The proper use of insulin preparations in the management of various types of diabetes is of paramount importance for the hospital pharmacist. Knowledge and expertise in the use of these products can contribute greatly to positive outcomes for diabetic patients, improving their quality of life and preventing complications.
Diabetes mellitus is a chronic, lifelong disease characterized by elevated levels of blood glucose resulting from insufficient insulin production, insulin resistance, or both. The 3 main types of diabetes are type 1, type 2, and gestational diabetes. An estimated 18.2 million persons in the United States?6.3% of the population?have diabetes. Each year, about 1.3 million persons aged 20 years or older are diagnosed with the disease, and diabetes is currently the sixth leading cause of death in the United States. All type 1 diabetics must use insulin to survive, and many type 2 patients require it for optimum blood glucose control.
There are 3 elements that comprise the cornerstone of diabetes treatment: diet, exercise, and medications (oral hypoglycemics and/or insulin). All 3 elements working together are required to keep patients symptomfree, to maintain near-normal glucose levels, and to prevent complications. For those patients requiring insulin for their medication treatment, insulin may be categorized by strength, source, and purity and by onset, peak, and duration of action. Besides knowledge of the various categories of insulin, it is equally important for the pharmacist to have a working knowledge of potential adverse effects, the variety of available methods for insulin injection, and po-tential future developments in insulin delivery.
Almost all patients in the United States use U-100 insulin, although U- 500 is available. U indicates the number of units of insulin per milliliter. Therefore, 10 units of insulin is equal to 0.1 mL. U-500 insulin is reserved for use in patients requiring more than 100 units as a single injection.
All insulin products currently marketed are 1 of 4 types: pork, beef?pork, biosynthetic human, or analogue. Pork insulin differs from human insulin by only 1 amino acid, whereas beef differs by 3 amino acid sequences. Both pork and beef?pork insulins are capable of causing antigenic reactions, and they are rarely used today. Biosynthetic insulins also are referred to as ?human? because their amino acid structure is identical to naturally occurring human insulin. Analogue insulin differs from human insulin only by substitution or position changes in the human insulin molecule. Biosynthetic and analogue insulins are created using recombinant DNA technology.
The purity of an insulin product relates to the amount of proinsulin and other impurities present. Before 1980, most insulins contained 300 to 10,000 parts per million of impurities, an amount large enough to elicit local reactions when injected as well as systemic effects. Today, all insulins marketed in the United States are ?purified,? indicating 10 ppm or less of impurities, and none are considered antigenic.
Onset and Duration of Action
The most important clinical considerations in the use of insulin products relate to their onset, peak, and duration of action. The generally accepted categories are rapid-acting (or shortacting), intermediate, and long-acting. The rapid-acting insulins are the only clear-solution insulins that may be given intravenously or subcutaneously. All other insulin products are cloudy suspensions that may be injected only subcutaneously. The rapid-acting insulins include regular, lispro, and aspart. These insulins have an onset of action within an hour or less and are used to reduce the peak of glycemia that occurs after meal ingestion. Regular insulin has an onset of action of 30 to 60 minutes, peaks within 2 to 4 hours, and may last for 6 to 8 hours. Lispro and aspart insu-lins both have an onset of action of 15 minutes, with a peak in 1 hour and a duration of action of 3 to 4 hours.
Common intermediate-acting insulins include Neutral Protamine Hagedorn (NPH; isophane), insulin zinc suspension (Lente), and combinations of NPH and regular insulins?usually a 70/30 mixture. These forms of insulin have a significantly longer delay in their onset and duration of action. In the setting of type 1 diabetes, they generally are used in combination with a rapidly acting form of insulin, although they may be given before bedtime to limit hyperglycemia over-night and in the early hours of the morning. NPH insulin has an onset of action of 1 to 3 hours, peaking within 6 to 8 hours and lasting for 12 to 16 hours, whereas Lente insulin has a slightly extended time frame with an onset of 1 to 4 hours, a peak of 6 to 10 hours, and a duration of 14 to 18 hours.
The long-acting insulins include extended insulin zinc suspension (Ultralente) and glargine. Even after an overnight fast, the normal pancreas continues to secrete insulin. Investigators have long attempted to develop forms of long-acting insulin with pharmacokinetic properties that simulate the basal production of insulin. Ultralente has an onset of 2 to 4 hours, peaking within 8 to 10 hours and lasting for 16 to 24 hours. The newest long-acting agent, known as glargine, has an onset of action of 6 hours, peaking and lasting upwards of 24 hours.
Adverse Effects of Insulin Therapy
Although insulin use is ubiquitous, complications and adverse effects occur as with any drug regimen. Complications may include hypoglycemia, weight gain, worsening of retinopathy, and allergic reactions. Hypoglycemia is most common in diabetics using an intensive insulin regimen of 2 to 4 injections per day, and it is the most common reason why these patients fail to achieve tight glucose control. In the Diabetes Control and Complications Trial, patients on an intensive insulin regimen were 3 times more likely to experience hypoglycemia than patients in the standard treatment group.
Weight gain also is common in insulin users, especially with intensive regimens. This effect may be due to a combination of factors, including appe-tite stimulation, reduced glycosuria from improved glycemic control, and increased food intake to prevent or treat hypoglycemia.
Intensive insulin regimens for tight glucose control also may exacerbate preexisting retinopathy, and proliferative retinopathy should be treated in patients with poor glucose control prior to initiating an intensive regimen. Allergic reactions to insulins are much less commonplace with the use of biosynthetic and analogue insulins, but they still may occur. Most reactions are local, but life-threatening anaphylaxis is still a possibility.
Many types of devices exist for insulin users to enhance comfort and convenience. Insulin syringes that are filled by the patient are most common, but insulin may be delivered via a prefilled ?pen? device, via an external pump, or with jet injectors. The prefilled pen cartridge enables patients to dial in a dose for delivery, whereas the external pump provides a continuous basal infusion that may be supplemented with bolus injections at mealtimes or when preprogrammed glucose levels are reached. Jet injectors deliver insulin through a fine spray under high pressure rather than through conventional needles.
On the Horizon
Many exciting developments are on the horizon in insulin delivery that may enhance quality of life for insulin users. These developments include an implantable insulin pump, a transdermal patch, and delivery by inhalation. The surgically implanted insulin pump functions in the same manner as an external pump, delivering both basal and bolus dosing. The patch delivers insulin in a transdermal system similar to nicotine patches, with a tab that allows users to supplement dosing before meals.
Perhaps the most promising delivery system is the inhaled insulin system. Danish researchers recently reported the results of a small clinical trial involving more than 100 patients, in which glycemic control levels were similar in patients using standard subcutaneous injections and in those using aerosolized droplets in an inhaled nasal spray. Further studies in larger patient populations are needed, but it appears that this system may be the next major development in insulin delivery.
Today?s diabetic patients who require insulin for glycemic control have a distinct advantage over previous generations of users because of improvements in insulin purity, the advent of the human insulins, and the wide variety of delivery systems available. Research is ongoing to improve the quality of life for diabetics who use insulin. The future remains bright for patients with this chronic disease, and pharmacists can and should play a role in helping to secure this future for patients with diabetes.
The opinions expressed in this article are those of the author and do not necessarily reflect the views of the US Public Health Service or the Indian Health Service.
One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
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