An update on insulin resistance and use of U-500 insulin

Insulin resistance can be described as a decrease in sensitivity or a decreased biological response to insulin.¹ No single etiological explanation has been described for insulin resistance because of the unique associations with cardiovascular risk, obesity, hypertension, and dyslipidemia. Research has shown that the pathogenesis of insulin resistance results from either lipid accumulation, the contribution of systemic inflammation, or through genetic mutations involving autoantibodies to the insulin receptor.²

There is considerable variation in how to identify and clinically measure insulin resistance in humans, according to researchers. Clinicians have used between 100-200 units per day as a cutpoint for diagnosing insulin resistance.³ A more direct measurement known as the “gold standard” for measuring insulin resistance is the euglycemic hyperinsulinemic clamp.¹ Similar direct measurements have been accepted as estimates of insulin resistance including the frequently sampled intravenous glucose tolerance test, the steady state plasma glucose method, the oral glucose tolerance test, and the homeostatic model assessment (HOMA)¹. Used in recent literature, the HOMA attempts to measure beta-cell function and quantify insulin resistance through mathematical formulas.¹ A unique advantage to the HOMA over the previously mentioned methods is it does not require invasive, time-consuming procedures. However, all the direct measurements of insulin resistance mentioned have not shown to be superior in comparison to fasting insulin levels.¹ Overall, there continues to be a lack of standardization among methods and measurements to define and quantify insulin resistance in humans.

Challenges for pharmacists

Based on recent surveillance data from the Centers for Disease Control and Prevention (CDC), the prevalence of diabetes among adults in the United States has grown by 45% over the past 20 years, with the greatest increase seen among seniors over the age of 65.⁴ As the diabetes epidemic grows, it is expected that clinicians will encounter more patients who are insulin resistant and present with challenging medication regimens. It continues to be challenging to reach target goals of therapy for these patients with regard to low-density lipoprotein cholesterol (LDL-C),  hemoglobin A_1C  (HbA_1C), blood pressure, fasting and postprandial glucose levels, and body mass index (BMI). The combination of these metabolic disorders has led to a need of higher total daily insulin requirements and the use of U-500 insulin in insulin-resistant patients in an attempt to optimize pharmacologic therapy and achieve glycemic goals.

Current use of U-500 insulin

In order to ensure the safe and effective use of insulin therapy, pharmacists should familiarize themselves with the use of U-500 insulin as its use is expected to rise with the diabetes epidemic. In insulin-resistant patients, the dose-response curve is significantly diminished at doses greater than 100 units in comparison to the insulin response in type 1 and 2 diabetes patients.³ However, it has been shown that insulin-resistant patients eventually achieve therapeutic goals at high doses of insulin.³ For this reason, the use of U-500 insulin should be considered in patients who are insulin resistant.

Current evidence for the use of U-500 insulin is limited to retrospective case series reports, which have demonstrated that either multiple daily injections or a continuous subcutaneous insulin infusion is effective at improving glycemic control.³ In comparison to U-100 insulin, U-500 insulin is five times more potent, with the pharmacokinetic profile being most closely related to NPH insulin.³

Due to the increased potency of U-500 insulin, it is important for pharmacists to counsel patients on the proper use of U-500 insulin. All other forms of insulin should be discontinued, the proper syringe (ie: tuberculin) should be utilized, and the pharmacist should instruct the patient on when and how to inject U-500 insulin.

A pharmacoeconomic analysis demonstrated that U-500 insulin provides a potential cost advantage over U-100 insulin because it costs less per unit due to the reduced volume required per injection and patients needing fewer syringes to inject.³ Additionally, because U-500 insulin is used alone, patients no longer require a bolus and basal insulin to achieve glycemic goals.

Future implication to diabetes care

According to the American Diabetes Association (ADA) guidelines, patients with more extreme forms of insulin resistance than type 2 diabetes patients are classified as having “other specific types of diabetes.”³ Pharmacists and providers are faced with challenges to help these patients reach glycemic goals not only due to their insulin resistance, but possibly due to the presence of the metabolic syndrome. To date, pharmacists and providers are forced to rely upon an arbitrary number of units required to achieve glycemic goals to classify a patient as insulin resistant. As the diabetes epidemic continues, further research should focus on population-based studies that determine a cutpoint for diagnosing insulin resistance in addition to providing insulin-resistant patients with evidence-based pharmacotherapy.

References

1.     Sinaiko A, Caprio S. Insulin resistance. J Pediatr. 2012;161(1):11–15.

2.     Samuel V, Shulman G. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148(1):852–854.

3.     Cochran E, Musso C, Gorden P. The use of U-500 in patients with extreme insulin resistance. Diabetes Care. 2005;28(5):1240–1244.

4.     Cheng Y, Imperatore G, Geiss L, et al. Secular changes in the age-specific prevalence of diabetes among U.S. adults, 1988–2010. Diabetes Care. 2013. [Epub ahead of print] Accessed June 26, 2013

Kevin Cowart, PharmD candidate 2015, attends the University of South Florida College of Pharmacy. He can be reached by email: kcowart1@health.usf.edu.