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Management of Diabetes in the Elderly
Jeffrey I. Wallace, MD, MPH
The prevalence of type 2 diabetes, which represents roughly 90% of all diabetes, increases with age and affects 1820% of people over age 65 in the United States (with a substantial percentage of these cases being undiagnosed).1Recent recommendations to screen all adults over 45 years of age for elevated glucose levels, with retesting every 3 years, should substantially reduce the number of undiagnosed diabetic patients.2 In addition to the 20% of the elderly population with frank diabetes, another 2025% fit criteria for impaired glucose tolerance, a state that is associated with a twofold increase in the incidence of macrovascular complications.3
The average life expectancy for a 65-year-old woman and man in the United States is 19 years and 15 years, respectively. At age 75, it is 12 and 9 years, respectively.4 Because many older diabetic patients can be expected to live a decade or more after diagnosis, clinicians must carefully weigh the potential risks and benefits of available interventions on reducing the excess morbidity and mortality associated with diabetes.
Risks of Diabetic Complications in Older Adults With Type 2 Diabetes
A recent prospective study indicated that patients with type 2 diabetes without a history of prior heart attack have equal, if not greater, risks of myocardial infarction (MI) compared to those without diabetes who have had prior heart attacks (20.2% vs. 18.8% incidence of MI, respectively, over 7 years).7 Although not from an intervention trial, these data suggest that older diabetic patients should be treated as aggressively for diabetes and cardiovascular risk factors as the secondary prevention efforts currently aimed at people with known cardiovascular disease.
Estimates of the lifetime risks of developing blindness due to diabetic retinopathy or of progressing to end-stage renal disease demonstrate the decline in these risks with advancing age of onset of type 2 diabetes (Table 1).9 These estimates are similar to the observed rates of renal failure in the UKPDS trials but are somewhat lower than observed rates of blindness, in part because UKPDS rates included all causes of blindness rather than only cases in which blindness was due to diabetic retinopathy.10
The risk estimates in Table 1 also indicate a nonlinear association between microvascular complications and glycemic control, such that the potential for reductions in complications is greater when glycemic control improves from poor to moderate (e.g., from HbA1c 11% to 9%) as compared to improvement from moderate to near-normal (e.g., from HbA1c 9% to 7%). To properly evaluate the potential benefits of therapeutic interventions on microvascular complications in type 2 diabetes, clinicians must carefully consider the patient's age at onset, overall health status/expected survival, and existing level of glycemic control.
Glycemic Management Issues in Older Diabetic Patients
The major risk of tight glucose control is hypoglycemia. Even among the relatively young and healthy population in the UKPDS trials, the incidence of hypoglycemia was two times greater in the intensive treatment compared to conventional treatment groups (excluding metformin). The annual rate of one or more major hypoglycemic episodes (help from another person or medical intervention needed) was 1.8% among people assigned to intensive therapy with insulin, 1.01.4% for those using oral sulfonylureas, and 0.7% for those in the conventional treatment group.10 Factors that may predispose older diabetic patients to more frequent or severe hypoglycemic events are listed in Table 2.
The goal for many otherwise healthy elderly diabetic patients should probably be the same as for younger patients, namely, near-normal fasting plasma glucose levels (<7 mmol/L, HbA1c <7%) without hypoglycemia. In elderly patients whose care is complicated by chronic medical illness, frailty, isolation, or a shortened life expectancy, a more realistic therapeutic goal may be reducing the signs and symptoms of hyperglycemia (i.e., polyuria, fatigue, and weight loss) rather than attaining euglycemia. Maintenance of fasting glucose levels <1114 mmol/L is generally adequate to achieve these goals, and in most cases a fasting plasma glucose level of <11mmol/L (corresponding to an HbA1c <8.1%) is attainable with few hypoglycemic episodes.
Of note, a recent short-term study further reinforced the argument to strive for good glycemic control among older type 2 diabetic patients. In a 12-week, placebo-controlled trial of glipizide (Glucotrol, Glucotrol XL) in type 2 diabetic patients aged 3085 years, improved glycemic control (HbA1c 9.3% vs. HbA1c 7.5%) was associated with enhanced quality of life scores and better general perceived health, cognitive functioning, sleep, depression, and vitality.11 Subjects with better glycemic control also experienced fewer bed-days and fewer restricted-activity days. These results indicate that the short-term health benefits of improved glycemic control are important considerations even for those patients in whom long-term health benefits of glycemic control may not be an issue.
Strategies to Reduce Diabetes Complications
However, despite their high prevalence, established CHD risk factors account for no more than half of the excess CHD observed in type 2 diabetes.12 While hyperglycemia appears to be independently associated with CHD, data demonstrating benefits of tight glycemic control on macrovascular disease in type 2 diabetes are currently more limited relative to the data supporting interventions for other CHD risk factors.
Glycemic control. While epidemiological data demonstrate that increased glucose levels are associated with increased macrovascular disease events, the impact of especially tight glycemic control on reducing macrovascular events is less certain. Although concern exists that higher insulin levels and weight gain associated with some diabetes treatments might adversely affect rates of macrovascular events,13 recently published UKPDS data showed no negative effects of intensive therapy with sulfonylureas or insulin on macrovascular events.10 To the contrary, MI rates were lower with improved glycemic control (HbA1c 7.9% vs. 7.0%), although the reduction did not quite reach statistical significance (RR 0.84, 95% CI 0.711.00, P =.052).10 The Diabetes Control and Complications Trial (DCCT) in type 1 diabetic patients also found lower macrovascular complications with improved glycemic control (HbA1c 9.0% vs. 7.0%), but again their results did not quite reach statistical significance (41% reduction, P = 0.08).14 These trials clearly show a lack of adverse effects and suggest a benefit of improved glycemic control with sulfonylureas or insulin on macrovascular outcomes.
Of note, metformin, an agent associated with less weight gain and fewer hypoglycemic attacks, did demonstrate statistically significant reductions in MI rates with improved glycemic control (HbA1c 8.0% vs. 7.4%) among overweight diabetic patients after 10 years of treatment (RR 0.61, 95% CI 0.410.89, P = 0.01).15 It is possible that macrovascular benefits of improved glycemic control with sulfonylureas or insulin are partially offset by adverse effects of weight gain on lipids and blood pressure, direct atherogenic effects of insulin, and/or acute events precipitated by hypoglycemia.13
Hypertension. The prevalence of hypertension in type 2 diabetic patients rises from 40% at age 45 to 60% by age 75, a factor that contributes significantly to both macro- and microvascular disease complications.16,17 Therefore, screening for and aggressive treatment of hypertension are critical components of diabetes care. In most cases, therapy should be instituted if blood pressure (BP) exceeds 140/90 mmHg, and expert opinion suggests a treatment goal of BP <130/85 for patients with type 2 diabetes.18
The UKPDS randomized trial of tight blood pressure (aiming at a BP <150/85) found that treated subjects (mean BP 144/82) had risk reductions of 34% and 37% in macrovascular and microvascular endpoints, respectively, compared to the group assigned to less tight control (mean BP 154/87).17 The statistically significant reductions in microvascular disease (P = 0.009) were predominantly due to a reduced risk for retinal photocoagulation, whereas the statistically significant risk reduction in the aggregate macrovascular endpoint (P = 0.019) included reductions of 21% for MI (P = 0.13), 44% for stroke (P = 0.01), 49% for peripheral vascular disease (P= 0.17), and 56% for congestive heart failure (P = 0.004). Although the agents of first choice in this trial (atenolol [Tenormin] and captopril [Capoten]) are thought to have potential advantages over other antihypertensive agents for diabetic patients, the beneficial effects observed were felt to be due to the blood pressure reduction itself more than to the specific treatment agents used.19,20
The findings of a subgroup analysis from the Systolic Hypertension in the Elderly Program is consistent with this conclusion. In this trial, older type 2 diabetic patients with isolated systolic hypertension were randomized to receive treatment with low-dose diuretics (chlorthalidone 12.525 mg/day) with step-ups to atenolol or reserpine as needed.21 The relative risk reduction of 34% in aggregate macrovascular events mirrors exactly that observed in the UKPDS trial, and the 56% reduction in CHD endpoints further supports the utility of blood pressure lowering with diuretic-based therapy in older type 2 diabetic patients.
Hyperlipidemia. Although the association between hyperlipidemia and cardiovascular events declines with age, a significant association has been shown to persist into the eighth decade of life.22 Further, primary prevention trials with older adults up to age 73 years and secondary prevention trials involving adults up to age 75 years clearly demonstrate that lowering cholesterol levels can significantly reduce cardiovascular event rates in older adults with and without diabetes.23-25
Because of their higher baseline risks, the actual number of macrovascular events prevented by treatment of hyperlipidemia may be greatest for older diabetic patients.25 Diabetic patients with elevated lipid levels who are expected to survive at least 12 years (the time frame to attain benefits conferred by lipid-lowering) should be strongly considered for primary and secondary prevention efforts at least as aggressive as those outlined by the National Cholesterol Education Program expert panel.26
Tobacco. The health benefits of tobacco cessation begin within 3-6 months and extend from reduced atherosclerotic disease and lower cancer rates to improved lung function. Smoking and diabetes are synergistic risk factors for atherosclerotic disease. All possible measures should be used to prevent and encourage discontinuation of tobacco use.
Use of -blockers in older diabetic patients. Abundant evidence indicates that -blockers reduce recurrent cardiac events when used in secondary prevention after MI for both diabetic and nondiabetic patients.27 Yet despite higher risks of post-infarct mortality compared with nondiabetic patients and evidence that diabetic patients may experience greater cardioprotection with -blockade than do nondiabetic patients,28 diabetic patients do not receive -blockers as often as nondiabetic patients do.27,29
There is little evidence to support withholding -blockers from diabetic patients based on concerns of adverse metabolic effects of -blockers or their masking of hypoglycemic symptoms.27,28,30 The safety and efficacy of atenolol in hypertensive diabetic patients was well demonstrated in the UKPDS trials.17 Further, data from other studies demonstrate that after MI, patients with conditions that are often considered contraindications to -blockade (including diabetes, asthma, chronic obstructive pulmonary disease, low blood pressure, and low left ventricular ejection fractions) do frequently tolerate and benefit from -blocker therapy.27,28 Unless absolute contraindications are present (heart block, bradycardia, hypotension, poorly controlled heart failure, severe pulmonary disease), diabetic patients with prior MIs should receive -blockers.
Similar risk reductions in microvascular risks were observed with intensive glycemic control efforts using metformin in overweight subjects (HbA1c 8.0 vs. 7.4% ).15 Diabetic neuropathy affects over 50% of patients who have had type 2 diabetes for more than 15 years, and, as with other microvascular complications, improved glycemic control appears to reduce the incidence of neuropathy.8,10,16
Because postprandial glucose elevations tend to be higher in elderly diabetic patients, intensive efforts to reduce HbA1c to normal or near-normal levels may greatly increase the risk of hypoglycemic events occurring between meals. Unless tight glycemic control can be accomplished with low rates of hypoglycemia (and low rates of other potential adverse treatment effects), the marginal benefits of lowering HbA1c below 8% may not be worth the attendant risks for many elderly diabetic patients. As previously noted, the age at onset, health status, and motivation of older diabetic patients are critical factors to consider in determining treatment goals.
Blood pressure control. Aggressive control of blood pressure may have beneficial effects on microvascular complications equal to or greater than that of tight glycemic control (at least within the relatively narrow range of improvements in HbA1c that occurred in the UKPDS trials).10,15 In a UKPDS trial of tight blood pressure control, the group assigned to tight control (BP 144/82) had a 37% reduction in microvascular disease endpoints compared to the group assigned to less tight control (BP 154/87).17 Further, the beneficial effects of improved blood pressure control extended to cardiovascular and stroke events, which occur with much greater frequency (and with greater morbidity and mortality) than microvascular complications in elderly diabetic patients. As outlined above, aggressive control of blood pressure should be a high priority in the management of older hypertensive diabetic patients.
Specific Interventions for the Management of Hyperglycemia
A low-fat diet and endurance exercise each can reduce insulin resistance, and both are associated with mild weight loss.3,31 Thus, many recommend a simple noncaloric-restricted, low-fat (<30% of calories), high-carbohydrate (>50% of calories) diet, in combination with endurance exercise for older diabetic patients. The exercise prescribed need not be intense to confer benefits. Even moderate leisure activity has been associated with a reduced risk of developing diabetes.32 Patients who do not achieve desired glycemic control with an individualized nutrition and exercise program are candidates for pharmacological therapy.
Although these characteristics make its use appealing for older overweight diabetic patients, metformin's potential for the rare, but often fatal, complication of lactic acidosis specifically limits its use in patients with renal or hepatic dysfunction or congestive heart failure requiring pharmacological therapy.33 The manufacturer's listed contraindications include a serum creatinine >133 mmol/L (1.5 mg/dl) for men; a creatinine >124 mmol/L (1.4 mg/dl) for women. In addition, because serum creatinine does not reflect renal function as well with advanced age, the manufacturer recommends that "treatment should not be initiated in patients >80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced."
Although the oldest patients treated with metformin in the UKPDS trial did not exceed age 75 and patients with current heart failure were excluded from the study, subjects with serum creatinine up to 175 mmol/L (2.0 mg/dl) were included without any reported cases of lactic acidosis.15
In addition to the above contraindications, which may greatly limit metformin's use in elderly diabetic patients, gastrointestinal side effects, including anorexia, nausea, and abdominal discomfort, are seen in up to 30% of patients.16 A starting dose of 500 mg per day can reduce these side effects, increasing the drug by 500 mg a week as necessary to achieve the desired level of glycemic control.
Sulfonylureas. The primary mechanism of action of sulfonylureas is enhanced pancreatic -cell secretion of insulin. Some experts suggest that these agents are the drugs of first choice for nonobese type 2 diabetic patients. Although there were no major differences in the efficacy or safety of the sulfonylureas used in the UKPDS trials (chlorpropramide [Diabinese], glibenclamide [glyburide; DiaBeta, Glynase, Micronase], and glipizide),10 the shorter-acting second-generation sulfonylureas are preferred, and chlorpropramide should not be used in the elderly due to its long half-life, antidiuretic effect, and association with severe and prolonged hypoglycemia.3,16 Further, of the second-generation sulfonylureas, glipizide has been associated with lower rates of hypoglycemia, an important consideration in the elderly.34 In one study, glipizide gastrointestinal therapeutic system (GITS) was associated with lower insulin secretion (as measured by C-peptide) while maintaining similar glycemic control compared to glyburide, although neither agent was associated with hypoglycemia in this short-term fasting study.35
All oral sulfonylureas can cause hypoglycemia. Doses should be started at the low end of the dosing range and cautiously increased while monitoring efficacy and adverse effects.
-glucosidase inhibitors. -glucosidase inhibitors such as acarbose (Precose) interfere with a family of enzymes in the intestine responsible for converting nonabsorbable dietary starch and sucrose into absorbable monosaccharides (e.g., glucose). Consequently, acarbose reduces the rate of uptake of glucose into the bloodstream and decreases postprandial blood glucose levels.
This mechanism of action is physiologically appealing because it helps reduce the increased postprandial hyperglycemia that older type 2 diabetic patients have relative to their younger counterparts, with little risk of hypoglycemia.3 However, reductions in HbA1c with acarbose tend to be modest (0.4-0.9%), and this agent may be most appropriate for use in patients with mild hyperglycemia or to help reduce postprandial glucose fluctuations in combination with other agents.36
Perhaps more importantly, compliance can be difficult because although acarbose produces few systemic effects, it does allow undigested carbohydrate to reach the large bowel where it ferments, causing flatulence, bloating, and diarrhea. These effects usually diminish over time, and a low starting dose (25 mg once a day) with gradual upward titration over 6 weeks can help reduce initial gastrointestinal side effects.16
Thiazolidinediones. Troglitazone (Rezulin), the first agent in this relatively new class of drugs, reduces peripheral and hepatic insulin resistance and appears to lower glucose levels primarily by augmenting insulin-mediated peripheral glucose disposal.37 Although troglitazone requires the presence of insulin to work, it does not stimulate insulin secretion and thus, by itself, is unlikely to cause hypoglycemia.
Well-conducted trials have demonstrated that troglitazone is effective in improving glycemic control when used alone or in combination with other oral agents.37,38 It can also improve glycemic control while reducing required insulin doses among type 2 diabetic patients who were previously on at least 30 U of insulin daily.39
However, clinical enthusiasm for troglitazone has been dampened by its potential to cause severe idiosyncratic hepatocellular injury that can be fatal, the need for regular monitoring of liver function tests, some reports of weight gain, and its relatively high cost.40 At this time, troglitazone is generally used in addition to a sulfonylurea or insulin and its place in the care older diabetic patients remains to be established.
Meglitinides. Repaglinide (Prandin) is a new oral glucose-lowering agent currently approved for monotherapy or combination use with metformin for type 2 diabetes.41 Similar to sulfonylureas, its primary action is to increase pancreatic insulin secretion, but it appears to act at a separate site on the pancreatic -cell and has a much shorter, quicker action than sulfonylurea agents.
Like sulfonylureas, repaglinide can cause serious hypoglycemia and is associated with increased insulin levels and weight gain. It may be advantageous for older patients with erratic meal schedules or those prone to hypoglycemia between meals with second-generation sulfonylureas (though its cost is substantially higher than sulfonylureas).
Insulin. Older patients being treated pharmacologically for diabetes generally follow the same treatment algorithm as younger patients, moving from monotherapy to combination therapy as needed to maintain glycemic control. If combination therapy with oral agents fails to achieve desired glycemic goals, treatment generally should be changed to daily insulin injections.
Although insulin treatment regimens in the elderly are similar to those in the young, the higher prevalence of poor vision, arthritis, and factors that increase the risks of and for hypoglycemia (Table 2) may be problematic for many older diabetic patients. Devices to aid in accurate insulin dose withdrawal and the use of premixed insulins or predrawn syringes may be necessary to facilitate insulin therapy.
Other Components of Comprehensive Care
Appropriate attention to these issues, combined with the careful management of glycemic control and macrovascular risk factors, has the potential to improve quality of life and increase life expectancy in older patients with type 2 diabetes.
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37Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hsueh W, Inzucchi S, Kelley D, Nolan J, Olefsky J, Polonsky K, Silver D, Valiguett Y, Shulman G: Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. Ann Intern Med 128:176-85, 1998.
38Inzucchi SE, Maggs DG, Spollett GR, Page S, Rife F, Walton V, Shulman G: Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338:867-72, 1998.
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40Imura H: A novel antidiabetic drug, troglitazonereason for hope and concern. N Engl J Med 338:908-909, 1998.
41Repaglinide for type 2 diabetes mellitus. Med Lett 40:55-56, 1998.
Dr. Wallace is the recipient of an NIA Academic Award (K08/AG00615) and is affiliated with the Clinical Nutrition Research Unit at the University of Washington (NIH, NID, P30DK35816).
Jeffrey I. Wallace, MD, MPH, is an assistant professor in the University of Washington Department of Medicine, Division of Gerontology and Geriatric Medicine, in Seattle.
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