Premixed insulin: Advantages, disadvantages, and future

Abstract

Premixed insulin combines two types of insulin in a single injection. This combination streamlines dosing for patients with type 1 or type 2 diabetes, thereby enhancing convenience. However, patients receiving premixed insulin commonly have less satisfactory blood glucose control. The fixed ratio of insulin in these formulations frequently fails to account for the nuanced demands of individualized glucose-lowering therapy. Moreover, local absorption of mixed insulin and potential systemic autoimmune responses may further compromise glycaemic control. The co-formulation of insulin degludec and insulin aspart introduces a new combination of the two insulin types within a single injection, offering a promising solution for mitigating the limitations inherent in premixed insulin.

Key Words: Premixed insulin; Blood glucose control; Insulin antibodies; Diabetes; Glucose-lowering therapy

Core Tip: Premixed insulin improved patient adherence because of its simplified treatment regimens, fewer injections, and low price. Therefore, premixed insulin is widely used, especially in developed countries. However, patients receiving premixed insulin commonly have less satisfactory blood glucose control. The fixed ratio of premixed insulin usually fails to meet the nuanced demands of individualized glucose-lowering therapy. Moreover, aberrant local absorption and potential systemic autoimmune responses of premixed insulin may further affect glycemic control. New insulin formulations offer improved blood glucose control, weight management, and reduced hypoglycemia. Further studies are needed to guide the optimization of insulin use through individualized treatment approaches or to mitigate the side effects of premixed insulin through novel drug combinations.

INTRODUCTION

Treatment of diabetes aims to manage the blood glucose levels, prevent complications and improve the quality of life. Lifestyle interventions and oral medications are mainly used in the early stages of type 2 diabetes, and insulin therapy is often required after the progression of the disease. Current insulin therapies include basal insulin to control the fasting blood glucose levels, mealtime insulin to manage the postprandial blood glucose levels, and a simplified regimen of premixed insulin. In China, 67% of patients with type 2 diabetes treated with insulin use premixed insulin, ranking first globally (Figure 1)[1]. Premixed insulin is an insulin formulation that combines short or rapid insulin with intermediate or long-acting insulin in a fixed ratio, aimed at simplifying treatment regimens for diabetes[2]. Common types of premixed insulin include human insulin and insulin analogues, such as Humulin 70/30, Novolin 30R, and Humalog Mix 25. This type of insulin is typically injected two to three times per day before meals, providing mealtime blood glucose control and basal glucose regulation[3]. Compared with traditional premixed insulin, newer premixed insulin formulations usually contain insulin analogues[4]. These analogues are genetically engineered to offer faster absorption or more stable action, enabling superior blood glucose control and reducing the risk of hypoglycaemia[5].

Figure 1  Insulin usage patterns in patients with type 2 diabetes mellitus in different countries.

ADVANTAGES: CONVENIENCE AND PORTABILITY

An important advantage of premixed insulin is that it simplifies the insulin treatment regimen[6]. By combining two types of insulin with different durations of action into a single injected dose, patients need to be injected only once to achieve short and intermediate-acting insulin effects[7]. This reduces the number of daily injections, typically requiring only two injections per day (morning and evening), making it more convenient and improving patient adherence compared to traditional multiple injection regimens[8]. These pen devices are easy to use, offer adjustable doses, and cause less injection-related discomfort, making them suitable for patients with little insulin injection experience, particularly for those who are new to insulin therapy[9]. Premixed insulin is particularly suitable for patients with regular lifestyles and regular eating patterns, as it has fixed peak action times and durations, allowing them to inject insulin at relatively consistent times each day[10].

DISADVANTAGES: CHALLENGES IN FLEXIBILITY AND PERSONALISED TREATMENT

Premixed insulin is a fixed-ratio combination insulin formulation[11]. This means that patients cannot adjust the ratio of short and intermediate-acting insulin based on fluctuation in their blood glucose or due to their lifestyle[12]. A cross-sectional study collected the data of glycaemic control using the FreeStyle Libre Pro™ system from 172 patients using premix insulin, and it showed that only 8.1% of patients achieved the composite goal of glycaemic control including glycosylated haemoglobin (HbA1c) < 7%, glycaemic variability < 36%, and time below range < 4%[13], which indicated the poor blood glucose control in patients being administered premixed insulin therapy (Figure 2). When physical activity and insulin sensitivity increase, it may be necessary to adjust insulin doses to avoid hypoglycaemia; however, the fixed ratio and duration of action of premixed insulin limit the space for such adjustments[12]. The effect of intermediate-acting insulin lasts throughout the night, potentially increasing the risk of nighttime hypoglycaemia, particularly if the dose is not adjusted after the evening meal[14]. Therefore, individualized treatment taking into account these factors is necessary and deserves further study. Short-acting insulin causes fewer persistent hypoglycaemic events due to its rapid clearance, particularly under reasonable dose adjustment and postprandial monitoring[15]. A prospective, randomized, open-label clinical trial in 200 insulin-naive patients with type 2 diabetes showed that in patients with type 2 diabetes, the glargine combined with quick-acting insulin group had better HbA1c, fasting and postprandial blood glucose, and lower incidence of hypoglycemia than that in the premixed insulin group[16]. These findings were also observed in patients with type 1 diabetes and further supported by meta-analysis[17,18]. Therefore, premixed insulin is less recommended than long-acting insulin analogues plus rapid-acting insulin analogues in type 1 diabetes[19]. However, the choice of insulin type is not specified in patients with type 2 diabetes yet[20].

Figure 2 Comprehensive glycemic control achievement rates in patients using premixed insulin. The Venn diagram shows the distribution of patients meeting the criteria for glycated hemoglobin < 7%, coefficient of variation < 36%, and time below range < 4%. HbA1c: Glycated hemoglobin; CV: Coefficient of variation; TBR: Time below range.

Insulin autoimmune syndrome (IAS) is a rare hypoglycaemic condition characterized by a high serum insulin level and the presence of insulin antibodies. Similar symptoms have been observed in patients with diabetes using exogenous insulin, leading to the term exogenous IAS (EIAS)[21]. Studies have reported that most patients with EIAS use premixed insulin, specifically Novolin 30R, Humulin 70/30, and other similar formulations[22]. Hypoglycaemia in these patients often occurs at night or in the early morning, with many having a serum insulin level > 100 U/mL and a low C-peptide level during hypoglycaemic episodes. When insulin associated with EIAS is discontinued, hypoglycaemic symptoms typically disappear within a few months[22]. Testing for insulin antibodies is the key to diagnosing IAS[23]. Adjusting treatment plans, such as changing the type of insulin or switching to oral medications, can effectively reduce the incidence of hypoglycaemia. Studies have found a significant correlation between the presence of insulin antibodies and a high fasting blood glucose level, particularly in patients using human insulin, where the positivity rate is higher (70.3%), whereas, the positivity rate is lowest in patients using insulin glargine (31.9%)[24]. Studies have also reported that the use of dipeptidyl peptidase 4, metformin, and insulin secretagogues, such as sulfonylureas, can significantly reduce the level of insulin antibodies[25]. Therefore, selecting the appropriate type of insulin and adjunctive oral medication can improve blood glucose control[26]. Further studies should explore the effect of antidiabetic medications on changes in the level of insulin antibodies.

Premixed insulin can cause local lipohypertrophy (fat accumulation), which significantly affects insulin absorption[27]. Lipohypertrophy is often associated with frequent insulin injections to the same site. Insulin can promote fat synthesis by stimulating fat cells to convert and store glucose[28]. The primary characteristic of lipohypertrophy is the thickening of subcutaneous fat tissue at the injection site, which forms fibrotic and poorly vascularized tissue. Studies have shown that insulin absorption in lipohypertrophic tissue is 25%-30% lower than that in normal tissue, which increases blood glucose variability[29,30]. Systematically avoiding these hyperplastic areas when injecting insulin significantly improves blood glucose control. Although all types of insulin have the potential to cause lipohypertrophy, certain formulations, including premixed insulin, may have a stronger effect on stimulating fat cell proliferation[31]. The long or intermediate-acting components of premixed insulin may stay longer at the injection site, further stimulating local fat cell proliferation[32]. Switching to more modern insulin analogues, such as insulin, glargine, or detemir, may reduce the incidence of lipohypertrophy. These insulin analogues are absorbed more evenly, have a longer duration of action, and exert a weaker stimulatory effect on fat cells[32]. Encouraging patients to regularly rotate the injection site to avoid repeated injections into the same area could effectively reduce the incidence of fat hypertrophy[33]. The injection site should not be pressed or kneaded, which will reduce the excessive spread of insulin under the skin, thereby reducing the possibility of local fat hypertrophy[34]. The use of ultra-short-acting or modified insulin preparations may reduce the risk of fat hypertrophy. The molecular design of these preparations can result in faster absorption and shorter action times, thereby reducing the local lipid-promoting effect[35].

THE FUTURE: DIABETES MANAGEMENT WITH NOVEL INSULIN THERAPIES

In recent years, new insulin or insulin/glucagon-like peptide 1-receptor agonists combinations, such as insulin degludec/insulin aspart (IDegAsp), insulin degludec/liraglutide, and insulin glargine/lixisenatide (IGlarLixi) have emerged, further optimizing the management of diabetes. Compared to traditional premixed insulin, these new formulations offer significant advantages and address the shortcomings of conventional premixed insulin, particularly in terms of immunogenicity, blood glucose control, weight management, and risk of hypoglycaemia[36].

A retrospective analysis showed that in patients with type 2 diabetes, switching from premixed insulin to IDegAsp can decrease HbA1c, fasting and postprandial blood glucose, total daily insulin dose, and injection frequency[37]. A randomized controlled trial showed that IGlarLixi was superior to IDegAsp at reducing the HbA1c level and led to weight loss. In addition, the rate of hypoglycaemic events was lower with IGlarLixi than with IDegAsp[38].

New medications usually come with a higher price tag. From 2011 to 2020, the expenditures of antidiabetic agents increased from 27.15 to 89.17 billion in the United States and insulin had the highest expenditure among antidiabetic agents[39]. The high cost of these new insulins may limit their widespread use. To promote the use of these new drugs, government and health agency may adjust their policies, such as drug price negotiations and financial subsidies, so that these innovative drugs can be provided to more patients with diabetes[40]. Updating clinical treatment guidelines and appropriately training medical staff should also be considered.

In the future, more and more “smart” insulin and insulin delivery devices may improve efficacy and convenience of insulin therapy. Recently, a new insulin “NNC2215” with the glucose-sensitive bioactivity has been introduced[41]. However, further studies are still needed to guide the optimization of premixed insulin use through individualized treatment approaches, or to mitigate the side effects of premixed insulin through novel drug combinations.

CONCLUSION

Premixed insulin improved patient adherence because of its simplified treatment regimens, fewer injections, and low price. Therefore, premixed insulin is widely used, especially in developed countries. However, the unsatisfactory glycemic control in patients on premixed insulin therapy needs to be evaluated more carefully, not only HbA1c, but also hypoglycemia and blood glucose variability. Lipohypertrophy and autoimmune insulin antibodies may also affect blood glucose control in these patients. Long-acting insulin analogues with or without rapid-acting insulin analogues and new insulin formulations will partially solve these problems.