A Review and Update of Insulins in the Management of Elderly Patients with Diabetes

This article is the fourth in a continuing series on diabetes in the elderly. The third article in the series, “Diabetes Agents in the Elderly: An Update of New Therapies and a Review of Established Treatments,” was published in the June issue of the Journal. The remaining articles in the series will discuss such topics as the role of exercise and dietary supplements in the management of diabetes, and microvascular and macrovascular complications of diabetes.

According to the Third National Health And Nutrition Examination Survey (NHANES III), approximately 20% of the U.S. population develops diabetes by the age of 75,1 and at least half of these patients are unaware that they have the disease. ² Both insulin resistance and relative insulin deficiency characterize type 2 diabetes. Therapy should entail diet, weight reduction, and exercise. Patients with persistent hyperglycemia are often started on one or more oral hypoglycemic drugs. Many patients with type 2 diabetes will require insulin as their beta cell function declines over time. Insulin is usually started when full doses of oral hypoglycemic agents are not achieving acceptable glycemic control. The clinician’s options have increased with new insulin analogues that physiologically attempt to match the insulin peaks of the normal glycemic state, enabling patients to achieve tighter glycemic control in a potentially safer way. In this article, we discuss the role of human insulin and new insulin analogues in managing diabetes in the elderly population.

Overview

Most diabetes guidelines emphasize intensive glucose control with a reduction in microvascular complications. However, too low a glycosylated hemoglobin (HbA1c) value can be associated with increased hypoglycemia. Clinical trials have demonstrated that it requires at least 8 years of treatment to get the long-term benefit of glycemic control.³ However, the benefit of lipid and blood pressure control takes only 2-3 years.^4,5 This may suggest that a less aggressive glucose management might be appropriate in a frail elderly population, while more emphasis should be given to aggressive blood pressure and lipid management and aspirin therapy. On the other hand, in 2005, a 65-year-old patient had a predicted 17-20–year life expectancy,⁶ and this span provides time to incur long-term complications. Thus, an individualized approach in managing elderly persons with diabetes is appropriate, acknowledging the variability and complexity of this population.

Age-related changes in functional ability, cognitive functions, eyesight, and impaired manual dexterity may affect the patient’s ability to administer insulin, monitor blood glucose, and manage hypoglycemia, which is a consideration in starting insulin therapy in the elderly population. The benefits and disadvantages of insulin therapy, including hypoglycemia, must be explained to and understood by the patients and family.⁷ The term conventional insulin therapy has been used to describe simpler insulin regimens, such as single daily injections, or two injections per day of combined regular and neutral protamine Hagedorn (NPH) insulin given in fixed amounts before breakfast and dinner. Intensive insulin therapy usually entails utilizing basal insulin with multiple premeal injections of a rapidly-acting insulin to provide a tighter glycemic control. The time to peak and the duration of action of human insulin preparations (NPH and regular insulin) do not replicate endogenous basal and postprandial insulin secretion. Thus, insulin analogues (lispro, aspart, glulisine, glargine, detemir) were developed with the goal of more nearly replicating endogenous insulin secretion.

Insulin is a polypeptide molecule with a molecular weight of 5808 dalton, consisting of an A and B chain connected by two disulfide bridges. Endogenous insulin is secreted into two phases: the “basal” component, when insulin is secreted continuously; and the stimulated or “bolus” component, when insulin is secreted in response to a nutrient or other challenge. Basal insulin limits lipolysis and hepatic glucose production in the fasting state.⁸ Prandial insulin primarily suppresses hepatic glucose production and stimulates utilization of glucose by muscle, thus preventing hyperglycemia after meals.⁹ In healthy, nonobese adults, the overall “basal” insulin is usually secreted at a rate of 0.5-1 U/hour,¹⁰ which maintains the fasting plasma glucose concentrations in the range of 70-110 mg/dL (3.9-5.6 mmol/L).¹¹ In response to a meal, insulin secretion increases rapidly, with plasma concentrations reaching a peak of 60-80 µU/mL (417-556 pmol/L) within 30-60 minutes and returning to basal levels approximately 2-4 hours later.¹² In obese subjects, these values are several fold higher, related to the degree of obesity.

An insulin pen is composed of an insulin cartridge and a dial to measure the dose. It is used with disposable pen needles to deliver the dose. Insulin pens can be durable or prefilled/disposable. Advantages of insulin pens over insulin syringes include accuracy, convenience, easier to use for those with visual or fine motor skill impairments, ease of transport, and potentially less pain with injection. All of these features make it more suitable for elderly persons with diabetes.

Continuous subcutaneous insulin infusion (CSII) pump is the acknowledged gold standard basal insulin replacement. Insulin pump therapy is recommended for children or for adults whose schedules vary from one day to the next and are willing to closely monitor blood glucose and amount of calorie intake. The pump is worn externally and is attached to the body with long, thin, flexible plastic tubing that has a soft cannula, which is inserted and then left in place beneath the skin. The cannula and tubing are changed every 48-72 hours. The pump delivers a small dose of rapid-acting insulin continuously as basal insulin. Additional doses of insulin can be given at meal time. The insulin pump offers the advantage of flexible timing of meals, no daily injections, and less variation in the amount of insulin absorbed. Financial considerations and long-term acceptability by patients limit insulin pumps to a minority of patients with type 1 and type 2 diabetes. Potential disadvantages include infection at the injection site, pump malfunction, and need for close monitoring.

The Insulins

Exogenous basal insulin delivery has traditionally involved the use of single or twice-daily or more injections of the “intermediate-acting” NPH insulin or combination insulins. The newer insulin analogues glargine and detemir offer improved pharmacokinetic and pharmacodynamic profiles as compared with NPH and, therefore, offer advantages with respect to safety, efficacy, and variability.

Long-Acting Insulin (Basal) Infusion
Insulin glargine. In 2000, insulin glargine became the first long-acting insulin analogue to be introduced into clinical practice. Glargine is an analogue of regular human insulin produced by recombinant DNA technology. Insulin glargine has an activity profile much closer to that of normal physiologic basal insulin. Insulin glargine must not be mixed with any other insulin because of difference in carrier pH. As compared with NPH insulin, insulin glargine is absorbed more slowly from the injection site and has a much slower onset of action, followed by a relatively steady activity plateau.¹³ The onset of action and duration of action for glargine are 2-4 and 20-24 hours, respectively, as compared to NPH at 2-4 and 10-18 hours, respectively (Table). Insulin glargine has a much longer and flatter time-activity profile as compared with NPH insulin. The 24-hour profile of glargine is not dose-dependent.^13,14 Once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine demonstrates a lower risk of nocturnal hypoglycemia in patients with type 1 and type 2 diabetes.^15,16 Although one study has shown less weight gain with glargine as compared with NPH, the majority of studies have shown little difference in weight gain between the two insulin treatments.¹⁴ The steady-state condition is achieved within a few days with no further accumulation when administered on a once-daily basis.¹⁰ The action profile of glargine appears nearly “peakless” as compared with the discernible peak of NPH at 4-6 hours, and thereby more closely mimics the gold standard (ie, CSII).¹⁰ Studies comparing once-daily glargine with multiple daily injection regimen with CSII showed no differences regarding the level of glycemic control (HbA1c) or the frequency of hypoglycemia, suggesting the suitability of glargine as basal insulin. ^10,17 There are limited data specifically in the elderly, and general issues of hypoglycemia—as with any insulin—are present.

Insulin detemir. Detemir is also an analogue of human insulin produced by recombinant DNA technology. Prolonged action of detemir is mediated by the strong self-association of detemir molecules at the injection site and albumin binding via the fatty acid side chain. Detemir has a slower, more prolonged absorption over 24 hours and a flatter time-action profile as compared with NPH^14,18 (Table). The duration of action of detemir is dose-dependent; the mean duration of action ranges from 6 to 23 hours at the doses of 0.1-1.6 U/kg.¹⁸ In clinical practice, detemir is typically administered twice daily. Detemir is associated with equivalent glycemic control, less risk of hypoglycemia, and lower within-subject day-to-day fasting glucose variability as compared with NPH.¹⁴ The incidence rate of hypoglycemia was comparable with glargine and detemir. ¹⁹ In the study comparing glargine with detemir,¹⁹ both insulins were associated with weight gain, although the magnitude of weight gain was significantly less with detemir (detemir, 3.0 kg; glargine, 3.9 kg; P < 0.012).

A cost analysis of the treatment of type 2 diabetes from one clinical trial conducted over 52 weeks in Spain indicated a potential savings of approximately 30% with glargine versus detemir.²⁰ It was estimated that the daily cost for a 100-kg person with type 2 diabetes was $8.74 (U.S. dollars) for insulin detemir versus $5.19 with glargine and $2.60 for NPH.²⁰ Thus, the insulin analogues glargine and detemir may offer advantages over NPH in terms of hypoglycemia, which is particularly important in the elderly population with diabetes. Detemir may be less suitable in the elderly population as basal insulin secondary to twice daily injection regimen and higher cost, though it does have lower risk of nocturnal hypoglycemia when compared with NPH.

Ultralente insulin. Lente insulin is a zinc-insulin complex precipitated in an acetate buffer in two physical forms, 70% crystalline (actually ultralente) and 30% amorphous (actually semilente). Ultralente insulin is a long-acting insulin with an onset of action 6-10 hours after injection, and a duration of action of 20-24 hours.²¹ Lente and ultralente are no longer in production and have been replaced with the newer generation of insulins.

Intermediate-Acting Insulin
NPH insulin. NPH was introduced in 1946 and was the mainstay basal insulin for the remainder of the 20th century. It is insoluble insulin suspension that requires resuspension prior to administration. However, NPH is limited by its activity profile, with peak activity occurring within 4-6 hours of subcutaneous administration²² (Table), and this is associated with an increased risk of hypoglycemia, particularly nocturnal hypoglycemia following bedtime injection.²³ This effect is accentuated by predinner regular insulin.¹⁰ Additionally, NPH demonstrates a high degree of variability in its absorption profile.¹⁰ This problem is accentuated by the need for resuspension prior to injection, an important step often forgotten or poorly managed by elderly subjects with diabetes, resulting in hyper- and/or hypoglycemia. ²⁴

Lente insulin. Lente insulin is an insulin with an intermediate duration of action. It has an onset of action of 3-4 hours after injection, a peak activity of 4-8 hours after injection, and a duration of action of 16-20 hours.²¹ The use of lente has not shown increased efficacy over NPH.²⁵ Lente and ultralente insulins have been largely replaced by newer insulin analogues with activity profiles much closer to normal physiologic basal insulin.

Premeal (Bolus) Insulin
Multiple injections of premeal insulin in addition to basal insulin attempt to provide tight glycemic control by reducing postprandial hyperglycemia. Premeal insulins can be either short-acting (regular insulin) or rapid-acting insulin analogues (lispro, aspart, and glulisine) that can be administered immediately before meals. Some modifications were made in the insulin molecule to produce insulin preparations with faster onset and shorter duration of action than regular insulin. These modifications in the insulin molecule prevent it from forming hexamers or polymers that slow absorption and delay action.^26,27 The insulins lispro, aspart, and glulisine were brought to the U.S. market in 1996, 1999, and 2004, respectively. Regular insulin has an onset of action within 30 minutes to 1 hour of injection, reaches a peak effect at 2-4 hours, and has effects that last 6-8 hours. The insulins lispro and aspart achieve peak concentration within 90 minutes and have a duration of action of approximately 3-5 hours,²⁸ while glulisine’s peak concentration is within an hour, and its duration of action is roughly 2 hours.²⁹ All three of these rapid-acting analogues have an onset of action within 15 minutes (Table). In clinical trials, postprandial increases in blood glucose levels were significantly less after treatment with insulin lispro or insulin aspart than with premeal regular insulin.³⁰ Insulin glulisine exhibits statistically significant HbA1c lowering in comparison with regular insulin in type 2 diabetes mellitus.³¹

Insulin lispro and aspart can be administered immediately before meals, while insulin glulisine can be administered immediately before or after meals, which provide the flexibility in dosing schedule for elderly persons with diabetes. When utilized as post-meal prandial insulin, insulin glulisine should be given within 20 minutes post-meal.³² Hypoglycemia is the most common complication of insulin glulisine use, but it occurs at a similar rate among recipients of insulin glulisine to that seen with other insulins.^32,33

In conclusion, rapid-acting insulin analogues are safe, effective, and well tolerated, and are a worthy option for prandial glucose control in elderly patients with diabetes if an intensive insulin regimen is used. Elderly patients and their families should be educated regarding the timing of administration of these insulin analogues, given the rapid onset of action and risk of hypoglycemia.

Premixed Insulin
Some elderly patients with type 2 diabetes who require premeal insulin in addition to basal insulin prefer premixed insulins for convenience. Premixed lispro/NPH in elderly persons with diabetes may be of some benefit for patients who will not comply with an intensive regimen requiring multiple daily injections. Insulin glargine and insulin detemir should not be mixed with other insulins due to the low pH of the diluents. As per the American Diabetes Association (ADA),³⁴ after mixing NPH with regular insulin, the formulation should be used immediately and within 15 minutes prior to a meal. As a result of drawing up both insulin preparations in the same syringe, serum insulin concentrations tend to approach a single peak. The accuracy of insulin injections has been shown to be improved in older patients when they are treated with premixed insulin.³ It may be more difficult to achieve excellent glycemic control with premixed insulins even though they are easier to use,³⁶ but glycemic control is usually adequate for the elderly person with diabetes who has functional limitations and life expectancy less than ten years. The administration of premixed insulin is associated with a lower risk of hypoglycemic events when compared with insulin aspart. However, this lower hypoglycemic risk is achieved at the expense of a potentially higher HbA1c.³⁷

Conclusions

Elderly people are at higher risk for hypoglycemia due to age-associated decreases in hepatic oxidative enzyme activity and concomitant decline in renal function, polypharmacy, inadequate and/or erratic nutritional intake, hypoglycemic unawareness secondary to loss of epinephrine and glucagons response to hypoglycemia, and cognitive impairment.²⁸ Hypoglycemic episodes are associated with a higher rate of injurious falls in older persons, which is a very common geriatric syndrome and affects the quality of life of the elderly.³⁸ Managing diabetes effectively involves patient and family education regarding signs and symptoms of hypoglycemia, regular home blood glucose monitoring, carrying replacement glucose in pocket, and practicing safe driving. It is important to know that annual self-management training is covered under Medicare in the United States.²⁸

Target HbA1c should be always be individualized in elderly patients based on their functional status, life expectancy, and cognitive function. While a goal of 7% or lower may be appropriate for most older adults who are healthy, such a target value for other older adults may be more challenging given issues of hypoglycemia. The new insulin analogues physiologically attempt to match the insulin peaks of the normal glycemic state, enabling patients to achieve the tighter diabetes control in a potentially safer way. The clinician must weigh many factors, as the risks and benefits of tight glycemic control in elderly patients are evaluated in the context of treatment strategies and priorities.

The authors report no relevant financial relationships.

Dr. Kant is a third-year Internal Medicine Resident and Dr. Chandra is a second-year Internal Medicine Resident, Johns Hopkins/Sinai Hospital Program in Internal Medicine, Baltimore, MD; and Dr. Thomas is Division Director, Division of Endocrinology, Sinai Hospital of Baltimore, and Associate Program Director, Johns Hopkins/Sinai Hospital Program in Internal Medicine.

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