New Long-Acting Insulin Analogs: From Clamp Studies to Clinical Practice

The NPH era started in 1946 and ended nearly 60 years later with the introduction to the market of the long-acting analogs, glargine in 2000 (1) and detemir in 2004 (2). More recently, a second-generation acylated long-acting insulin analog, degludec (3), has become available in some countries outside the U.S. In this issue of the journal, Becker et al. (4) report on pharmacokinetics (PK) and pharmacodynamics (PD) of a new long-acting insulin analog, glargine U300 (Gla-300). This is the same glargine molecule concentrated three times (300 units in 1 mL). It was approved by the U.S. Food and Drug Administration and received a positive opinion from the European Medicines Agency at the end of February 2015.

Becker et al. (4) compared Gla-300 to the original glargine (Lantus, U-100; Gla-100) in a clamp experiment in subjects with type 1 diabetes (T1D). They studied the right population (absent endogenous insulin secretion) in which the observed PK/PD after subcutaneous (s.c.) injection of an insulin preparation are specifically attributable to the injected insulin. When clamp studies are instead run in subjects without diabetes or with type 2 diabetes (T2D), the PK/PD results are confounded by endogenous insulin secretion. Becker et al. (4) correctly studied the subjects after 1 week of treatment at “steady state.” However, they did use a fixed dose of basal insulin (0.4 units/kg/day glargine, either Gla-300 or Gla-100). This approach has the advantage of simplicity but the disadvantage of inducing a pharmacological overinsulinization with risk of hypoglycemia as the previously daily basal insulin dose used by the subjects with T1D was lower (mean 0.30 units/kg/day). Indeed, the majority of subjects needed a robust glucose infusion rate (GIR) during the 6 h prior to injection of glargine (time zero) to prevent hypoglycemia, and several subjects had baseline plasma insulin concentrations higher before than after glargine clamp dosing. These baseline conditions, partly due to the automated biostator for glucose clamping (5), make it more difficult to interpret PK and PD.

However, the experiments of Becker at el. may still serve for interpretation of PK/PD data of Gla-300 versus Gla-100 as the baseline GIR and plasma insulin concentrations were similarly elevated in both conditions. After s.c. injection, plasma insulin concentration was smoother in the first 12 h and more sustained in the second 12 h with Gla-300 versus Gla-100.

The PD mirror effect was a smoother and longer glucodynamic effect with Gla-300. This is possibly explained by the fact that the three times more concentrated insulin Gla-300 results in a two-thirds lower s.c. spheric depot with a surface area reduced by 50% as compared with Gla-100, with consequent slower and more prolonged insulin absorption of Gla-300. In fact, in 2000, Jørgensen et al. (6) showed slower insulin absorption from s.c. tissue with more concentrated NPH insulin in a pig model.

In addition to the averaged PK/PD, Becker et al. (4) provide us with raw data and clamp profiles on all subjects studied. This is important because it shows how large the interindividual differences in insulin absorption and action are. Of note, a measure of dispersion (SD or interquartile range) is still not given in the graph on the primary outcome, the GIR over time, whereas it is given for insulin levels over time. Nevertheless, the data package provided for insulin Gla-300 is much more comprehensive than those provided for the recent new long-acting analog insulin degludec (7) and the investigational insulin peglispro (8). The hypothesis that Gla-300 might be more beneficial than Gla-100 in basal insulin replacement in T1D and T2D by approaching nocturnal near-normoglycemia with less risk for hypoglycemia has been tested in the EDITION studies (9–16).

In all EDITION studies, Gla-300 appears noninferior to Gla-100 in lowering A1C while conferring risk reduction of hypoglycemia primarily at night in T2D (9–12). In a study with 549 subjects with T1D, no convincing hypoglycemia difference was reported (13), although Gla-300 resulted in a 34% risk reduction for nocturnal and 20% for 24-h hypoglycemia in a study with 243 Japanese subjects with T1D. In a predefined meta-analysis of T2D studies (EDITION 1, 2, and 3, 6-month data) (16), the risk for nocturnal confirmed and severe hypoglycemia was reduced by 31%. These results are achieved on Gla-300 with a 10–17% greater insulin dose and less increase in body weight, a difference modest in absolute terms (∼0.26 kg in T2D, ∼0.56 kg in T1D) but consistently present in all EDITION studies and statistically significant. It might be that some of the Gla-300 is degraded locally rather than fully absorbed. The slight reduction in weight gain is awaiting a mechanistic explanation. It is unlikely that it is the result of less compensatory food intake needed to counter hypoglycemia, as it was seen both when Gla-300 reduced the risk for hypoglycemia (14) and when it did not (13).

How does Gla-300 differ from other new long-acting insulin analogs such as degludec, which is expected to have a flat action profile for >24 h? PK/PD data of degludec have been presented in T2D (8), not in T1D. A head-to-head study of insulin degludec versus Gla-300 would be needed. In automated steady-state clamp studies, insulin degludec did show less variability in T1D than Gla-100 (17). In clinical studies of T2D, degludec is noninferior to Gla-100 in lowering A1C and reduces nocturnal hypoglycemia by 32% (18). As compared with Gla-100, the risk reduction for 24-h hypoglycemia with degludec is 14% and with Gla-300, 17%. Notably, the advantage in reducing hypoglycemia in T1D is less convincing, similar to Gla-300. However, these comparisons should be made with the utmost caution as not only the hypoglycemia definition used in degludec and Gla-300 studies differs (plasma glucose threshold of 3.1 and 3.9 mmol/L, degludec and Gla-300, respectively) but also the time of evening injection for the two insulins differs. In addition the meta-analysis on Gla-300 has only been published in abstract form so far, necessitating an even more cautionary interpretation. Also, the reduction of hypoglycemia risk versus Gla-100 in absolute terms is not very large with either degludec (from 4.8 to 4.1 episodes/patient-year) (estimated from 18) and Gla-300 (from 17.7 to 15.2 episodes/patient-year) (16) (overall 24-h confirmed hypoglycemia as defined in respective studies). Head-to-head comparisons of insulin degludec and Gla-300 will be needed in the future. Also, although both insulin degludec and Gla-300 appear to be “flatter” insulins than the original Gla-100, it could be argued that there is still not a completely even distribution of glucose-lowering action over time with both insulins (4,6). Notably, in a meta-analysis of the phase 3 program on Gla-300 (16), the highest prevalence of hypoglycemia was between 6:00 and 10:00 a.m. when insulin glargine was dosed at bedtime. A similar analysis for insulin degludec is warranted. Furthermore, the U.S. Food and Drug Administration requested a cardiovascular outcome study for insulin degludec, although it is already marketed outside the U.S.

How does Gla-300 differ from other investigational insulins appearing at the horizon, such as the PEGylated insulin lispro (19)? In automated steady-state clamp studies in patients with T2D, it showed a flatter profile than Gla-100 (8), but again no data in T1D were presented. Although the use of this insulin was associated with weight loss rather than weight gain, which is usually seen with insulin, its less potent action at the level of the adipocyte seems to result in an increased flux of fatty acids to the liver, giving rise to an increase in triglycerides and elevations of ALT, which may be worrisome to regulatory bodies.

Pricing of Gla-300 is still unknown, but it is likely to be competitive compared with insulin degludec. Insulin degludec entered the market at a premium price compared with insulin glargine, as high as 70% in several markets. Insulin Gla-300 may enter at a more realistic price because of the price pressure from insulin glargine biosimilars, now that the patents are lapsing. Also, the price of Gla-300 should take into account the 10–17% higher insulin dose needed as compared with Gla-100.

What do we need to learn more about Gla-300 in the future? The PK/PD should be studied at the individual doses in the real life of people with T1D. People with T2D should also be studied because PK/PD differ from T1D and circadian changes in insulin sensitivity influence PD of injected insulin (20). Safety of Gla-300 has been already investigated and metabolism after s.c. injection with formation of metabolite 1 presented (21), likewise with Gla-100 (22). As Gla-300 in the s.c. and circulation releases glargine, cardiovascular safety shown for Gla-100 should apply to Gla-300 as well (23).

Additional clinical questions for Gla-300 need to be answered. Day-to-day reproducibility of the metabolic effects of Gla-300 should be explored in both the experimental clamp and clinical setting with continuous glucose monitoring in subjects with T1D to confirm preliminary data (24) as compared with degludec (17). The expected benefits from PK/PD data (4), not only of reduction of hypoglycemia, especially nocturnal, but also of more efficient insulinization 24 h postinjection with Gla-300 versus Gla-100, should be assessed in subjects with T1D. The flexibility in dosing time in T1D and T2D should also be investigated beyond the ±3-h interval presently reported (25). This is an important aspect of personalized insulin treatment, usually appreciated by insulin-treated subjects. Degludec has been extensively investigated in this regard (26). Most important, we need head-to head studies, primarily degludec versus Gla-300, to directly appreciate the differences between these two basal insulins.

An active and growing research activity is notable in the field of basal insulins in the post-NPH era. This is positive as we are and will be offered several options to replace basal insulin in T1D and T2D. However, we need to learn and become familiar with the individual characteristics of the new long-acting insulin analogs to understand their benefits and limitations in the interest of the individuals with diabetes. Sound head-to-head studies are needed. In this regard, the article by Becker et al. (4) is a good step forward.