders (eg, Graves' disease, Hashimoto's thyroiditis, idiopathic Addison's disease).

Symptoms and Signs

Type 2 DM may be asymptomatic or cause symptoms and signs of hyperglycemia (polydipsia, polyphagia, polyuria), nonketotic hyperosmolar syndrome (NKHS), or diabetic complications. In the elderly, hyperglycemia and NKHS may manifest subtly as depression, cognitive impairment (including dementia), falls, urinary incontinence, lethargy or fatigue, chronic pain, or unexplained weight loss.

Complications

Years of poorly controlled hyperglycemia lead to multiple, primarily vascular complications that affect both large and small vessels. Prevalence of these complications is highest in the elderly because of their long exposure to elevated glucose levels.

Vascular disorders result from glycosylation of circulating and tissue proteins with formation of advanced glycation end products; production of superoxides; activation of protein kinase C, a signaling molecule that increases vascular permeability and causes endothelial dysfunction; and acceleration of hexosamine biosynthetic and polyol pathways. Ultimately, sorbitol accumulates within tissues, hypertension and dyslipidemias ensue, arterial microthromboses occur, and vascular autoregulation becomes impaired by the proinflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia.

Immune dysfunction, another major complication, develops because hyperglycemia directly affects cellular immunity.

Macrovascular disease: Large-vessel atherosclerosis results from hyperinsulinemia, dyslipidemia, and hyperglycemia. Hyperglycemia may not be as important as dyslipidemia in the development of macrovascular disease, and intensive control of plasma glucose alone may not prevent macrovascular disease. Patients tend to have atherogenic dyslipidemia, which is a combination of high levels of triglyceride and small, dense, low density lipoprotein (LDL) particles and low levels of high density lipoprotein cholesterol (HDL-C). The combination may result from obesity, poor control of plasma glucose, or both. Atherogenic dyslipidemia is often exacerbated by the increased caloric intake and physical inactivity that characterize the lifestyles of elderly patients with type 2 DM. In elderly women with DM, this form of dyslipidemia may particularly increase risk of cardiovascular disease.

Manifestations are angina pectoris and MI, transient ischemic attacks, strokes, and peripheral arterial disease. Diabetic cardiomyopathy, a less well-recognized manifestation, may result from epicardial atherosclerosis, hypertension-induced left ventricular hypertrophy, microvascular complications, endothelial and autonomic dysfunction, obesity, and metabolic disturbances. Heart failure results from impairment in left ventricular systolic or diastolic function. Patients with DM are also more likely to develop heart failure after MI.

Microvascular disease: Microvascular disease underlies 3 common and devastating diabetic complications: retinopathy, nephropathy, and neuropathy. It also dramatically impairs skin healing, so that even minor skin breaks can develop into deeper ulcers and easily become infected. In combination with large vessel disease, amputation of a lower limb becomes common. These complications take years of hyperglycemia to develop.

Diabetic retinopathy is characterized initially by retinal capillary microaneurysms (see Photo 64-1) and later by macular edema and neovascularization (see Photo 64-2) with or without retinal detachment or hemorrhage. The latter changes can cause abrupt or gradual vision loss, increasing the risk of falls, social isolation, and depression.

Diabetic nephropathy causes the glomerular basement membrane to thicken and mesangial expansion and glomerular sclerosis to occur. These changes cause glomerular hypertension and progressive decline in GFR, although GFR may be increased in the early stages of hyperglycemia. Systemic hypertension is a typical feature and accelerates progression to renal failure. Diabetic nephropathy is usually asymptomatic until nephrotic syndrome or renal failure develops.

Diabetic neuropathy results from nerve ischemia due to microvascular disease, direct effects of hyperglycemia on neurons, and intracellular metabolic changes that impair nerve function. Symmetric polyneuropathy (with small- and large-fiber variants) and autonomic neuropathy occur. Symmetric polyneuropathy is most common and affects the distal feet and hands (stocking-glove distribution). It manifests as paresthesias; dysesthesias; or painless loss of touch, vibration, proprioception, or temperature sensation. In the lower extremities, these symptoms can lead to blunted perception of foot trauma due to ill-fitting shoes or abnormal weight bearing, which can in turn lead to foot ulceration (see Photo 64-3) and infection or to fractures, subluxation, and dislocation or destruction of normal foot architecture (Charcot's joint).

Small-fiber neuropathy is characterized by pain, numbness, and loss of temperature sensation; vibration and position sense are preserved. Patients are prone to foot ulceration and neuropathic joint degeneration and have a high incidence of autonomic neuropathy. Large-fiber neuropathy is characterized by muscle weakness, loss of vibration and position sense, and lack of deep tendon reflexes. Atrophy of intrinsic muscles of the feet and footdrop are common.

Autonomic neuropathy can lead to orthostatic hypotension, exercise intolerance, resting tachycardia, abnormal sweating, dysphagia (due to esophageal dysmotility), nausea and vomiting (due to gastroparesis), constipation and diarrhea (including dumping syndrome), fecal incontinence, urinary retention and incontinence, erectile dysfunction and retrograde ejaculation, and decreased vaginal lubrication. A blunted decrease in heart rate in response to the Valsalva maneuver or standing and a blunted decrease in heart rate slowing with deep breathing indicate autonomic neuropathy. Other signs include lack of variation in the R-R interval on ECG and abnormal sympathetic response to postural changes during tilt table testing. Lack of variation in the R-R interval is specific for cardiac autonomic neuropathy and indicates increased mortality risk.

Radiculopathies, cranial neuropathies, and mononeuropathies occur more often in elderly than in younger patients with DM and are attributed to nerve infarction. Radiculopathies most often affect the proximal L2 through L4 nerve roots, causing pain, weakness, and atrophy of the lower extremities (diabetic amyotrophy), or the proximal T4 through T12 nerve roots, causing abdominal pain (thoracic polyradiculopathy). Cranial neuropathies cause diplopia, ptosis, and anisocoria when they affect the 3rd cranial nerve and motor palsies when they affect the 4th or 6th cranial nerve. Mononeuropathies cause finger weakness and numbness (median nerve involvement) or footdrop (peroneal nerve involvement). Elderly patients with DM are also prone to nerve compression disorders, such as carpal tunnel syndrome. Mononeuropathies can occur in several places simultaneously (mononeuritis multiplex). All of these neuropathies tend to abate spontaneously over months.

Other complications: Risk of fungal or bacterial infection is increased because microvascular disease is present and because hyperglycemia decreases cellular immunity. Mucocutaneous fungal infections (eg, oral and vaginal candidiasis, tinea pedis) and bacterial foot infections are most common. A fungal infection may cause moist lesions, cracks and fissures (eg, in interdigital spaces--see Photo 64-4), and ulcerations that predispose to secondary bacterial invasion. Infection is exacerbated by lower extremity vascular insufficiency and neuropathy.

Diabetic foot complications (skin changes, ulceration, infection, gangrene) may result from vascular disease, neuropathy, and relative immunosuppression. Other complications include depression, cognitive impairment (including dementia; DM is a risk factor for vascular dementia and Alzheimer's disease), and connective tissue disorders (eg, muscle infarction, Dupuytren's contracture, adhesive capsulitis, sclerodactyly). Diabetes increases risk of developing ophthalmologic disorders unrelated to diabetic retinopathy (eg, cataracts, glaucoma, corneal abrasions, optic neuropathy), hepatobiliary disorders (eg, nonalcoholic fatty liver disease [steatosis and steatohepatitis], cirrhosis, hepatocellular carcinoma, hepatitis C infection, and gallstones), and dermatologic disorders (eg, tinea infections, lower-extremity ulcers, diabetic dermatosis, necrobiosis lipoidica diabeticorum, diabetic scleredema, vitiligo, granuloma annulare, acanthosis nigricans [a sign of insulin resistance]). DM may exacerbate urinary incontinence, chronic pain, and the complications of falls and may complicate treatment of other disorders.

Diagnosis

Risk factors for type 2 DM in patients > 65 include obesity; sedentary lifestyle; family history of DM; history of impaired glucose regulation; gestational DM or delivery of a baby > 4.1 kg; history of hypertension or dyslipidemia; polycystic ovary syndrome; and black, Hispanic, or American Indian ethnicity. Increasing age is one of the strongest risk factors, and people >= 60 should be screened regardless of whether additional risk factors are present, although treatment begun when asymptomatic DM is diagnosed through screening has not been proved to improve outcomes. See the US Preventive Services Task Force's Summary of Recommendations for Screening for Diabetes Mellitus, Adults Type 2.

Diagnosis is suggested by typical symptoms and signs and confirmed by measurements of plasma glucose. Measurement after an 8- to 12-h fast (fasting plasma glucose [FPG]) is best (see Table 64-1). Alternatively, plasma glucose can be measured 2 h after ingestion of 75 g of anhydrous glucose dissolved in water (oral glucose tolerance testing [OGTT]). OGTT is more sensitive for diagnosing DM and is necessary to detect impaired glucose tolerance (glucose level of 140 to 199 mg/dL), but OGTT is more expensive and less convenient and reproducible than FPG and is therefore rarely used. FPG should be measured at least once every 3 yr if levels are normal and at least annually if levels are elevated, indicating impaired glucose regulation.

In practice, DM is often diagnosed using random measures of plasma glucose or glycosylated hemoglobin (HbA_1C). A random glucose level > 200 mg/dL (> 11.1 mmol/L) may be diagnostic, but elevated levels should be confirmed by repeat testing; testing twice may not be necessary if typical diabetic symptoms are present. HbA_1C measurements reflect glucose levels over the preceding 2 to 3 mo. Values > 6.5% usually indicate abnormally high plasma glucose levels. However, assays and reference ranges are not standardized, and values may be falsely high or low. For these reasons, HbA_1C is not considered as reliable as FPG or OGTT testing for diagnosing DM and should be used mainly for monitoring glucose control.

Testing for secondary causes of DM may be indicated when history or examination suggests a pancreatic disorder, endocrinopathy, or drug-induced DM.

Patients with type 2 DM should be screened for diabetic complications at the time of diagnosis and at regular intervals. Screening intervals may be modified based on how age-related changes (see Table 64-2), functional status, and life expectancy affect treatment objectives.

At each visit, the entire foot, especially skin beneath the metatarsal heads, should be examined for skin cracking and signs of ischemia (eg, ulcerations, gangrene, fungal nail infections, deceased pulses, hair loss). Feet should be examined at least annually for impaired sensation (touch, vibration, pain, and temperature), which is characteristic of peripheral neuropathy. Touch is best tested with a monofilament esthesiometer (see Figure 64-1). Symmetric polyneuropathy is diagnosed by detection of sensory deficits and diminished ankle reflexes. Electromyography and nerve conduction studies may be needed to diagnose some forms (eg, small-fiber neuropathy) and are sometimes used to exclude other causes of neuropathic symptoms, such as radiculopathy and carpal tunnel syndrome.

Many experts recommend baseline ECG because coronary artery disease is a risk. The lipid profile should be checked at least annually, more often if abnormalities are present. At routine visits, patients should be asked questions to screen for depression, cognitive impairment, falls, and urinary incontinence.

Diabetic retinopathy is diagnosed by funduscopic examination, which should be repeated by an ophthalmologist. The screening interval is controversial but ranges from annually for patients with established retinopathy to every 3 yr for those who have had at least one examination in which no retinopathy was detected.

Renal function should be assessed annually. Diagnosis of diabetic nephropathy is by detection of urinary albumin; albuminuria may develop after about 5 yr of DM. A urine dipstick that is positive for protein signifies albumin excretion > 300 mg/24 h and advanced diabetic nephropathy (or an improperly collected or stored specimen). If the dipstick is negative for protein, the albumin:creatinine ratio in a spot urine specimen or albumin in a 24-h urine collection should be measured. A ratio > 30 mg/g or an albumin concentration 30 to 300 mg/24 h signifies microalbuminuria and early diabetic nephropathy.

Treatment

See also the American Diabetes Association's position statements on diabetes care.

Treatment consists of control of glucose and coexisting risk factors for cardiovascular disease; objectives are to reduce symptoms and slow progression of complications while minimizing hypoglycemic episodes. Most elderly patients can be treated as aggressively as younger patients, but some require modifications based on their life expectancy, functional status, cognitive abilities, preferences, and multiple other factors (see Table 64-2). Goals for treatment (which may be modified based on these factors) are maintenance of plasma glucose 80 to 120 mg/dL (4.4 to 6.7 mmol/L) during the day and 100 to 140 mg/dL (5.6 to 7.8 mmol/L) at bedtime (as determined by home monitoring) and maintenance of HbA_1C levels at < 7%.

Key elements are patient education, weight management via diet and exercise counseling, use of antihyperglycemic drugs, and glucose monitoring.

Education about causes of DM, diet, physical activity, drugs, self-monitoring with finger-stick testing, the symptoms and signs of hypoglycemia and hyperglycemia, and diabetic complications is crucial for optimizing care. When the patient is unlikely or unable to process the information, the information should also be given to a caretaker. Education should be reinforced at every health care visit and hospitalization. Formal diabetes education programs for both patient and caregiver are usually conducted by diabetes nurses and nutrition specialists; these programs are often very effective and provide beneficial social contact for otherwise isolated elderly patients.

Weight management is important; weight loss is usually the goal. Insulin sensitivity increases when overweight or obese patients are in negative caloric balance, which occurs within weeks of starting a weight-loss diet (long before much of the extra weight is lost). As hyperglycemia lessens, glucose toxicity may decline, leading to better glucose control. In frail elderly people, including many nursing home residents, the objective is to maintain weight; such patients should not be placed on weight-loss diets. Rarely, for elderly patients who are lean, weight gain is the goal; some of these patients may be in a catabolic state, and institution of antihyperglycemic therapy (usually insulin) often leads to weight gain, which may be viewed as a positive response to treatment.

Diet adjusted to individual circumstances can help patients control fluctuations in their glucose levels and lose weight. Patients usually need to be taught to follow a diet that is low in saturated fat and cholesterol and that contains moderate amounts of carbohydrate, preferably from whole-grain sources with high-fiber content. Although dietary protein and fat contribute to caloric intake (and thus, to weight gain or loss), only carbohydrates have a direct effect on plasma glucose levels. Some experts also recommend dietary protein restriction to <= 0.8 g/kg/day to prevent progression of nephropathy. Consistency of meal content and timing often facilitates glucose control. Dietitian consultation should complement health care practitioner counseling; the patient and the person who prepares the patient's meals should both be present.

Exercise should involve an incremental increase in physical activity to whatever level the patient can tolerate. Activities for the elderly include walking, swimming, and resistance training. Exercise may increase insulin sensitivity; exercise is also key to promoting weight loss. If hypoglycemia occurs during vigorous activity, patients may need to ingest carbohydrates during the workout period or adjust the drug dosage before exercising (as determined by a health care practitioner).

Monitoring: Glucose control can be monitored using plasma glucose, HbA_1C, or fructosamine levels. Self-monitoring of plasma glucose using fingertip blood, test strips, and a glucose meter is most important. Monitoring provides feedback to patients about dietary intake and exercise and helps health care practitioners recommend adjustments in the timing and doses of drugs. Nearly all monitoring devices require test strips and a means of pricking the skin (eg, a spring-powered lancet) to obtain a sample. Choice among devices is usually based on patient preferences for features such as time to results (usually 5 to 30 sec), size of display panel (large screens may be useful for patients with poor eyesight), and need for calibration. Meters that allow for testing at sites less painful than the fingertips (palm, forearm, upper arm, abdomen, thigh) are available.

Patients with poor glucose control and those given a new drug or a new dose of an existing drug may be asked to self-monitor once (usually morning fasting) to >= 5 times/day, depending on the patient's needs and abilities, complexity of the treatment regimen, and level of glucose control.

HbA_1C levels reflect glucose control over the preceding 2 to 3 mo and thus help assess control between practitioner visits. HbA_1C should be measured annually in patients who have DM and whose plasma glucose appears stable; HbA_1C should be measured more frequently when control is uncertain. Home testing kits are available for patients who can meticulously follow testing instructions. HbA_1C values sometimes appear to differ from levels suggested by daily glucose measurements. The most common cause for discrepancy is limited or inaccurate home glucose testing. Less commonly, HbA_1C may be falsely elevated or falsely low. False elevations occur because of renal insufficiency (urea interferes with measurement), low RBC turnover (eg, due to iron, folate, or vitamin B₁₂ deficiency anemia), high-dose aspirin, or high blood alcohol concentrations. Falsely low values occur because of high RBC turnover (eg, due to hemolytic anemias and hemoglobinopathies such as sickle cell disease or HbC disease) or during treatment of deficiency anemias. (See also the Agency for Healthcare Research and Quality's evidence report, Use of Glycated Hemoglobin and Microalbuminuria in the Monitoring of Diabetes Mellitus.)

Fructosamine, which is mostly glycosylated albumin but also contains other glycosylated proteins, reflects glucose control over the previous 1 to 2 wk. Fructosamine monitoring may be used during intensive treatment of DM and for patients with Hb variants or high RBC turnover (which cause false HbA_1C results), but it is mainly used in research.

Oral antihyperglycemic drugs: Oral antihyperglycemic drugs (see Tables 64-3 and 64-4) are the primary drugs used for treatment of type 2 DM, although insulin is often added when 2 oral drugs taken together do not provide adequate glucose control. Oral antihyperglycemic drugs include secretagogues (which enhance pancreatic insulin secretion), sensitizers (which sensitize peripheral tissues to insulin), and drugs that impair GI absorption of glucose. Drugs with different mechanisms of action may be synergistic.

Biguanides decrease hepatic glucose production (gluconeogenesis and glycogenolysis) and may improve insulin sensitivity. Biguanides lower lipid levels and may also decrease GI nutrient absorption, increase -cell sensitivity to circulating glucose, and decrease levels of plasminogen activator inhibitor 1, thereby exerting an antithrombotic effect. Biguanides rarely, if ever, cause hypoglycemia, and they may promote weight loss, perhaps by suppressing appetite.

Metformin, the only biguanide available in the US, should be considered the drug of choice for patients with newly diagnosed type 2 DM. Metformin alone is as effective as a sulfonylurea alone in controlling plasma glucose and is synergistic when used with a sulfonylurea. Moreover, some evidence suggests that glucose control with metformin reduces risk of MI more than does equivalent control with insulin or sulfonylureas. Metformin is contraindicated in patients at risk of acidemia (eg, those with a creatinine level >= 1.4 mg/dL [>= 120 µmol/L]), heart failure, hypoxia or severe respiratory disease, a liver disorder, or alcoholism) because biguanides can cause lactic acidosis. Because renal function declines with aging and may not be accurately assessed by measuring plasma creatinine, metformin should not be used in patients > 80 unless creatinine clearance measured in a 24-h urine collection is normal. Metformin should be withheld during surgery, administration of IV contrast, and any serious disorder. GI adverse effects (eg, dyspepsia, flatulence, diarrhea) are common but often resolve spontaneously and may be prevented if the drug is taken with meals and if the dose is increased gradually (at weekly intervals by 500 mg/day or at 2-wk intervals by 850 mg/day, up to 2.55 g/day). Doses exceeding 2 g/day are usually better tolerated if divided and given tid rather than bid.

Short-acting insulin secretagogues (repaglinide, nateglinide) stimulate insulin secretion in a manner similar to sulfonylureas. However, they are faster-acting and may stimulate insulin secretion more during meals than at other times. Thus, they may be especially effective for reducing postprandial hyperglycemia and appear to have a lower risk of hypoglycemia. Like sulfonylureas, they can cause weight gain. Repaglinide appears to be as effective as sulfonylureas or metformin in lowering glucose levels; nateglinide may be somewhat less effective and therefore more appropriate for patients with mild hyperglycemia. Patients who have not responded to drugs in other classes (eg, sulfonylureas, metformin) are unlikely to respond to these drugs.

-Glucosidase inhibitors (acarbose, miglitol) may be ideal for elderly patients with mild hyperglycemia (fasting plasma glucose levels 100 to 150 mg/dL [5.6 to 8.3 mmol/L]) or with postprandial hyperglycemia. Acarbose competitively inhibits hydrolysis of oligosaccharides and monosaccharides and thus delays carbohydrate digestion in the small intestine and subsequent absorption, resulting in lower postprandial plasma glucose levels. Acarbose or miglitol increases glucagon-like peptide-1, which increases insulin release from the pancreas. Monotherapy with acarbose has a weaker antihyperglycemic effect than that with metformin or the sulfonylureas. GI adverse effects are common among the elderly but are often transient. Miglitol may cause less flatulence. Acarbose and miglitol should be started at 25 mg once/day to minimize GI adverse effects. The dose should be increased after 1 wk to 25 mg tid; each dose is taken with the first bite of each main meal. The dosage can be increased as needed at weekly intervals to a maximum of 100 mg tid.

Thiazolidinediones (TZDs--rosiglitazone, pioglitazone) are insulin sensitizers; they decrease peripheral insulin resistance. However, their specific mechanisms of action are not well understood. The drugs bind peroxisome-proliferator-activated receptor- (PPAR), a nuclear receptor that is present primarily in fat cells; it is involved in the transcription of genes that regulate glucose and lipid metabolism. TZDs increase HDL-C levels and lower triglyceride levels. They may also have anti-inflammatory and antiatherosclerotic effects. TZDs improve insulin sensitivity in skeletal muscle and suppress hepatic glucose output.

TZDs often cause weight gain and fluid retention. They may be most appropriate as adjuvant drugs to control plasma glucose in patients taking other oral antihyperglycemic drugs or insulin. TZDs are useful in elderly patients with impaired renal function when metformin and sulfonylureas are contraindicated.

Sulfonylureas are insulin secretagogues; they lower plasma glucose levels primarily by stimulating pancreatic -cell insulin secretion, but they also improve peripheral and hepatic insulin sensitivity. First-generation drugs are rarely used (some are more likely to have adverse effects); 2nd-generation sulfonylureas (eg, glipizide, glyburide, glimepiride) are substantially more potent and often safer.

All sulfonylureas promote hyperinsulinemia and weight gain of 2 to 5 kg, which over time may potentiate insulin resistance and limit their usefulness. All can cause hypoglycemia; risk factors for this effect include age > 65, use of long-acting drugs (especially chlorpropamide or glyburide), erratic eating and exercise patterns, and renal or hepatic insufficiency. Hypoglycemia caused by long-acting drugs may last for days after treatment stops; it can cause permanent neurologic disability and can be fatal. For these reasons, some practitioners hospitalize elderly patients who become hypoglycemic while taking these drugs. For initial treatment, many experts prefer shorter-acting sulfonylureas. There is no rationale for using a combination of sulfonylureas.

Sulfonylureas are started at a low dose, which is adjusted after several days until a satisfactory response is obtained or the maximum recommended dose is reached. About 10 to 20% of patients do not respond, and most patients who do not respond to one sulfonylurea are unlikely to respond to others.

Most patients taking sulfonylureas alone eventually require additional drugs to achieve normoglycemia, suggesting that sulfonylureas may exhaust -cell function. However, worsening insulin secretion and increasing insulin resistance are probably related more to DM itself than to the drugs used to treat it.

Insulin: Insulin is often helpful for management of type 2 DM when oral drugs do not adequately control glucose. Universal use of recombinant human insulin has eliminated the hypersensitivity reactions that were once common with animal-derived preparations. However, very low but detectable insulin antibody levels develop in most insulin-treated patients, including those receiving human insulin preparations.

Insulin is injected sc with disposable syringes. The 0.5-mL syringes are preferred by most patients who routinely inject doses of <= 50 units because these syringes facilitate accurate measurement of smaller insulin doses. Various multiple-dose insulin injection devices commonly referred to as insulin pens are available; they use a cartridge containing dosages for several days. The accuracy and simplicity of this method may benefit elderly patients, especially those who are just beginning to use insulin. Insulin should be refrigerated but never frozen; however, most insulin preparations are stable at room temperature for several weeks, facilitating their use when patients are working or traveling. Some elderly patients have difficulty accurately measuring insulin doses. Magnifying lenses and syringe guides may help; alternatively, a visiting nurse can prepare enough syringes for a week.

Insulin preparations are rapid-acting (short-acting), intermediate-acting, or long-acting. Each type differs in usual onset of action, time of peak action, and duration of action (see Table 64-5), but these data should be used only as guidelines because different patients may respond differently to the same doses of a preparation. Also, one patient may respond differently to a given dose and preparation in various circumstances. Mixtures of insulin preparations that differ in onset and duration of action are often given in a single injection by drawing measured doses of 2 preparations into the same syringe immediately before use. Premixed insulins (eg, 70/30 insulin) are also available and may be more suitable for some elderly patients who are easily confused or who do not have the manual dexterity or eyesight to mix or administer 2 different insulins. Insulin glargine should not be mixed with other insulins. The critical determinant of onset and duration of action is the rate of insulin absorption from the injection site.

Insulin should be added when glucose is inadequately controlled with 2 oral drugs. The rationale for combination therapy is strongest for use of insulin with biguanides or TZDs, because both act as insulin sensitizers, albeit in different ways. Regimens vary from a single daily injection of long- or intermediate-acting insulin (usually at bedtime) to a multiple injection regimen. Generally, the simplest effective regimen is preferred.

Treatment may be started with neutral protamine Hagedorn (NPH) insulin at bedtime. The insulin dose is adjusted to maintain a morning preprandial plasma glucose level at 80 to 150 mg/dL (4.4 to 8.3 mmol/L). Adjustments in the amounts, types, and timing are based on plasma glucose measurements. If fasting plasma glucose is controlled in the morning, some patients may respond adequately to oral drugs during the day (eg, the bedtime insulin--daytime sulfonylurea [BIDS] regimen). Other patients may require daytime insulin (eg, a 2nd injection of NPH) or a longer-acting insulin with no peak (eg, glargine). If fasting glucose is consistently at target levels but increases after meals, addition of shorter-acting prandial insulin (regular, lispro, aspart) may be useful. Increments in insulin dose are usually restricted to 10% at a time, and the effects are assessed over about 3 days before any further adjustment is made. More rapid adjustments of insulin are indicated if hypoglycemia is a risk. An initial total daily dose may be divided so that ½ is administered before breakfast (NPH plus short-acting), ¼ before dinner (short-acting), and ¼ at bedtime (NPH).

Because of insulin resistance, some elderly patients with type 2 DM require very large doses (> 2 units/kg/day). A common complication of very large doses is weight gain, which is mostly attributable to reduction in loss of glucose in urine and improved metabolic efficiency.

Hypoglycemia is the most common complication of insulin treatment and occurs more often as patients strive for strict glucose control. It may occur because of an error in insulin dosage; a small, missed, or otherwise irregularly scheduled meal; renal or hepatic insufficiency; or unplanned physical activity. Patients should be taught to recognize symptoms of hypoglycemia (see Table 64-6). However, autonomic neuropathy, dementia, and the use of -blockers or sedative-hypnotics make elderly patients less likely to be aware of hypoglycemia; these patients are at highest risk of CNS dysfunction and rapid deterioration into a hypoglycemic coma. Caregivers should be instructed to look for excessive hunger or sweating and for abnormal behavior. All patients with DM should carry candy, sugar packets, or glucose tablets. An identification card, bracelet, or necklace indicating that the patient is an insulin-treated diabetic helps in an emergency. If the patient is unresponsive, family members or caregivers should be instructed to administer glucagon, which is available with an easy-to-use injection device.

Hyperglycemia may follow hypoglycemia because too much sugar was ingested as a treatment for hypoglycemia or because hypoglycemia caused a surge in counterregulatory hormones (glucagon, epinephrine, cortisol, growth hormone). A bedtime dose of insulin that is too high can drive glucose down and stimulate a counterregulatory response, leading to morning hyperglycemia (Somogyi phenomenon). However, a more common cause of unexplained morning hyperglycemia is an early morning increase in growth hormone (dawn phenomenon). In this case, the evening insulin dose should be increased, changed to a longer-acting preparation, or injected later.

Local allergic reactions at the site of insulin injections are rare, especially when human insulin is used, but they may still occur in patients with latex allergy because of the natural rubber latex contained in vial stoppers. These reactions can cause immediate pain or burning followed by erythema, pruritus, and induration. Induration sometimes persists for days. Most reactions spontaneously disappear after weeks of continued injection and require no specific treatment; antihistamines may be used to relieve symptoms.

Generalized insulin allergy (usually to the insulin molecule) is rare but can occur when treatment is stopped and restarted after a lapse of months or years. Symptoms usually develop shortly after an injection and may include urticaria, angioedema, pruritus, bronchospasm, and, in some patients, circulatory collapse. Treatment with antihistamines may help, but epinephrine and IV glucocorticoids may be required. If insulin treatment must be continued after the condition stabilizes, skin testing with a panel of purified insulin preparations and desensitization should be done by an experienced health care practitioner.

Local fat atrophy or hypertrophy at injection sites is relatively rare with human insulin and may be prevented by rotating injection sites.

Patients may develop high levels of circulating antibodies to insulin, which could interfere with insulin action and lead to erratic glucose levels, but this phenomenon rarely occurs with current insulin preparations. Remission may be spontaneous.

Combination therapy: Oral antihyperglycemic drugs with different mechanisms of action may be used together or with insulin. For example, the combination of metformin and glyburide is likely to decrease HbA_1C by about 2% more than glyburide alone. When metformin or a TZD is used with insulin, insulin dosage can be decreased, and glucose control is improved. The incidence of hypoglycemia is low when metformin or TZDs are used alone, but hypoglycemia is more likely to occur when they are used with insulin. Patients should be instructed to monitor plasma glucose levels regularly, especially after any dose adjustment.

Newer drugs: Glucagon-like peptide-1 (GLP-1) analogs simulate effects of endogenously secreted GLP-1, an incretin hormone. They improve glucose metabolism by enhancing meal-stimulated insulin release, delaying gastric emptying, and suppressing glucagon secretion (thus lowering hepatic glucose production). Exenatide is a synthetic analog of GLP-1; it can be used to treat type 2 DM in combination with metformin, a sulfonylurea, or both. Exenatide is given by injection before breakfast and dinner and appears to lower glucose levels particularly effectively after meals. The most common adverse effect is nausea. Modest weight loss is common. Nausea and weight loss may limit the usefulness of exenatide in elderly patients. Oral therapy with GLP-1 analogs, which works by inhibiting breakdown of endogenously produced GLP-1, may be better tolerated and is currently under development.

Pramlintide is a synthetic analog of the -cell hormone amylin. Pramlintide can be used to treat type 1 DM and can be combined with insulin to treat type 2 DM. Pramlintide limits postprandial glucose increases by delaying gastric emptying and suppressing glucagon secretion. Its use in the elderly may be limited because it is difficult to administer (it is given by injection before each meal, but it cannot be mixed with insulin) and because of its adverse effects, which include nausea and weight loss.

Adjunctive treatments: Adjunctive treatments to prevent or treat diabetic complications and physiologic derangements that often accompany DM as part of the metabolic syndrome are critical. ACE inhibitors, angiotensin II receptor blockers, or both are indicated for patients with evidence of early nephropathy (microalbuminuria or proteinuria), even in the absence of hypertension; they also are good choices for treating hypertension in patients who have DM but do not yet have renal impairment. ACE inhibitors also help prevent cardiovascular events in patients with DM. Aspirin 81 to 325 mg once/day provides cardiovascular protection and, unless specifically contraindicated, should be used by most elderly patients with DM.

Patients with type 2 DM tend to have high levels of triglycerides and small, dense LDL particles and low levels of HDL-C. Lipid-lowering treatment and treatment goals for these patients should be the same as those for patients with known coronary artery disease; goals are LDL cholesterol < 70 mg/dL (< 1.81 mmol/L), HDL-C > 40 mg/dL (> 1.03 mmol/L), and triglycerides < 150 mg/dL (< 1.69 mmol/L).

Orlistat, an intestinal lipase inhibitor, reduces dietary fat absorption; it reduces serum lipids in patients with type 2 DM by promoting weight loss. It may be useful for selected patients as part of a comprehensive weight loss program, but long-term safety and efficacy of orlistat and other weight loss aids (fluoxetine, sibutramine) are unproven. (See the Cochrane review abstract on pharmacotherapy for weight loss in adults with type 2 diabetes mellitus.) Surgical treatment of obesity, such as gastric resection or bypass, also leads to weight loss and improved glucose control in patients unable to lose weight through other means.

Regular professional podiatric care, including trimming of toenails and calluses, is important for patients with sensory loss or circulatory impairment. Such patients should be advised to inspect their feet daily for cracks, fissures, calluses, corns, and ulcers. Feet should be washed daily in lukewarm water, using mild soap, and dried gently and thoroughly. A lubricant (eg, lanolin) should be applied to dry, scaly skin; nonmedicated foot powders should be applied to moist feet. Toenails should be cut straight across and not too close to the skin. To prevent trauma, elderly patients with toenail abnormalities and impaired sight or coordination should have another person, preferably a podiatrist, cut their toenails. Adhesive plasters and tape, harsh chemicals, corn cures, water bottles, and electric pads should not be used on skin. Patients should change stockings daily and not wear constricting clothing (eg, garters, socks or stockings with tight elastic tops). Shoes should fit well, be wide-toed without open heels or toes, and be changed frequently. If the foot is deformed (eg, previous toe amputation, hammer toe, bunion), special shoes should be prescribed to reduce trauma. Walking barefoot should be avoided.

Strict glucose control may lessen neuropathy. Symptoms are relieved with topical capsaicin cream (applied to affected skin 4 times/day), tricyclic antidepressants (eg, desipramine 25 to 150 mg po at bedtime, nortriptyline 25 to 75 mg po at bedtime), serotonin-norepinephrine reuptake inhibitors (eg, duloxetine 60 mg po once/day), anticonvulsants (eg, gabapentin 300 to 600 mg po tid, carbamazepine 200 mg po qid, pregabalin 50 to100 mg po tid), or the antiarrhythmic mexiletine (150 mg po tid). -Lipoic acid (100 mg po tid) may also be effective.

Patients with neuropathic foot ulcers should avoid weight bearing until ulcers heal. If they cannot, they should wear appropriate orthotic protection. Because most patients with these ulcers have little or no macrovascular disease, debridement and antibiotics frequently result in good healing and may prevent major surgery. After the ulcer has healed, appropriate inserts or special shoes should be prescribed. In refractory cases, especially if osteomyelitis is present, surgical removal of the metatarsal head (the source of pressure), amputation of the involved toe, or transmetatarsal amputation may be required. A neuropathic joint can often be satisfactorily managed with orthopedic devices (eg, short leg braces, molded shoes, sponge-rubber arch supports, crutches, prostheses).

Yearly funduscopic examination with dilation, preferably by an ophthalmologist, should be done to check for diabetic retinopathy (some experts indicate that the interval can be increased to every 2 to 3 yr if there is no retinopathy on the initial examination). Early treatment is effective in preventing vision loss. Treatment of advanced diabetic retinopathy is argon laser photocoagulation or vitrectomy.

All patients with DM should be vaccinated against Streptococcus pneumoniae (every 6 yr) and influenza virus (annually).

Brittle diabetes (rapid fluctuations in plasma glucose): Some patients with type 2 DM have dramatic, recurrent swings in glucose levels that often occur for no apparent reason and that are difficult to control (sometimes called brittle diabetes). These swings are more likely to occur in patients with type 1 DM because no endogenous insulin is produced. Patients experience disabling episodes of hyperglycemia or hypoglycemia that typically lead to recurrent emergency department visits and hospitalizations. Known causes include occult infection (eg, osteomyelitis, soft-tissue abscess), gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrine disorders (eg, Addison's disease, hypothyroidism). In most cases, rapid fluctuations in plasma glucose can be attributed to an inappropriate insulin regimen or to errors in insulin administration and diet choices due to inadequate patient education or understanding, psychologic distress (eg, anger, depression, anxiety) that expresses itself in erratic patterns of food intake and physical activity, nonadherence to medical recommendations, or inappropriate self-titration of drugs.

The initial approach to patients with such rapid fluctuations in plasma glucose is to thoroughly review DM self-care techniques, including insulin preparation and injection and glucose testing. Increased frequency of self-testing may reveal previously unrecognized patterns and provide patients with helpful feedback. A thorough dietary history, including timing of meals, should be taken to identify potential contributors to poor control. Other causes (eg, hyperthyroidism) should be ruled out by physical examination and appropriate laboratory tests. For some insulin-treated patients, changing to a more intensive regimen that allows frequent dose adjustments (based on glucose testing) is helpful. In some patients, the frequency of hypoglycemic and hyperglycemic episodes diminishes over time even without specific treatment, suggesting life circumstances may contribute to causation.

Hospitalization: All patients with DKA, NKHS, or severe, prolonged hypoglycemia should be hospitalized. Others with sulfonylurea-induced hypoglycemia, poorly controlled hyperglycemia, or acute worsening of diabetic complications may benefit from brief hospitalization. Control may worsen after discharge when insulin regimens developed in a regimented inpatient setting prove inadequate in the less restrictive setting outside the hospital.

When hospitalization results from disorders other than DM, glucose control may be difficult and is often neglected when other disorders are more acute. Many patients do well without any change in their usual regimen. Restricted physical activity and an acute disorder worsen hyperglycemia in some patients, whereas dietary restrictions and symptoms that accompany a disorder (eg, nausea, vomiting, diarrhea, anorexia) precipitate hypoglycemia in others--especially when antihyperglycemic drug doses are not changed. In addition, adequate glucose control may be difficult in hospitalized patients because usual hospital routines (eg, timing of meals, drugs, procedures) are inflexibly timed relative to DM treatment regimens. Inpatients who can eat may continue their usual outpatient regimen; others may be appropriately treated with basal insulin with or without supplemental short-acting insulin. A sliding-scale for insulin (in which a dose of short-acting insulin is administered in response to plasma glucose readings and is adjusted 1 to 2 units for each 50 mg/dL above or below the target glucose level) should not be the only intervention used to correct hyperglycemia; it is reactive rather than proactive, and no data suggest it leads to outcomes equivalent to or better than other approaches. Longer-acting insulins should be adjusted to prevent hyperglycemia rather than just using short-acting insulins to correct it.

Inpatient hyperglycemia worsens short-term prognosis for patients with many acute disorders, most notably stroke and acute MI, and often prolongs hospital stay. Critical disorders cause insulin resistance and hyperglycemia even in patients without known DM. Insulin infusion to maintain plasma glucose at 100 to 150 mg/dL (4.4 to 6.1 mmol/L) prevents adverse outcomes such as organ failure, enhances recovery from stroke, and leads to improved survival in patients requiring prolonged (> 5 days) critical care. Severely ill patients, especially those receiving glucocorticoids or pressors, may need very high doses of insulin (> 5 to 10 units/h) because of insulin resistance. Insulin infusion should also be considered for patients receiving TPN and for patients with type 1 DM who cannot ingest anything orally.

Surgery: The physiologic stress of surgery can increase plasma glucose. Most patients with type 2 DM who are treated with oral antihyperglycemic drugs maintain acceptable glucose levels when fasting and may not require special treatment during the perioperative period. Most oral drugs, including sulfonylureas and metformin, should be withheld on the day of surgery, and plasma glucose levels should be measured preoperatively, postoperatively, and every 6 h while patients receive IV fluids. Oral drugs may be resumed when patients are able to eat, but metformin should be withheld until normal renal function is confirmed 48 h after surgery. When necessary, regular insulin can be given sc every 4 to 6 h as needed to maintain the plasma glucose level at 100 to 150 mg/dL (5.55 to 11.01 mmol/L).

Patient and caregiver issues: Many elderly patients are enthusiastic, motivated learners and are actively involved in all aspects of their treatment. When provided with appropriate education, they can adhere to a treatment plan and self-monitor their glucose levels as accurately as younger patients. Other patients may have significant limitations, such as dementia, depression, or physical disabilities, which impair their ability to participate in their own care. Family members or other caregivers of such patients must be included in the assessment and education process.

Treatment regimens may need to be modified, for example, by prescribing a single daily insulin injection (glargine) rather than multiple injections for patients who must rely on others to administer the injection. Treatment goals may need to be modified (eg, less stringent glucose control) for patients unable to recognize symptoms of hypoglycemia and respond appropriately or for those with a limited life expectancy due to other serious disorders.

Aids to circumvent some of the patient's limitations (eg, poor vision, limited dexterity) should be provided. Glucose meters should be easy to use, have large display screens and memory capabilities, and require no cleaning. Labeled pill boxes and other reminder devices and insulin pens are often helpful.

Patients and caregivers must recognize indications for seeking immediate medical attention, and appropriate foot care is crucial.

This topic was last updated February 2006.