Insulin is the most effective means of lowering blood glucose, allowing the body to maintain glucose within a normal range. In people with diabetes, there is either a complete absence of this naturally occurring hormone (type 1 diabetes) or there is an issue with diminished insulin secretion and/or insulin resistance (type 2 diabetes). The treatment of gestational diabetes may also include insulin therapy as oral agents are generally not approved for use in pregnancy. Exogenous insulin improves the body's ability to metabolize carbohydrate, store glucose in the liver, and convert glycogen to fat storage (Lilley et al., 2014). This article will review the various available insulin products and their use in the treatment of diabetes mellitus.
Commercially produced insulin was not available in the United States until 1923 when short-acting regular insulin required multiple injections a day (White, 2014). Prior to that time, people with type 1 diabetes died without insulin and those with type 2 slowly succumbed to multiple complications. Longer-acting insulin preparations were developed over the subsequent years but it was not until 1946 that neutral protamine Hagedorn (NPH) insulin was developed. NPH could be combined with regular insulin for injection. Until 1983 when DNA technology was used to develop human insulin, animal sources (mostly pork and beef) were used in the production of insulin (White). Since that time, a wide variety of human insulins have entered the market allowing more predictable insulin action and better individualization of insulin therapy. All insulin can be used in the treatment of type 1 and type 2 diabetes.
Insulin is the primary treatment in all patients with type 1 diabetes. It is essential for life, which is why type 1 diabetes was once called insulin-dependent diabetes mellitus or IDDM. In 1997, the American Diabetes Association (ADA) published new recommendations for the classification and diagnosis of diabetes stipulating the use of type 1 and type 2 with Arabic numbers only (not roman numerals) rather than IDDM/Type I and NIDDM/Type II (ADA, 1997). Although IDDM is still used to describe type 1 diabetes, it is no longer the preferred abbreviation. People with type 2 diabetes may also require insulin to attain glucose control due to a high level of insulin resistance and/or the decreasing ability of the pancreas to meet the bodily demands. The treatment of people with type 2 diabetes (previously referred to as NIDDM or Type II diabetes) will always include diet and exercise therapy and usually metformin as the first-line drug; however, insulin is considered in combination with oral agents when A1c is ≥7.5%. It is essential for treatment in those with an A1c >9% (Garber et al., 2015). With the insulin preparations available today, patients have more flexibility in timing meals but matching the insulin action to individual needs may be more complex.
Patients with type 1 diabetes typically require initiation with multiple daily injections (i.e., mealtime or bolus doses with rapid-acting agents and a once-daily dose of long-acting or basal insulin) at time of diagnosis. This is known as basal/bolus therapy (see below). The preferred method of insulin initiation in type 2 diabetes is to begin by adding a long-acting (basal) insulin to oral agents (Garber et al., 2015). If desired glucose targets are not met, rapid-acting (bolus or prandial) insulin can be added at mealtime to control the expected postprandial raise in glucose.
Basal/Bolus Insulin Therapy
Basal–bolus insulin therapy best mimics the natural insulin secretion of the body. Basal insulins such as glargine have a longer duration of action representing the ongoing low levels of insulin secretion needed to maintain normal glucose levels regardless of food intake. Bolus insulins such as aspart, glulisine, or lispro are shorter-acting agents given to manage glucose increase in response to food intake. Bolus insulin is often administered three times daily with meals (Freeland & Farber, 2015). Different types and formulations of insulin can be used to accomplish basal–bolus insulin dosing. Further details on these individual insulin types are described below.
Types of Insulin
The multiple types of insulin are characterized by differing pharmacokinetic profiles such as their onset, peak, and duration of action as well as their concentration (Table 1).
Basal or Long-Acting Insulin
Manipulating various side chains and/or amino acids in the insulin molecule has permitted availability of long-acting insulin (e.g., detemir, glargine, and degludec), allowing for slower absorption, “peakless” concentrations, and long duration of action. This better replicates normal basal secretion or constant insulin secretion providing a relatively steady level of daily insulin (Gururaj Setty et al., 2016). For many patients, initiation of insulin therapy begins with basal or long-acting insulin. Basal insulin slows hepatic glucose production and is required in a fasting state to maintain glucose homeostasis and provides a more consistent, background level of insulin. In general, basal insulin is administered once daily, every 24 hours at the same time each day. It is important to note that basal insulin (e.g., glargine) should almost always be administered regardless of food intake as this serves as the constant background insulin normally secreted by the pancreas to maintain normal glucose levels independent of food intake. Patients with diabetes who have normal glucose values should continue to receive their basal insulin doses even in the absence of caloric intake. NPH insulin can be administered as basal insulin; however, it requires twice-daily administration. The primary advantage of NPH as a basal insulin is financial, as it is typically less costly than long-acting insulin analogs.
Bolus or Prandial Insulin
The addition of a rapid-acting insulin for mealtime coverage along with a basal insulin as background gives flexibility in dosing. In this case, it is referred to as bolus insulin. These newer products or insulin analogs (e.g., aspart, glulisine, and lispro) differ from the human preparations (e.g., regular, NPH) by small substitutions in amino acid chains, which in turn prevent formation of polymers or hexamers that delay absorption and onset of action. The onset and peak action of the rapid-acting insulin analogs more closely represent endogenous postprandial insulin secretion in response to a meal. Because of its rapid onset it may be administered just prior to, during, or after meals. The mealtime dose can be adjusted to account for the carbohydrate content of a meal or the delay/absence of a meal. For patients whose appetite is widely variable, the prandial insulin dose can be increased, reduced, or omitted. Regular insulin may also be used as bolus or mealtime (prandial) insulin; however, it requires administration 30 to 45 minutes prior to meals. This need for specific timing in relation to meals makes regular insulin a less desirable choice for mealtime.
Premixed insulin preparations combine short/rapid and intermediate/long-acting insulin in a fixed ratio. Although this provides convenience for some and may be appealing to those who refuse more than two injections a day, it does not allow for flexibility in mealtime or changes in ratio of short- to long-acting insulin doses. Combining protamine with aspart or lispro allows for slow, continuous release and serves as the basal component of the combination with the lower percent of aspart or lispro serving as the bolus or mealtime component. The numbers expressed in the ratio after the insulin name refer to the percentage of the insulin in the premixed solution. For instance, Humalog® Mix 75/25™ is 75% insulin lispro protamine and 25% insulin lispro. Combining regular and NPH insulins is the least expensive way to premix insulin; however, it may be less desirable given the delayed onset of regular insulin.
Insulin that is two to five times more concentrated than commonly used U-100 is now available for patients requiring more than 200 units a day, such as those with severe insulin resistance or receiving high-dose steroids (Elliott & Reece, 2015). There are now concentrated insulins for regular, lispro and the long-acting basal insulins, glargine and degludec. The concentrated formulations allow subcutaneous administration of large doses of insulin in less liquid volume (Table 2). Timing of administration of concentrated insulins corresponds to their U-100 counterparts (e.g., 30 minutes before meals for U-500 regular, just prior to, during or after a meal for U-200 lispro, and once daily for the basal insulin). Additionally, U-500 regular insulin provides a slightly longer duration of action than U-100 regular (Lamos et al., 2016).
The least often used preparation is human insulin inhalation powder (Afrezza®). Administered at the beginning of a meal, it is an alternative to injectable bolus/prandial insulin. Pulmonary function must be assessed before initiation, after 6 months, and annually thereafter. It is contraindicated in patients with chronic lung diseases and has been associated with acute bronchospasm in patients with asthma and chronic obstructive pulmonary disease (Afrezza® Package Insert, 2015).
Given the numerous products and concentrations currently available, medication safety with regard to insulin dosing, administration, and monitoring is exceedingly important. There are several look-alike/sound-alike (LASA) products that are easily confused especially when brand or trade names are prescribed. For example, Novolin® is often confused with NovoLog® and Humulin® confused with Humalog®. Various concentrations of insulin further amplify the potential for LASA errors. It is most important that every practitioner be certain that the correct type and specific concentration of insulin is administered without error. If one were to inadvertently administer U-500 regular insulin in place of U-100 regular insulin at the volume indicated for U-100, the patient would receive a fivefold insulin overdose. Strategies such as auxiliary colorful labels highlighting insulin type and concentration may be used to safeguard against potential errors. Also, storing a basal insulin (e.g., in the bedroom area if dosed at bed time) separate from the bolus or mealtime insulin may help to diminish the potential for error. Using unsafe abbreviations such as using “u” rather than spelling out the word “units,” has contributed to significant insulin-related medication errors. The hand written “u” can be read as a zero causing 10u to appear and be given as 100, resulting in a 10-fold dose increase of insulin dose (Cobaugh et al., 2013). Practitioners should ALWAYS write or type out the word “unit” for any type of communication regarding insulin doses.
Another potential for error is type of syringe used to draw up insulin doses. Insulin syringes have markings to indicate “units” that correlate with U-100 insulin. Some are marked in 2-unit increments, others in 1-unit increments. These syringes are NOT to be used when withdrawing concentrated insulin. Very often tuberculin syringes are used to administer concentrated insulin by volume in milliliters rather than units. This can lead to significant confusion. It is extremely important that attention is paid to selection of the appropriate type of syringe used for U-100 insulin or one that simply provides degradations in milliliters as needed with concentrated insulin. Fortunately, insulin pen devices are now readily available to enable “dialing of a dose” corresponding to the type and concentration of insulin that eliminates errors associated with syringe sizes. Pens provide convenience and portability for patients in addition to more accurate dosing (Pfützner et al., 2013). Despite these potential advantages, use of insulin pen devices is associated with medication safety concerns as well. Insulin pens should NEVER be shared between patients. Reports of contamination and cross-contamination between patients have occurred when pen devices are shared between patients (Herdman et al., 2013). As with insulin vials, insulin pen devices can easily be confused if labels are not closely read each and every time insulin is administered. Again, use of additional external labels with large font and color may assist in safeguarding against potential errors.
Although commonly utilized, sliding scale insulin is not recommended as a routine method of glycemic management (ADA, 2016). Patients discharged from the hospital and/or new to insulin may have difficulty managing the complexities of this regimen in addition to learning to use a glucose meter and administer insulin. The extremes in fluctuating glucose values resulting from sliding scale administration are deemed to be far worse than continuous glucose elevation. The safest course is a consistent dose of basal insulin administration with an adjustable dose of mealtime or bolus insulin (Guthrie et al., 2011). This practice is endorsed by the ADA (2016).
Finally, although some insulin can be “mixed” and administered together in the same syringe, some should never be combined because of their differing pH levels. Insulins that should NOT be combined or mixed in the same syringe include: glargine, detemir, degludec, and U-200 lispro (Lilley et al., 2014). Regular and NPH insulin can be safely drawn up in the same syringe and administered. The appearance of NPH is “cloudy.” For this reason, when mixing two insulins (e.g., regular and NPH), it is recommended to draw up the clear product first (i.e., regular) and the cloudy insulin (i.e., NPH) second. The most important point to note is that not all insulin can be safely combined. When in doubt, always consult the specific product package insert under dosage and administration and/or reliable diabetes reference.
Patient Assessment and Teaching
For patients new to insulin, those changing to a different preparation, and even those who have been taking insulin for some time, assessment of diabetes self-care is imperative (Table 3). Glucose monitoring is an essential skill for patients taking insulin and should be evaluated by direct observation. Understanding personal glucose targets helps patients evaluate how insulin, activity, and food intake affect diabetes control.
All patients taking any type of insulin and their caregivers must be aware of the risk of hypoglycemia and be alert to the signs of low blood (glucose less than 70 mg/dL). They should be able to initiate treatment immediately. The most effective treatment for hypoglycemia is ingestions of 15 g of glucose in the form of glucose liquid or glucose tablets (both are available without prescription). A blood glucose less than 50 mg/dL requires 30 g of glucose for treatment. Treatment options should be at hand at all times. Pure glucose is preferred over other carbohydrate foods (ADA, 2016, p. S44). Although absorption and response are less predictable, other treatment options include 4 oz of fruit juice (fructose) or 6 oz of nondiet soft drink (Evert, 2014). Protein is not recommended for the treatment of hypoglycemia. Verifying hypoglycemia with a glucose meter and retesting/retreating after 15 minutes is considered standard practice (ADA, 2016). Treatment should not be delayed if hypoglycemia is suspected but a glucose meter is not immediately available. Caregivers of patients with type 1 diabetes should be knowledgeable in the use of glucagon for the treatment of severe hypoglycemia. All episodes of severe hypoglycemia or repeated episodes of mild hypoglycemia should be reported to the provider.
Directly observing insulin injection technique can reveal misconceptions and errors not only for insulin preparation and injection, but also site selection. Patients new to using an insulin pen device may need extra teaching. Video demonstrations and printable instructions are available at drug company Web sites. There is variation in the devices so that specific instructions should be provided for the specific pen to be used. All people with diabetes should receive education according to national standards (ADA, 2016), so referring patients to a Diabetes Self-Management Education Program is important. Another excellent source for patient education tools is the National Diabetes Education Initiative™. This program is sponsored by the National Institutes of Health and the Centers for Disease Control and Prevention. Resources are available at http://ndep.nih.gov/resources/diabetes-healthsense.
It is an exciting time in diabetes care given the expanding options available for both oral antidiabetic agents and insulin. But with the multitude of products now available, it is extremely important that practitioners understand the differences in products. Insulin is an essential drug in the treatment of diabetes but it is also a high-risk medication. Errors in its use can have devastating consequences. Understanding the differences in insulin preparations and their use reduces errors. The use of insulin in the home care setting is a common occurrence. Both patients and caregivers are frequently asked to manage diabetes care and maintain a safe glucose range at home. Clinicians with a clear understanding of insulin therapy can assist in this effort by ensuring safe insulin use and careful glucose monitoring. Understanding the onset, peak, and duration of various insulin preparations assists in troubleshooting glucose excursions. Close attention must be paid to each and every insulin dose administered. Supporting patients on optimal insulin use, monitoring, and safe practices will promote glycemic control and overall positive outcomes.
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