How can we optimize titration with new basal insulins?
In this article I will lay out key strategies for titrating the newer basal insulins in people with type 2 diabetes, specifically the long-acting, “concentrated” basal insulin analogs, insulin degludec and insulin glargine U300.
While these newer analogs possess a longer duration of action and produce less hypoglycemia than human NPH insulin, insulin detemir, and insulin glargine U100, it is important to remember that the medication, in itself, does not get the person with diabetes to their target glucose levels. Rather, it is proper optimization via titration that enables patients to achieve their glucose targets.
Why “concentrated” insulins?
As discussed by Dr Kalra in his article on insulin U500 use, higher insulin dose requirements in the type 2 diabetes population have established a need for large volumes of insulin to be delivered in just one or two injections, either to improve patient comfort or to circumvent the limitations that a pen-like form factor imposes.
We have been introduced to several concentrated insulins in the past few years. Each has worked by reducing the volume of diluent, rather than making changes to the insulin molecule. For example, U100 contains 100 units of insulin per mL, U200 contains 200 units of insulin per mL, and U300 contains 300 units of insulin per mL.
As a practical point when discussing concentrated insulin, the term “concentrated” implies that the medication is more powerful. For this reason, some prescribers may hesitate to transition patients to what is perceived to be a “stronger” form of insulin. However, it is critical to note that the potency of the medication being delivered is not different between the different forms, rather, the medication is being delivered at lower dilution.
Concentrated basal insulin therapy
Insulin glargine U300 was developed to meet the needs of patients requiring low-volume, high-concentration insulin therapy. However, during its clinical development it was noted that the lower volume of insulin glargine U300 resulted in a slightly different time-action profile to that of insulin glargine U100. Indeed, the EDITION program has demonstrated longer duration of action, less hypoglycemia, less glucose variability but a slight increase in the dose required when compared with U100.
Insulin degludec was made available in the USA (2015) and Canada (2017) in two formulations - U100 and U200. Research regarding the time-action profile of this insulin analog demonstrated the same activity regardless of the concentration. The introduction of the U100 formulation was helpful to individuals with type 1 diabetes, particularly those who do not require large basal insulin doses, as well as for individuals with type 2 diabetes who may be particularly insulin sensitive or have a smaller body size, hence requiring smaller doses of basal insulin or titration by single unit doses.
Key benefits of concentrated insulins
Generally, using concentrated insulins is not difficult. However, healthcare professionals can be prone to overthinking the dosing. A common assumption is that a calculation is required, particularly when switching insulin preparations. For insulin glargine U300 and insulin degludec U200 the safety is incorporated in the device. Both of these insulins only are available in prefilled insulin pens. Individuals only need to dial the prescribed dose of insulin – for example a starting dose of 10 units: The user dials in 10 units; the user receives 10 units, albeit with a lower total volume. When insulin glargine U300 is injected one-third of the usual amount of vehicle is administered, whereas for insulin degludec, U200 it is half of the usual amount of vehicle. As long as individuals use the pens correctly and do not use a syringe to draw out these concentrated insulins, dosing is relatively simple.
The differences are in the devices
The dosage of insulin glargine U300 can be increased by 1 unit at a time to a maximum of 80 units within a single injection. Insulin degludec U200 can only be increased by 2 units at a time, to a maximum dose of 160 units in a single injection. Quite honestly, the titration schedule used in clinical trials and in real life are in some ways reflective of the dosing ability of the pen. So let’s talk about that – titrating concentrated insulin.
Successful titration in type 2 diabetes
Starting basal insulin in people with type 2 diabetes comes with a “recipe.” Each insulin has a recommended starting dose, typically 10 units daily (insulin degludec) or 0.2 units per kg (insulin glargine U300). This recipe tends to be easy to follow and is often adapted according to the prescriber’s own comfort. However, prescribers often face difficulty in moving the insulin dose forward, leading to clinical inertia.
Optimal titration begins at initiation
Setting clear expectations while providing effective patient education and support is incredibly important at insulin initiation and beyond.
Prescriber or patient: Who should do the titration?
Research has shown us that patient self-titration is extremely effective, and is often achieved with greater insulin doses, less hypoglycemia and similar glycated hemoglobin (HbA1c) than physician-driven titrations. Empowering individuals to take control over their insulin therapy is an essential component of diabetes self-care.
Which clinical studies have demonstrated how we can optimize insulin titration?
Insulin glargine U300
The EDITION Program
In this series of studies titration was performed by the participant’s healthcare provider. Fasting glucose levels were obtained daily and titration was performed at least once a week, at a maximum frequency of every 3 days. Insulin doses were adjusted based on the mean glucose level of the previous 3 days, and dose adjustments of +/-3 units were made based on the glucose value and/or detection of hypoglycemia within that period.
Insulin glargine U100
The TITRATION study
This study built on the success of the INSIGHT trial, which involved participants self-titrating once per day. Dosages were increased at a rate of 1 unit per day until the target glucose was achieved. This approach has also been deemed as safe and efficacious for insulin glargine U300.
Insulin degludec U200
The BEGIN Program
Titration was performed once per week by a healthcare provider. Fasting glucose levels were obtained daily and insulin doses were adjusted based on the mean glucose level in 2-unit increments.
Insulin Degludec Once-Daily in Type 2 Diabetes: Simple or Step-Wise Titration (BEGIN: Once Simple Use)
Once weekly patient titration with either a simple +/- 4 units of insulin or 2-unit incremental adjustment based on the lowest fasting glucose level from the previous 3 days. With the longer half-life of insulin degludec, it is important not to increase insulin more frequently than every 3 days.
There are various recipes for insulin titration. While their ingredients (eg, frequency, who performs, etc.) may differ, there is not one perfect approach for all patients.
In my opinion, the most important factors are to establish a titration schedule and ensure that insulin doses are adjusted to achieve target glucose levels in a timely manner.
It is important to provide guidance to your patient; they need to know:
- How much insulin they may need
- How long it may take to get to their target glucose level
- What is their target glucose level
- When they should call their healthcare provider
- Most importantly, what is hypoglycemia and how should they manage it
As healthcare providers we are best placed to advise patients on when to stop titrating insulin and the scenarios in which to return to the clinic or to call in for follow-up.
You may find some titration tools particularly helpful to guide patients; these can include written instructions or prefilled glucose diaries. Regardless of the approach adopted it is important to ensure that instructions are clear, expectations are set, and support/follow-up is provided.
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