Strategies for Managing Severe Insulin Resistance

San Francisco—Severe insulin resistance (eg, requiring >200 units of insulin per day) poses unique challenges that can undermine glycemic control. Current research and practical considerations in the use of concentrated insulin and other strategies to manage severe insulin resistance in type 1 and type 2 diabetes was addressed during the ADA meeting at a satellite symposium supported by an educational grant from Lilly USA, LLC.

Prevalence of the Disease
Diabetes affects 25.8 million people in the United States, translating to 8.3% of the US population, and another 79 million people have prediabetes, according to ADA statistics. Of the adults with type 1 and type 2 diabetes, the Centers for Disease Control and Prevention’s National Diabetes Fact Sheet, 2011, estimated that 26% use insulin, with 12% using insulin only and 14% using insulin plus oral antidiabetes drugs.

Bruce Bode, MD, FACE, Atlanta Diabetes Associates, clinical associate professor, department of medicine, Emory University School of Medicine, opened the symposium by discussing insulin resistance and severe insulin resistance. A total daily insulin dose is a simple, practical, and clinically meaningful
assessment of insulin sensitivity, according to a study by Ovalle in Diabetes Research and Clinical Practice in 2010, who defined severe insulin resistance as requiring >200 to 300 units of insulin a day and extreme insulin resistance as needing >300 units a day.

It is unclear how many people have severe or extreme insulin resistance, but the number is growing, according to Dr. Bode. A study by Segal et al, published in American Journal of Health-System Pharmacy in 2010, found that from June 2007 to June 2009, use of U-500 regular insulin increased by 137%. The increase is attributed primarily to greater numbers of obese, clinically insulin-resistant patients with type 2 diabetes. The age-adjusted prevalence of obesity in US adults has increased from 23% (1988-1994) to 36% (2009-2010). “Obesity is the major driver of increased rates of severe insulin resistance,” said Dr. Bode.

A systematic approach to the evaluation of patients with diabetes and very-high insulin requirements is necessary to facilitate an appropriate diagnosis, select the most reasonable therapy, and hopefully improve the long-term outcome of these patients, according to the study by Ovalle. The study proposed a simple alphabetic mnemonic approach to help remember the differential diagnosis, and a clinical algorithm to help guide the work-up of these patients. Using this mnemonic approach, the letter “D,” for example, may help remind clinicians to consider “drugs” that contribute to the development or worsening of insulin resistance (eg, glucocorticoids, terbutaline, HIV-1 protease inhibitors). “Insulin resistance has profound pathophysiologic effects on numerous organs and tissues,” stressed Dr. Bode.

Management of Severely Insulin-Resistant Patients
Irl B. Hirsch, MD, professor of medicine, University of Washington, continued the symposium with a focus on management options for treating patients with severe insulin resistance. He provided a brief overview of traditional treatment of insulin resistance and the development of U-500 insulin. In 1952, beef U-500 was introduced to meet high insulin requirements in type 1 diabetes; high prevalence of insulin antibodies developed in response to animal insulin. This insulin was also used for severely insulin-resistant type 2 diabetes patients. Beef U-500 was replaced by pork U-500 regular insulin in 1980. It was not until 1997 that pork U-500 was replaced by human U-500 regular insulin.

High-dose insulin requirements necessitate higher-volume injections as well as more injections per day. For more resistant patients, U-100 regular insulin is both impractical and inconvenient. Using >100 units (1 mL) at once requires >1 injection. The larger volume of insulin is painful and a large depot of insulin impedes absorption, making insulin bioavailability unpredictable. Therefore, U-500 regular insulin may be an alternative option for patients who use >200 units per day, explained Dr. Hirsch.

He noted that insulin lispro U-200, insulin aspart U-200, insulin degludec U-200, and insulin glargine U-300 are under investigation. Dr. Hirsch highlighted a study by Wang et al published in Diabetes Care in 2010 that assessed infusion rates for different glargine doses injected into the abdomen. Considering the results, he said that although it is possible that the duration of insulin action is prolonged with increasing doses of glargine, there is no difference in insulin action for the 24 hours after injection once the dose is >1 unit/kg.

Some patients may require a rapid-acting insulin analog to manage their mealtime hyperglycemic spikes. For these patients, Dr. Hirsch said U-500 regular insulin may be an option since it can be considered both a basal and a prandial insulin. He said the main secret for success with U-500 regular insulin is frequent self-monitoring of blood glucose.

In summary, Dr. Hirsch said the primary objective when treating a patient with severe insulin resistance is to determine the etiology. Syndromic forms of insulin resistance can often be improved with specific therapies. Also, there are novel ways to think about the current U-100 regular insulins when managing patients with severe insulin resistance. Furthermore, in many situations, more concentrated insulins appear to help this growing population.

U-500 Regular Insulin
The final presentation, given by Wendy S. Lane, MD, clinical endocrinologist, director of research, Mountain Diabetes and Endocrine Center, addressed practical considerations and safety issues for using U-500 regular insulin.
She started her presentation by discussing patients with the following medical conditions that may be considered for U-500 regular insulin therapy:

     • Type 2 diabetes with obesity and/or severe insulin resistance
     • Type 2 diabetes with insulin requirements >200 units per day
     • Gestational diabetes mellitus with severe insulin resistance
     • Genetic defects of insulin action (eg, type A insulin resistance syndromes, lipodystrophic diabetes)
     • Rare forms of immune-mediated diabetes, such as anti-insulin receptor antibodies (eg, type B
       insulin resistance syndrome)

Advantages of U-500 regular insulin in type 2 diabetes patients and severe insulin resistance include improved insulin absorption leading to improved glycemic control; fewer injections and lower volume injections enhancing patient comfort and compliance; and cost savings. Dr. Lane referenced a study conducted by Daily et al, published in Diabetes Research and Clinical Practice in 2010, that followed 36 patients receiving U-500 regular insulin for 6 months who were given a quality of life questionnaire to assess whether satisfaction changed after starting therapy. Researchers found significant improvement (P<.001) in satisfaction with diabetes treatment, time needed for diabetes management, knowledge about diabetes, ability to determine blood sugar, and overall diabetes control.

To limit insulin-associated weight gain, U-500 regular insulin can be used concurrently with other glucose-lowering agents, including metformin, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors. She noted that using thiazolidinediones in combination with U-500 regular insulin is not advised due to fluid retention and weight gain.

Dr. Lane concluded the presentation with a review of the dosage and administration and safety with U-500 regular insulin. Patients should use a U-100 insulin syringe or tuberculin syringe. She cautioned that the lack of a syringe marked specifically for U-500 regular insulin contributes to confusion and risk of dosing errors. A prototype of a U-500 syringe is in development. In the meantime, carefully worded instructions to patients and pharmacists are essential to ensure safe use. When prescribing, the amount of U-500 regular insulin should be written in actual units and unit markings on the U-100 syringe or actual units and volume (mL) for the tuberculin syringe.

Because U-500 regular insulin takes effect within 30 minutes, a meal should follow within 30 minutes of administration. The insulin should only be administered subcutaneously. Most patients require 2 or 3 injections daily. There is no data to support mixing U-500 regular insulin with other insulins or concurrent use with oral diabetes medications.

She noted the safety concerns associated with U-500 regular insulin as outlined in the Prescribing Information:

     • Extreme caution must be used in measuring U-500 regular insulin dosage; inadvertent overdose
       may result in serious adverse reaction or life-threatening hypoglycemia
     • Hypoglycemia is the most common adverse reaction of all insulin therapies, including U-500
       regular insulin
     • Hypoglycemia can occur suddenly, symptoms may vary among individuals, and can be different
       or less pronounced under certain conditions
     • Severe hypoglycemia may develop 18 to 24 hours after the original injection of U-500 regular
       insulin
     • Any change of insulin therapy should be made cautiously and only under medical supervision
     • When initiating U-500 regular insulin, patients require close observation until the appropriate
       dosage is established

As with all insulin therapies, patients need to work closely with their healthcare providers to ensure that treatment is being executed safely and effectively.—Eileen Koutnik-Fotopoulos