Should We Convert our Patients to Concentrated Insulins?

Concentrated insulins are no longer just for patients who have obesity or insulin resistance.

Decreasing the quantity of insulin and the number of insulin injections significantly improves patient-reported quality of life, clinical outcomes, and compliance. Providers should also recognize that all concentrated insulins are not created equal. Pharmacokinetic and pharmacodynamic relationships and bioequivalence vary among the concentrated insulins. Understanding these components is essential to proper clinical use.

The advantages of concentrated insulins include a decreased number of injections, reduced pain, less frequent pen changes, ease of delivering larger doses, and better pen mechanics. Numerous studies show these advantages lessen the burden of diabetes management. Results of a randomized control trial that assessed post-injection pain in type 1 and type 2 diabetes patients confirmed that high injection volumes are associated with more injection pain compared to lower volumes. A study by Kabul et al. demonstrated clinical improvements in insulin-resistant type 2 diabetes patients when changed to concentrated insulin. This could be because patients on high doses of insulin may reduce the dose to avoid associated injection pain. Another study evaluated the pain level and patient-reported quality of life in adults with type 2 diabetes on conventional U-100 and high-concentration U-300 insulin glargine. This study reflected a strong patient preference for concentrated insulin glargine and associated it with a better quality of life.

Insulin pumps are not currently calibrated to be used with concentrated insulins and are only labeled to be used with U-100 insulin. Concentrated insulins are currently considered off-label and not recommended for insulin pumps, but this is expected to change. A conversion to concentrated insulins for continuous subcutaneous insulin infusions could provide more discreet, compact pumps, with smaller reservoirs.

Additional advantages of using concentrated insulin in pumps include higher maximum bolus and basal rate, less frequent reservoir fill, and expanded use in patients who have obesity or are insulin-resistant and require larger doses of insulin.

These various studies show the benefits and potential advantages of choosing concentrated insulin over conventional insulin, but we must also understand the variations in the pharmacokinetic and pharmacodynamic profile. A larger dose or more concentrated insulin results in a reduced diffusion area compared to the amount of insulin being absorbed. This results in a delayed and longer peak and longer duration of action. Concentrated insulins have a smaller surface area and take longer to diffuse into tissues. The greater the concentration of insulin, the slower the absorption and appearance in plasma. Due to these dynamics, a larger insulin dose of conventional insulin also leads to a right shift in the pharmacokinetic profile.

The pharmacokinetic and pharmacodynamic differences were observed in a randomized, double-blind, glargine U-100 and U-300 study. U-300 achieved a similar A1C reduction as U-100 and produced less hypoglycemia. U-300 had a slower onset and longer duration of action compared to U-100. This study demonstrates that Glargine U-100 and U-300 are not bioequivalent. When comparing regular U-100 and U-500, both had an onset of action of 15 minutes, but U-500 had a longer mean duration of action. Therefore, regular U-100 and U-500 are not considered bioequivalent.

To counteract the right shift seen in insulin glargine U-300 and regular U-500, concentrated versions of insulin degludec and lispro were created. Separate trials were created to study the pharmacokinetic and pharmacodynamic differences, and these drugs were considered bioequivalent to their conventional versions. The improved profile of these drugs is partially due to a greater proportion of the insulin already in monomeric and dimeric form, improving the absorption profile.

When these pharmacokinetic and pharmacodynamic differences are considered, concentrated insulins can serve as an alternative therapy for most patients with type 1 and type 2 diabetes. Concentrated insulins can improve diabetes outcomes and compliance in all patients, not just those patients with obesity or insulin resistance.

Practice Pearls:

• Conversion to concentrated insulin can improve drug compliance, patient quality of life, and delivery of large doses.
• Clinicians must recognize the different units for different devices, pharmacokinetic and pharmacodynamic variations, and bioequivalence of insulins.
• The use of concentrated insulin for insulin pumps could provide numerous benefits for patients with diabetes but needs additional research.

Murata, Takashi, et al. “The Effect of High-Concentration Insulin Glargine on the Quality of Life of Patients with Type 2 Diabetes Mellitus: A Pre-Post Study (HIGH-QOL STUDY).” Internal Medicine, 2020, doi:10.2169/internalmedicine.1794-18.

“Concentrated Insulins: Clinical Applications & Use In Practical Settings.” Endocrine Practice, vol. 23, no. Supplement 1, 2017, pp. 1–30., doi:10.4158/1934-2403-23.s1.1.

 Kassey James, Pharm.D.Candidate, LECOM School of Pharmacy