Clinical Experience with U500 Insulin: Risks and Benefits

doi:10.4158/EP11163.OR

Endocrine Practice

Volume 18, Issue 1, January–February 2012, Pages 56-61

https://doi.org/10.4158/EP11163.OR Get rights and content

ABSTRACT

Objective

To describe our clinical experience with U500 insulin in insulin-resistant patients, including change in glucose control, body weight, insulin dose, and hypoglycemic episodes.

Methods

In September 2010, we undertook a retrospective chart review of patients who had U500 insulin in their medication list in the preceding 2 years who were treated in the endocrinology section at Dartmouth Hitchcock Medical Center. Glycosylated hemoglobin (A1C), body weight, and insulin dosage were documented before U500 insulin introduction, after 6 months of U500 insulin use, and at the last clinic visit when the patient was still taking U500 insulin. Hypoglycemic episodes and number of daily injections were recorded.

Results

Records of 53 patients were analyzed, one of the largest reports of U500 insulin use published to date. The mean A1C level decreased from 10.1% before U500 insulin was initiated to 9.1% after 6 months of U500 use to 8.6% at the last follow-up visit (mean follow-up was 36.6 ± 24 months). At the last charted visit, body weight increased by a mean of 6.8 kg and insulin dosage increased by a mean of 0.44 units/kg. We observed a significant increase in the number of nonsevere hypoglycemic episodes and a decrease in the number of daily injections.

Conclusion

Patients with uncontrolled, severely insulin-resistant diabetes can be satisfactorily treated with U500 insulin with the potential to improve glycemic control. An increase in body weight, insulin dosage, and the number of nonsevere hypoglycemic episodes was observed. (Endocr Pract. 2012;18:56-61)

Section snippets

INTRODUCTION

Patients with severe insulin resistance need very high insulin dosages, resulting in a large volume of injection and consequently discomfort. If 1 injection exceeds 100 units (1 mL of U100 insulin), 1 syringe is not enough, necessitating multiple injections of high volumes daily. This may lead to poor adherence to treatment, and the absorption of high volumes of insulin may be unpredictable (1, 2). Although there are many rare syndromes of extreme insulin resistance such as lipodystrophies,

PATIENTS AND METHODS

In September 2010, we undertook a retrospective chart review of all patients followed up in the endocrinology section at Dartmouth Hitchcock Medical Center who had U500 insulin recorded on their medication list in the preceding 2 years, independent of the year it was started. With these criteria, we reviewed medical records from January 14, 2000, to September 2, 2010. To accurately depict the effectiveness of this preparation, we excluded patients who simultaneously received pramlintide,

RESULTS

We identified 53 patients who received U500 insulin in the preceding 2 years for at least 6 months before the data collection began. The patients were followed up for 6 months to 110 months, with a mean (standard deviation) of 36.6 ± 24 months. The mean age at introduction of U500 insulin was 52.8 ± 11 years and 27 were women (51%). The mean time since diagnosis of diabetes was 13 ± 8 years. The patient population included 50 patients with type 2 diabetes mellitus and 3 patients with type 1

DISCUSSION

In this retrospective review of medical records of 53 patients with severe insulin resistance primarily due to obesity who were followed up for a mean of 36.6 months, we found that the use of U500 insulin was associated with a significant improvement in A1C level (mean of 1.5%). There was a significant increase in insulin dose by a mean of 0.44 units of insulin/kg and a significant increase in weight (6.8 kg). No episodes of severe hypoglycemia were observed.

At baseline, patients exhibited

CONCLUSION

Patients with uncontrolled, severely insulin-resistant diabetes can be satisfactorily treated with U500 insulin with the potential to improve glycemic control. The A1C decrease observed with U500 insulin was significant over time. There was an increase in body weight and insulin/kg dose with the use of U500 insulin, as well as an increase in nonsevere hypoglycemia episodes. Patients taking U500 insulin need fewer injections per day.

DISCLOSURE

Dr. Comi is the coinvestigator for a postmarketing study of liraglutide (LEADER) sponsored by the insulin manufacturer NovoNordisk. He receives no financial compensation or salary support for this study. There is no direct relationship between the LEADER study and this article on U500 insulin. Dr. Boldo has no multiplicity of interest to disclose.

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Treatment patterns and outcomes before and after human regular U-500 insulin initiation via KwikPen® among US veterans with type 2 diabetes mellitus
2021, Journal of Diabetes and its Complications
A dedicated Humulin R U-500 (U-500R) prefilled disposable insulin pen (KwikPen) became available in 2016, yet limited evidence exists on treatment patterns and outcomes of U-500R via KwikPen (U500-KP).
This is a retrospective observational study among adults with ≥2 claims for type 2 diabetes initiating U500-KP (index date: first claim) identified in Veterans Health Administration database. Treatment patterns and outcomes were evaluated in 9-month pre- and post-index periods, including dispensed total daily insulin dosage derived from claims expressed in units (dTDD) and units/kg, HbA1c, symptomatic hypoglycemia, and body weight. Multivariable modeling was used to confirm the associations between U500-KP initiation and outcomes.
A total of 647 U500-KP initiators were identified. The mean age was 64 years, and mean Quan-Charlson Comorbidity-index score was 3.8. Before U500-KP initiation, 62% of patients had dTDD ≤ 200 units with mean A1c 9.5%. Mean dTDD increased from 188.2 to 269.9 units after U500-KP initiation with mean A1c decreased by 0.83% (SD = 1.67) and mean weight gain of 1.5 kg (SD = 6.74). Hypoglycemia events increased from 4.3 to 5.3 (p < 0.05) per person per year.
Initiation of U500-KP brought significant improvement in dispensed insulin dose and glycemic control accompanied by moderate increases in hypoglycemia and weight.
Case Series of U-500 Insulin Use in Adults With Type 2 Diabetes and Severe Insulin Resistance
2021, Canadian Journal of Diabetes
Severe insulin resistance results in large volumes of insulin to achieve glycemic control. These large volumes can result in patient discomfort and decreased satisfaction. Using the more concentrated U-500 insulin provides a solution to this problem. This case series demonstrates real-world use of U-500 insulin in a Canadian population.
Seventeen patients were identified to have been started on U-500 insulin at an endocrinology clinic in Vancouver, British Columbia, Canada. The retrospective chart review looked at patients’ characteristics before starting U-500 insulin and at their 1-year follow-up appointment.
At follow up, patients demonstrated improved glycated hemoglobin with a mean improvement of 1.6% at 1 year (p<0.05). There was a statistically significant increase in hypoglycemia (p<0.05), and, on average, patients gained 5.6 kg over the course of the year (p<0.05). There was no statistically significant change in number of units of insulin, injections, lipids, renal function or blood pressure.
The initiation of U-500 insulin results in improved glycemic control at the cost of increased hypoglycemia and weight gain.
L’insulinorésistance sérieuse aboutit à de larges volumes d’insuline pour atteindre la régulation de la glycémie. Ces larges volumes peuvent entraîner l’inconfort et la diminution de la satisfaction des patients. L’utilisation de l’insuline concentrée U-500 offre une solution à ce problème. Ces séries de cas démontrent l’utilisation concrète de l’insuline U-500 au sein d’une population canadienne.
Dix-sept patients d’une clinique d’endocrinologie de Vancouver, en Colombie-Britannique, au Canada ont été sélectionnés pour commencer la prise d’insuline U-500. La revue rétrospective des dossiers a permis d’examiner les caractéristiques des patients avant le début de la prise d’insuline et à leur rendez-vous de suivi après 1 an.
Au suivi, les patients ont démontré une amélioration de l’hémoglobine glyquée, c’est-à-dire une amélioration moyenne de 1,6 % après 1 an (p < 0,05). Il y a eu une augmentation statistiquement significative de l’hypoglycémie (p < 0,05) et, en moyenne, les patients ont pris 5,6 kg au cours de l’année (p < 0,05). Il n’y a eu aucun changement statistiquement significatif dans le nombre d’unités d’insuline, d’injections, de lipides, le fonctionnement rénal ou la pression artérielle.
L’utilisation de l’insuline U-500 a entraîné une amélioration de la régulation de la glycémie au détriment d’une augmentation de l’hypoglycémie et d’un gain de poids.
A retrospective review of insulin requirements in patients using U-500 insulin hospitalized to a Veterans Affairs Hospital
2017, Journal of Diabetes and its Complications
The aim of this study was to compare the changes in the total daily dose (TDD) of insulin of patients on U-500 insulin; before hospitalization, during hospitalization and six weeks after discharge.
A retrospective chart review of veterans with type 2 diabetes receiving U-500 insulin in the ambulatory setting and who were admitted between 2012 and 2015 was performed. During hospitalization, patients were transitioned to receive U-100 insulin (detemir or glargine for basal and aspart for bolus). Paired t-tests were conducted to compare TDD of insulin during hospitalization to prior to admission and at six week of follow-up.
The average hemoglobin A1_c at the time of hospital admission was 8.3 ± 1.5% (n = 20). The average TDD of insulin during hospitalization (124 ± 67 units) was significantly less than prior to admission (295 ± 123 units) and at six week follow-up (310 ± 105 units). The average glucose during hospitalization was 180 ± 36 mg/dL. Hypoglycemia was less than 0.5%.
We showed that patients received significantly less total daily insulin while hospitalized compared to their insulin doses in the ambulatory setting, and we demonstrate that patients receiving U-500 insulin can be safely transitioned to U-100 insulin while hospitalized, with minimal hypoglycemia.
Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward
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The growing worldwide prevalence of overnutrition and underexertion threatens the gains that we have made against atherosclerotic cardiovascular disease and other maladies. Chronic overnutrition causes the atherometabolic syndrome, which is a cluster of seemingly unrelated health problems characterized by increased abdominal girth and body-mass index, high fasting and postprandial concentrations of cholesterol- and triglyceride-rich apoB-lipoproteins (C-TRLs), low plasma HDL levels, impaired regulation of plasma glucose concentrations, hypertension, and a significant risk of developing overt type 2 diabetes mellitus (T2DM). In addition, individuals with this syndrome exhibit fatty liver, hypercoagulability, sympathetic overactivity, a gradually rising set-point for body adiposity, a substantially increased risk of atherosclerotic cardiovascular morbidity and mortality, and – crucially – hyperinsulinemia.
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In this review, we discuss the origins of the atherometabolic syndrome in our historically unprecedented environment that only recently has become full of poorly satiating calories and incessant enticements to sit. Data are examined that indicate the magnitude of daily caloric imbalance that causes obesity. We also cover key aspects of healthy, balanced insulin action in liver, endothelium, brain, and elsewhere. Recent insights into the molecular basis and pathophysiologic harm from SEIRR in these organs are discussed. Importantly, a newly discovered oxide transport chain functions as the master regulator of the balance amongst different limbs of the insulin signaling cascade. This oxide transport chain – abbreviated ‘NSAPP’ after its five major proteins – fails to function properly during chronic overnutrition, resulting in this harmful pattern of SEIRR.
We also review the origins of widespread, chronic overnutrition. Despite its apparent complexity, one factor stands out. A sophisticated junk food industry, aided by subsidies from willing governments, has devoted years of careful effort to promote overeating through the creation of a new class of food and drink that is low- or no-cost to the consumer, convenient, savory, calorically dense, yet weakly satiating. It is past time for the rest of us to overcome these foes of good health and solve this man-made epidemic.
A 24-week, prospective, randomized, open-label, treat-to-target pilot study of obese type 2 diabetes patients with severe insulin resistance to assess the addition of exenatide on the efficacy of U-500 regular insulin plus metformin
2014, Endocrine Practice
To compare the efficacy of 500 U/mL (U-500) regular insulin + metformin with U-500 regular insulin + metformin + exenatide in improving glycemic control in patients with severely insulin-resistant type 2 diabetes mellitus (T2DM).
Thirty patients with T2DM and severe insulin resistance were screened, and 28 were randomized to regular insulin U-500 + metformin or the GLP-1 analog exenatide, U-500, and metformin. Glycated hemoglobin (HbA_1c) levels, body weight, and insulin doses were documented at baseline and at 3 and 6 months. The number and severity hypoglycemic episodes were noted.
There were 7 males and 7 females in each group (U-500 + metformin and U-500 + metformin + exenatide). Overall, U-500 insulin + metformin, either alone or with the addition of exenatide, resulted in a significant improvement in HbA_1c in both groups, with no significant difference between the 2 groups. There was no meaningful weight change in those utilizing exenatide. Those on U-500 insulin and metformin alone had a tendency toward some weight gain. No severe hypoglycemia occurred during the study period. Symptomatic hypoglycemia was more common in the group on exenatide, but this occurred in only 5 patients, and the clinical significance of this is uncertain. Insulin dosage changes on U-500 regular insulin were variable but tended to be lower in those subjects on exenatide.
U-500 regular insulin + metformin is effective for the treatment of T2DM patients with severe insulin resistance. The addition of exenatide may ameliorate potential weight gain but provides no additional improvement in glycemia. (Endocr Pract. 2014;20:1143-1150)

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Original ArticleClinical Experience with U500 Insulin: Risks and Benefits

ABSTRACT

Objective

Methods

Results

Conclusion

Section snippets

INTRODUCTION

PATIENTS AND METHODS

RESULTS

DISCUSSION

CONCLUSION

DISCLOSURE

Endocr Pract

Am J Med

Diabetes Res Clin Pract

Absorption of injected insulin. A clinical-pharmacological study

Acta Pharmacol Toxicol (Copenh)

Insulin pharmacokinetics

Diabetes Care

Use of concentrated insulin human regular (U-500) for patients with diabetes

Am J Health Syst Pharm

Insulin resistance-mechanisms, syndromes, and implications

N Engl J Med

Original Article
Clinical Experience with U500 Insulin: Risks and Benefits