The Nuances Surrounding Insulin Prescribing (2024)

Abstract

Knowledge of and expertise in insulin prescribing is crucial for health care providers who care for people with diabetes. This article reviews the available insulin preparations, how they are packaged, and nuances related to storage and use that inform the prescribing of this life-saving medication for patients. Insulin prescribing that is done correctly will save time and reduce problematic errors that could put patients at risk.

Approximately 34 million people in the United States (10.5% of the population) have diagnosed or undiagnosed diabetes (1). Insulin is an absolute requirement for people with type 1 diabetes and is necessary for glucose control for up to one-third of those with type 2 diabetes. Throughout the past century, the initial prototype insulin product has undergone multiple improvements with regard to purity, extended duration with the addition of protamine, and, more recently, recombinant technology that has allowed the development of insulin analogs with different pharmaco*kinetic properties (2). These advances have resulted in a plethora of new insulin formulations and have been accompanied by technological advances including the development of disposable insulin pens with fine needles, insulin pumps, and digital connected, or “smart” insulin pens. A recent categorical change of insulin from a drug to a biologic by the U.S. Food and Drug Administration (FDA) will foster an increase in available biosimilar insulin products that will add options, but also complexity, for health care providers (HCPs) (3).

This article discusses the currently available insulin products, including different formulations and concentrations of insulin as well as available delivery devices. Its goal is to assist HCPs in better understanding the nuances of insulin prescribing, which in turn will improve care for people who either use insulin injections or continuous subcutaneous insulin infusion (insulin pump therapy). Knowledge of the many formulations of insulin and their delivery devices will allow insulin prescribers to match their patients’ needs with the most appropriate type of insulin and the most appropriate delivery method, while reducing prescribing errors.

Diabetes HCPs should be able to accurately prescribe insulin to individuals with differing insulin requirements, from those requiring very low doses to those needing hundreds of units of insulin per day. People with type 2 diabetes and moderate hyperglycemia on noninsulin therapies may require only long-acting insulin, whereas those with type 1 diabetes, severe type 3c diabetes, or type 2 diabetes not well managed with basal insulin alone will require more complex regimens for physiologic insulin replacement. Patients who use a multiple daily injection (MDI) insulin regimen require both long-acting and rapid-acting insulins, generally delivered by either pen devices or insulin pumps. Most are taught to adjust their insulin doses, and variations in total daily dose (TDD) requirements are common.

The American Diabetes Association recommends that people with type 1 diabetes or those with type 2 diabetes on MDI therapy consider using an insulin pump with automated insulin delivery (AID) functionality to improve overall glucose control and reduce hypoglycemia (4). As these modern pumps and other insulin delivery devices become the standard of care, all diabetes HCPs will need to know how to manage the care of people who use them, including how to appropriately prescribe insulin, which is the focus of this review.

Insulin Preparations and Packaging

Insulin is packaged in various ways that can be broadly classified as vials, prefilled pens, and cartridges and allow insulin to be administered via different modalities (Supplementary Table S1). Vials of insulin are available for long-, intermediate-, short-, rapid-, and ultra-rapid-acting insulins, as well as premixed insulin products and the concentrated U-500 (500 units/mL) regular insulin formulation. Paying attention to the various sizes of vials and to the concentration of the insulin prescribed is important because these factors determine the number of units of insulin available per prescription. The most common type of insulin vials contain 10 mL and can be prescribed for all of the available insulins except for some long- acting products, including glargine-aglr, glargine U-300 (300 units/mL), and the glargine biosimilar Basaglar, which are only available in pen devices. For patients requiring very low doses of insulin, 3-mL vials are available for the rapid-acting lispro biosimilar Admelog, short-acting regular insulin, intermediate-acting NPH insulin, and the premixed 70/30 isophane/regular insulin combination (5–7). The difference between a 10-mL and a 3-mL vial is important. For example, if the insulin concentration is 100 units/mL (U-100), then a 10-mL vial will contain 1,000 units of insulin compared with 300 units in a 3-mL vial. U-500 regular insulin, which is ultra-concentrated, is uniquely available in a 20-mL vial, which holds 10,000 units and should be used with a dedicated U-500 insulin syringe (8). Using insulin from vials requires that it be drawn up with a syringe before it can be injected or added to a pump cartridge or reservoir. Patients need adequate vision and dexterity to manage this process and sufficient training to avoid errors. For these reasons, and for more accurate dosing, most insulins are now available in prefilled pens.

Prefilled insulin pens are available for every type of insulin, including long-, intermediate-, short-, rapid-, and ultra-rapid-acting formulations, as well as premixed insulin, and U-200 (200 units/mL), U-300, and U-500 insulin formulations. Insulin pens typically contain 3 mL of insulin, which equates to 300 units of insulin per pen, assuming the insulin concentration is 100 units/mL. Insulin lispro and lispro-aabc are also available in a concentrated U-200 formulation, which increases the 3-mL pen capacity to a total of 600 units (9,10). Similarly, U-200 insulin degludec is available in a 3-mL pen containing a total of 600 units. U-500 regular insulin is the most concentrated insulin available in a prefilled pen, with each pen containing 1,500 units of insulin (8).

The long-acting insulins are generally available in concentrations of 100 units/mL with two exceptions: glargine U-300 and degludec U-200 (11,12). The standard U-100 pens deliver insulin in 1-unit increments to a maximum bolus of 60–80 units. Lispro and lispro-aabc are also available in U-100 pens that deliver doses in 0.5-unit increments up to a 30-unit maximum bolus (9,10). U-200 lispro and lispro-aabc insulin pens deliver insulin in 1-unit increments up to 60 units. Degludec U-200 pens deliver insulin in 2-unit increments. Glargine U-300 is available in 1.5- or 3-mL pens that hold 450 and 900 units, respectively (11). Glargine U-300 also comes in a pen that delivers 1-unit increments up to an 80-unit maximum bolus and another pen that delivers 2-unit increments up to a 160-unit maximum single dose (11). The U-500 regular insulin pen delivers insulin in 5-unit increments to a 300-unit maximum dose for highly insulin-resistant patients (8).

When prescribing insulin to be delivered by either pens or vials and syringes, HCPs must account for the 2 units of insulin required to prime a pen before each dose to eliminate air bubbles that can lead to erroneous dosing. Priming (sometimes called “air shots”) can add 6–8 units/day to a patient’s TDD with U-100 insulins and even more with concentrated insulins. The prescription should reflect this added requirement.

A sample prescription might provide these directions: “Take up to 10 units before meals, up to 6 units for snacks, plus 8 units for priming of the pen (or syringe), for a total daily dose of up to 44 units.” A 30-day supply of insulin increases from 900 units (three pens or one vial per month for the dose typically administered) to 1,320 units (five pens per month or five vials for 3 months) when the additional factors are considered. When prescribing insulin pens, the quantity of insulin to be dispensed can be ordered in milliliters (e.g., “15 mL” will provide a box of five pens of most insulins).

The two newer formulations of ultra-rapid-acting insulin aspart and lispro-aabc retain the same structure as their rapid-acting analogs but have altered excipients for faster absorption (9,13). This change allows both insulins to be used before meals or within 20 minutes after the start of meals, which can be helpful for people who are unable to take prandial doses several minutes before their meals. Insulin cartridges of rapid- and ultra-rapid-acting insulins are available for lispro, lispro-aabc, aspart, and faster-acting aspart insulins. These 3-mL cartridges contain 300 units of insulin and are sold in packs of five for use in reusable pens and smart insulin pens.

The choice of pens versus vials should be based on patient characteristics and shared decision-making. Vials and syringes are less expensive and may be appropriate for people taking moderate to larger doses of insulin. Insulin pens provide more accurate dosing, particularly at low doses. Note that people with vision impairment can often self-manage their diabetes with insulin pens by listening and sensing the number of clicks, which represent the number of units that will be taken. Prescribers should watch patients with tremor or other dexterity problems administer insulin to ensure that they are able to manage the prescribed pen device. Some pens require users to forcefully push a thumb screw or dose knob, whereas others use a push button mechanism with low injection force needed per dose.

The most rapidly acting of all insulin products is the ultra-rapid-acting inhaled insulin Afrezza, which is human insulin powder absorbed to technosphere particles to allow for alveolar absorption (14). The insulin is available in 4-, 8-, and 12-unit single-use cartridges that are placed in a small inhaler device. To achieve the right dose, one or more cartridges (necessitating one or more inhalations) can be administered per meal. Packaging includes three cartridges per blister strip, which are placed on a card with 15 total cartridges per card. Afrezza is available in packages containing 90–180 cartridges with varying cartridge doses and two inhalers per pack. The inhaler device should be replaced every 15 days. Opened cartridges within opened strips must be stored at room temperature and used within 3 days. Afrezza has the advantage of avoiding injections while offering the most rapid absorption and peak of all of the available insulins.

Insulin Administration

Insulin that is administered subcutaneously with insulin syringes or insulin pens or through infusion sets connected to an insulin pump share some of the same potential problems. Instructing patients on the art of injecting insulin is crucial to avoid a gamut of possibilities, including total lack of absorption; repetitive injection into the same site, leading to lipohypertrophy; or injection into muscle, leading to too-rapid absorption. Certain areas of the body absorb insulin more quickly than others. The difference is proportional to the average thickness of the skin that must be penetrated to reach the subcutaneous layer (28). The following body areas are ordered from most rapid to least rapid insulin absorption: abdomen, back of arms, thighs, and buttocks (28). Site rotation is a crucial step to avoid lipohypertrophy. In one study, 21% of individuals who administered two to five injections per day used the same injection site for the entire day or even for a few days, a practice that may result in lipohypertrophy or other skin changes (29).

Insulin syringes are plastic and disposable and are available with various needle gauges and lengths. Insulin syringes come in different sizes, including 0.3-, 0.5-, and 1.0-mL sizes that hold up to 30, 50, and 100 units of insulin, respectively. Needle gauges are 28–31, with 31 being the finest gauge. Needle lengths are typically 5, 6, 8, and 12.7 mm (3/16, 5/16, 8/16, and 1/2 inch, respectively). Similarly, pen needles have various lengths and gauges, including lengths of 4, 5, 6, 8, and 12.7 mm and gauges from 29 to 32. The thickness of the needle, known as the gauge, is important in that the higher the gauge is, the thinner the needle will be. The thinnest available pen needle is 32 gauge, and the thinnest insulin syringe needle is 31 gauge. Although thinner needles are more comfortable for patients, they also have a tendency to bend more easily (30).

Based on guidance from the 2015 Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop, a 4-mm needle is considered the safest pen needle for adults and children regardless of age, sex, ethnicity, or BMI (31). In patients with obesity, a 4-mm needle can still be used effectively and safely, although a 5-mm needle is also acceptable (31). Longer needles are generally not needed for insulin injection, but they might make it easier to withdraw insulin from a vial. Insulin syringes or pens should be held at a 90° angle for most individuals or injected into a skinfold at <90°. A 45° angle may be used for individuals who are unable to lift a skinfold and are using a 6-mm needle (28,31).

When prescribing pen needles, it is helpful to know that pharmacies package them in boxes in quantities of 50 or 100. Insulin syringes are supplied in packages of 10 or boxes of 100. At a minimum, insulin pump users need to have a supply of insulin syringes on hand for pump failure situations. Infusion sets deliver insulin from the pump to the subcutaneous space via tubing and cannula. Infusion sets are broadly divided as either angled (inserted at a 30° angle) or straight (inserted at a 90° angle). Site rotation every 2–3 days has been the standard wear-time (32). Medtronic pumps now offer a 7-day infusion set.

Additionally, NPH or premixed insulins (70/30 isophane and short-acting regular insulin, 75/25 insulin lispro protamine and insulin lispro, and 70/30 insulin aspart protamine and insulin aspart) require suspension of the insulin by rolling and turning the vial or pen prior to injection. In one study, 35% of individuals did not resuspend their insulin as recommended (29).

Pharmacy Issues

When calculating how much insulin a patient requires each month, HCPs must take into account the patient’s maximum daily insulin requirements, including what will be needed for patients who use carbohydrate counting and a correction scale to determine bolus doses. According to the Centers for Medicare & Medicaid Services, when calculating day supply (i.e., how many days a prescription will cover) of insulin, one first needs to calculate the total number of units to be dispensed by multiplying the number of units/mL (e.g., 100 units/mL) by the number of millimeters to be dispensed (e.g., a 3-mL pen). Then divide the total number of units to be dispensed (e.g., 300 units) by the total units prescribed per day (e.g., 10 units). In this example, a total of 300 units will be dispensed for a 30-day supply (36). Prescribers should consider small, 3-mL vials or pens for patients who use low doses of insulin. When determining day supply, prescribers also need to take into account the expiration date of the vial or pen after it is opened. For example, insulin lispro is only stable for 28 days at room temperature; thus, the maximum day supply should be 28 days. Prescribers may need to add notes to the pharmacy for insulin quantities that do not match the day supply limit.

The day supply limit is the number of days the prescription is written to cover plus the extra days of insulin supplied because of the fixed amount of insulin in vials and pens. Rounding to the next available vial and/or pen size to meet the required day supply has caused issues for pharmacies through the years. To meet the day supply limit covered by insurance companies and pharmacist benefit managers, it was common practice for pharmacy personnel to split pen boxes and dispense pens outside of their original cartons. The concern with this practice is that the insulin pens are not labeled by the manufacturer for individual dispensing. To circumvent this issue, some retail pharmacies dispense and bill for a full carton of insulin pens. If a patient’s health plan denied a claim because of a day supply limit, the pharmacy would reduce the day supply to conform with the plan day supply limit without adjusting the quantity of the insulin dispensed (37). This resulted in dispensing additional insulin pens in greater quantities than required for patients during a fill period.

The United States filed a health care fraud lawsuit against Walgreens for improperly billing federal health care programs using this billing practice. A settlement occurred in 2019, and Walgreens was required to pay $269.2 million to resolve allegations that it improperly billed federal health care programs for thousands of insulin pens that were not required (38,39). In November 2019, the FDA approved labeling revisions to emphasize the dispensing of insulin pens in the original sealed carton.

Individual community pharmacies and pharmacy corporations will have their own policies for handling insulin pen dispensing, breaking boxes, and addressing day supply issues. However, many pharmacists will submit for or call a patient’s insurance company to request an override for the day supply limit, and this approval is at the discretion of the insurance company (40). The majority of insulin pen cartons contain two to five pens; however, the FDA approved the first single-pen carton (for the glargine biosimilar product Semglee) on 11 June 2020 (41). Whether other insulin manufacturers will relabel pens for individual sale is unknown.

Conclusion

The landscape around insulin and its available preparations, new technologies, and cost and coverage issues has changed dramatically since its discovery in 1921. Various formulations and delivery modalities have altered the way HCPs treat their insulin-requiring patients, and this, in turn, has led to improvements in patient care. Awareness of the complexities surrounding insulin prescribing is invaluable to today’s HCPs. Understanding the history of insulin manufacturing, relevant federal and state laws, and pharmacy-level constraints can improve insulin prescribing. HCPs who treat people with diabetes can improve patient care by selecting the optimal insulin product, delivered in the most appropriate device, to meet each patient’s needs. To accomplish this goal, HCPs must be aware of all available insulin and insulin delivery options.

Article Information

Footnotes

References