Insulin degludec (IDeg) and insulin glargine 300U/mL (IGlar-U300) represent the latest developments in insulin therapy, seeking to extend the duration of action beyond 24 hours, but with a flat peak action profile and lower variability.1 At the 23rd Hong Kong Medical Forum (HKMF) hosted by the University of Hong Kong, Prof. Richard Holt, Professor in Diabetes and Endocrinology within Medicine at the University of Southampton, UK, shared the latest findings regarding the ultra-long acting basal insulins.
“Some of the early developments after the first commercialization of insulin in the 1920s was to look for prolongation of insulin, to create a basal insulin that would allow patients with diabetes to inject just once a day,” Prof. Holt said.
The intermediate-acting neutral protamine Hagedorn (NPH) was then developed in the 1940s, but not without its shortcomings.2 “It (NPH insulin) did not have a flat profile, so that 2-3 hours after injection, there is the peak of insulin. When this insulin is used at nighttime (10-11pm), this leads to unphysiological peak of insulin at around 2-3am, which increases the risk of low blood sugar overnight,” he said. “A major disadvantage (with NPH insulin) is that there’s a lot of variability in the delivery of insulin from one injection to the next.”
The search for the ideal insulin therapy continues, and the longer-acting insulin glargine 100U/mL (IGlar-U100) and insulin detemir (IDet) were developed in the 1990s.2 Both IGlar-U100 and IDet have shown a very similar pharmacokinetics (PK)/pharmacodynamics (PD) profile, with an approximate 24 hours duration of action and flat peak action profile.2 However, a low-dose once-daily injection may not provide sufficient coverage for the whole day.2 This led to the development of the more recent IDeg and IGlar-U300, which possessed an even longer action profile, extending substantially beyond 24 hours.2
“We now have another generation of ultra-long basal insulins, and again, two different approaches have been taken in order to prolong the duration of action, even beyond what we saw with IDet and IGlar-U100,” Prof. Holt explained. “In the case of IGlar-U300, the idea was to increase the concentration of the insulin to three times the strength of the standard preparation. In the case of IDeg, a simpler process was used for IDet, but in this situation, the fatty acid residue was longer than that used for IDet.”
With regards to the cardiovascular (CV) safety of IDeg, this has been investigated in a double-blind, treat-to-target, event-driven CV outcomes trial.3 In DEVOTE, ~7,600 type 2 diabetes patients at high risk for CV events were randomly assigned to receive either IDeg or IGlar-U100 once-daily between dinner and bedtime.3 As compared to IGlar-U100, IDeg was noninferior in terms of cardiovascular events, but superior in terms of the risk of hypoglycemia.3
Two real-world studies, known as LIGHTNING and DELIVER D, tried to compare IDeg and IGlar-U300 in ~10,000 type 2 diabetes patients who were switched from IGlar-U100.4 At present, the full reports of these two studies have not been published yet, but the results presented at the 2017 World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease suggested comparable rates of severe hypoglycemia during the 6-month follow-up period.4 There were also no differences in HbA1c in patients receiving either IDeg and IGlar-U300.4 However, the press releases of these studies do not say “what actually happens between the switch and afterwards,” Prof. Holt said.
Similarly, reductions in hypoglycemia risk was also found in the EUropean TREsiba AudiT (EU-TREAT) study, which is considered as the largest real-world study for IDeg.5 Of note, EU-TREAT recruited ~2,500 patients with either type 1 or type 2 diabetes, who were switched from either IGlar-U100 or IDet.5
Meanwhile, HbA1c reductions from baseline appear to be smaller in real-world studies, as compared to those reported in the phase III randomized clinical trials. “When we look at these [real-world] studies, the first thing that we can see is the consistent reduction of HbA1c when individuals were switched to insulin degludec. That’s in contrast to what we see in the clinical trials, and that’s largely because the design of the trials was treat-to-target,” Prof. Holt explained. Nonetheless, he believed that the real-world experience complements the clinical trial results of the ultra-long basal insulins.