Abstract and Introduction
Abstract
With appearance of new insulins on the market, new clinical challenges, much like unintended consequences, came into light in our daily practice. One of the most pressing issues has become an issue of switching patients to and from newer insulins in various clinical situations. A proper switch from 1 medication to another requires understanding of pharmacokinetics (PK) and pharmacodynamics (PD) of both drugs. Unfortunately, there is no research in this area and, as a result, there are no guidelines nor is there even a consensus. We present 5 clinical scenarios in which the patients were transitioned to or from insulin degludec. Because there are no data and no current consensus, we have polled 200 diabetes care providers soliciting their opinion as to how they would handle these clinical situations. Our poll of endocrinologists revealed multiple approaches as well as elements of confusion among providers. Even though all answers, summarized following each case, might be reasonable, and there might not be a single correct answer, we wish to express our opinion that is based on PK and PD of these insulins. Because there is more than 1 correct way of implementing these transitions, we urge our colleagues to institute a very close follow-up of these patients with frequent adjustments of insulin dose to avoid stacking with potential hypoglycemia.
Introduction
With appearance of new insulins on the market, new clinical challenges, much like unintended consequences, came into light in our daily practice. One of the most pressing issues has become an issue of switching patients to and from newer insulins in various clinical situations. Unfortunately, there is no research in this area and as a result, there are no guidelines nor is there even a consensus.
A proper switch from 1 medication to another requires understanding of pharmacokinetics (PK) and pharmacodynamics (PD) of both drugs. PK is the study of a drug absorption, distribution, metabolism, and elimination from the body. In the case of insulin, it is influenced greatly by its absorption from the site of injection[1] and by its degradation and elimination.[2,3] One can assess PK of insulin by measuring the insulin levels after the injection of the drug over the course of hours or days
With PK, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. After 1 half-life, 50% of steady state is reached.[4] After 2 half-lives, 75% of steady state is reached. The rule of thumb is that steady state will be achieved after 4 to 5 half-lives (92% to 97% of steady state achieved). Obviously, there are many factors that can change when steady state is met, including in this case the clearance of the insulin.
In contrast, PD describes what the drug does to the body. It refers to the metabolic effect of insulin,[5] including onset of action, peak, and duration. For insulin, PD measuring insulin action is best quantified with the euglycemic insulin clamp, where glucose is clamped at a given level of euglycemia while insulin is administered, and glucose is infused to keep glycemia at that level. The glucose infusion rate measures insulin activity and reflects PD of insulin action.
With insulin degludec, based on its PK, the time to reach steady state is consistently between 3 and 4 days[6,7] (Figure 1A).
Figure 1.
Conceptual drawing of achieving steady-state insulin concentration and basal insulin stacking. (A) Degludec: with half-life of insulin degludec of 25 hours, steady state of its concentration is achieved after approximately 4 days of its administration. (B) Glargine: when a subsequent injection of glargine is given after at least 2 half-lives of the previously administered insulin (every 24 hours), steady state may never be achieved. (C) Basal insulin stacking: when 40 units of glargine is given in 1:1 ratio to insulin degludec, but only 1 half-life (24 hours) after previously injected degludec, 20 units of insulin degludec are still on board and the total insulin concentration in the circulation is 60 units. Panels A and B are modified from reference (6).
It is impossible, however, to compare PD between degludec and any other insulin because there are no data assessing insulin degludec starting with its first injection and observing how long it takes to obtain a stable glucose infusion rate. On the other hand, we are able to compare PK of the various basal insulins.[8–10] Figure 1B shows the PK data of insulin glargine administered every 24 hours. In this case, in contrast to insulin degludec, glargine's half-life is approximately 12 hours and steady state may never be achieved as each subsequent injection is given 2 half-lives after the previous one.
J Clin Endocrinol Metab. 2020;105(6) © 2020 Endocrine Society
