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Update on Diabetes in the Elderly and in Nursing Home Residents
REVIEW
Update on Diabetes in the Elderly and in Nursing Home Residents Alexandra Migdal, BS, Shadi S. Yarandi, MD, Dawn Smiley, MD, and Guillermo E. Umpierrez, MD
Diabetes is common in the elderly population and in nursing home residents. More than 20% of adults aged 65 to 75 years and 40% of adults older than 80 years suffer from diabetes. Physiological changes in elderly individuals, such as decreased physical activity, abdominal obesity, and increased inflammatory state, increase insulin resistance in peripheral tissue and reduce glucose-dependent insulin release, leading to carbohydrate intolerance and diabetes. The clinical presentation in the elderly and nursing home residents is frequently guided by the high rate of comorbidities such as hypertension, depression, and cardiovascular diseases. Treatment recommendations for glycemic control in elderly ambulatory patients are similar to those in long-term care facilities. Healthy patients with diabetes should aim for nearnormal fasting plasma glucose and an HbA1C of about 7%; however, treatment goals must be individ-
ualized in patients with impaired cognitive and physical ability, reduced life expectancy, and heavy burden of comorbid disease. Elderly individuals and nursing home residents are at increased risk of hypoglycemia during pharmacological treatment. In general, a conservative and stepwise approach to the treatment of the elderly patient with diabetes is suggested. Treatment may be initiated with dietary and physical activity modification and with a single oral agent, followed by a combination of oral agents and insulin therapy if needed. Evidence from clinical trials indicates that improving glycemic control, as well as cardiovascular risk factors, reduces morbidity and mortality in older individuals with diabetes. (J Am Med Dir Assoc 2011; 12: 627–632)
The prevalence of diabetes in the United States is increasing exponentially. The Centers for Disease Control and Prevention recently estimated that 8.3% of the total population has diabetes,1 and forecasted that the incidence will increase 200% by 2050.2 Diabetes disproportionally affects the elderly, with more than 20% of adults aged 65 to 75 years and 40% of adults older than 80 years suffering from diabetes.3,4 The prevalence is higher among residents of long-term care facilities, with approximately 30% having a diagnosis of diabetes.5–7 As life expectancy increases, it is expected that the prevalence of diabetes in the elderly will continue to increase.4,8 The total estimated cost of diabetes care in 2007 was $174 billion, including $116 billion in excess medical expenditures
and $58 billion in reduced national productivity.9 People with diabetes, on average, have medical expenditures that are approximately 2.3 times higher than what expenditures would be in the absence of diabetes.9 Inpatient diabetes care accounts for 50% of total cost. The estimated annual cost for providing nursing home care for patients with diabetes is about $56 billion, more than twice the cost for inpatient services for patients with diabetes.9 The impact and health benefits of improving diabetes treatment in the elderly and in nursing home subjects is not known; however, it is reasonable to speculate that the economic value of improvement in health status will be similar to populations with type 2 diabetes.10
Keywords: Diabetes; long-term care facilities; nursing home; insulin; hypoglycemia
PATHOPHYSIOLOGY Department of Medicine, Division of Endocrinology at Emory University, Atlanta, GA (A.M., S.S.Y., D.S., G.E.U.). G.E.U. is supported by research grants from the American Diabetes Association (7–03-CR-35), and National Institutes of Health: R03 DK073190–01 and General Clinical Research Center Grant M01 RR-00039. Address correspondence to Guillermo E. Umpierrez, MD, Endocrinology Fellowship Program, Emory University School of Medicine , 49 Jesse Hill Jr Drive, Atlanta, GA 30303. E-mail: [email protected]
Published by Elsevier Inc. on behalf of the American Medical Directors Association, Inc. DOI:10.1016/j.jamda.2011.02.010 REVIEW
Physiological changes in elderly adults contribute to the increased prevalence of carbohydrate intolerance and diabetes. Aging is associated with reduced glucose-dependent insulin release and increased insulin resistance in peripheral tissues, primarily in muscle and adipose tissue.11 Both basal and first-phase insulin release are affected; however, differences seem to exist between lean and obese elderly patients with diabetes. Lean elderly patients have a primary defect in glucoseinduced insulin release, whereas obese patients are more likely to have a defect in insulin resistance.12 Interestingly, Migdal et al 627
neither group has increased fasting hepatic glucose production, which is often seen in younger adults.13 Increasing age is also associated with abdominal obesity and decreased physical activity, both of which are associated with reduced insulin sensitivity.14 Abdominal obesity is associated with increased circulating levels of free fatty acids (FFAs), inflammatory cytokines (tumor necrosis factor-a, interleukin [IL]-6, monocyte chemoattractant protein [MCP]-1, and IL-8), and the multifunctional proteins leptin and osteopontin.15 Aging is also associated with chronic low-grade inflammation and higher levels of tumor necrosis factor-a and IL-6, which have been described to be indicators of morbidity in elderly individuals.15,16 In addition, elderly patients are also more likely to receive medications that exacerbate hyperglycemia, including diuretics, beta-blockers, nonsteroidal anti-inflammatory drugs, and glucocorticoids. CLINICAL PRESENTATION Typical symptoms of hyperglycemia, such as polyuria and polydypsia, are less common in elderly patients because the renal threshold for glucosuria increases with age and the thirst mechanisms are more likely to be impaired. Elderly patients often present with symptoms of weight loss, fatigue, and nocturia. Frequently, these symptoms tend to go unnoticed or are attributed to old age, failure to thrive, confusion, and incontinence.17 Because of the atypical presentation, 25% to 41% of elderly individuals with diabetes remain undiagnosed.18 BURDEN OF DISEASE The burden of diabetes in the elderly and in nursing home residents is significant. Diabetic residents of nursing homes are more often transferred from acute care hospitals, have longer lengths of stay, take more medications, and have higher odds of having emergency department visits than nondiabetic residents.17,19 Compared with nondiabetic patients, diabetic patients have significantly greater incidence of hypertension, depression, heart failure, cerebrovascular events, kidney disease, visual impairment, and foot problems (including amputations), and require more staff assistance for activities of daily living. Up to 80% of nursing home residents with diabetes have coexisting cardiovascular disease, 56% to 67% have hypertension, and 69% suffer from 2 or more chronic conditions in addition to diabetes.20,21 Patients with diabetes have increased excess mortality at every age group compared to nondiabetic subjects.22 The American Geriatrics Society has reported that elderly persons with diabetes have higher rates of disability and premature death compared with individuals without diabetes.23 Poorly controlled diabetes is associated with increased cognitive decline, along with higher occurrence of infections and pressure ulcers.24,25 Diabetes is also an independent risk factor for falls in elderly nursing home residents and diabetic residents suffer more fractures than nondiabetic patients.26,27 GLYCEMIC TARGET Management of diabetes is challenging in the geriatric population in long-term care facilities. General goals of 628 Migdal et al
treatment for elderly diabetic patients include avoiding symptoms and complications of hyperglycemia and hypoglycemia, minimizing or delaying microvascular and macrovascular complications, and maximizing daily function.23 Emphasis should also be placed on reducing pain, infections, and nocturia; improving incontinence; preventing injurious falls; and limiting cognitive impairment.28 Preventing hypoglycemia can be problematic in elderly patients who are at increased risk because of impaired renal function, which modifies drug elimination, as well as the use of multiple medications, which places patients at risk for drug-associated hypoglycemia.29 The American Diabetes Association recommends similar treatment goals for elderly and younger patients with diabetes (Table 1). Glycemic targets include an HbA1c of \7%, a fasting blood glucose between 70 and 130 mg/dL, and a postprandial blood glucose less than 180 mg/dL, as well as a nutrition and exercise program, antiplatelet treatment, and blood pressure and lipid control. The American Geriatrics Society emphasizes that the target HbA1c should not be a concrete number, but instead should be individualized based on the patient’s functional status. Those with good functional status should be maintained at HbA1c lower than 7%, whereas those patients who are frail, have multiple comorbidities or increased risk of hypoglycemia, or who have a life expectancy of fewer than 5 years should be maintained at a less stringent target of lower than 8%.14,23 These guidelines, although designed to address outpatient management, also apply to nursing home residents. Several studies have reported on adherence to treatment guidelines in nursing home residents. One study in diabetic residents from an academic nursing home reported a blood pressure lower than 130/80 in 84% and serum low-density lipoprotein lower than 100 mg/dL in 89% of residents.30 These results are comparable to levels of control seen among nondiabetic residents, in whom 80% of residents have an lowdensity lipoprotein level lower than 100 mg/dL and 85% have an adequate blood pressure.31,32 Aspirin use is reported in only 42% of diabetic residents.33 Glycemic control is achieved in most residents, with 67% of subjects meeting HbA1c goals of lower than 7%, and up to 94% meeting the American Geriatrics Society guideline of HbA1c lower than 8%.34–36 Despite the seemingly good control of blood glucose among nursing home residents, only 15% of facilities have an established algorithm for treating patients with diabetes. Just 30.8% of facilities have a policy for blood glucose monitoring and only 7.1% of facilities have a policy in place regarding frequency of HbA1c testing, indicating that there is much room for improvement in the management and quality of care for diabetic patients in nursing homes.35 In addition, it should be noted that hypoglycemic events are more common in elderly individuals and are reported in up to 48% of nursing home residents.37 Fortunately, hospitalization for hypoglycemia is required in only 1% of residents.35 Cognitive status of individual nursing home residents may influence the physician’s approach to diabetes management. It is estimated that nearly 50% of nursing home residents have dementia, regardless of diabetes status.38,39 Those residents with functional and cognitive impairment are less likely JAMDA – November 2011
Table 1.
Summary of Recommendations for Diabetic Care in the Elderly Population
American Diabetes Association Functional, cognitively intact, and with significant life expectancy Impaired cognitive and limited life expectancy
American Geriatrics Society Functional, cognitively intact, and with significant life expectancy Impaired cognitive and limited life expectancy
Fasting Glucose, mg/dL
Random Glucose, mg/dL
HbA1C, %
70–130
\180
\7%
Not determined, but prevent significant hyperglycemia (blood glucose .180 mg/dL)
Not determined
Not determined; levels to be individualized based on functional status and life expectancy
Not determined
\180
\7%
Not determined
Not determined
\8% for persons with life expectancy of less than 5 years
to be placed on a special diet, have monitoring of lipid panels, or have routine ophthalmologic exams compared with residents without impairment. However, there were no differences in the frequency of glucose monitoring, HbA1c measurement, use of sliding scale insulin, or referral for routine podiatry examination.28 For some elderly patients, the risks of intensive glucose control outweigh the benefits. Although improved glycemic control has been associated with lower rates of stroke, blindness, nephropathy, cardiovascular disease, and cognitive dysfunction in elderly individuals,23 tight glycemic control in the elderly and nursing home residents may not be attainable or desirable because of the risk of hypoglycemia,13 and the increased risk of falls and cardiovascular events with episodes of hypoglycemia.13 The following age-related changes increase the risk of hypoglycemia in the elderly: decreased renal function, slowed hormonal regulation and counter-regulation, suboptimal hydration, variable appetite and nutritional intake, polypharmacy, and slowed intestinal functioning (absorption).23 For these reasons, treatment goals must be individualized in elderly patients with reduced cognitive and physical ability, reduced life expectancy, and with heavy burden of comorbid disease.37 In elderly patients, avoidance of hypoglycemia has great potential to enhance the quality of life and to optimize compliance with treatment than in any other age group.40
patients, however, is not routinely recommended because of the increased risk of loss of lean body mass, malnutrition, and dehydration.41 In fact, most elderly diabetic patients are not overweight.42 Weight loss among elderly patients has actually been associated with increased mortality.43 Therefore, it is recommended to focus on medical management of diabetes rather than diet restriction in elderly individuals who are already at risk for poor nutritional status.44 Despite evidence that restrictive diets can be detrimental in elderly patients, Feldman et al35 have shown that more than 50% of long-term care residents had dietary restrictions, which may contribute to malnutrition in this population. Tube feedings are commonly used among nursing home patients. Among patients with advanced cognitive impairment, up to 40% are fed using enteral feedings.45 Despite the widespread use of these feedings, there is insufficient evidence to suggest that enteral feeding is beneficial in terms of prolonging survival, improving quality of life, decreasing risk of pressure sores, or improving nourishment in patients with advanced dementia.46 About half of long-term care patients receiving enteral nutrition suffer from diabetes, with 44% of those being undiagnosed.47 Early identification of these patients may allow use of diabetic-specific formulas that might improve glucose control and lower HbA1c levels.48
TREATMENT OPTIONS
Several studies have demonstrated benefits of physical activity in the prevention and management of type 2 diabetes.49 Exercise improves insulin sensitivity and glucose disposal in the skeletal muscle, increases expression of nitric oxide synthase in endothelial cells, and facilitates weight control and body fitness. Elderly individuals and nursing home subjects with good functional status should be encouraged to remain active with frequent light to moderate exercise (ie, walking, age-tailored water aerobics). It may be beneficial to schedule exercise regimens following meals, as exercise can lower postmeal hyperglycemia to a greater extent that premeal exercise.50 The presence of diabetic complications, such as coronary or peripheral artery disease, advanced retinopathy, neuropathy, and diabetic foot disease, should be noted before recommending an exercise program.
Management of the elderly and nursing home residents with type 2 diabetes consists of education of the patient and caretaker(s) on metabolic goals, medical nutrition therapy, physical activity, home glucose monitoring, use of oral antidiabetic agents, and insulin administration. Medical Nutrition Therapy Medical nutrition therapy (MNT), an important component of a healthy lifestyle, remains a cornerstone of diabetes prevention and management. MNT has been shown to cause sustained reduction in HbA1c in diabetic patients. Randomized controlled community-based nutrition and exercise intervention improves glycemia and cardiovascular risk factors of diabetic patients. Promotion of weight loss in elderly REVIEW
Exercise
Migdal et al 629
Pharmacologic Therapy for Glycemic Control The choice of antidiabetic agents in type 2 diabetes should be guided by medical needs and treatment goals based on the patient’s clinical and functional status, tolerability and sideeffect profile, ease of administration and convenience, and cost. Table 2 itemizes the different interventions available for the management of elderly patients with type 2 diabetes. Most antidiabetic agents reduce HbA1c by 0.5 to 1.5. It is important to keep in mind that the risk of hypoglycemia is higher in elderly patients compared with younger patients with diabetes.51 Insulin Secretagogues Insulin secretagogues stimulate insulin secretion by the b cells by interacting with the sulfonylurea receptor. They include the sulfonylureas and the meglitinides. The sulfonylureas are commonly used because they are readily available, affordable, and have convenient dosing. Sulfonylurea monotherapy decreases HbA1c levels by approximately 1.5%.52 The major side effect with the use of sulfonylureas is the development of hypoglycemia. This can represent a significant problem in elderly individuals because of altered counterregulatory hormone response to hypoglycemia, decreased renal function, poor or irregular caloric intake, and polypharmacy.53 When individual sulfonylurea agents are considered, drugs with longer time-action characteristics have an increased potential for causing hypoglycemia. Glyburide (glibenclamide) treatment is associated with the highest rate of hypoglycemic events with a reported incidence of 16.6% in elderly patients, a rate that is twice that of glipizide and fivefold greater than the rate for tolbutamide.29 The development of hypoglycemia may have significant impact on morbidity and mortality in individuals with type 2 diabetes.54 The recently reported ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study evaluated links between severe hypoglycemia and adverse outcomes in 11,140 patients with type 2 diabetes mellitus. The study compared intensive glycemic management (target HbA1c \6.5%) with standard glucoselowering strategies (target HbA1c \7.5%). The overall risk of severe hypoglycemia (blood glucose \ 50 mg/dL or 2.8 mmol/L), over a median follow-up period of 5 years, was 2.1% of the patients including 2.7% of patients in the intensive regimen and 1.5% of patients treated with standard regimen. Severe hypoglycemia was associated with an increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67).54 The authors concluded that severe hypoglycemia, like hyperglycemia, is a marker of poor outcome but not necessarily a direct cause of mortality. A systematic review of the literature also reported a high mortality rate among patients with sulfonylurea-induced hypoglycemia ranging between 7% and 10%.55 Meglitinides, nateglinide and repaglinide, are nonsulfonylurea insulin secretagogues with similar mechanism of action 630 Migdal et al
as sulfonylureas. Meglitinides are rapidly absorbed and cleared through hepatic mechanism. These agents are typically administered 30 minutes before meals and work primarily on postprandial glucose levels, leading to an HbA1c decrease of approximately 1%. Common side effects include headaches, weight gain, diarrhea, and hypoglycemia. Despite the risk of hypoglycemia, these agents are appealing in the elderly because of their short half-lives. Metformin Metformin is the most commonly used antidiabetic drug for the treatment of type 2 diabetes, but special concerns limit its use in elderly individuals. Metformin decreases gluconeogenesis and increases glycogenolysis leading to an HbA1c decrease of approximately 1.5%. Treatment with metformin has been associated with decreased risk of cardiovascular mortality and diabetes-related death compared with other oral agents or placebo.56,57 In addition, metformin has a low risk of hypoglycemia when used as monotherapy and absence of weight gain.58 Assessment of renal function should be assessed before initiation of metformin therapy, as patients with glomerular filtration rate lower than 60 mL/min may be at risk of developing lactic acidosis.59 Contraindications to the use of metformin include impaired hepatic function, congestive heart failure, renal failure (glomerular filtration rate \ 60 mL/min), pulmonary disease with chronic hypoxia, and metabolic acidosis. In addition, metformin should be withheld in hospitalized patients with severe acute illness and in those undergoing radio contrast studies or surgery, because of increased risk of lactic acidosis.60 Thiazolidinediones Thiazolidinediones act as peroxisome proliferatoractivated receptor (PPAR)-g agonists and regulate carbohydrate and lipid metabolism, enhance tissue response to insulin, and have favorable effects on endothelial dysfunction and inflammation.61 HbA1c can be expected to decrease 0.9% to 1.5% with low risk of hypoglycemic events when used as monotherapy.62 Because thiazolidinediones are metabolized through the liver, impaired renal function is not a contraindication; however, their use can cause fluid retention and peripheral edema, weight gain, and heart failure.63 The ADOPT study showed that rosiglitazone caused edema in 14.1% of patients compared with 7.2% for those patients on metformin.64 Similarly, a study of thiazolidinedione therapy in patients older than 60 years reported that rosiglitazone therapy is associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other oral hypoglycemic agents.65 Several studies and meta-analyses have indicated that rosiglitazone is associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes.66 The Food and Drug Administration recently restricted access to rosiglitazone,67 limiting its use to patients who are unable to achieve glycemic control using other medications. The European Medicines Agency also took regulatory action on rosiglitazone by JAMDA – November 2011
REVIEW
Table 2. Antidiabetic Agents for the Treatment of Diabetes in Elderly Individuals
Migdal et al 631
Name of Drug
Mechanism of action
Advantage
Disadvantage
Sulfonylureas (glipizide, glimepiride, glyburide)
Stimulate insulin secretion by blocking potassium channels in pancreatic b-cells
Decrease HbA1c 1%–2% Short lag time before response Once-daily dosing Low cost
Meglitinides(repaglinide, nateglinide)
Stimulate insulin secretion by blocking potassium channels in pancreatic b-cells
Biguanides (metformin)
Improve insulin sensitivity Decrease reduces hepatic gluconeogenesis and endogenous glucose production Improve peripheral glucose utilization
Decrease HbA1c 0.5%–1% Short half-life resulting in lower risk of hypoglycemia, better postprandial glycemic control than sulfonylureas Decrease HbA1c 1%–2% Low risk of hypoglycemia Long-term safety record Weight neutral Low cost Diabetes prevention Improvement of atherogenic dyslipidemia Reduce risk of cardiovascular events Reduce risk of certain malignancies
Risk of hypoglycemia May cause weight gain Decreased response over time— primary failure rate of 20% , secondary failure about 5% to 10% per year Risk of hypoglycemia Multiple daily dosing Less potent and higher cost than sulfonylureas
Thiazolidinediones (pioglitazone, rosiglitazone)
Improve insulin sensitivity in peripheral tissues
Alpha glucosidase inhibitors (acarbose, miglitol)
Reduce digestion of carbohydrates in the small intestine
Dipeptidyl-peptidase 4 (DPP-4) inhibitors (sitagliptin, saxagliptin)
Improve insulin secretion and suppresses release of glucagon
Glucagonlike peptide 1 (GLP-1) agonists (exenatide, liraglutide)
Augment insulin release and suppresses release of glucagon Delay gastric emptying
Decrease HbA1c 1%–2% Low risk of hypoglycemia Diabetes prevention Improvement of atherogenic dyslipidemia Can be used in patients with renal failure Decrease HbA1c 0.5%–1.0% Low rate of hypoglycemia Reduce postprandial hyperglycemia Diabetes prevention Decrease HbA1c 0.5%–1.0% Low rate of hypoglycemia Reduce postprandial hyperglycemia Can be used in renal insufficiency Decrease HbA1c 0.8%–1.5% Low rate of hypoglycemia Reduce postprandial hyperglycemia Weight loss
Anorexia and gastrointestinal side effects Risk of lactic acidosis Contraindicated in patients with impaired renal function (glomerular filtration rate \60 mL/ min or serum creatinine .1.5 mg/dL in males and .1.4 mg/dL in females), congestive heart failure requiring treatment with pharmacologic agents, perioperative period and use of imaging studies using iodinated media Weight gain Fluid retention (edema) and increased risk of congestive heart failure Increased risk of bone fractures Increased risk of ischemic heart disease (rosiglitazone) Flatulence Contraindicated in patients with inflammatory bowel disease, partial bowel obstruction, and severe renal or hepatic disease Increase in upper respiratory tract infections Risk of pancreatitis Cost Gastrointestinal (nausea, vomiting and diarrhea) Injectable Cost
suspending the marketing authorization for the rosiglitazonecontaining antidiabetes medicines. Alpha-1 Glycosidase Inhibitors Alpha-1 glycosidase inhibitors slow carbohydrate absorption by blocking the action of brush border enzymes (alpha glucosidases), as well as increasing glucagonlike peptide-1 (GLP-1) levels.68 There are 2 available drugs: miglitol and acarbose. The primary effect of these agents is on postprandial hyperglycemia. The effect on HbA1c when used as monotherapy is modest with an average reduction of 0.5% to 1.0%. The benefit of using these agents is the lack of associated hypoglycemia and limited drug interaction.69 To be effective, alpha glucosidase inhibitors must be administered with the first bite of food. To avoid discontinuation of the medication because of the common gastrointestinal side effects (flatus, abdominal pain, abdominal cramps), it is important to initiate administration of these medications at very low doses. Dipeptidyl Peptidase-IV Inhibitors GLP-1 is an incretin produced in the small intestine that has various effects on glucose metabolism, including stimulating insulin secretion and inhibiting glucagon secretion. Dipeptidyl peptidase IV (DDP-IV) breaks down GLP-1, so by inhibiting DDP-IV, the action of GLP-1 can be prolonged.70 DDP-IV inhibitors improve fasting and postprandial glucose levels by stimulating insulin secretion and inhibiting glucagon secretion. These drugs are well tolerated with few side effects and are approved for use as monotherapy or combined with metformin, thiazolidinediones, or sulfonylurea medications. HbA1c reductions are approximately 1%. Unlike many other oral agents, these medications can be used in patients with impaired renal function. These drugs are attractive in elderly patients because of their limited side effects and low rate of hypoglycemia53; however, these agents are expensive, which may present a significant burden for individuals with limited incomes or without a pharmacy benefit plan. GLP-1 Analogs GLP-1 analogs mimic the action of GLP-1 and stimulate insulin production, inhibit hepatic glucose production, and delay gastric emptying. HbA1c can be expected to decrease 1% with the use of these agents. The safety of GLP1 analogs has not been determined in prospective randomized trials in elderly individuals; however, their use may be associated with nausea, gastrointestinal distress, and weight loss, which could be detrimental in elderly individuals who are already at risk for malnutrition.53 These agents should also be used with caution in patients with hepatic failure or severe renal impairment. Insulin In elderly patients with type 2 diabetes, insulin therapy is indicated during severe hyperglycemia despite treatment with oral agents or during intercurrent illness, perioperative period, and severe liver or renal disease. The most common indication is as add-on therapy in patients with type 2 diabe632 Migdal et al
tes who have experienced primary or secondary failure to oral antidiabetic agents. Insulin is frequently recommended for diabetic patients in long-term care facilities.71,72 Various insulin preparations are available, including short-acting insulin (lispro, glulisine, and aspart), intermediate-acting insulin (neutral protamine hagedorn, and long-acting insulin analogs (glargine and detemir). Long-acting analogs are commonly favored in elderly patients because of the peakless profile, which reduces the frequency of hypoglycemic events compared with intermediate-acting (neutral protamine hagedorn) insulin.18 In patients older than 65 years, the use of insulin glargine in combination with oral agents results in greater reduction in HbA1C and fasting blood glucose concentration and in a lower rate of hypoglycemic events compared with treatment with premixed 70/30 insulin.73,74 Once-daily dosing of basal insulin analogs increases compliance and may allow greater treatment flexibility, which is essential in elderly patients who often have erratic eating habits.74 One concern in the treatment of diabetes in nursing home residents is the high use of the sliding scale insulin (SSI) regimen as the sole means to control glucose levels. Among newly admitted patients, 54% were started on SSI and another 33% were later switched to SSI.75 This regimen is not physiological and is reactive rather than proactive, which allows periods of hyperglycemia to persist for long periods.76 Basal bolus insulin regimens have been shown to significantly lower glucose levels compared with SSI without any increased risk of severe hypoglycemia.77 Therefore, nursing home residents who are being treated with SSI regimens might be better served by changing to a more physiological regimen with basal insulin.75 CONCLUSION Evidence-based guidelines for diabetes control tend to emphasize safe and reasonable glycemic control in the elderly population. Although glucose control may be beneficial in decreasing diabetic complications, the risk of hypoglycemic events with intensive glucose control, which can precipitate complications, such as falls and cardiovascular events, may be detrimental in elderly individuals. A few retrospective studies in elderly patients have reported on the quality of diabetes care and glycemic control in long-term care facilities; however, no randomized clinical trials have focused on benefits of glycemic control on outcome and quality of life in elderly individuals and in nursing home residents. Future research is needed to address the following important clinical questions in elderly subjects: What is the optimal glycemic control? What is the best insulin regimen? What is the role of insulin analogs versus human insulin in preventing diabetic complications? Until these studies become available, safe and moderate glycemic control, minimizing the risk of hypoglycemic events, is indicated in elderly individuals and nursing home populations. REFERENCES References available at www.jamda.com with your JAMDA login. JAMDA – November 2011
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27. Maurer MS, Burcham J, Cheng H. Diabetes mellitus is associated with an increased risk of falls in elderly residents of a long-term care facility. J Gerontol A Biol Sci Med Sci 2005;60:1157–1162. 28. McNabney MK, Pandya N, Iwuagwu C, et al. Differences in diabetes management of nursing home patients based on functional and cognitive status. J Am Med Dir Assoc 2005;6:375–382. 29. Chelliah A, Burge MR. Hypoglycaemia in elderly patients with diabetes mellitus: Causes and strategies for prevention. Drugs Aging 2004;21: 511–530. 30. Joseph J, Koka M, Aronow WS. Prevalence of a hemoglobin A1c less than 7.0%, of a blood pressure less than 130/80 mm Hg, and of a serum low-density lipoprotein cholesterol less than 100 mg/dL in older patients with diabetes mellitus in an academic nursing home. J Am Med Dir Assoc 2008;9:51–54. 31. Koka M, Joseph J, Aronow WS. Prevalence of adequate and of optimal control of serum low-density lipoprotein cholesterol in an academic nursing home. J Am Med Dir Assoc 2007;8:604–606. 32. Koka M, Joseph J, Aronow WS. Adequacy of control of hypertension in an academic nursing home. J Am Med Dir Assoc 2007;8:538–540. 33. Messinger-Rapport BJ, Thomas DR, Gammack JK, Morley JE. Clinical update on nursing home medicine: 2008. J Am Med Dir Assoc 2008;9: 460–475. 34. Holt RM, Schwartz FL, Shubrook JH. Diabetes care in extended-care facilities: Appropriate intensity of care? Diabetes Care 2007;30: 1454–1458. 35. Feldman SM, Rosen R, DeStasio J. Status of diabetes management in the nursing home setting in 2008: A retrospective chart review and epidemiology study of diabetic nursing home residents and nursing home initiatives in diabetes management. J Am Med Dir Assoc 2009;10:354–360. 36. Meyers RM, Reger L. Diabetes management in long-term care facilities: A practical guide. J Am Med Dir Assoc 2009;10:589. 37. Sjoblom P, Tengblad A, Lofgren UB, et al. Can diabetes medication be reduced in elderly patients? An observational study of diabetes drug withdrawal in nursing home patients with tight glycaemic control. Diabetes Res Clin Pract 2008;82:197–202. 38. Magaziner J, German P, Zimmerman SI, et al. The prevalence of dementia in a statewide sample of new nursing home admissions aged 65 and older: Diagnosis by expert panel. Epidemiology of Dementia in Nursing Homes Research Group. Gerontologist 2000;40:663–672. 39. Quinn CC, Gruber-Baldini AL, Port CL, et al. The role of nursing home admission and dementia status on care for diabetes mellitus. J Am Geriatr Soc 2009;57:1628–1633. 40. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003;26:1902–1912. 41. Kyrou I, Tsigos C. Obesity in the elderly diabetic patient: Is weight loss beneficial? No. Diabetes Care 2009;32:S403–S409. 42. Rodriguez-Saldana J, Morley JE, Reynoso MT, et al. Diabetes mellitus in a subgroup of older Mexicans: Prevalence, association with cardiovascular risk factors, functional and cognitive impairment, and mortality. J Am Geriatr Soc 2002;50:111–116. 43. Wedick NM, Barrett-Connor E, Knoke JD, Wingard DL. The relationship between weight loss and all-cause mortality in older men and women with and without diabetes mellitus: the Rancho Bernardo study. J Am Geriatr Soc 2002;50:1810–1815. 44. Tariq SH, Karcic E, Thomas DR, et al. The use of a no-concentratedsweets diet in the management of type 2 diabetes in nursing homes. J Am Diet Assoc 2001;101:1463–1466. 45. Lopez RP, Amella EJ, Strumpf NE, et al. The influence of nursing home culture on the use of feeding tubes. Arch Intern Med 2010;170:83–88. 46. Sampson EL, Candy B, Jones L. Enteral tube feeding for older people with advanced dementia. Cochrane Database Syst Rev 2009;(2). CD007209. 47. Arinzon Z, Shabat S, Shuval I, et al. Prevalence of diabetes mellitus in elderly patients received enteral nutrition long-term care service. Arch Gerontol Geriatr 2008;47:383–393. 48. Vaisman N, Lansink M, Rouws CH, et al. Tube feeding with a diabetesspecific feed for 12 weeks improves glycaemic control in type 2 diabetes patients. Clin Nutr 2009;28:549–555. 49. Pi-Sunyer X, Blackburn G, Brancati FL, et al. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: Migdal et al
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One-year results of the look AHEAD trial. Diabetes Care 2007;30: 1374–1383. Colberg SR, Zarrabi L, Bennington L, et al. Postprandial walking is better for lowering the glycemic effect of dinner than pre-dinner exercise in type 2 diabetic individuals. J Am Med Dir Assoc 2009;10:394–397. Miller CD, Phillips LS, Ziemer DC, et al. Hypoglycemia in patients with type 2 diabetes mellitus. Arch Intern Med 2001;161:1653–1659. UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853. Silverberg AB, Ligaray KP. Oral diabetic medications and the geriatric patient. Clin Geriatr Med 2008;24:541–549, viii. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risks of vascular events and death. N Engl J Med 2010;363:1410–1418. Seltzer HS. Drug-induced hypoglycemia. A review of 1418 cases. Endocrinol Metab Clin North Am 1989;18:163–183. Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med 2008; 168:2070–2080. UK Prospective Diabetes Study (UKPDS) Group. Group U. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352: 854–865. Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res 1998;6:47–53. Squibb B-M. Glucophage Package insert. 2009. Available at: http:// packageinserts.bms.com/pi/pi_glucophage.pdf. Accessed December 2010. Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13:1–68. Albertini JP, McMorn SO, Chen H, et al. Effect of rosiglitazone on factors related to endothelial dysfunction in patients with type 2 diabetes mellitus. Atherosclerosis 2007;195:e159–e166. Oiknine R, Mooradian AD. Drug therapy of diabetes in the elderly. Biomed Pharmacother 2003;57:231–239. Day C. Thiazolidinediones: A new class of antidiabetic drugs. Diabet Med 1999;16:179–192.
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64. Karalliedde J, Buckingham RE. Thiazolidinediones and their fluidrelated adverse effects: Facts, fiction and putative management strategies. Drug Saf 2007;30:741–753. 65. Lipscombe LL, Gomes T, Levesque LE, et al. Thiazolidinediones and cardiovascular outcomes in older patients with diabetes. JAMA 2007;298: 2634–2643. 66. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356: 2457–2471. 67. Woodcock J, Sharfstein JM, Hamburg M. Regulatory action on rosiglitazone by the US Food and Drug Administration. N Engl J Med 2010;363: 1489–1491. 68. Scheen AJ. Clinical efficacy of acarbose in diabetes mellitus: A critical review of controlled trials. Diabetes Metab 1998;24:311–320. 69. Rabasa-Lhoret R, Chiasson JL. Potential of alpha-glucosidase inhibitors in elderly patients with diabetes mellitus and impaired glucose tolerance. Drugs Aging 1998;13:131–143. 70. Mazza AD, Morley JE. Update on diabetes in the elderly and the application of current therapeutics. J Am Med Dir Assoc 2007;8:489–492. 71. Summary of revisions for the 2009 Clinical Practice Recommendations. Diabetes Care 2009;32:S3–S5. 72. American Medical Directors Association. Diabetes management in the long-term care setting. Columbia, MD: American Medical Directors Association; 2007. 73. Janka HU, Plewe G, Busch K. Combination of oral antidiabetic agents with basal insulin versus premixed insulin alone in randomized elderly patients with type 2 diabetes mellitus. J Am Geriatr Soc 2007;55: 182–188. 74. Pandya N, Nathanson E. Managing diabetes in long-term care facilities: Benefits of switching from human insulin to insulin analogs. J Am Med Dir Assoc 2010;11:171–178. 75. Pandya N, Thompson S, Sambamoorthi U. The prevalence and persistence of sliding scale insulin use among newly admitted elderly nursing home residents with diabetes mellitus. J Am Med Dir Assoc 2008;9: 663–669. 76. Michota F. What are the disadvantages of sliding-scale insulin? J Hosp Med 2007;2:20–22. 77. Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basalbolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care 2007;30:2181–2186.
JAMDA – November 2011
Update on Diabetes in the Elderly and in Nursing Home Residents Alexandra Migdal, BS, Shadi S. Yarandi, MD, Dawn Smiley, MD, and Guillermo E. Umpierrez, MD
Diabetes is common in the elderly population and in nursing home residents. More than 20% of adults aged 65 to 75 years and 40% of adults older than 80 years suffer from diabetes. Physiological changes in elderly individuals, such as decreased physical activity, abdominal obesity, and increased inflammatory state, increase insulin resistance in peripheral tissue and reduce glucose-dependent insulin release, leading to carbohydrate intolerance and diabetes. The clinical presentation in the elderly and nursing home residents is frequently guided by the high rate of comorbidities such as hypertension, depression, and cardiovascular diseases. Treatment recommendations for glycemic control in elderly ambulatory patients are similar to those in long-term care facilities. Healthy patients with diabetes should aim for nearnormal fasting plasma glucose and an HbA1C of about 7%; however, treatment goals must be individ-
ualized in patients with impaired cognitive and physical ability, reduced life expectancy, and heavy burden of comorbid disease. Elderly individuals and nursing home residents are at increased risk of hypoglycemia during pharmacological treatment. In general, a conservative and stepwise approach to the treatment of the elderly patient with diabetes is suggested. Treatment may be initiated with dietary and physical activity modification and with a single oral agent, followed by a combination of oral agents and insulin therapy if needed. Evidence from clinical trials indicates that improving glycemic control, as well as cardiovascular risk factors, reduces morbidity and mortality in older individuals with diabetes. (J Am Med Dir Assoc 2011; 12: 627–632)
The prevalence of diabetes in the United States is increasing exponentially. The Centers for Disease Control and Prevention recently estimated that 8.3% of the total population has diabetes,1 and forecasted that the incidence will increase 200% by 2050.2 Diabetes disproportionally affects the elderly, with more than 20% of adults aged 65 to 75 years and 40% of adults older than 80 years suffering from diabetes.3,4 The prevalence is higher among residents of long-term care facilities, with approximately 30% having a diagnosis of diabetes.5–7 As life expectancy increases, it is expected that the prevalence of diabetes in the elderly will continue to increase.4,8 The total estimated cost of diabetes care in 2007 was $174 billion, including $116 billion in excess medical expenditures
and $58 billion in reduced national productivity.9 People with diabetes, on average, have medical expenditures that are approximately 2.3 times higher than what expenditures would be in the absence of diabetes.9 Inpatient diabetes care accounts for 50% of total cost. The estimated annual cost for providing nursing home care for patients with diabetes is about $56 billion, more than twice the cost for inpatient services for patients with diabetes.9 The impact and health benefits of improving diabetes treatment in the elderly and in nursing home subjects is not known; however, it is reasonable to speculate that the economic value of improvement in health status will be similar to populations with type 2 diabetes.10
Keywords: Diabetes; long-term care facilities; nursing home; insulin; hypoglycemia
PATHOPHYSIOLOGY Department of Medicine, Division of Endocrinology at Emory University, Atlanta, GA (A.M., S.S.Y., D.S., G.E.U.). G.E.U. is supported by research grants from the American Diabetes Association (7–03-CR-35), and National Institutes of Health: R03 DK073190–01 and General Clinical Research Center Grant M01 RR-00039. Address correspondence to Guillermo E. Umpierrez, MD, Endocrinology Fellowship Program, Emory University School of Medicine , 49 Jesse Hill Jr Drive, Atlanta, GA 30303. E-mail: [email protected]
Published by Elsevier Inc. on behalf of the American Medical Directors Association, Inc. DOI:10.1016/j.jamda.2011.02.010 REVIEW
Physiological changes in elderly adults contribute to the increased prevalence of carbohydrate intolerance and diabetes. Aging is associated with reduced glucose-dependent insulin release and increased insulin resistance in peripheral tissues, primarily in muscle and adipose tissue.11 Both basal and first-phase insulin release are affected; however, differences seem to exist between lean and obese elderly patients with diabetes. Lean elderly patients have a primary defect in glucoseinduced insulin release, whereas obese patients are more likely to have a defect in insulin resistance.12 Interestingly, Migdal et al 627
neither group has increased fasting hepatic glucose production, which is often seen in younger adults.13 Increasing age is also associated with abdominal obesity and decreased physical activity, both of which are associated with reduced insulin sensitivity.14 Abdominal obesity is associated with increased circulating levels of free fatty acids (FFAs), inflammatory cytokines (tumor necrosis factor-a, interleukin [IL]-6, monocyte chemoattractant protein [MCP]-1, and IL-8), and the multifunctional proteins leptin and osteopontin.15 Aging is also associated with chronic low-grade inflammation and higher levels of tumor necrosis factor-a and IL-6, which have been described to be indicators of morbidity in elderly individuals.15,16 In addition, elderly patients are also more likely to receive medications that exacerbate hyperglycemia, including diuretics, beta-blockers, nonsteroidal anti-inflammatory drugs, and glucocorticoids. CLINICAL PRESENTATION Typical symptoms of hyperglycemia, such as polyuria and polydypsia, are less common in elderly patients because the renal threshold for glucosuria increases with age and the thirst mechanisms are more likely to be impaired. Elderly patients often present with symptoms of weight loss, fatigue, and nocturia. Frequently, these symptoms tend to go unnoticed or are attributed to old age, failure to thrive, confusion, and incontinence.17 Because of the atypical presentation, 25% to 41% of elderly individuals with diabetes remain undiagnosed.18 BURDEN OF DISEASE The burden of diabetes in the elderly and in nursing home residents is significant. Diabetic residents of nursing homes are more often transferred from acute care hospitals, have longer lengths of stay, take more medications, and have higher odds of having emergency department visits than nondiabetic residents.17,19 Compared with nondiabetic patients, diabetic patients have significantly greater incidence of hypertension, depression, heart failure, cerebrovascular events, kidney disease, visual impairment, and foot problems (including amputations), and require more staff assistance for activities of daily living. Up to 80% of nursing home residents with diabetes have coexisting cardiovascular disease, 56% to 67% have hypertension, and 69% suffer from 2 or more chronic conditions in addition to diabetes.20,21 Patients with diabetes have increased excess mortality at every age group compared to nondiabetic subjects.22 The American Geriatrics Society has reported that elderly persons with diabetes have higher rates of disability and premature death compared with individuals without diabetes.23 Poorly controlled diabetes is associated with increased cognitive decline, along with higher occurrence of infections and pressure ulcers.24,25 Diabetes is also an independent risk factor for falls in elderly nursing home residents and diabetic residents suffer more fractures than nondiabetic patients.26,27 GLYCEMIC TARGET Management of diabetes is challenging in the geriatric population in long-term care facilities. General goals of 628 Migdal et al
treatment for elderly diabetic patients include avoiding symptoms and complications of hyperglycemia and hypoglycemia, minimizing or delaying microvascular and macrovascular complications, and maximizing daily function.23 Emphasis should also be placed on reducing pain, infections, and nocturia; improving incontinence; preventing injurious falls; and limiting cognitive impairment.28 Preventing hypoglycemia can be problematic in elderly patients who are at increased risk because of impaired renal function, which modifies drug elimination, as well as the use of multiple medications, which places patients at risk for drug-associated hypoglycemia.29 The American Diabetes Association recommends similar treatment goals for elderly and younger patients with diabetes (Table 1). Glycemic targets include an HbA1c of \7%, a fasting blood glucose between 70 and 130 mg/dL, and a postprandial blood glucose less than 180 mg/dL, as well as a nutrition and exercise program, antiplatelet treatment, and blood pressure and lipid control. The American Geriatrics Society emphasizes that the target HbA1c should not be a concrete number, but instead should be individualized based on the patient’s functional status. Those with good functional status should be maintained at HbA1c lower than 7%, whereas those patients who are frail, have multiple comorbidities or increased risk of hypoglycemia, or who have a life expectancy of fewer than 5 years should be maintained at a less stringent target of lower than 8%.14,23 These guidelines, although designed to address outpatient management, also apply to nursing home residents. Several studies have reported on adherence to treatment guidelines in nursing home residents. One study in diabetic residents from an academic nursing home reported a blood pressure lower than 130/80 in 84% and serum low-density lipoprotein lower than 100 mg/dL in 89% of residents.30 These results are comparable to levels of control seen among nondiabetic residents, in whom 80% of residents have an lowdensity lipoprotein level lower than 100 mg/dL and 85% have an adequate blood pressure.31,32 Aspirin use is reported in only 42% of diabetic residents.33 Glycemic control is achieved in most residents, with 67% of subjects meeting HbA1c goals of lower than 7%, and up to 94% meeting the American Geriatrics Society guideline of HbA1c lower than 8%.34–36 Despite the seemingly good control of blood glucose among nursing home residents, only 15% of facilities have an established algorithm for treating patients with diabetes. Just 30.8% of facilities have a policy for blood glucose monitoring and only 7.1% of facilities have a policy in place regarding frequency of HbA1c testing, indicating that there is much room for improvement in the management and quality of care for diabetic patients in nursing homes.35 In addition, it should be noted that hypoglycemic events are more common in elderly individuals and are reported in up to 48% of nursing home residents.37 Fortunately, hospitalization for hypoglycemia is required in only 1% of residents.35 Cognitive status of individual nursing home residents may influence the physician’s approach to diabetes management. It is estimated that nearly 50% of nursing home residents have dementia, regardless of diabetes status.38,39 Those residents with functional and cognitive impairment are less likely JAMDA – November 2011
Table 1.
Summary of Recommendations for Diabetic Care in the Elderly Population
American Diabetes Association Functional, cognitively intact, and with significant life expectancy Impaired cognitive and limited life expectancy
American Geriatrics Society Functional, cognitively intact, and with significant life expectancy Impaired cognitive and limited life expectancy
Fasting Glucose, mg/dL
Random Glucose, mg/dL
HbA1C, %
70–130
\180
\7%
Not determined, but prevent significant hyperglycemia (blood glucose .180 mg/dL)
Not determined
Not determined; levels to be individualized based on functional status and life expectancy
Not determined
\180
\7%
Not determined
Not determined
\8% for persons with life expectancy of less than 5 years
to be placed on a special diet, have monitoring of lipid panels, or have routine ophthalmologic exams compared with residents without impairment. However, there were no differences in the frequency of glucose monitoring, HbA1c measurement, use of sliding scale insulin, or referral for routine podiatry examination.28 For some elderly patients, the risks of intensive glucose control outweigh the benefits. Although improved glycemic control has been associated with lower rates of stroke, blindness, nephropathy, cardiovascular disease, and cognitive dysfunction in elderly individuals,23 tight glycemic control in the elderly and nursing home residents may not be attainable or desirable because of the risk of hypoglycemia,13 and the increased risk of falls and cardiovascular events with episodes of hypoglycemia.13 The following age-related changes increase the risk of hypoglycemia in the elderly: decreased renal function, slowed hormonal regulation and counter-regulation, suboptimal hydration, variable appetite and nutritional intake, polypharmacy, and slowed intestinal functioning (absorption).23 For these reasons, treatment goals must be individualized in elderly patients with reduced cognitive and physical ability, reduced life expectancy, and with heavy burden of comorbid disease.37 In elderly patients, avoidance of hypoglycemia has great potential to enhance the quality of life and to optimize compliance with treatment than in any other age group.40
patients, however, is not routinely recommended because of the increased risk of loss of lean body mass, malnutrition, and dehydration.41 In fact, most elderly diabetic patients are not overweight.42 Weight loss among elderly patients has actually been associated with increased mortality.43 Therefore, it is recommended to focus on medical management of diabetes rather than diet restriction in elderly individuals who are already at risk for poor nutritional status.44 Despite evidence that restrictive diets can be detrimental in elderly patients, Feldman et al35 have shown that more than 50% of long-term care residents had dietary restrictions, which may contribute to malnutrition in this population. Tube feedings are commonly used among nursing home patients. Among patients with advanced cognitive impairment, up to 40% are fed using enteral feedings.45 Despite the widespread use of these feedings, there is insufficient evidence to suggest that enteral feeding is beneficial in terms of prolonging survival, improving quality of life, decreasing risk of pressure sores, or improving nourishment in patients with advanced dementia.46 About half of long-term care patients receiving enteral nutrition suffer from diabetes, with 44% of those being undiagnosed.47 Early identification of these patients may allow use of diabetic-specific formulas that might improve glucose control and lower HbA1c levels.48
TREATMENT OPTIONS
Several studies have demonstrated benefits of physical activity in the prevention and management of type 2 diabetes.49 Exercise improves insulin sensitivity and glucose disposal in the skeletal muscle, increases expression of nitric oxide synthase in endothelial cells, and facilitates weight control and body fitness. Elderly individuals and nursing home subjects with good functional status should be encouraged to remain active with frequent light to moderate exercise (ie, walking, age-tailored water aerobics). It may be beneficial to schedule exercise regimens following meals, as exercise can lower postmeal hyperglycemia to a greater extent that premeal exercise.50 The presence of diabetic complications, such as coronary or peripheral artery disease, advanced retinopathy, neuropathy, and diabetic foot disease, should be noted before recommending an exercise program.
Management of the elderly and nursing home residents with type 2 diabetes consists of education of the patient and caretaker(s) on metabolic goals, medical nutrition therapy, physical activity, home glucose monitoring, use of oral antidiabetic agents, and insulin administration. Medical Nutrition Therapy Medical nutrition therapy (MNT), an important component of a healthy lifestyle, remains a cornerstone of diabetes prevention and management. MNT has been shown to cause sustained reduction in HbA1c in diabetic patients. Randomized controlled community-based nutrition and exercise intervention improves glycemia and cardiovascular risk factors of diabetic patients. Promotion of weight loss in elderly REVIEW
Exercise
Migdal et al 629
Pharmacologic Therapy for Glycemic Control The choice of antidiabetic agents in type 2 diabetes should be guided by medical needs and treatment goals based on the patient’s clinical and functional status, tolerability and sideeffect profile, ease of administration and convenience, and cost. Table 2 itemizes the different interventions available for the management of elderly patients with type 2 diabetes. Most antidiabetic agents reduce HbA1c by 0.5 to 1.5. It is important to keep in mind that the risk of hypoglycemia is higher in elderly patients compared with younger patients with diabetes.51 Insulin Secretagogues Insulin secretagogues stimulate insulin secretion by the b cells by interacting with the sulfonylurea receptor. They include the sulfonylureas and the meglitinides. The sulfonylureas are commonly used because they are readily available, affordable, and have convenient dosing. Sulfonylurea monotherapy decreases HbA1c levels by approximately 1.5%.52 The major side effect with the use of sulfonylureas is the development of hypoglycemia. This can represent a significant problem in elderly individuals because of altered counterregulatory hormone response to hypoglycemia, decreased renal function, poor or irregular caloric intake, and polypharmacy.53 When individual sulfonylurea agents are considered, drugs with longer time-action characteristics have an increased potential for causing hypoglycemia. Glyburide (glibenclamide) treatment is associated with the highest rate of hypoglycemic events with a reported incidence of 16.6% in elderly patients, a rate that is twice that of glipizide and fivefold greater than the rate for tolbutamide.29 The development of hypoglycemia may have significant impact on morbidity and mortality in individuals with type 2 diabetes.54 The recently reported ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study evaluated links between severe hypoglycemia and adverse outcomes in 11,140 patients with type 2 diabetes mellitus. The study compared intensive glycemic management (target HbA1c \6.5%) with standard glucoselowering strategies (target HbA1c \7.5%). The overall risk of severe hypoglycemia (blood glucose \ 50 mg/dL or 2.8 mmol/L), over a median follow-up period of 5 years, was 2.1% of the patients including 2.7% of patients in the intensive regimen and 1.5% of patients treated with standard regimen. Severe hypoglycemia was associated with an increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67).54 The authors concluded that severe hypoglycemia, like hyperglycemia, is a marker of poor outcome but not necessarily a direct cause of mortality. A systematic review of the literature also reported a high mortality rate among patients with sulfonylurea-induced hypoglycemia ranging between 7% and 10%.55 Meglitinides, nateglinide and repaglinide, are nonsulfonylurea insulin secretagogues with similar mechanism of action 630 Migdal et al
as sulfonylureas. Meglitinides are rapidly absorbed and cleared through hepatic mechanism. These agents are typically administered 30 minutes before meals and work primarily on postprandial glucose levels, leading to an HbA1c decrease of approximately 1%. Common side effects include headaches, weight gain, diarrhea, and hypoglycemia. Despite the risk of hypoglycemia, these agents are appealing in the elderly because of their short half-lives. Metformin Metformin is the most commonly used antidiabetic drug for the treatment of type 2 diabetes, but special concerns limit its use in elderly individuals. Metformin decreases gluconeogenesis and increases glycogenolysis leading to an HbA1c decrease of approximately 1.5%. Treatment with metformin has been associated with decreased risk of cardiovascular mortality and diabetes-related death compared with other oral agents or placebo.56,57 In addition, metformin has a low risk of hypoglycemia when used as monotherapy and absence of weight gain.58 Assessment of renal function should be assessed before initiation of metformin therapy, as patients with glomerular filtration rate lower than 60 mL/min may be at risk of developing lactic acidosis.59 Contraindications to the use of metformin include impaired hepatic function, congestive heart failure, renal failure (glomerular filtration rate \ 60 mL/min), pulmonary disease with chronic hypoxia, and metabolic acidosis. In addition, metformin should be withheld in hospitalized patients with severe acute illness and in those undergoing radio contrast studies or surgery, because of increased risk of lactic acidosis.60 Thiazolidinediones Thiazolidinediones act as peroxisome proliferatoractivated receptor (PPAR)-g agonists and regulate carbohydrate and lipid metabolism, enhance tissue response to insulin, and have favorable effects on endothelial dysfunction and inflammation.61 HbA1c can be expected to decrease 0.9% to 1.5% with low risk of hypoglycemic events when used as monotherapy.62 Because thiazolidinediones are metabolized through the liver, impaired renal function is not a contraindication; however, their use can cause fluid retention and peripheral edema, weight gain, and heart failure.63 The ADOPT study showed that rosiglitazone caused edema in 14.1% of patients compared with 7.2% for those patients on metformin.64 Similarly, a study of thiazolidinedione therapy in patients older than 60 years reported that rosiglitazone therapy is associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other oral hypoglycemic agents.65 Several studies and meta-analyses have indicated that rosiglitazone is associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes.66 The Food and Drug Administration recently restricted access to rosiglitazone,67 limiting its use to patients who are unable to achieve glycemic control using other medications. The European Medicines Agency also took regulatory action on rosiglitazone by JAMDA – November 2011
REVIEW
Table 2. Antidiabetic Agents for the Treatment of Diabetes in Elderly Individuals
Migdal et al 631
Name of Drug
Mechanism of action
Advantage
Disadvantage
Sulfonylureas (glipizide, glimepiride, glyburide)
Stimulate insulin secretion by blocking potassium channels in pancreatic b-cells
Decrease HbA1c 1%–2% Short lag time before response Once-daily dosing Low cost
Meglitinides(repaglinide, nateglinide)
Stimulate insulin secretion by blocking potassium channels in pancreatic b-cells
Biguanides (metformin)
Improve insulin sensitivity Decrease reduces hepatic gluconeogenesis and endogenous glucose production Improve peripheral glucose utilization
Decrease HbA1c 0.5%–1% Short half-life resulting in lower risk of hypoglycemia, better postprandial glycemic control than sulfonylureas Decrease HbA1c 1%–2% Low risk of hypoglycemia Long-term safety record Weight neutral Low cost Diabetes prevention Improvement of atherogenic dyslipidemia Reduce risk of cardiovascular events Reduce risk of certain malignancies
Risk of hypoglycemia May cause weight gain Decreased response over time— primary failure rate of 20% , secondary failure about 5% to 10% per year Risk of hypoglycemia Multiple daily dosing Less potent and higher cost than sulfonylureas
Thiazolidinediones (pioglitazone, rosiglitazone)
Improve insulin sensitivity in peripheral tissues
Alpha glucosidase inhibitors (acarbose, miglitol)
Reduce digestion of carbohydrates in the small intestine
Dipeptidyl-peptidase 4 (DPP-4) inhibitors (sitagliptin, saxagliptin)
Improve insulin secretion and suppresses release of glucagon
Glucagonlike peptide 1 (GLP-1) agonists (exenatide, liraglutide)
Augment insulin release and suppresses release of glucagon Delay gastric emptying
Decrease HbA1c 1%–2% Low risk of hypoglycemia Diabetes prevention Improvement of atherogenic dyslipidemia Can be used in patients with renal failure Decrease HbA1c 0.5%–1.0% Low rate of hypoglycemia Reduce postprandial hyperglycemia Diabetes prevention Decrease HbA1c 0.5%–1.0% Low rate of hypoglycemia Reduce postprandial hyperglycemia Can be used in renal insufficiency Decrease HbA1c 0.8%–1.5% Low rate of hypoglycemia Reduce postprandial hyperglycemia Weight loss
Anorexia and gastrointestinal side effects Risk of lactic acidosis Contraindicated in patients with impaired renal function (glomerular filtration rate \60 mL/ min or serum creatinine .1.5 mg/dL in males and .1.4 mg/dL in females), congestive heart failure requiring treatment with pharmacologic agents, perioperative period and use of imaging studies using iodinated media Weight gain Fluid retention (edema) and increased risk of congestive heart failure Increased risk of bone fractures Increased risk of ischemic heart disease (rosiglitazone) Flatulence Contraindicated in patients with inflammatory bowel disease, partial bowel obstruction, and severe renal or hepatic disease Increase in upper respiratory tract infections Risk of pancreatitis Cost Gastrointestinal (nausea, vomiting and diarrhea) Injectable Cost
suspending the marketing authorization for the rosiglitazonecontaining antidiabetes medicines. Alpha-1 Glycosidase Inhibitors Alpha-1 glycosidase inhibitors slow carbohydrate absorption by blocking the action of brush border enzymes (alpha glucosidases), as well as increasing glucagonlike peptide-1 (GLP-1) levels.68 There are 2 available drugs: miglitol and acarbose. The primary effect of these agents is on postprandial hyperglycemia. The effect on HbA1c when used as monotherapy is modest with an average reduction of 0.5% to 1.0%. The benefit of using these agents is the lack of associated hypoglycemia and limited drug interaction.69 To be effective, alpha glucosidase inhibitors must be administered with the first bite of food. To avoid discontinuation of the medication because of the common gastrointestinal side effects (flatus, abdominal pain, abdominal cramps), it is important to initiate administration of these medications at very low doses. Dipeptidyl Peptidase-IV Inhibitors GLP-1 is an incretin produced in the small intestine that has various effects on glucose metabolism, including stimulating insulin secretion and inhibiting glucagon secretion. Dipeptidyl peptidase IV (DDP-IV) breaks down GLP-1, so by inhibiting DDP-IV, the action of GLP-1 can be prolonged.70 DDP-IV inhibitors improve fasting and postprandial glucose levels by stimulating insulin secretion and inhibiting glucagon secretion. These drugs are well tolerated with few side effects and are approved for use as monotherapy or combined with metformin, thiazolidinediones, or sulfonylurea medications. HbA1c reductions are approximately 1%. Unlike many other oral agents, these medications can be used in patients with impaired renal function. These drugs are attractive in elderly patients because of their limited side effects and low rate of hypoglycemia53; however, these agents are expensive, which may present a significant burden for individuals with limited incomes or without a pharmacy benefit plan. GLP-1 Analogs GLP-1 analogs mimic the action of GLP-1 and stimulate insulin production, inhibit hepatic glucose production, and delay gastric emptying. HbA1c can be expected to decrease 1% with the use of these agents. The safety of GLP1 analogs has not been determined in prospective randomized trials in elderly individuals; however, their use may be associated with nausea, gastrointestinal distress, and weight loss, which could be detrimental in elderly individuals who are already at risk for malnutrition.53 These agents should also be used with caution in patients with hepatic failure or severe renal impairment. Insulin In elderly patients with type 2 diabetes, insulin therapy is indicated during severe hyperglycemia despite treatment with oral agents or during intercurrent illness, perioperative period, and severe liver or renal disease. The most common indication is as add-on therapy in patients with type 2 diabe632 Migdal et al
tes who have experienced primary or secondary failure to oral antidiabetic agents. Insulin is frequently recommended for diabetic patients in long-term care facilities.71,72 Various insulin preparations are available, including short-acting insulin (lispro, glulisine, and aspart), intermediate-acting insulin (neutral protamine hagedorn, and long-acting insulin analogs (glargine and detemir). Long-acting analogs are commonly favored in elderly patients because of the peakless profile, which reduces the frequency of hypoglycemic events compared with intermediate-acting (neutral protamine hagedorn) insulin.18 In patients older than 65 years, the use of insulin glargine in combination with oral agents results in greater reduction in HbA1C and fasting blood glucose concentration and in a lower rate of hypoglycemic events compared with treatment with premixed 70/30 insulin.73,74 Once-daily dosing of basal insulin analogs increases compliance and may allow greater treatment flexibility, which is essential in elderly patients who often have erratic eating habits.74 One concern in the treatment of diabetes in nursing home residents is the high use of the sliding scale insulin (SSI) regimen as the sole means to control glucose levels. Among newly admitted patients, 54% were started on SSI and another 33% were later switched to SSI.75 This regimen is not physiological and is reactive rather than proactive, which allows periods of hyperglycemia to persist for long periods.76 Basal bolus insulin regimens have been shown to significantly lower glucose levels compared with SSI without any increased risk of severe hypoglycemia.77 Therefore, nursing home residents who are being treated with SSI regimens might be better served by changing to a more physiological regimen with basal insulin.75 CONCLUSION Evidence-based guidelines for diabetes control tend to emphasize safe and reasonable glycemic control in the elderly population. Although glucose control may be beneficial in decreasing diabetic complications, the risk of hypoglycemic events with intensive glucose control, which can precipitate complications, such as falls and cardiovascular events, may be detrimental in elderly individuals. A few retrospective studies in elderly patients have reported on the quality of diabetes care and glycemic control in long-term care facilities; however, no randomized clinical trials have focused on benefits of glycemic control on outcome and quality of life in elderly individuals and in nursing home residents. Future research is needed to address the following important clinical questions in elderly subjects: What is the optimal glycemic control? What is the best insulin regimen? What is the role of insulin analogs versus human insulin in preventing diabetic complications? Until these studies become available, safe and moderate glycemic control, minimizing the risk of hypoglycemic events, is indicated in elderly individuals and nursing home populations. REFERENCES References available at www.jamda.com with your JAMDA login. JAMDA – November 2011
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