Safe and Effective Use of U-200 Insulin With Automated Insulin Delivery Systems

Continuous subcutaneous insulin infusion (CSII) devices are approved for use with rapid-acting insulin analogs at the standard concentration of 100 units/mL (U-100). Patients on CSII therapy using U-100 insulin with high insulin dose requirements must administer large volumes, necessitating frequent pump reservoir or pod changes. However, this challenge can be addressed by using more concentrated insulin formulations. The adoption of concentrated insulin with CSII is limited by concerns about hypoglycemia with algorithms designed for U-100 insulin and a lack of data demonstrating safety and efficacy. Here, we report our experience with three patients using widely available automated insulin delivery (AID) systems and U-200 insulin.

Case Presentation 1

A 32-year-old man with insulin-deficient diabetes resulting from pancreatitis was being managed with the Omnipod 5 AID system. His insulin requirements increased substantially over several years, resulting in an increase in the frequency of pod changes to, on average, every 1.5 days. This change was not only an inconvenience, but also a growing financial burden because it lacked insurance approval. Consequently, he was transitioned to U-200 insulin to reduce the volume needed per dose and allow less frequent pod changes.

Upon switching to U-200 insulin, adjustments to the pump settings were made. Prior to the transition, his basal rates were midnight (MN) to 3:00 a.m.: 1.4 units/hour, 3:00–10:00 a.m.: 1.7 units/hour, and 10:00 a.m. to MN: 1.3 units/hour. His insulin-to-carbohydrate ratio (ICR) was 1:3 throughout the day, and his insulin sensitivity factor (ISF) varied from 1:25 to 1:20. While using U-100 insulin, his glycemic time in range (TIR) was 78%, with 4% time below range (TBR) and 18% time above range (TAR). His average glucose was 139 mg/dL with an SD of 47 mg/dL and a glucose management indicator (GMI) of 6.6%. He used 115 units of insulin per day, with his pump in automated mode 100% of the time.

Upon transitioning to U-200 insulin, his basal rates were halved, the ICR was adjusted to 1:6, and the ISF was adjusted to 1:40. He was taken off of automated mode for 4 days during the transition. Three months after switching to U-200 insulin, his continuous glucose monitoring (CGM) system showed an improvement in TIR to 84%, with reductions in both TBR and TAR (3% and 13%, respectively). His average glucose decreased to 134 mg/dL with an SD of 39 mg/dL and a GMI of 6.5%, all while using slightly less insulin (averaging 54.6 units of U-200 insulin daily). He reported that the decreased frequency of pod changes significantly improved his quality of life, and he was able to maintain uninterrupted insurance coverage for the CSII supplies.

Case Presentation 2

A 31-year-old woman with type 1 diabetes was seen for follow-up while using a multiple daily injection (MDI) regimen of U-100 insulin and CGM. Her total daily basal insulin dose was 150 units, with 20–75 units of insulin lispro per meal, and her total daily dose (TDD) of insulin typically exceeded 300 units. Her A1C ranged between 9 and 10% for the past year. She desired to try CSII therapy and began using the Tandem t:slim X2 with Control-IQ technology AID system with U-100 insulin. Her initial basal rate was 4.5 units/hour throughout the day, her ICR was 1:3, and her ISF was 1:10.

Her last CGM sensor data report before starting CSII showed a TIR of 35%, TAR of 65%, average glucose of 211 mg/dL with an SD of 70 mg/dL, and a GMI of 8.4%. Upon starting the AID system, she used >250 units of insulin per day, which raised concern about the need to change the insulin cartridge daily. Consequently, she was switched to U-200 insulin within the first week of starting CSII. Her basal rate was reduced from 4.5 to 3.0 units/hour throughout the day, her ICR was adjusted from 1:3 to 1:6, and her ISF was adjusted from 1:10 to 1:20.

Three months after starting U-200 insulin with her AID system, her TIR improved to 56% with no increase in hypoglycemia (0% TBR). Her average glucose and GMI also improved (190 mg/dL and 7.8%, respectively). She kept the AID system in automated mode 97% of the time and was using 138.4 units of U-200 insulin daily. She expressed increased satisfaction, specifically noting the reduced frequency of cartridge changes.

Case Presentation 3

A 47-year-old man with type 2 diabetes and HIV was using an MDI insulin regimen and fingerstick blood glucose testing. He was diagnosed with diabetes at 21 years of age with an A1C of 13% and had taken insulin since his diagnosis. On presentation, he was using 80 units of basal insulin per day, a fixed dose of 60 units of insulin lispro with each meal, and metformin. He worked night shifts and had an erratic eating and sleeping pattern. Thus, his TDD varied significantly but was typically ∼200 units. Physical examination was notable for a BMI of 30.5 kg/m² and significant lipohypertrophy involving abdominal insulin injection sites. At our initial encounter, semaglutide was added, and the patient began using CGM.

After titrating the semaglutide to 2 mg weekly, CGM revealed a TIR of 16%, TAR of 84%, average glucose of 261 mg/dL, and GMI of 9.6%. He elected to try the Medtronic MiniMed 780G AID system. Considering his poor glycemic control in the context of a high TDD, he switched to U-200 insulin upon initiating the AID pump. Metformin and semaglutide were continued at the same doses. The AID system was programmed to begin with a basal rate of 1.6 units/hour, an ICR of 1:4, an ISF of 1:20, a target glucose of 100 mg/dL, and active insulin time (AIT) of 3 hours. During the patient’s first month using CSII and U-200 insulin, his AID system stayed in automated mode 73% of the time. His TIR improved dramatically to 69%, with an average glucose of 163 mg/dL, a GMI of 7.2%, and a coefficient of variation of 28.7%, while his TBR remained 0%. The improvement in glycemic control was accompanied by a significant reduction in TDD to 116 units. The AID system reservoir was changed every 2.3 days, suggesting that the patient may have had to change the reservoir daily if he had used U-100 insulin when starting CSII.

Questions

1. What factors should clinicians consider when deciding to switch a patient from U-100 to U-200 insulin with CSII?

2. What are the key considerations when adjusting pump settings during the transition to U-200 insulin, and how do these adjustments vary across AID systems?

3. How does using U-200 insulin affect the risk of hypoglycemia or hyperglycemia in patients using an AID system?

Commentary

Managing diabetes in patients with high insulin requirements presents unique challenges, particularly regarding the practical aspects of insulin therapy. For those using CSII with AID, U-100 insulin may require frequent reservoir or pod changes in patients with a high TDD. Concentrated insulin formulations may offer a useful alternative by extending the time between refills.

U-200 insulin has pharmacokinetic and pharmacodynamic profiles similar to U-100 insulin (1,2). However, it offers the significant advantage of potentially doubling the life span of each pump reservoir by reducing insulin volume. This feature may also enhance insulin absorption, leading to better control of meal-related glucose excursions due to shorter time of bolus delivery (3). These factors can facilitate improved adherence and ease of diabetes management, offering significant benefits to patients with a high TDD. Here, we demonstrated the practical application of U-200 insulin across different commercially available CSII systems with AID algorithms.

To our knowledge, this is the first reported case series featuring U-200 insulin with CSII or any concentrated insulin with AID systems. Patients experienced improved glucose control, had less frequent hypoglycemia, and maintained their AID system in automated mode. Switching to U-200 insulin also reduced the TDD for all three patients (Table 1), reduced their frequency of reservoir and pod changes, and improved their quality of life and adherence. Our results show that U-200 insulin can effectively address logistical challenges associated with high insulin requirements while maintaining safety and efficacy.

Table 1.

Glycemic Data Before and After Transitioning to U-200 Insulin With CSII Therapy

Patient Demographics		Insulin Requirements, units/day		TIR, %		TBR, %		GMI, %		Additional Therapies
Case	Age, Sex	Before	3 Months	Before	3 Months	Before	3 Months	Before	3 Months
1*	32, M	115	109	78	84	4	3	6.6	6.5	None
2†	31, F	300	277	35	56	0	0	8.4	7.8	Metformin
3†	47, M	200	116	16	69	0	0	9.6	7.2	Semaglutide and metformin

*Baseline data reflect CSII therapy.

†Baseline data reflect MDI therapy.

The transition to U-200 insulin requires careful adjustment of pump settings. Attention is needed to ensure that an AID system delivers the correct dose in half the insulin volume. Each AID system algorithm operates uniquely, necessitating specific considerations. For example, the Tandem AID system dynamically adjusts basal insulin delivery and supports multiple customizable profiles, allowing users to create distinct profiles for U-100 and U-200 insulins (4). The Omnipod 5 AID system calculates basal insulin delivery based on TDD, updated with each pod change (5). When transitioning from U-100 to U-200 insulin, it may be advisable to keep the system in manual mode for one to two pod changes to allow the system to adjust to the new, reduced TDD with U-200 insulin. The Medtronic AID system derives its automated basal insulin delivery from the average TDD over the previous 6 days (6). Therefore, transitioning may require using manual mode for 5–6 days or, alternatively, for 2–3 days followed by the use of a temporary target for a couple of days.

Basal rates, ICRs, and ISF calculations for U-200 insulin are shown in Table 2. Patient education and strategies to minimize hypoglycemia risk are crucial during this transition. As more clinicians gain experience with U-200 insulin in various AID systems, it may become a more widely accepted tool, improving diabetes management and quality of life for individuals with diabetes. Further research with larger cohorts is needed to confirm these findings and optimize U-200 integration in AID systems.

Table 2.

Practical Recommendations for Optimizing U-200 Insulin With Different AID Systems

Recommendations	Tandem t:slim X2 with Control-IQ Technology	Omnipod 5	Medtronic 780G
Specific considerations based on AID system	System uses CGM data to dynamically adjust basal insulin delivery by increasing, decreasing, or suspending programmed rates and allows for modifications to basal rates, ICR, and ISF.	Automated basal insulin delivery is calculated based on TDD, which is updated with each pod change, while also allowing adjustments to ICR and ISF for bolus settings.	Automated basal insulin delivery is derived from TDD over the past 6 days and adjusted based on CGM trends, with the option to modify the ICR.
Transition	System supports multiple customizable profiles, enabling users to create distinct settings for U-100 and U-200 insulins, thereby allowing them to remain in automated mode while transitioning.	When transitioning, it may be advisable to remain in manual mode for one to two pod changes to allow adaptation to the reduced TDD associated with U-200 insulin.	Transitioning may require using manual mode for 5–6 days or, alternatively, for 2–3 days followed by the use of a temporary target for a couple of days.
Basal rates	Consider starting by reducing basal rates by half when transitioning from U-100 to U-200 insulin.
ICR	If TIR is >70% with U-100 and no pump setting adjustments are needed, the ICR can be doubled (e.g., from 1:4 with U-100 to 1:8 with U-200).
	If TIR is 50–70%, consider reducing the ICR by 25% (e.g., from 1:8 to 1:6).
	Users can also recalculate the ICR if TIR is at goal based on the current TDD of U-100. Divide the TDD by half and then apply a “fudge factor” of 350–400 to adjust for U-200 insulin (e.g., a TDD of 100 units with U-100 would become 50 units with U-200, and using a fudge factor of 350/50 results in an ICR of 1:7).
ISF	If TIR is >70% with U-100 and no setting changes are necessary, double the ISF (e.g., from 1:20 with U-100 to 1:40 with U-200).
	If TIR is 50–70%, decrease the ISF by 25% (e.g., from 1:40 to 1:30).
	Similarly, if TIR is not ideal, you can recalculate the ISF based on the TDD of U-100, dividing by half, and applying a fudge factor of 1,600–1,700 when calculating the new ISF for U-200 insulin (e.g., a TDD of 100 units with U-100 would become 50 units with U-200, and using a fudge factor of 1,700/50 results in an ISF of 34).
Patient education	Provide education on U-200 insulin, dose adjustments, and the importance of frequent glucose monitoring during the transition.
Monitoring	Closely monitor glucose levels after transitioning to U-200 insulin. Consider scheduling a follow-up clinic visit in 2 weeks or sooner, if necessary.

Clinical Pearls

• U-200 insulin can be considered for patients with high insulin requirements who experience frequent reservoir changes, financial constraints, or discomfort with large bolus volumes.

• Pump settings should be adjusted proportionally to the insulin concentration.

• Reducing the frequency of reservoir or pod changes can enhance patient satisfaction, adherence, quality of life, and glycemic control.

• Close monitoring of glucose levels during the transition period is essential to refine pump settings and minimize risks of hypoglycemia or hyperglycemia.