New insulin preparations: A primer for the clinician

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ABSTRACTThe importance of glycemic control in preventing the chronic and devastating complications of diabetes is well established. Insulin administration is an important therapeutic option for managing diabetes, particularly for patients with profound insulin deficiency. Many insulin formulations are on the market, including short-acting insulin analogues, inhaled insulin, concentrated insulin, and basal insulin. Each category has a unique onset, peak, and duration of action. This article reviews the differing pharmacokinetic and pharmacodynamic properties and safety and efficacy data, and discusses the implications for clinical practice.


  • Insulin extracted from an animal pancreas was first administered in 1921; the first insulin analogue was marketed in 1996.
  • Insulin is considered the therapeutic standard in patients with advanced insulin deficiency.
  • Types of available insulin products have differing onset, peak, and duration of action ranging from ultra-short-acting to ultra-long-acting.
  • The US Food and Drug Administration approved an inhaled insulin product in 2014; all other products are administered subcutaneously.
  • Concentrated insulin preparations provide an alternative for patients requiring consistently high daily doses of insulin.



The first isolation and successful extraction of insulin in 1921 opened an important chapter in the management of diabetes, especially for patients with profound insulin deficiency. At that time, a 14-year-old patient who was dying from type 1 diabetes received the first insulin injection—a canine pancreatic extract. It was a lifesaving treatment. Within a few months of insulin administration, the patient regained weight and health and went on to live another 13 years before succumbing to pneumonia and chronic complications of hyperglycemia.

While the introduction of regular insulin from animal extracts provided lifesaving therapy for patients with type 1 diabetes, it was the introduction of protaminated insulin in 1946 that provided more extended “basal” coverage to taper some of the large glycemic fluctuations that occurred with the administration of regular insulin two to three times daily. The use of a split-mix approach with twice-daily administration of a combination of regular insulin plus either insulin neutral protamine Hagedorn (NPH) or insulin lente provided overall better control with fewer episodes of hypoglycemia or severe hyperglycemia.

Insulin was the first protein to be sequenced (in 1955), and it became the first human protein to be manufactured through human recombinant technology. It was introduced into clinical practice in 1982 as synthetic “human” insulin, with the advantage of being less allergenic than animal insulin preparations. Human insulin eventually replaced all of the animal insulin preparations in the US market.

The pursuit of tight glycemic control as an effective strategy to prevent the chronic and devastating complications of the disease was confirmed in 1993 by publication of the Diabetes Control and Complications Trial (DCCT), which undeniably established the relationship between normalization of glycemia and prevention of microvascular complications in patients with type 1 diabetes.1 The UK Prospective Diabetes Study, demonstrating a similar relationship in type 2 diabetes, was soon to follow.2 In both trials, the follow-up observation periods further underscored the importance of early glycemic control by showing both sustained reductions in microvascular complications (retinopathy, nephropathy, and neuropathy) and statistically significant decreases in the risk of a cardiovascular event.3,4 Of note, it was the introduction in clinical practice of safer and more user-friendly insulin options that made these gains in glycemic control possible.

With the publication of the DCCT results,1 physio­logic insulin replacement became the therapeutic standard in patients with advanced insulin deficiency, demonstrating that lowering hemoglobin A1c (HbA1c) and mitigating glycemic variability translated into microvascular risk reduction. The use of longer-acting insulin preparations, such as ultralente insulin, and the delivery of the basal component through continuous subcutaneous (SC) insulin infusion using an insulin pump further facilitated achievement of near-normal glycemia.

Insulin products marketed in the US

Insulin products continue to be refined and new formulations and molecular entities developed (Table 1). The following sections review the current insulin products, their pharmacologic profiles, and their clinical roles in diabetes practice.


In 1996, the first short-acting insulin analogue (or insulin-receptor ligand), lispro, was brought to market. In lispro, the penultimate lysine and proline amino acids on the end of the C-terminal of the beta-chain of human insulin are reversed, facilitating faster absorption of the insulin through the greater availability of insulin monomers following SC depot injection.

The three short-acting insulin analogues—lispro, aspart, and glulisine—have similar pharmacokinetic and pharmacodynamic properties, with earlier onset and peak of biologic action, and shorter duration of activity than regular insulin. Potentially, these characteristics should translate into greater administration flexibility (patients can inject anywhere from 20 minutes before to 20 minutes after the start of the meal), better control of postprandial hyperglycemia, and less risk of late prandial hypoglycemia (3 to 6 hours after the meal). In a meta-analysis comparing short-acting analogues with human regular insulin, the most relevant difference reported was a lower risk of severe hypoglycemia with the analogue preparations5 (Table 2). There might be an advantage with regards to bedtime and overnight hypoglycemia when using short-acting analogues, especially if a protaminated insulin is used for overnight basal coverage.6

While short-acting analogues have been approved for administration following a meal, postprandial control is clearly better if these preparations are injected prior to the meal, ideally 15 to 20 minutes before, to allow time to enter the circulation.7 Additionally, the pharmacokinetics and biologic activity of short-acting insulin analogues appear to be very different when administered to obese, insulin-resistant patients with type 2 diabetes, in whom the onset of action is delayed and the biologic activity considerably reduced.8


Data from Afrezza (insulin human) inhalation powder [package insert]. Danbury, CT: MannKind Corp; 2014.
FIGURE 1. Serum insulin concentrations and glucose infusion rate of inhaled insulin for inhaled vs insulin lispro in patients with type 1 diabetes.

A recent entry into the short-acting insulin marketplace—Technosphere oral-inhaled insulin (Afrezza)—was US Food and Drug Administration (FDA)-approved in 2014. Inhaled insulin has low bioavailability but is absorbed much more rapidly into the circulation than the current short-acting insulin analogues and has a shorter duration of biologic activity. However, the pharmacodynamics of inhaled insulin, when compared with insulin lispro, show only a slightly faster onset of action and a lower peak of biologic activity9 (Figure 1). Studies comparing the efficacy and safety of inhaled insulin with short-acting analogues or premix insulin have demonstrated equivalent or less effective blood glucose-lowering effect and equivalent or lower risk of hypoglycemia.10 For example, in trials of aspart insulin in patients with type 1 diabetes, inhaled insulin had statistically less reduction in HbA1c; in only one of the two trials did it show less hypoglycemia risk. Another trial comparing inhaled insulin plus basal insulin to premix aspart 70/30 showed equivalent HbA1c reductions, but less hypoglycemia with inhaled insulin.10

Inhaled insulin should not be used by smokers, patients with chronic lung disease (such as asthma and chronic obstructive pulmonary disease), and those with acute episodes of bronchospasm. In patients who have a history of or are at risk for lung cancer, the benefits of using inhaled insulin need to be carefully weighed against the potential risks, especially given the increase in lung cancer events in smokers that was observed with the prior inhaled-insulin preparation Exubera.11 Baseline and follow-up spirometry needs to be implemented for those using inhaled insulin to exclude clinically significant changes in forced expiratory volume in 1 second. Dosing of inhaled technosphere insulin is done via single-use cartridges of 4-, 8-, or 12-unit composition, making titration of smaller insulin increments more of a challenge. Patient reported outcomes in trials of inhaled insulin report variable effect (equivalent or favorable) on diabetes worries, health-related quality of life, or perceptions of insulin therapy, satisfaction, or preference.12,13


Concentrated insulin preparations have been available in clinical practice for many years and have been implemented with variable success. For example, Humulin R U-500 is a concentrated human regular insulin product (five times more concentrated than U-100) that has been used in patients requiring consistently high daily doses of insulin (usually > 200 U/day). Nonrandomized studies have shown significant improvement in glycemic control comparing pre- and post-intervention periods in patients switched from U-100 prandial insulin preparations to U-500 regular insulin.14 Given the slight differences in pharmacodynamic profiles between regular U-100 and U-500 insulin preparations,15 a randomized controlled trial comparing a U-500 insulin strategy with other currently available alternatives in very insulin-resistant patients will be needed to draw objective conclusions regarding the efficacy and safety of this concentrated insulin preparation.

For patients and providers who opt for a trial of regular U-500 insulin, a number of issues need to be considered to mitigate risks and optimize benefits of using this concentrated insulin. First and foremost is the frequent confusion in the communication between provider, pharmacy, and patient regarding the correct insulin dose to be administered. Because regular U-500 insulin is administered with U-100 insulin syringes, a 1-unit measure of U-500 corresponds to a 5-unit delivery of regular insulin.

To minimize confusion, regular U-500 prescriptions should be made out in volume rather than units, but this difference must be clearly explained to patients to avoid overdosing. For example, 0.01 mL of U-500 equates to 5 units of insulin, but it corresponds to the 1-unit mark of the standard U-100 insulin syringe. Newer concentrated insulin preparations on the market have avoided this confusion by providing measured doses in an insulin pen delivery system. For example, insulin lispro U-200 (Humalog U-200), a twofold concentration of insulin lispro U-100 with similar pharmacodynamics, is only available in a prefilled pen. Using insulin pen technology, a 1-unit dose of insulin actually corresponds to 1 unit of insulin, thereby removing any possible confusion regarding the prescription or administration of the correct insulin dose. Insulin lispro U-200 offers the convenience of holding more insulin per pen; it contains 600 units of insulin per pen compared with 300 units in the lispro U-100 pen.

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