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Advancements in the Delivery of Biologics for the
Treatment of Diabetes


Introduction

Diabetes is a chronic metabolic disease that affects nearly 30.3 million people in the United States and an estimated 425 million worldwide.1 Type 1 diabetes (T1D) is characterized by persistent hyperglycemia and requires regular administration of insulin or other diabetes treatments to maintain blood glucose levels within the recommended target range (glycated hemoglobin [A1C] <7%; however, more or less stringent targets may be appropriate for certain patients).2 Type 2 diabetes (T2D) is often initially treated with non-insulin regimens, although insulin may be implemented as the disease progresses to further reduce hyperglycemia and prevent long-term complications.3

Management of glycemic parameters is the main goal when treating patients with T1D or T2D, yet many treatment options have distinct clinical shortcomings in this regard. Patients from both diabetes subtype groups are often concerned with the risk of hypoglycemia and treatment-induced weight gain. For those from either group who are dependent on insulin, the complexity of administering the agent is a major additional concern.4-6 The advent of continuous glucose monitoring that is easy to perform and cost-effective has given patients more control, however, it has also heightened worry about glucose variability associated with their treatment regimens.7 In addition, patient adherence to medications is often influenced by the complexity of their treatment regimens and how busy they are with daily activities.8

In the last few decades, diabetes care has seen improvements in drug delivery, together with advances in insulin (from animal to human and now rapid to long-acting) and the development of other biologics (made from recombinant therapeutic proteins).9 Biologics, such as recombinant human insulin, insulin analogs, pramlintide (modified human amylin), and glucagon-like peptide-1 (GLP-1) receptor agonists have been revolutionary in the treatment of diabetes and have the potential to be even more so going forward. Although biologics offer high specificity, potency, and additional advantages, their susceptibility to degradation poses a significant delivery challenge. Continual modifications have been introduced to optimize absorption, stability, route of administration, and dosing frequency. This article summarizes the progress that has been made over the last century in the management of diabetes due to advances in biologics and options for their administration to patients.

Insulin

Insulin was first introduced as a treatment for diabetes in 1922; before this, diabetes was generally fatal within weeks of diagnosis. The earliest insulin was derived from the pancreases of cows (bovine) or pigs (porcine) and required purification, as the treatment often elicited mild allergic reactions in patients. Although monumentally lifesaving, the animal-derived insulins required frequent injections because of their short duration of action. Therefore, patients often experienced alternating states of hyperglycemia and hypoglycemia.

In 1978, recombinant DNA technology was used for the first time to produce synthetic human insulin by inserting the human insulin gene in Escherichia coli bacteria (FIGURE 1). This recombinant insulin was more physiologically similar to endogenous insulin and had the advantage of being less likely than animal insulin to cause allergic reactions. The amino acid sequences of human-analog insulins were further modified to alter the pharmacodynamic properties of the molecule. This led to the advent of rapidly acting insulins, along with long-acting and basal insulins to allow for control of postprandial glucose and fasting glucose, respectively.


FIGURE 1. How insulin was made from recombinant DNA


Reproduced with permission from the US National Library of Medicine. US National Library of Medicine. How did they make insulin from recombinant DNA? https://www.nlm.nih.gov/exhibition/fromdnatobeer/exhibition-interactive/recombinant-DNA/recombinant-dna-technology-alternative.html. Accessed October 24, 2018.



These newer insulins were life-altering for patients with T1D. And, initially, they were used early on for patients with T2D. But insulin therapy, if not properly executed, can lead to inadequate blood sugar control and serious hypoglycemic and hyperglycemic consequences. Many patients were, and still are, hesitant to initiate insulin therapy due to the complexities often associated with its use, such as the need to carefully monitor blood glucose and adjust the insulin dose based on meal content, exercise, and other factors. Importantly, the major clinical limitations of insulin therapy, including the risk of hypoglycemia, weight gain, and impact on social life, are often listed as major patient concerns.10

The traditional vial-and-syringe method of insulin administration requires both time and practice to achieve optimal technique. The process includes removing air bubbles prior to administration, understanding the markings on a syringe (which vary with syringe capacity), drawing the correct volume of air and drug, and proper syringe disposal. Furthermore, having to perform these steps in a social setting, such as in a workplace, classroom, or restaurant, may be considered at best an inconvenience and at worst an embarrassment to many patients. All of these factors can serve as barriers to effective insulin therapy.

Over time, use of the vial-and-syringe method has diminished as newer methods for administering insulin have been introduced. One option is pre-filled, disposable insulin pens, which eliminate many of the barriers discussed above. The first insulin pen was introduced in 1985 and has led to improvements in dosing accuracy, convenience, and ease of physical manipulation.11 As the name suggests, insulin pens (FIGURE 2) are similar in appearance to ink pens. They contain an insulin cartridge and disposable needle and have an adjustable dosage setting, which allows the patient to easily and accurately dial the correct dose of insulin they require. The insulin is delivered when the patient activates the pen, which is often done with the push of a button. An open-label, randomized, crossover, multicenter study assessed patient and health care provider (HCP) preferences for the vial-and-syringe method vs the insulin pen.12 Patients reported a significant (P<.0001) preference for pens over vials and syringes, and HCPs strongly recommended pens over vials and syringes (P<.0001). Furthermore, physicians found the insulin pens easier to handle and more accurate in delivering the appropriate dose compared with the vial-and-syringe method.


FIGURE 2. Syringe, autoinjector, and diabetes pen


Another method that has become very popular with T1D patients, and patients with T2D requiring basal or bolus insulin, is continuous subcutaneous insulin infusion (CSII) with an insulin pump.13 CSII is most frequently used in patients with T1D and in patients with T2D who have failed multiple daily injection (MDI) therapy.14,15 The demand for advanced insulin delivery devices supports the adoption of insulin pumps, which are projected to increase in use over time (FIGURE 3). These devices are filled with insulin and are controlled with a smartphone or alternative device to set an infusion rate that can be adjusted to bolus around meals. These devices eliminate the need to deliver a once-daily injection of basal insulin and 3 injections of mealtime insulin each day. Interestingly, with the advancement in continuous glucose monitoring technology, the first hybrid closed-loop system has recently been approved.16 With this system, the insulin infusion rates can be adjusted in real-time based on continuous glucose monitoring. However, these advancements also have drawbacks as the systems can be complicated to program and set up.


FIGURE 3. Insulin delivery devices market, by product, 2014-2025 (USD Million)


Reproduced with permission from Grand View Research Inc. Grant View Research. Insulin Delivery Devices Market Analysis By Product (Insulin Syringes, Insulin Pens, Insulin Pumps, Insulin Injectors), By End Use (Hospitals, Homecare, Assisted Living Centers, & Nursing Homes), And Segment Forecasts, 2018 – 2025.
https://www.grandviewresearch.com/industry-analysis/insulin-delivery-devices-market. Published Date: November 2016. Accessed October 24, 2018.



The management of T2D with CSII has been explored as an alternative to MDIs of insulin. However, current clinical evidence supporting CSII use is mixed, with very few studies comparing its effectiveness to MDI.17 The widespread adoption of CSII among T2D patients proves challenging for several reasons. Patients using CSII must frequently monitor blood glucose levels to ensure the pump is working properly and to avoid adverse effects, such as ketoacidosis. Additionally, patients with T1D are most often cared for by specialists in endocrinology, while patients with T2D are often cared for by primary care providers, who may have minimal knowledge of, and training in, CSII.18 Finally, cost serves as another barrier, as many insurance companies prefer to cover MDI therapy, which is perceived as being less expensive. Although MDI therapy often involves more than 3 injections per day, it is still less expensive than acquiring an insulin pump, the additional required supplies, and training.18 However, if improvements in clinical outcomes can outweigh the cost, CSII may find a place in the standard care of T1D and advanced T2D.

Alternative methods of administration

Patients with T1D and advanced T2D require chronic treatment to achieve and maintain healthy blood glucose levels; therefore, the availability of novel therapeutic options and devices that are both effective and patient-friendly is important. While advances in insulin treatment have undoubtedly helped to improve glucose control, patients continue to struggle with complex regimens. Barriers to effective insulin use may be categorized as emotional (eg, fear of injection pain), cognitive (eg, perception of personal failure), relational (eg, HCP influence), or social (eg, stigma).19 The development of devices that can meet user expectations and overcome these obstacles have the potential to improve patient compliance and adherence.

To continue improvements from the vial-and-syringe method, autoinjectors (AIs) were eventually implemented in diabetes treatment. AIs were initially introduced in the 1970s for the quick delivery of epinephrine to patients experiencing anaphylaxis—a serious and potentially fatal allergic reaction with rapid onset. AIs are similar in appearance to insulin pens; however, the needle is housed within a spring-loaded device to deliver the drug using automatic insertion. With a push of the button, the AI injects a hidden needle into the skin, administers the drug, and withdraws the needle back into the device (FIGURE 2). The AI’s design removes many of the barriers that may be associated with both the vial-and-syringe method and insulin pens and improves multiple aspects of drug delivery, such as ease of administration and portability.20 Ready-to-use AIs have an added advantage for needle-adverse patients—the needle is not visible, and the devices improve needle safety. Additionally, the automatic nature of the device allows it to be used more easily by patients who have diminished strength and/or dexterity. Other methods require a certain amount of force or the ability to push a plunger and simultaneously hold it in place, as with insulin pens.

Because of the negative associations patients have with insulin injections, there has been much interest in developing alternative methods that deliver insulin in a minimally invasive manner (TABLE 1). Inhaled insulin (Afrezza) was approved by the US Food and Drug Administration (FDA) on June 27, 2014, as a way of providing ultra-rapid-acting insulin to improve postprandial glycemic control in an easy-to-use oral inhaler.21 The powdered human insulin was formulated to adsorb onto technosphere particles, allowing entry into the lungs, where insulin diffuses across the membrane to yield its therapeutic effect.22 The faster pharmacokinetics and pharmacodynamics of this inhaled insulin surpass the currently available rapid-acting insulin analogs—aspart, glulisine, and lispro—which are administered subcutaneously. Peak insulin concentrations occur within 12 to 17 minutes after inhalation of 20, 50, or 100-unit (U) doses, while peak glucose-lowering activity occurs in under 1 hour, compared with 2 hours for the insulin analogs at a 10-U dose.23 The downside to inhaled insulin is low bioavailability (about 20% to 25%), compared with 70% seen with subcutaneously administered insulin.23

TABLE 1. The advantages and disadvantages of insulin delivery methods

  Advantages Disadvantages  
Methods Insulin delivery through subcutaneous  
route
Remarks
Vial and syringe ↓Expense vs pen and CSII ↑Pain vs pens

Psychosocial issues

Inconvenience
to carrying it

↓Accuracy vs pens

↓Patient friendliness
Most frequently used method
Pen device Convenient

↓Pain vs syringes

↑Accuracy, precision vs syringes

Easier to use
↑Expense vs syringes

Can’t mix 2 insulins
No superiority of pen devices vs syringes for glycemic control
CSII (Accu-Chek Spirit, OneTouch Ping, MiniMed Paradigm, DANA Diabecare IIS, Omnipod, Nipro Amigo, T:slim X2) Continuous delivery of insulin

↑Glycemic control

↑Patient compliance and acceptance
↑Cost

↑Risk of DKA if pump fails; injection site infection
Successful CSII requires patient education and motivation
SAP (any of the above pumps + Dexcom G4, Minimed, FreeStyle Navigator)

Same as CSII + ↑ glycemic control

↓Hypoglycemia
Same as CSII

CGM accuracy
↑Glycemic control requires contentious CGM use
TS (Paradigm Revel 2.0 insulin pump and Enlite glucose sensor) Provides all the advantages of SAP + reduces hypoglycemia by 30% vs CSII Same as CSII and SAP

Hypoglycemia algorithms not predictive
Approved recently by FDA

Phase 4 survey underway
Intra-peritoneal (MIP 2007) Direct insulin delivery to the portal vein

More physiologic
Invasive

↑Cost

Infection, ↑portal vein thrombosis risk
Long-term data not available
Inhaled (Afrezza, Exubera, Technosphere, AERx Insulin Diabetes Management System) Noninvasive

↑Patient compliance

Rapid onset of action (10-15 min)

↑PPBG control
↓Bioavailability

Inhalation device issues

↓Lung function

Transient cough
Exubera withdrawn from the market

Technosphere under FDA review
Oral (Capsulin, ORMD-0801, IN-105) ↑Portal insulin concentration

Noninvasive

Patient friendly
GI degradation of insulin

↓Bioavailability
Awaiting results of phase 3 trial for IN-105
Buccal (Oral-Lyn, Recosulin) Same as oral + bypass

GI degradation
↓Bioavailability  
Nasal (Nasulin) Same as oral and buccal insulin + no interference with pulmonary functions ↓Bioavailability (15%-25%)

Local irritation

Nasal irritation
Awaiting phase 3 trial results

Awaiting phase 2 and 3 clinical trial results
Transdermal (Microneedles, iontophoresis, electrophoresis, sonophoresis microdermabrasion) Needle free Skin irritation, blisters, pain,
and redness
No long-term trials; safety not established


Abbreviations: ↑, increased; ↓, decreased; +, plus; CGM, continuous glucose monitor; CSII, continuous subcutaneous insulin infusion; DKA, diabetic ketoacidosis; FDA, US Food and Drug Administration; GI, gastrointestinal; PPBG, postprandial blood glucose; SAP, sensor-augmented pump therapy; TS, threshold suspend insulin pump.

Reproduced with permission from Wolters Kluwer Medknow Publications: Shah RB, Patel M, Maahs DM, Shah VN. Insulin delivery methods: past, present and future. Int J Pharm Investig. 2016;6(1):1-9. Accessed October 17, 2018.


Another minimally invasive route of insulin administration is through the buccal cavity, where insulin is delivered via the inner lining of the cheek. Oral-lyn, a liquid spray of human insulin, is currently being assessed for approval by the FDA. Peak insulin concentrations were observed to occur within 23 minutes of administering a 150-U dose compared with 83 minutes following a 0.1-U/kg dose of subcutaneously injected human insulin. The peak glucose-lowering activity was shown to occur approximately 44 minutes after Oral-lyn use vs 100 minutes for subcutaneously injected insulin.24 Similar to the concerns seen with inhaled insulin, the bioavailability of buccally administered insulin is poor, with the original formulation having a bioavailability of approximately 10%.25

For needle-adverse patients, diabetes treatment, which often involves skin penetration, is associated with fear of injection pain. The use of needle-free devices could, therefore, potentially improve patient adherence and compliance. A jet injector is a type of syringe that utilizes a high-pressure system to disperse insulin into the subcutaneous adipose tissue compartments instead of penetrating the epidermis with a hypodermic needle. Previous studies have shown that postprandial peak absorption and action of rapid-acting insulin is achieved more quickly with a jet injector than with a pen.26 In addition, jet injectors have been shown to produce pharmacokinetics that more closely resemble those of endogenous insulin secretion when compared with pens.27 The faster postprandial glucose control and the minimally invasive nature of these devices may especially benefit needle-phobic patients who have difficulty controlling postprandial glucose excursions. However, there is currently no jet injector approved for use by patients with diabetes.

Despite many advances in insulin analog formulations and delivery systems, the need to minimize weight gain and the risk of hypoglycemia remains.

Alternative treatments for diabetes

Biologics work through well-worn evolutionary hormonal pathways and feedback mechanisms leading to a high degree of specificity and the ability to address core defects of the disease rather than simply treating the symptoms. The approval of newer biologics, including insulin analogs, amylin mimetics, and GLP-1 receptor agonists (also known as incretin mimetics), in patients with diabetes has dramatically expanded the armamentarium for physicians. The amylin mimetic, pramlintide, and the GLP-1 receptor agonist, exenatide, were the first peptide drugs approved for the treatment of T1D and T2D. These drugs offer benefits that extend beyond glucose control and address the clinical limitations of traditional antihyperglycemic drugs. Namely, they reduce weight by decreasing caloric intake and because they are glucose-dependent, they tend to be associated with a lower risk of hypoglycemia. Research has also shown that the GLP-1 receptor agonists decrease major adverse cardiovascular events in patients with T2D and established cardiovascular disease.28 The most common adverse effects of biologics are nausea, vomiting, and injection-site reactions; however, the risks of drug-induced pancreatitis and thyroid carcinomas are also present (TABLE 2).28

TABLE 2. Advantages, adverse effects, and risks of non-insulin biologics

Non-insulin biologic Advantages Adverse effects Risks
GLP-1 receptor agonists Improvements in blood glucose control, preservation of beta-cell function, weight loss, increased insulin sensitivity28 Nausea, vomiting, injection-site reactions28 Pancreatitis, thyroid cell carcinomas28
Pramlintide Regulation of postprandial glucose appearance, slow gastric emptying, suppression of postprandial glucagen secretion, reduction in mealtime insulin use, weight loss, reduction of food intake31 Hypoglycemia, nausea, vomiting, anorexia31 Severe hypoglycemia31
Abbreviation: GLP, glucagon-like peptide-1.

Biologics are usually given subcutaneously, as oral administration results in a high degree of inactivation or degradation in the digestive tract. A few of these agents—pramlintide (Symlin), exenatide (Byetta), liraglutide (Victoza), and albiglutide (Tanzeum)—utilize pen devices, similar to the insulin pen. Byetta was first introduced as an immediate-release formulation, given twice daily to provide coverage for 2 major meals. Although Byetta provided ease of use in terms of drug delivery, patient adherence to a twice-daily regimen was often suboptimal.29

The introduction of newer biologic treatments, such as the extended release formulations of exenatide (Bydureon), dulaglutide (Trulicity), and semaglutide (Ozempic), allowed for a simplified treatment regimen with less frequent dosing. Bydureon was initially available as a single-dose tray, requiring the patient to prepare their dose with a vial and syringe, which lacked convenience. The development of Bydureon as a pre-filled, dual-chamber, single-use pen, which contained the same formulation and dose as the single-dose tray, sought to overcome these challenges. The pen eliminated the need for patients to transfer the medication between the vial and syringe as reconstitution occurs by simply turning a knob on the device.

Ease of use was further enhanced by widespread application of AIs that encourage patient self-reliance and help improve adherence.16 Of note, the newer GLP-1 receptor agonists, Bydureon (Bydureon BCise) and Trulicity are administered using AIs. In addition to the administration benefits observed with AIs, Bydureon BCise no longer requires reconstitution, allowing for easier and more convenient administration.

As new treatments have greater success at helping patients manage weight gain and the risk of hypoglycemia, the emphasis of diabetes care has shifted to utilizing technology to improve the patient experience. Although already available as an injectable, a formulation of semaglutide with once-daily oral administration is currently in phase III clinical trials.30 Until recently, oral delivery for GLP-1 receptor agonists was not feasible due to membrane impermeability and the susceptibility of peptides to the acidic environment of the stomach.24 This novel formulation, however, comprises an absorption-enhancing excipient to promote passive transcellular transport across the intestinal lumen so that it can exert its therapeutic effects. In addition, this oral formulation may facilitate patient acceptance and adherence.

Conclusions

Despite an expanding array of available therapeutic options, many patients with diabetes remain inadequately managed, due largely to a lack of adherence to prescribed treatment regimens, which, in turn, is due largely to drug and device shortcomings. The development of new treatments and new ways to deliver these treatments are becoming increasingly important as the prevalence of diabetes increases. Subcutaneous injection, as well as inhaled, oral, and buccal administration, are all methods whose pros and cons may be considered. The improved simplicity of newer devices, as well as the discovery of formulations that allow for less frequent dosing, contribute to increased compliance and adherence rates. As we continue to move toward the development of alternative options, it is evident that the treatment and management of diabetes has progressed with safer and more patient-friendly options.


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