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12-05-2017 | Insulin resistance | Editorial | Article

A pragmatic and practical guide to U500 regular insulin usage

Author: Sanjay Kalra



James lives with type 2 diabetes. He has to take 50 units of regular insulin three times daily and 40 units of glargine twice daily to achieve fair glycemic control. James requests a simpler insulin regimen from his doctor.

Jane lives with type 2 diabetes too. She is on a basal-bolus insulin regimen, taking a total of 150 units per day, but complains of pain at the insulin injection site. She asks for a better tolerated method of taking insulin.

Jalal has poorly controlled, post-transplant diabetes as he is on high doses of corticosteroids. He has tried various types of insulin regimens and U100 preparations, but nothing seems to work. He enquires if there is any insulin preparation available which can control diabetes in patients like him.

Such scenarios are common in clinical practice, and diabetes care professionals often struggle to deal with refractory diabetes. In spite of best possible adherence to lifestyle modification, oral glucose-lowering agents, and conventional insulin, it is sometimes a challenge to achieve safe and effective glycemic control.

There exists a wide variety of insulin preparations, strengths, and delivery devices for use in diabetes management. U500 regular insulin is a recent addition to this list. This article shares some pragmatic and practical suggestions which help to identify persons who may benefit from U500 regular insulin, and explains how to initiate, monitor, and titrate this insulin to achieve safe and effective glycemic control in type 2 diabetes.

Unmet needs with U100 insulin

As diabetes spreads across the world, so do the challenges for diabetes care professionals. The rising prevalence of type 2 diabetes, coupled with insulin resistance, has led to an increase both in the number of insulin prescriptions and in average insulin doses. A greater understanding of the complexity and heterogeneity of diabetes has been accompanied by an expanding range of insulin regimens, preparations, and delivery devices.

Across most of the world, U40 and U100 insulins are used to manage diabetes, and some insulin analogs are also available in U200 and U300 strengths. These preparations, available in a variety of devices, can be used as part of basal, premixed, prandial, or basal-bolus regimens. While these insulins suffice for the majority of patients, they are unable to meet the needs of everyone.

Affected populations include individuals who require very high doses of insulin, or need multiple injections to administer their dose (due to functional limitations of the delivery device), as well as those who have to take multiple injections per day in order to meet glycemic targets. For such patients, highly-concentrated insulins like U500 regular insulin offer an attractive alternative.

U500 regular insulin

High-dose U500 regular insulin has a dual-action profile, with both short-acting (prandial) and long-acting (basal) activity, making it similar to premixed insulin. When compared with U100 regular insulin, U500 insulin has a similar time to effect (<20 minutes) and a lower peak concentration. In doses of 0.4–0.6 U/kg (50 U) and 0.8–1.3 U/kg (100 U), longer times to maximal effect (6 hours and 5 hours, respectively) and greater durations of action (24 hours and 18 hours, respectively) are noted. On the other hand, U100 regular insulin has a time to peak effect of 3 hours and a duration of action of 8 hours [1, 2].

The efficacy and safety of U500 regular insulin was established in a large randomized study, the U500 Titration-to-Target trial [3]. This study was conducted in patients with inadequately controlled type 2 diabetes, using high-dose U100 insulins with or without oral antihyperglycemic drugs. It demonstrated that equivalent glycated hemoglobin reduction could be achieved with U500 regular insulin, regardless of whether a twice-daily or three-times daily regimen was used. Non-severe hypoglycemia was less frequent in the three-times daily cohort and the overall occurrence of severe hypoglycemia was low. While weight gain was modest, patients reported improvement in satisfaction scores over the 24 weeks of therapy with U500 insulin [3, 4]. 

Advantages of U500 insulin

U500 insulin administers highly concentrated insulin with a lower injection volume. This results in less pain and may reduce adverse reactions at the injection site. Additionally, the prolonged duration of action of U500 insulin allows for less frequent administration of injections, which is welcomed by patients. Significantly, the dual, basal, and prandial action removes the need for a basal-bolus regimen or premixed insulin preparation.

Dose planning

Switching from U100 to U500 regular insulin should be done if high doses of the former are required [5]. One should reduce the total dose of U100 insulin by 20% while calculating the initial dose of U500 insulin. U500 regular insulin can be used as a twice-daily regimen in a 60:40 am:pm ratio, or in a three-times daily regimen in 40:30:30 dosage ratio. Initial injection frequency may be based upon patient preference, but further titration and intensification may be required, as per glucose monitoring [5]. Three-times daily U500 insulin may be needed in individuals who are prone to post-lunch and/or pre-dinner hyperglycemia (eg, those with post-transplant diabetes or on corticosteroid therapy), as well as those who develop nocturnal hypoglycemia.


U500 regular insulin is available in both prefilled pens and vials. Vials must be used with green-capped 250 U capacity U500 insulin syringes, which have increments of 5 U. Education of physicians, pharmacists, diabetes nurses, and patients is of utmost importance to prevent errors in prescription, dispensing, and administration. The entire healthcare team must be aware of the difference between various concentrations of insulin and of the need to use the appropriate insulin delivery device.

A higher frequency of follow-up visits should be instituted, at least for the first few weeks after prescription of U500 regular insulin [6]. This may be done via telephone or in person, and may vary according to the clinical situation.

Doses of U500 regular insulin are titrated in a manner similar to those of premixed insulin. A U500 insulin dose targets pre-prandial glucose values before the subsequent meal, eg, the breakfast dose targets pre-dinner glycemia and the dinner injection targets the next day’s fasting glucose. A high fasting glucose value, therefore, should prompt an increase in the dinner dose of U500 insulin. Uncontrolled pre-dinner glycemia implies the need to either increase the breakfast dose of U500 insulin, or to add a third dose at lunch time. Fasting glucose and pre-dinner glucose levels should be normalized first, followed by a focus on post-prandial control. 


Potential or relative contraindications to U500 insulin include suspected non-adherence, high risk of hypoglycemia, hypoglycemia unawareness, old age, cognitive/ psychiatric impairment, and the inability to take regular meals (Box 1). U500 regular insulin should not be administered with other insulin preparations such as basal or premixed insulin. Sensitizers and incretin-based therapies may be used in combination with U500 insulin, as per judgment of the treating physician.

Box 1. Practical tips for U500 regular insulin usage.
Persons who stand to benefit:
  • have a high total daily dose requirement of insulin;
  • have a high dose requirement which cannot be fulfilled by a single injection due to limited capacity of delivery device;
  • have an intensive insulin regimen requiring multiple injections per day; and/or
  • experience pain due to the high volume of injections.
Persons who may not benefit:
  • are elderly or frail;
  • have brittle diabetes;
  • are at high risk of hypoglycemia;
  • have hypoglycemia unawareness;
  • have an erratic meal pattern;
  • suffer from cognitive dysfunction; 
  • have poor adherence;
  • are unable to perform regular self-monitoring of blood glucose; and/or
  • cannot remain in touch with their medical team.


If used correctly, U500 regular insulin can help achieve efficient, effective, and safe glucose control in persons requiring high doses of insulin and who are unable to respond to, or find it difficult to manage, conventional insulin regimens.

  1. Eli Lilly and Company. Humulin® R (U-500) (regular U-500 [concentrated] insulin human injection, USP [rDNA origin]) [prescribing information]. 2016. Available at [Accessed October 23, 2017].
  2. Eli Lilly and Company. Humulin® R (U-100) (regular insulin human injection, USP [rDNA origin]) [prescribing information]. 2015. Available at [Accessed October 23, 2017].
  3. Hood RC, Arakaki RF, Wysham C, Li YG, Settles JA, Jackson JA. Two treatment approaches for human regular U-500 insulin in patients with type 2 diabetes not achieving adequate glycemic control on high-dose U-100 insulin therapy with or without oral agents: a randomized, titration-to-target clinical trial. Endocr Pract 2015; 21: 782–793.
  4. Kabul S, Hood R, Duan R, DeLozier AM, Settles J. Patient-reported outcomes in transition from high-dose U-100 insulin to human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes: analysis of a randomized clinical trial. Health Qual Life Outcomes 2016; 14: 139.
  5. de la Peña A, Ma X, Reddy S, Ovalle F, Bergenstal RM, Jackson JA. Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin. J Diabetes Sci Technol 2014; 8: 821–829.
  6. Bergen PM, Kruger DF, Taylor AD, Eid WE, Bhan A, Jackson JA. Translating U-500R Randomized Clinical Trial Evidence to the Practice Setting: A Diabetes Educator/Expert Prescriber Team Approach. Diabetes Educ 2017; 43:311–323.

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