Insulin degludec
degludec, NN1250, LysB29(Nε-hexadecanedioyl-γ-Glu) des(B30) human insulin, insulin degludec U100, insulin degludec U200
Insulin degludec is an ultra-long-acting basal insulin analogue with a half-life of about 25 hours and a duration of action beyond 42 hours. Its distinguishing feature is that it self-assembles into long soluble chains of hexamers under the skin, which then release insulin slowly and remarkably consistently from day to day. It is the basal insulin with the strongest randomised evidence for a reduction in severe hypoglycaemia.
Mechanism
Insulin degludec is human insulin with the terminal threonine at B30 removed and a side chain attached to the epsilon-amino group of lysine B29: hexadecanedioic acid, a sixteen-carbon fatty diacid, connected through a gamma-L-glutamyl spacer. Two design features interact. In the vial, in the presence of zinc and phenol, degludec exists as stable dihexamers. On injection, the phenolic preservative diffuses away rapidly while zinc leaves much more slowly. Loss of phenol triggers a conformational change that exposes the fatty diacid side chains, and these mediate end-to-end association between dihexamers, so the injected depot converts within minutes into long, soluble multihexamer chains. This is a genuinely different mechanism from every other basal insulin: glargine works by precipitation, detemir by albumin binding, isophane insulin by protamine crystal dissolution. Degludec works by forming a soluble polymer.
Zinc then diffuses gradually out of the multihexamer chains, and as each terminal hexamer loses its zinc it dissociates and releases monomers into the circulation. Because release comes from the ends of very long chains, the rate is close to constant and, importantly, far less sensitive to injection depth, site, temperature and blood flow than a precipitated or crystalline depot. Clamp studies show roughly four times lower day-to-day variability in glucose-lowering effect than insulin glargine U100, which is the pharmacological basis for the reduced nocturnal hypoglycaemia seen in trials. In the circulation the fatty diacid also binds albumin reversibly, providing a further buffering reservoir. At the receptor, degludec binds the insulin receptor with somewhat reduced affinity but proportionately reduced IGF-1 receptor affinity, preserving a normal metabolic-to-mitogenic ratio, and signals through the standard IRS/PI3K/AKT pathway with GLUT4 translocation and suppression of hepatic glucose output.
What the research shows
Degludec is the basal insulin with the cleanest evidence for a hypoglycaemia advantage, and the reason is methodological rather than promotional. Almost all basal insulin comparisons are open-label, which biases hypoglycaemia reporting; SWITCH 1 and SWITCH 2 were double-blind crossover trials specifically powered for hypoglycaemia, and DEVOTE was a double-blind cardiovascular outcome trial with independently adjudicated events. All three found consistent reductions (roughly 30% in overall symptomatic hypoglycaemia in type 2 diabetes, roughly 40% in severe hypoglycaemia in DEVOTE, and roughly 36 to 53% in nocturnal episodes across trials) at identical HbA1c. That pattern maps neatly onto the clamp pharmacology, where day-to-day variability in glucose-lowering effect is about fourfold lower than glargine U100.
What degludec does not do is improve glycaemic control. Every BEGIN trial was designed as a non-inferiority study and every one showed equivalent HbA1c; there is no efficacy advantage to be had. DEVOTE was a safety trial and its cardiovascular result was neutral, not beneficial: a hazard ratio of 0.91 with a confidence interval crossing unity establishes that degludec does not increase cardiovascular risk, nothing more. No trial has shown that degludec reduces microvascular complications, mortality or hospitalisation. The practical case for degludec therefore rests almost entirely on hypoglycaemia and on dosing flexibility (the long half-life means a dose can be taken at varying times of day, which matters for shift workers, older people and those with erratic routines), set against a cost that in most health systems is a substantial multiple of isophane insulin. The 2018 real-world data on basal analogues generally, showing no reduction in hypoglycaemia-related emergency attendances outside trial conditions, is a fair caution against assuming trial benefits transfer intact to ordinary practice.
Evidence assessment
High-quality evidence
Approved in the European Union in 2013 and by the FDA in 2015 on the basis of the BEGIN phase 3 programme, and supported by an event-driven cardiovascular outcome trial in 7,637 participants (DEVOTE) and two large double-blind randomised crossover hypoglycaemia trials (SWITCH 1 and SWITCH 2) published in JAMA. Uniquely among basal insulins, the hypoglycaemia benefit has been tested in double-blind designs specifically powered for that endpoint, which removes the open-label bias that weakens most basal insulin comparisons.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial Preclinical only
HbA1c reduction was equivalent (−0.40% with degludec versus −0.39% with glargine). The rate of nocturnal confirmed hypoglycaemia was about 25% lower with degludec. Overall hypoglycaemia rates and serious adverse events did not differ.
Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN Once Long) Preclinical only
Degludec was non-inferior to glargine for HbA1c reduction. Nocturnal confirmed hypoglycaemia was approximately 36% lower with degludec, while overall confirmed hypoglycaemia rates were similar.
Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes Preclinical only
Degludec was non-inferior to glargine U100 for major adverse cardiovascular events (hazard ratio 0.91, 95% CI 0.78-1.06). The striking result was hypoglycaemia: severe hypoglycaemia occurred approximately 40% less often with degludec, and severe nocturnal hypoglycaemia approximately 53% less often, both statistically significant. This is the strongest randomised evidence of a hypoglycaemia benefit for any basal insulin.
Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial Preclinical only
Degludec significantly reduced the rate of severe or blood-glucose-confirmed symptomatic hypoglycaemia (roughly 11% lower) and nocturnal episodes (roughly 36% lower) at equivalent HbA1c. The double-blind crossover design is important: it removes the open-label bias that inflates hypoglycaemia differences in most basal insulin trials.
Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial Preclinical only
Overall symptomatic hypoglycaemia was approximately 30% lower with degludec and nocturnal symptomatic hypoglycaemia approximately 42% lower, at equivalent HbA1c. Together with SWITCH 1, this is the highest-quality evidence available comparing hypoglycaemia rates between basal insulins.
Safety
Hypoglycaemia remains the dose-limiting adverse effect, even though rates are lower than with comparator basal insulins. The very long half-life has two consequences that require particular care: steady state is not reached for two to three days, so the full effect of a dose change is not visible for at least three days and titration must be unhurried; and if hypoglycaemia does occur it can be protracted, requiring longer observation than with shorter-acting insulins. Weight gain, hypokalaemia, injection-site lipohypertrophy and local reactions occur as with all insulins. Less common effects include systemic insulin allergy, lipoatrophy, peripheral oedema and transient refractive change on rapid glycaemic improvement. Renal or hepatic impairment reduces insulin clearance. Concurrent thiazolidinedione therapy increases fluid retention and heart-failure risk. Degludec must not be mixed in a syringe with any other insulin, since dilution and loss of phenol outside the subcutaneous environment disrupts the multihexamer mechanism. The existence of 100 and 200 units/mL products in similar devices is a recognised source of dosing error; both deliver units, not volume, but confusion has occurred. Recurrent hypoglycaemia causes hypoglycaemia unawareness with implications for driving, and UK drivers on insulin must comply with DVLA rules. Non-medical use by people without diabetes has caused deaths and hypoglycaemic brain injury; with an ultra-long-acting insulin such an episode is exceptionally difficult to reverse, since the depot cannot be removed.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Licensed by the MHRA for the treatment of diabetes mellitus in adults, adolescents and children from 1 year of age. Prescription-only medicine (POM). Positioned in NICE guidance NG17 and NG28 as a basal insulin option, particularly where recurrent nocturnal hypoglycaemia is a problem. Included on the WHO Model List of Essential Medicines since long-acting insulin analogues were added in 2021. |
| United States | FDA-approved in September 2015 for adults with type 1 or type 2 diabetes, with paediatric indications added subsequently; available in 100 and 200 units/mL. The US prescribing information was subsequently updated to incorporate the DEVOTE cardiovascular outcome data after that trial reported in 2017. Regulated as a biological product since March 2020. Prescription-only. |
| WADA (sport) | Prohibited at all times, in and out of competition, under section S4 of the WADA Prohibited List (Hormone and Metabolic Modulators), which covers insulins and insulin-mimetics. Athletes with diabetes require a Therapeutic Use Exemption. |
Questions
A fatty diacid side chain on lysine B29. In the vial, zinc and phenol hold the molecule as dihexamers. On injection the phenol diffuses away quickly, which exposes the side chains and lets dihexamers link end to end into long soluble multihexamer chains. Zinc then leaks out slowly, and insulin monomers are released from the ends of those chains at a nearly constant rate. It is a soluble polymer depot, not a precipitate or a crystal.
For HbA1c, no: every head-to-head trial was designed as and confirmed non-inferiority. For hypoglycaemia, the evidence is genuinely in its favour: two double-blind crossover trials and a double-blind cardiovascular outcome trial all showed lower rates, with severe hypoglycaemia around 40% lower in DEVOTE. Because those trials were blinded, that finding is more reliable than most basal insulin comparisons, which are open-label.
With a 25-hour half-life, plasma concentrations take roughly four to five half-lives (two to three days) to reach a new steady state. Adjusting the dose more often than every three or four days means reacting to a level that has not yet stabilised, which tends to produce over-correction in both directions.
No. DEVOTE was a non-inferiority safety trial required by regulators, and its cardiovascular hazard ratio of 0.91 with a confidence interval crossing 1.0 shows only that degludec does not increase cardiovascular risk relative to glargine. The trial's genuinely positive finding was the roughly 40% reduction in severe hypoglycaemia, which was a prespecified secondary endpoint.
Its long half-life means that timing flexibility is greater than with shorter-acting basal insulins, and the licensed product information reflects this. That is a practical advantage for shift workers and people with irregular routines. Any change to how an insulin regimen is timed is a clinical decision for the prescribing team, not something to alter independently.