One of the most significant challenges in the management of type 2 diabetes mellitus (T2DM) is the titration of insulin in patients with severe insulin resistance. This is particularly true of obese, sedentary patients whose severe insulin resistance may require daily amounts of 200 units of insulin or more to obtain target A1C levels.1 This volume of insulin, injected subcutaneously, often leads to inadequate absorption, poor adherence, and increased drug and supply costs.2
U-500 regular concentrated insulin offers insulin treatment without large volumes of insulin. It is a viable alternative to U-100 insulin formulations in select patients and may result in improved A1C control, enhanced adherence, and increased patient satisfaction.3,4 However, some primary care providers may be unaware or clinically uncomfortable with the use of U-500 insulin.
The purpose of this article is to describe the evaluation and management of a patient with T2DM with severe insulin resistance who is a candidate for U-500 regular concentrated insulin. This case-based approach will highlight important considerations, describe the dosing of U-500 insulin, and review potential challenges.
Case report
Mr. D, 47, presents as a new patient to an NP-managed health center. His medical history is significant for the following: T2DM, onset age 36 with associated peripheral neuropathy and nonproliferative retinopathy; morbid obesity; and chronic lower back pain with L4-5 radiculopathy. Mr. D is currently taking metformin hydrochloride, 1,000 mg twice daily; insulin glargine, 95 units twice daily; and insulin lispro, 70 units with each meal four times daily.
Mr. D reports that he lives alone and is disabled because of his lower back pain. He states that he checks his blood glucose level three times a day with a glucometer and has an average level of 244 mg/dL. He also describes symptoms of fatigue, blurred vision, and thirst. At the initial primary care clinic visit, Mr. D weighed 384 lb (174.8 kg) with a body mass index of 53.6, and his A1C was 10.9%. He told the NP that he was worried it was "impossible" to control his diabetes.
Defining insulin resistance
Insulin resistance is the impaired ability of insulin (either endogenous or exogenous) to lower blood glucose.5 Most patients with T2DM require an insulin dosage of 1.0 to 1.5 units/kg/day.1 When requirements exceed 200 units per day, the insulin resistance is termed "severe." When the insulin need reaches over 300 units per day, it is considered "extreme insulin resistance."6
Numerous causes for insulin resistance exist and must be carefully evaluated (see Causes of insulin resistance). Mr. D's sedentary lifestyle and morbid obesity could account for his increased insulin requirements. The NP recommended an initial evaluation by an endocrinologist. A chemistry panel, lipids, urine for microalbumin, 24-hour cortisol, glucagon level, insulin antibodies, testosterone, thyroid functions, and 24-hour urine for catecholamines and metanephrine were obtained to not only reveal comorbidities, but also explore the possibility of other causes for his insulin resistance.
Mr. D's tests revealed elevated triglycerides, low high-density lipoprotein cholesterol, and low testosterone. An HMG-CoA reductase inhibitor (statin) for the elevated cholesterol and a topical testosterone preparation for the low testosterone were given. His prescribed dosage of insulin glargine was increased to 100 units twice daily with a titration schedule to increase the insulin glargine to obtain a fasting glucose goal of 80 mg/dL to 120 mg/dL.
Three months later, Mr. D returned for his follow-up appointment. The NP noted he had gained 6 lb (2.7 kg), and his A1C was 9.9%. Mr. D stated he was taking all of his medication and insulin injections as prescribed, but he complained of tender subcutaneous nodules at the site of his insulin injections. He asked, "Do you think my insulin is absorbing? Sometimes it leaks at the injection site when I give myself the dose."
Mr. D was up to 120 units of insulin glargine twice daily, had stopped eating his fourth meal, and was taking 70 units of insulin lispro with each of his three meals. He was trying to walk for 15 minutes each day but felt discouraged, especially since his weight had increased to 390 lb (176.9 kg). Management of Mr. D's severe insulin resistance could include more lifestyle changes; use of insulin-sensitizing medication (such as the metformin he was on); adding an incretin mimetic; converting from U-100 insulin to U-500 insulin injections; or bariatric surgery.
After carefully considering his options, Mr. D decided to try U-500 insulin, increase his activity level, and more carefully consider his food choices.
Use of U-500 insulin
U-500 insulin is five times the concentration of U-100 regular insulin and is indicated to improve glycemic control in adults and children with type 1 diabetes mellitus and T2DM. It is available in an insulin pen or in multiple-dose vials with a U-500 syringe to avoid dosage conversion.7 It is useful for insulin-resistant patients who require daily dosages of insulin over 200 units because it can be given in a smaller volume.8 With the recent increase in obesity, use of U-500 insulin is becoming more common. As in Mr. D's case, large volumes of insulin can lead to uncomfortable nodules under the skin and leaking at the site of injection with questionable absorption.7,8
Because it is a less commonly prescribed medication, providers, nurses, and pharmacists lack a working knowledge of U-500 insulin. Classified as "regular" insulin, the timing of U-500 is more like intermediate-acting insulin, such as NPH insulin, which has a duration of more than 12 hours. The concentration of the insulin causes a delay in absorption and slow delivery. U-500 insulin has an onset of 15 minutes, peak of 1 to 8 hours, and can last up to 24 hours.7-11 The pharmacokinetics have not been extensively studied, but it is known that with its prolonged action, U-500 insulin can be used by itself.8 This eliminates the need for other basal insulin or any other fast-acting insulin. Dosing is usually 2 to 3 injections a day 30 minutes before meals.11-14
Studies have shown that U-500 insulin improves A1C and may increase adherence to insulin use with less potential for pain or leaking at the injection site.1,4,15,16 The literature on associated weight gain with U-500 insulin is mixed, with some studies demonstrating weight gain and others no change in weight.3,17,18
Provider and patient education is essential. Potential for confusion between U-500 insulin and insulins of different strengths is possible. In hospitals, nursing staff administering U-500 insulin should double-check the dosage with a second nurse before administration and follow the Joint Commission's recommendations for high-alert medications because insulin is considered a high-alert medication.19,20 Patients should be thoroughly educated on the use of the Humulin R U-500 KwikPen and how to dial a dosage. The pen contains 1,500 units of insulin and is dialed in 5-unit increments. If U-500 insulin is prescribed in the multidose vial, the accompanying U-500 syringe should be prescribed as well, and no other type of syringe should be used.21
Dosing is usually two to three times daily 30 minutes before a meal. To determine the appropriate U-500 insulin dose, the total daily dosage (TDD) of insulin must be calculated. For Mr. D, 120 units of insulin glargine administered subcutaneously twice daily, plus 70 units of insulin lispro three times daily (120+120+70+70+70), equaled a TDD of 450 units. Next, the TDD should be adjusted based on the A1C level. That is, if the A1C is 8% or less, the TDD should be reduced by 10% to 20%. If the A1C is 10% or more, the TDD should be increased by 10%.13 Mr. D's A1C was 9.9%, so the TDD was not adjusted.
Finally, Mr. D needed his units of U-500 distributed throughout the day. For patients taking a TDD between 200 and 299 units, the U-500 can be divided by giving 60% of the dosage 30 minutes before breakfast and 40% of the dosage 30 minutes before dinner or 30 minutes before three meals (such as 40% of the dosage before breakfast, 30% of the dosage before lunch, and 30% of the dosage before dinner). Other combinations are possible based on the individual's needs and response.12,13
If the TDD is between 300 and 599 units, the U-500 can be divided before three meals daily. In addition, if needed to help with late-evening snacking or a high fasting glucose, part of the dosage can be given before bed (30% of the dosage before breakfast, 30% of the dosage before lunch, 30% of the dosage before dinner, and 10% of the dosage before bed).12,13 If the TDD is over 600 units, the U-500 should always be divided four times daily to include the bedtime dosage.12,13
Mr. D required 450 units of U-500, so the dosage was divided as 40%-30%-30% or 180 units 30 minutes before breakfast, 135 units 30 minutes before lunch, and 135 units 30 minutes before dinner. The prescription with instruction was written as:
Dispense: U-500 regular insulin using a U-500 syringe or U-500 KwikPen inject 180 units subcutaneously 30 minutes before breakfast, 135 units subcutaneously 30 minutes before lunch, and 135 units subcutaneously 30 minutes before dinner.21
Mr. D went home with instructions on the use of U-500 insulin. He had initial problems with obtaining the U-500 insulin at his pharmacy and with insurance authorization, so he did not get started fully on the U-500 insulin for 1 month. However, at his 3-month follow-up visit, Mr. D reported that he was feeling better with more energy, less thirst, and no more painful subcutaneous nodules at injection sites. His A1C had reduced one point to 8.9%, and his fasting blood glucose was still above goal, as were his prelunch and dinner measures, but they were rarely over 200 mg/dL.
The NP increased his U-500 insulin by 5 units before each meal. Mr. D's dosages of U-500 were 185 units before breakfast, and 140 units before both lunch and dinner. More instruction on healthy lifestyle was given, and Mr. D agreed he would try to walk for longer periods of time.
One month prior to Mr. D's next follow-up, he called his NP and complained that since he had become more active and was now walking 30 minutes daily, he was having hypoglycemic episodes between breakfast and lunch and again between lunch and dinner. These episodes had occurred on 4 of the last 7 days. His insulin was immediately adjusted and lowered to the original dosage of U-500 insulin.
Mr. D presented to the clinic the following month, and the first thing the NP noticed was that Mr. D's weight had decreased to 378 lb (171.5 kg), notwithstanding his improved A1C control of 7.2%. Mr. D reported that he felt much better and found it easy to be more active. He was also encouraged by his progress and began to cook more of his meals in order to include more vegetables.
Summary of Mr. D's journey
Mr. D came to the health center with poorly controlled diabetes mellitus, morbid obesity, and severe insulin resistance. An increase in his U-100 insulin only slightly reduced his A1C, and he complained of tender subcutaneous nodules and insulin leakage at the injection sites. Mr. D was evaluated by an endocrinologist who determined that his severe insulin resistance was the result of his morbid obesity and sedentary lifestyle.
After initiating U-500 insulin, Mr. D experienced improved A1C control with a reduction in symptoms. As his diabetes control improved, he became more engaged with lifestyle modifications, increased his activity level, lost weight, and experienced some hypoglycemic episodes after an increase in dosage required reduction of his dosage. Over 6 months, his A1C went from 9.9% to 7.2% on U-500 insulin.
A new tool
Mr. D's case illustrates an example of management of T2DM in the presence of "severe" or "extremely severe" insulin resistance. U-500 insulin offers an option that may lower A1C levels, reduce the volume of injected insulin, and increase patient satisfaction and adherence.
While the improvement in control has potential for weight gain, patient education and encouragement of lifestyle changes has the ability to minimize this problem. Patient and provider education is also essential to properly prescribe and administer U-500 insulin. This is particularly important as some healthcare providers may be unfamiliar with U-500.
With an increased number of patients with diabetes and severe insulin resistance, primary care NPs should consider the use of U-500 insulin as another tool in the tool kit of diabetes treatment.
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