Liraglutide Effective in the Severely Insulin-Resistant Patient with Type 2 Diabetes Requiring U-500 Insulin: A Case Report

Introduction

S evere insulin resistance is becoming increasingly common in obese patients with type 2 diabetes mellitus (DM-2). Eventually, a subset of patients requires switching from the standard U-100 insulin to concentrated U-500 insulin. ^1,2 Despite the use of U-500 insulin, obtaining adequate glycemic control can remain difficult. Moreover, undesirable U-500 treatment-related weight gain may become a barrier to attaining glycemic control goals.

The obese, severely insulin-resistant patient with DM-2 is a great candidate for glucagon-like peptide (GLP)-1 receptor agonist therapy. This class of medications has been demonstrated to assist with the management of hyperglycemia via multiple mechanisms: increasing insulin biosynthesis and secretion, reducing glucagon secretion and thereby inappropriate hepatic glucose output, delaying gastric emptying, and increasing satiety, the latter of which often results in a reduction in caloric intake and weight loss. ^3,4 Even a small reduction in weight may provide multiple health benefits and assist in the management of common comorbid conditions (hypertension, hyperlipidemia, etc.) observed in the obese patient with DM-2. In patients taking U-500 insulin, the addition of the once-daily GLP-1 receptor agonist liraglutide may help to curtail the weight gain and assist with weight loss, while improving glycemic control and reducing insulin requirements. ⁵

We describe the clinical history of a 65-year-old morbidly obese man whose insulin requirements decreased dramatically (>50% decrease in total daily insulin dose) after 5 months of once-daily liraglutide, while also experiencing a concurrent improvement in hemoglobin A1c (HbA1c) and weight loss of more than 20 kg.

Research Design and Methods

A morbidly obese (body mass index, 67.3 kg/m²; weight, 156.2 kg) patient presented with a 20-year history of uncontrolled DM-2. His glycemic control deteriorated to U-500 insulin requirement. He continued on metformin (1,000 mg twice daily), but despite up-titration to a total daily dose of 575 units of U-500 insulin daily (200 units at breakfast, 150 units at lunch, and 225 units at dinner), his glycemic control remained poor (HbA1c, 9.1%). Given his inadequate glycemic control, high insulin requirements, and state of obesity, he was offered a trial of once-daily liraglutide therapy.

Results

Glycemic control improved dramatically after the initiation of liraglutide. He reported a rather robust decrease in appetite with a resultant diminution in prandial intake but denied any of the other common side effects observed with GLP-1 therapy (nausea, vomiting, diarrhea, etc.). Despite an empirical U-500 dose reduction from 575 to 400 units daily at the time liraglutide 0.6 mg daily was initiated, he started to have frequent symptomatic episodes of mild to moderate hypoglycemia (range, 50–70 mg/dL), approximately three or four times per week, which resolved with supplemental glucose intake. No severe episodes of hypoglycemia occurred, and none required the assistance of a third party. As the liraglutide was titrated upward, the daily dose of U-500 insulin was reduced further in order to avoid hypoglycemia. After 5 months of therapy, a total daily U-500 dose of 250 units (100 units with breakfast, 50 units with lunch, and 100 units with dinner), metformin 1,000 mg twice daily, and liraglutide 1.8 mg daily resulted in much improved glycemic control (HbA1c, 6.9%). Moreover, he experienced a weight loss of 22.6 kg (approximately 14.5% of initial body weight). Table 1 presents a summary of the results.

Discussion

The addition of once-daily liraglutide to patients with uncontrolled DM-2 requiring U-500 insulin should be considered and may help to reduce insulin requirements, improve glycemic control, and assist with weight management. The literature pertaining to the use of liraglutide in patients taking U-500 insulin is limited. ⁵ Lane et al. ⁵ reported significant improvements in glycemic control, weight loss, and reduced insulin requirements with the addition of liraglutide in patients with uncontrolled DM-2 taking U-500 insulin. However, the reduction in insulin requirements, improvement in glycemic control, and weight loss observed in our patient appear to be much more pronounced compared with their experience. Our report, combined with the report by Lane et al., ⁵ demonstrates the utility of adding the GLP-1 receptor agonist liraglutide to patients requiring U-500 insulin. Because the response to liraglutide in such patients appears to be variable, we feel it prudent to recommend a substantive reduction in insulin doses when initiating liraglutide therapy in order to obviate the risk of hypoglycemia. A dose reduction needs to be individualized depending largely on the level of glycemic control at the time that liraglutide is initiated. Lane et al. ⁵ reported empirical dose reductions of U-500 insulin on the order of 0–30%, at the time of liraglutide initiation, in 15 patients, at the discretion of the treating physician. Given our patient's response, in view of patient safety, we recommend a dose reduction of U-500 insulin by at least 30% when initiating liraglutide therapy.