Basal Insulin Therapy in Type 2 Diabetes Management: What the Pharmacist Should Know

Introduction

In 2018, an estimated 26.9 million Americans had a diagnosis of diabetes, with type 2 diabetes (T2D) accounting for 90%–95% of cases.¹ Community pharmacists are in a unique position to provide education and advice regarding the management of diabetes using basal insulin (BI) therapy. The importance of this role is likely to increase as the number of people with diabetes continues to grow.²

The year 2021 marks the 100th anniversary of the discovery of insulin by Frederick Banting and John Macleod;^3,4 since then, insulin therapy has evolved considerably (Figure 1^4-6). The first BI analog, insulin glargine 100 units(U)/mL⁷ (Gla-100), introduced in 2000, was a breakthrough in the field of insulin therapy and continues to be a gold standard treatment.⁸

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This was followed by insulin detemir U100⁹ (IDet) in 2005. It was another decade before the second-generation BIs, insulin glargine 300 U/mL¹⁰ (Gla-300) and insulin degludec (IDeg U100 and IDeg U200)¹¹ were approved. Many people with long-standing T2D require insulin therapy. Table 1 summarizes recommendations for the use of BIs in people with T2D.^12,13

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Here, we provide guidance on the use of BIs and insulin pens to enable pharmacists to answer questions regarding the safe and effective use of BI for the management of diabetes.

Why is insulin needed?
T2D is a progressive, multifactorial disease with several pathophysiologic abnormalities (in muscle, pancreas [alpha- and beta-cells], fat, and the liver, gut, kidneys, and brain), known as “the ominous octet” (Figure 2).^14-16 In particular, the decline in function of pancreatic beta-cells is a constant, worsening feature resulting in an inability to produce insulin.

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In fact, by diagnosis, approximately 40%–50% of beta-cell function is lost, with a further loss of 4%–5% each year thereafter.¹⁷ Therefore, exogenous insulin is needed to replace that which would normally be produced by beta-cells.

The aim of using BI is to provide glucose control throughout the day, achieved through a duration of action of up to 24 hours or, in the case of second-generation BIs, 36–42 hours (Table 2^7,9-11,18-22). Thus, BI is often the first type of insulin used in the management of T2D.¹²

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Key Differences in BI Formulations: (1) Stable vs Peaks in Insulin Activity; (2) Duration of Action (≤24 vs >24 h); (3) Variability in Insulin Exposure

Several different BIs are available (Table 2). The second-generation BIs Gla-300 and IDeg provide a longer duration of action than Gla-100 or IDet (Figure 3). Gla-300 and IDeg-U200 deliver the same number of units as the first-generation BIs and IDeg-U100, in a smaller volume—one-third of the volume for Gla-300 and half for IDeg-U200.^19,23

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In studies comparing pharmacokinetic (PK)/pharmacodynamic (PD) profiles of Gla-300 or IDeg-U100/U200 with Gla-100, the second-generation BIs have shown a longer duration of action (>24 vs ≤24 h) and more stable glucose profiles with less variability throughout the day and between days.^24-26 Second-generation BIs have longer half-lives than first-generation BIs (19 and 25 h for Gla-300 and IDeg, respectively), so it takes 4–5 days to reach 80%–90% steady state.¹⁹

Therefore, it is not recommended to make dose increases more often than every 3–4 days. To those receiving insulin, this may be perceived as a delay in efficacy; it is recommended to proactively inform people about this.

Understanding insulin concentration is critical. In general, when converting from one BI to another, a 1:1 conversion is used. For example, 10 units of Gla-100 or IDet or IDeg-U100 is the same as 10 units of Gla-300 or IDeg-U200. The second-generation BIs deliver the same number of units of insulin in a smaller volume. Some patients may require a slightly higher dose of Gla-300 when converting from glargine 100U.¹⁰ Dosing changes are summarized in Table 3.

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When should I request further information from the prescriber or query the prescription?

BIs are usually administered once daily. If a patient has a prescription for a first-generation BI prescribed twice a day, this could be because it may not be providing 24-hour coverage, or the prescribed dose is greater than 80U. Second-generation BIs (Gla-300 or IDeg), which are administered once daily due to their longer half-lives, and because of availability of higher capacity pens that allow up to 160U per injection, could simplify delivery of insulin for those in whom doses >80U are required.

To avoid over-basalization, it is important to contact the prescriber if it appears that the BI dose has been titrated beyond an appropriate level without achieving glycemic control, which can occur because treatment guidelines do not provide a definitive upper dose limit.²⁷

The American Diabetes Association Standards of Care state that BI doses greater than ∼0.5 U/kg, high bedtime-morning or post-preprandial glucose differential (e.g. ≥50 mg/dL), hypoglycemia, and high variability, are all clinical signals that should prompt evaluation for over-basalization.¹² This could be an indication that mealtime insulin coverage is required.

Other situations for pharmacist intervention are if the prescribed insulin is not covered by a patient’s health plan or is not listed as a preferred formulary item, or if the patient has a duplicate prescription. If the patient has received unclear or incorrect instructions regarding titration, this may be solved by providing the correct information, or by referring the patient to the prescriber or diabetes educator.

How is BI Administered?

BI can be taken in addition to oral antihyperglycemic medications and GLP-1 RA therapies. When starting BI, oral medications (except for sulfonylureas) and GLP-1 RAs are usually continued. Metformin is continued unless there is a contraindication (estimated glomerular filtration rate <30 mL/min/1.73 m2).¹² Sulfonylureas may need to be discontinued to avoid hypoglycemia.

BI is usually injected via an insulin pen. Many people prefer insulin pens to the vial and syringe method²⁸ because they are perceived to be safe and convenient to use with low risk for medication errors.²⁹ The second-generation BIs have more units of insulin per pen, which means each pen will last longer.

Insulin pens are generally packaged in boxes of 1 to 5. In 2019, the FDA issued a recommendation that insulin pens should be dispensed in the original sealed box and not individually; however, the FDA recognizes that HCPs may use their professional judgement to dispense individual pens.³⁰ An overview of the different insulin pens is provided in Table 4.^7,9-11,18,31

Injection guidelines recommend use of a 4-mm pen needle to avoid intramuscular injection.³² Needles should be used only once. All BIs are recommended to be injected at the same time each day, except IDeg, which can be taken at any time as long as there is an 8-hour window between doses.¹¹ If a patient misses a BI dose, they should be advised to contact their health care provider for advice.

Use and Storage of Insulin Pens

The pharmacist should be knowledgeable about the differences between insulin pens. Unopened insulin should be refrigerated (39.2 to 46.4^oF). As injection of cold insulin can be painful, insulin pens should be removed from the refrigerator at least 30 minutes before use. Once removed, pens can be stored at room temperature; storage times at room temperature vary between pens (Table 4). When traveling, it is advisable to pack double the amount of insulin needed and prearrange to pick up extra supplies in case insulin is lost or is not useable.³³

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If traveling by air, insulin should be kept in hand luggage, such as a coolbag/box, polystyrene container, or wide-necked vacuum flask.³³ In a hot climate it is advised to keep insulin in a refrigerator, otherwise in the coolest, darkest part of the room, and if it gets too hot, cover it with a cold, wet cloth.³³

The insulin pen needle has several components (Figure 4). To install the needle, remove the paper tab from the outer shield, screw the needle onto the pen (do not over-tighten), pull the outer shield off and put it aside (it will be needed to remove the needle from the pen), then pull the inner shield off and discard.

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The pen needs to be primed prior to each use to ensure it is working properly and to remove any air bubbles. To do this, dial the number of units per the pen instructions and then press the button to shoot some insulin into the air. If insulin drops are not seen after repeated priming and ensuring proper placement of the pen needle, the pen should not be used.

Sometimes when the pen needle is attached to the pen, insulin drops may be seen, but priming still needs to be performed. Once primed, turn the dial to the correct dose. Patients should be aware of the number of units by which the dial increases the dose (1U or 2U, depending on the pen; Table 4). Double-check the dose before injecting. Clean the chosen injection site with alcohol and allow to dry.

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Do not inject into areas that have wounds or bruising and vary/rotate the injection site to avoid lumps or swelling. After injection, wait before removing the needle from the skin as indicated in the specific instructions for the pen in use (Table 4). Bleeding is rare; if blood is seen, press on the injection site for 5–10 seconds, do not rub the skin. Put the outer shield back on the needle and remove and safely dispose of the needle. Replace the cap on the pen.

BI Titration

The ADA Standards of Care state that starting doses of BI can be estimated based on body weight (0.1–0.2 U/kg/day) and degree of hyperglycemia.¹² The most common titration schedules specify following a treat-to-target schedule or increasing dose by a set amount every 2–3 days,³⁴ or every 3–4 days for the second-generation BIs, Gla-300 and IDeg (U100/U200).^10,11

The decision on which schedule to use should be based on a discussion between the clinician and the patient, comfort of both parties, and follow-up plans.³⁴ Other evidence-based algorithms may be used.³⁵ Patient-led titration has been shown to be non-inferior to physician-led titration, suggesting that diabetes self-management education and support programs on BI should be widely adopted in clinical practice.³⁵

What are the Adverse Effects of BI?

Hypoglycemia

Regardless of the type of insulin taken, people who receive insulin therapy need to be aware of the symptoms of hypoglycemia (sweating, tiredness, dizziness, hunger, tingling lips, feeling shaky, palpitations, turning pale, and being easily irritated, tearful, anxious, or moody).³⁶

Hypoglycemia is a particular concern during intensification of insulin treatment, for example, when a prandial insulin is added to BI. Fasting self-monitored blood glucose, use of real-time continuous glucose monitoring systems, and appropriate titration of BI can reduce the risk of hypoglycemia, as can dietary and lifestyle changes.

Studies have demonstrated a reduced risk of overall documented or severe hypoglycemia, and severe nocturnal hypoglycemia in those receiving second-generation BIs versus first-generation BIs; the reduction in A1C is comparable.^37-42

All patients injecting BI should be educated on management of hypoglycemia. Having glucagon available for use in an emergency would be prudent and is another area in which a pharmacist can make an intervention.

Weight gain

Modest weight gain is a common adverse effect of insulin therapy and is similar for second-generation and first-generation BIs.^38-40

Individual weight loss needs can be addressed on personal and cultural preference. For those who are overweight or obese, diet, physical activity, and behavioral therapy designed to achieve and maintain ≥5% weight loss are recommended.¹²

Other adverse effects

It is important to be aware of other adverse reactions that can occur after injection of BIs.^{7, 9-11} With all insulin products, allergic reactions, including severe life threatening allergic reactions (anaphylaxis), can occur, however these are rare.⁴³ Injection site reactions, including pruritus, rash and edema can also occur,^{7, 9-11} these are often self-limiting. Some patients may experience lipodystrophy (abnormal fat distribution) with long term use of insulin.^{7, 9-11}

Conclusions

The advent of the BIs in the early 2000s provided an important treatment option to help people with T2D achieve glycemic control. Second-generation BIs have more stable and longer PK/PD profiles with similar efficacy to first-generation BIs, but with lower risk of hypoglycemia. In addition, second-generation BIs have a variety of pen options with larger capacities and the ability to offer once-daily dosing, even for patients who require high doses.

By being able to explain why BI is needed and how to administer and titrate BI, and educate on the potential adverse effects, the pharmacist can play a vital role in empowering people with T2D to control their blood glucose more effectively.

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Authorship

Jennifer Goldman, PharmD, CDES, BC-ADM, FCCP, Department of Pharmacy Practice, School of Pharmacy, MCPHS University, Boston, MA, USA and Clinical Pharmacist, Well Life Medical, Peabody, MA.

Dhiren Patel, PharmD, CDE, BC-ADM, BCACP, Department of Pharmacy Practice, School of Pharmacy, MCPHS University, Boston, MA, USA and Department of Endocrinology, VA Boston Healthcare System, Boston, MA, USA.

Viral N. Shah, MD, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Acknowledgments

The authors received medical writing support in the preparation of this manuscript provided by Barrie Anthony, PhD, CMPP, and Helen Jones, PhD, CMPP, of Evidence Scientific Solutions, funded by Sanofi US.

Disclosures

VNS reports receiving research support through University of Colorado from Sanofi US, NovoNordisk, Eli Lilly, Insulet, Dexcom, vTv Therapeutics, Mylan GmbH, NIH, and JDRF. VNS served on the advisory boards of Sanofi US and Medscape LLC.

JDG reports being a member of speakers’ bureaus for Abbott, Amarin, Eli Lilly, NovoNordisk, Sanofi, and Xeris.

DP is an advisor/consultant for Bayer, Eli Lilly, Insulet, Novo Nordisk, and Sanofi, and is on speakers’ bureaus for Abbott, Amarin, AstraZeneca, Boehringer Ingelheim, Dexcom, Eli Lilly, Merck, Novo Nordisk, Xeris, and Zealand.

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