Longer-acting basal insulin analogs: What, how, why, when, and who?
There has been no shortage of new products approved for the treatment of diabetes in recent years, including a host of new insulin products and delivery devices. In 2015, two new basal insulin analogs, U-300 insulin glargine (Toujeo®) and insulin degludec (Tresiba®), were approved by the US Food and Drug Administration (FDA). These analogs boast a duration of action in excess of 24 hours, making them longer acting when compared with other basal insulin products. The following article provides a discussion of what these products are, how they are recommended to be initiated and titrated in patients with diabetes, why they are available in pens only, when they should be administered, and who may benefit from the potential advantages of these products.
What are longer-acting basal insulin analogs?
U-300 insulin glargine is a concentrated insulin product that contains 300 units/mL of insulin glargine. This concentrated glargine product has a longer duration of action when compared with U-100 insulin glargine (Lantus®). U-300 insulin glargine is commercially available in disposable prefilled pens only . U-300 insulin glargine was approved by the FDA in 2015 for use in patients with type 1 and type 2 diabetes mellitus.
Insulin degludec, like U-300 insulin glargine, is available in prefilled pens only and is available in two formulations: U-100 and U-200. Insulin degludec was also approved by the FDA in 2015 for use in patients with both type 1 and type 2 diabetes.
Table 1 provides a summary of product availability and dosing capabilities for these longer-acting basal insulin products.
Table 1. U-300 insulin glargine and insulin degludec product availability [1, 2]
|Product||Availability||Dosing range (per injection)|
|U-300 insulin glargine||Prefilled pens (450 units/pen)||1–80 units (1 unit increments)|
|Insulin degludec||U-100 prefilled pen (300 units/pen)||1–80 units (1 unit increments)|
|U-200 prefilled pen (600 units/pen)||2–160 units (2 unit increments)|
How is it recommended that these longer-acting basal insulins be initiated and titrated?
Manufacturer recommendations for longer-acting insulin initiation/conversion
The manufacturers for both U-300 insulin glargine and insulin degludec provide guidance on how to start patients on these longer-acting basal insulin products (Table 2) [1, 2].
Table 2. Recommendations for U-300 insulin glargine and insulin degludec initiation [1, 2]
|Prior treatment||U-300 insulin glargine starting dose (administered once daily)||Insulin degludec starting dose (administered once daily)|
|Insulin naïve (type 2 diabetes)||0.2 units/kg body weight||10 units|
|Once-daily intermediate- or long-acting insulin||1:1 (unit per unit) conversion||1:1 (unit per unit) conversion*|
|Twice-daily NPH||80% of total daily NPH dose|
|* In pediatric patients 1 year of age and older with type 1 or type 2 diabetes, it is recommended that insulin degludec be started at 80% of the total daily long or intermediate-acting insulin dose to minimize the risk of hypoglycemia.|
NPH=neutral protamine Hagedorn
Caveats for converting patients from another intermediate or long-acting basal insulin
There are a few caveats that should be considered with both products when converting to a longer-acting basal insulin from an intermediate- or long-acting basal insulin.
U-300 insulin glargine
When converting patients from U-100 insulin glargine it should be expected that a higher dose of the concentrated product will be required to maintain the same level of glycemic control . In clinical studies, patients required a 14% higher dose of U-300 insulin glargine to reach comparable effectiveness with U-100 insulin glargine [3, 4].
The general recommendation when converting patients from intermediate or long-acting insulin to insulin degludec is to do so in a 1:1 fashion . The exception to this is in pediatric patients, in which case it is recommended to start conservatively at 80% of the total daily dose of intermediate or long-acting insulin to minimize the risk of hypoglycemia.
Considerations for titration
As with all insulin products, U-300 insulin glargine and insulin degludec should be titrated based on patient-specific goals and blood glucose monitoring data. It is also important to keep in mind that, due to the relatively long half-life and duration of action of these insulin products, they should be titrated no more frequently than every 3–4 days to avoid over accumulation and associated risk for hypoglycemia.
Why are longer-acting basal insulins available in prefilled pens only?
A primary concern with concentrated insulin products is the risk for insulin overdose. Prior to the recent approval of U-200 and U-300 insulin products, the primary experience with concentrated insulins was with U-500 regular insulin. The recent marketing of U-500 insulin pens and U-500 insulin syringes has drastically improved the safety of U-500 insulin use. Prior to the introduction of these delivery devices, U-500 insulin was associated with the risk of fivefold dosing errors when administered via U-100 insulin syringes .
Given the risk and historical experience with U-500 insulin, manufacturers of U-200 and U-300 insulin products have wisely marketed these products in prefilled pens only. Why is this important? Patients need only dial their prescribed dose and no conversion or calculation is needed when dosing these concentrated insulin products. In essence, the patient need only dial the desired number of units and the pen will deliver the appropriate dose and volume of insulin. This eliminates the risk of two- and threefold dosing errors with these products.
Important counseling points
- Patients need only dial the prescribed dose of insulin on the insulin pen. No dose conversion is needed as the pen will deliver the appropriate volume of insulin.
- Never use an insulin syringe to remove insulin from the prefilled insulin pens.
When should longer-acting basal insulins be administered?
Historically, an important counseling point with basal insulin products has been ensuring patients administer their insulin at the same time each day. This recommendation is well founded for the following reasons.
- First, patients develop a routine and are less likely to forget to take their insulin.
- Second, basal insulin products like insulin detemir (Levemir®) and U-100 insulin glargine have durations of action that do not exceed 24 hours; therefore, consistent injection timing from one day to the next is required to achieve consistent basal insulin coverage and avoid end-of-dose wearing off and associated hyperglycemia.
Because longer-acting insulin analogs have a duration of action that exceeds 24 hours, these insulins are less dependent on consistent administration timing to provide adequate basal coverage. Indeed, the manufacturers of both U-300 insulin glargine and insulin degludec conducted clinical trials to test the impact of flexible administration timing on glycemic outcomes [5, 6]. In the study of U-300 insulin glargine, patients dosed their insulin every 24±3 hours , while in the insulin degludec study patients were scheduled to dose their insulin to create dosing intervals that ranged from 8 to 40 hours between injections . Both studies reported that flexible dosing had no impact on efficacy or safety [6, 7].
Who may benefit from use of a longer-acting basal insulin?
Considering these longer-acting basal insulins are more costly than other intermediate- and long-acting basal insulin options, who may benefit from the potential advantages that these longer-acting basal insulins have to offer?
- Patients in whom their current basal insulin does not last a full 24 hours. While many patients do well on once-daily U-100 insulin glargine or insulin detemir, some patients experience end-of-dose wearing off, where their blood glucose tends to rise at the end of the dosing interval. Transitioning such a patient to a longer-acting basal insulin product can help them achieve better fasting glucose control with a single daily injection.
- Patients with hectic/erratic schedules. For patients with inconsistent work/life schedules that makes dosing their basal insulin at the same time each day difficult or impossible, switching to a longer-acting product may allow for flexible insulin dosing.
- Patients who require large daily doses of basal insulin. For patients with large basal insulin requirements, the U-200 insulin degludec product allows for the administration of up to 160 units in a single injection.
- Patients experiencing nocturnal hypoglycemia with their current basal insulin. Longer-acting basal insulin products have been shown to cause less nocturnal hypoglycemia when compared with U-100 insulin glargine .
Among an ever growing assortment of medications available for the treatment of diabetes, U-300 insulin glargine and insulin degludec provide basal insulin options with a duration of action in excess of 24 hours. Clinicians will need to weigh the potential benefits of these agents against product cost and other patient-specific considerations.
- sanofi-aventis US. Toujeo® (insulin glargine injection) U-300 prescribing information. Available at http://products.sanofi.us/toujeo/toujeo.pdf. [Accessed 6 Nov 2017].
- Novo Nordisk A/S. Tresiba® (insulin degludec) prescribing information. Available at www.novo-pi.com/tresiba.pdf. [Accessed 6 Nov 2017].
- Riddle MC, Bolli GB, Ziemen M et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care 2014; 37: 2755–2762.
- Yki-Järvinen H, Bergenstal R, Ziemen M et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care 2014; 37: 3235–3243.
- Institute for Safe Medication Practices (ISMP). As U-500 insulin safety concerns mount, it’s time to rethink safe use of strengths above U-100. Available at www.ismp.org/newsletters/acutecare/showarticle.aspx. [Accessed 6 Nov 2017].
- Riddle MC, Bolli GB, Home PD et al. Efficacy and safety of flexible versus fixed dosing intervals of insulin glargine 300 U/mL in people with type 2 diabetes. Diabetes Technol Ther 2016; 18: 252–257.
- Meneghini L, Atkin SL, Gough SC et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: A 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care 2013; 36: 858–864.
- Heise T, Mathieu C. Impact of the mode of protraction of basal insulin therapies on their pharmacokinetic and pharmacodynamic properties and resulting clinical outcomes. Diabetes Obes Metab 2017; 19: 3–12.