New insulin preparations: A primer for the clinician
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.
KEY POINTS
- 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.
BASAL INSULIN
Currently available basal insulin preparations include insulin NPH (Humulin N, Novolin N), insulin glargine U-100 (Lantus), insulin detemir (Levemir), and the 2015 FDA-approved formulations insulin glargine U-300 (Toujeo) and insulin degludec (Tresiba). The basal analogues introduced in the year 2000 with glargine U-100 were meant to fill the void left when the long-acting insulin ultralente animal preparations were pulled from the market in the early 1990s. The basal analogues have a longer duration of action than insulin NPH and, more importantly, have more stable and consistent biologic activity over a 24-hour period, resulting in more predictable glycemic levels and a lower risk of hypoglycemia.16–18
Three insulin analogue preparations—glargine U-300 and degludec (both FDA-approved) and pegylated lispro (currently in phase 3 trials)—have demonstrated longer protraction of biologic activity than glargine U-100, considered the current technical standard for basal insulin replacement. These three “second-generation” basal insulin analogues have pharmacodynamic activity that extends beyond 24 hours. When compared with glargine U-100 insulin, they exhibited fewer pronounced peaks of biologic activity and less pharmacokinetic variability, with similar glycemic control (as determined by HbA1c) but with an even lower risk of hypoglycemia, especially nocturnal hypoglycemia.19–21
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The extended biologic activity raises concern for potential insulin stacking and subsequent hypoglycemia, which should be easily mitigated by restricting basal insulin dose adjustments to no more frequently than every 3 to 4 days, which corresponds to the time needed for these preparations to reach 90% or more of their effective steady state22 (Figure 2). Indeed, most of the clinical trials comparing these basal insulin preparations with glargine U-100 show a lower risk of hypoglycemia when basal dose adjustments are carried out weekly and no more frequently than every 3 days.23
Insulin glargine U-300 is essentially a threefold concentrated preparation of insulin glargine U-100 that results in a two-thirds volume reduction and a one-half reduction in depot surface following SC administration. The reduced depot surface area is presumed to account for much of the protracted absorption of glargine U-300 from the SC tissues. The metabolism and elimination of glargine U-300 is similar to that of the original compound, with formation of two active metabolites: M1 (the principal active moiety) and M2. Biologic steady state is achieved after 4 to 5 days of once-daily injections.24
When compared with glargine U-100 in patients with type 1 diabetes, insulin glargine U-300 at doses of 0.4 U/kg produced more stable insulin concentrations and glucose-lowering effect with a longer duration of action at steady state, as reflected by tight glucose control being maintained for about 5 hours longer (median of 30 hours).25 A meta-analysis of the EDITION I to III clinical trials in patients with type 2 diabetes at various stages of treatment found similar glucose-lowering effects for glargine U-300 compared with glargine U-100 but a lower rate of nonsevere hypoglycemia.20 Of note was the need for 10% to 15% more units of insulin for glargine U-300 in these clinical trials. Insulin glargine U-300 is available only in a 1.5 mL disposable prefilled pen, which contains 450 units of insulin. Because the dose counter on the pen window corresponds to the actual number of units of insulin to be injected, no dose recalculation is required by the patient or provider.
Insulin degludec is another ultra-long-acting basal insulin analogue with a half-life at steady state of greater than 25 hours.26 In comparison, the half-life of insulin glargine U-100 in that same study was reported as 12.1 hours. Further, insulin degludec exhibited flatter and more stable biologic activity, more evenly distributed over the course of a 24-hour period than insulin glargine U-100. The protraction mechanism is based on the formation of long strings of multihexamers, facilitated by a 16-carbon fatty acid chain linked via a glutamic acid spacer to the terminal end of the B-chain of the insulin molecule.27 In studies of patients with type 2 diabetes at various stages of treatment, insulin degludec also demonstrated lower risk of nonsevere hypoglycemia for an equivalent level of HbA1c control achieved.19
The flexibility of administration time for an ultra-long-acting insulin preparation such as degludec was tested by asking patients to alternate the injection of degludec between morning and evening, in effect creating administration intervals of up to 8 to 40 hours.28 Even within such drastic parameters, the efficacy and safety of insulin degludec were maintained when compared with insulin glargine U-100 injected at the same time of the day every day.
Because of an increase in major adverse cardiovascular events in phase 3 trials, degludec is undergoing a cardiovascular safety trial in patients with type 2 diabetes. The DEVOTE trial, which started in October 2013, will include 7,500 patients and will continue for up to 5 years. Interim results have recently been submitted to the FDA resulting in conditional approval of degludec in the US (Clinical Trials.gov Registration: NCT01959529). Degludec is available in disposable pen or cartridge format in U-100 and U-200 formulations.
COST
These new insulin preparations have introduced clinical options that have efficacy similar to that of available insulin products but, for the most part, have advantages of safety (less risk of nonsevere hypoglycemia) and patient convenience (flexibility in timing of insulin dose administration). While the latter is presumed to improve patient adherence, this has yet to be confirmed. Compared with synthetic human insulin preparations (regular insulin, NPH, and premix 70/30 insulin), which can be obtained in certain pharmacies at a discount (usually around 3 cents per unit of insulin), the currently available insulin analogues are considerably more expensive (around 16 to 27 cents per unit of insulin).
Within the guidelines for initiation and intensification of the insulin regimen using basal insulin formulations, the clinician will need to balance the potential benefits and current costs for the treatment of the individual patient. Clearly, as patients with diabetes are brought closer to their glycemic goals with insulin options, they stand to increasingly benefit from formulations that provide more consistent glycemic response and less risk of hypoglycemia. For those who are unable to afford the higher costs, especially if their glycemic control is far from the desired target, the use of synthetic human insulin formulations may be entirely appropriate. In this era of individualized care and prescriptions, clinicians have a range of insulin treatment options that will facilitate patients reaching appropriate goals.
