Insulin degludec
The basal insulin engineered to form chains under the skin, and the trial that proved its heart safety
Insulin degludec forms long multi-hexamer chains in the subcutaneous depot that unwind slowly, giving an effect beyond 42 hours. Approved in 2015, it is one of the few insulins with a dedicated cardiovascular outcomes trial, in 7,637 patients.
What is it?
Degludec's trick is structural. The fatty-acid side chain lets the molecules link into long chains when injected, and they come apart one at a time. The label records the result: after eight days of once-daily dosing in type 1 diabetes, peak concentration was reached at a median of nine hours, with an effect long enough that the dosing time can move day to day. At steady state the half-life is about 25 hours, independent of dose.
The label covers people from one year of age. Adults inject once daily at any time of day, children at the same time every day, into the thigh, upper arm or abdomen, rotating sites to avoid lipodystrophy and localised amyloidosis; children who need fewer than 5 units a day use the vial. It is not recommended for diabetic ketoacidosis.
Its distinguishing evidence is DEVOTE, a double-blind cardiovascular outcomes trial in 7,637 people with type 2 diabetes at high cardiovascular risk. Major cardiovascular events occurred in 8.5% on degludec and 9.3% on glargine (hazard ratio 0.91), meeting non-inferiority. Few insulins have been tested that way. Its most useful secondary result was on severe hypoglycaemia, adjudicated by a committee: 4.9% on degludec against 6.6% on glargine (rate ratio 0.60), with HbA1c identical at 7.5% in both groups after two years and fasting glucose slightly lower on degludec.
Hypoglycaemia is where it differs from glargine. The SWITCH trials crossed patients over between degludec and glargine U100: in type 1 diabetes, symptomatic hypoglycaemia was 11% lower on degludec (rate ratio 0.89), and in type 2 diabetes 30% lower (rate ratio 0.70), with 22.5% against 31.6% of patients having an episode during maintenance.
Two further trials filled in particular groups. In EXPECT, 225 pregnant women with type 1 diabetes were randomised to degludec or detemir alongside mealtime aspart; HbA1c before delivery was 6.2% against 6.3%, meeting non-inferiority. In InRange, a head-to-head trial of 343 adults with type 1 diabetes wearing continuous glucose monitors, time in the target range was 55.1% on degludec and 52.7% on glargine U300, and the trial showed glargine U300 non-inferior.
It is now the comparator rather than the newcomer. Once-weekly icodec lowered HbA1c slightly more than daily degludec in insulin-naive type 2 diabetes (7.0% against 7.2% at 26 weeks, a 0.2-point difference), and once-weekly efsitora was non-inferior over 52 weeks (6.97% against 7.05%). Against tirzepatide in the SURPASS-3 substudy, liver fat fell more on tirzepatide.
The label's warnings are those of any insulin: never share pens or needles, hypoglycaemia including from medication errors, glucose changes when the regimen changes, low potassium, hypersensitivity, and fluid retention and heart failure when combined with a PPAR-gamma agonist (a thiazolidinedione). Many drugs raise or lower the risk of hypoglycaemia, and beta-blockers, clonidine, guanethidine and reserpine can blunt its warning signs.
Mechanism of Action
Insulin degludec is a long-acting insulin analogue whose fatty-acid side chain makes it self-assemble under the skin, so it is released slowly and steadily.
Multi-hexamer depot
After injection the molecules link into long chains that release monomers one at a time (design paper).
Flat, long profile
Steady-state half-life about 25 hours, independent of dose (label).
Insulin action
Lowers glucose like human insulin; its degradation is similar to human insulin (label).
Published Research
The studies behind insulin degludec, read from their PubMed abstracts: its cardiovascular outcomes trial, the hypoglycaemia crossover trials, and the weekly insulins tested against it.
The cardiovascular outcomes trial
In 7,637 people with type 2 diabetes at high cardiovascular risk, major cardiovascular events occurred in 8.5% on degludec and 9.3% on glargine (HR 0.91), meeting non-inferiority. Severe hypoglycaemia was 4.9% against 6.6% (rate ratio 0.60).
SWITCH 1: hypoglycaemia in type 1 diabetes
In a crossover trial of 501 patients, symptomatic hypoglycaemia during maintenance was 2,200.9 against 2,462.7 episodes per 100 patient-years on degludec and glargine U100 (rate ratio 0.89).
SWITCH 2: hypoglycaemia in type 2 diabetes
In 721 patients, symptomatic hypoglycaemia was 185.6 against 265.4 episodes per 100 patient-years (rate ratio 0.70), and 22.5% against 31.6% had an episode during maintenance.
EXPECT: pregnancy in type 1 diabetes
In 225 pregnant women, HbA1c before delivery was 6.2% on degludec and 6.3% on detemir, both with insulin aspart, meeting non-inferiority.
InRange: against glargine U300 on CGM
In 343 adults with type 1 diabetes, time in range was 55.1% on degludec and 52.7% on glargine U300, showing glargine U300 non-inferior.
Beaten by a weekly insulin
In 588 insulin-naive adults, HbA1c fell to 7.0% on weekly icodec and 7.2% on daily degludec at 26 weeks, a 0.2-point difference meeting superiority.
Against another weekly insulin
In 928 adults without previous insulin, HbA1c fell to 6.97% on weekly efsitora and 7.05% on daily degludec at 52 weeks, showing non-inferiority.
Against tirzepatide on liver fat
In the SURPASS-3 MRI substudy of 296 participants, liver fat fell more on tirzepatide 10 and 15 mg (about 8 percentage points from a 15.7% baseline) than on insulin degludec.
How the molecule was designed
The design paper: insulins acylated at B29 with fatty acids via glutamic acid spacers were compared to find the structure that self-assembles into long multi-hexamer chains after injection, giving degludec its protracted action.
Dosing Data
Tresiba is injected once daily, with the dose individualised to blood glucose.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the Tresiba prescribing information (DailyMed set 456c5e87, version 14, effective July 1, 2022) and the trials above.
Contraindications & Cautions
From the label's warnings.
Legal Status
An approved insulin.
Frequently Asked Questions
?Why does degludec last so long?
The fatty-acid side chain lets molecules link into long chains in the injection depot, which come apart slowly. The label records a median peak at nine hours and an effect extending beyond a day.
?Does the injection time have to be the same each day?
Its duration is what allows flexibility in adults, who may inject at any time of day; the label gives the detail by age group.
?Is it safe for the heart?
DEVOTE, a double-blind trial in 7,637 high-risk patients, found it non-inferior to glargine for major cardiovascular events.
?How does it compare with weekly insulins?
In insulin-naive type 2 diabetes, weekly icodec lowered HbA1c more than degludec at 26 weeks, with a higher rate of combined hypoglycaemia.
?Does it cause less hypoglycaemia than glargine?
In the SWITCH trials, symptomatic hypoglycaemia was 11% lower in type 1 and 30% lower in type 2 diabetes than on glargine U100.
?What is its half-life?
About 25 hours at steady state, independent of dose (label).
?Which drugs affect it?
Many raise or lower the risk of hypoglycaemia, and beta-blockers and clonidine can mask its warning signs (label, section 7).
?Can it be used in pregnancy?
In the EXPECT trial in pregnant women with type 1 diabetes, degludec was non-inferior to detemir for HbA1c before delivery.
References
- [fda-pi] Tresiba (insulin degludec) prescribing information, sections 1, 2 and 12.3 (DailyMed SPL version 14, effective July 1, 2022; read October 1, 2026).
- [pubmed] Marso SP, et al. "Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes." N Engl J Med, 2017;377(8):723-732. PMID: 28605603.
- [pubmed] Lane W, et al. "Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes: The SWITCH 1 Randomized Clinical Trial." JAMA, 2017;318(1):33-44. PMID: 28672316.
- [pubmed] Wysham C, et al. "Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial." JAMA, 2017;318(1):45-56. PMID: 28672317.
- [pubmed] Mathiesen ER, et al. "Insulin degludec versus insulin detemir, both in combination with insulin aspart, in the treatment of pregnant women with type 1 diabetes (EXPECT): an open‑label, multinational, randomised, controlled, non-inferiority trial." Lancet Diabetes Endocrinol, 2023;11(2):86-95. PMID: 36623517.
- [pubmed] Battelino T, et al. "Continuous glucose monitoring-based time-in-range using insulin glargine 300 units/ml versus insulin degludec 100 units/ml in type 1 diabetes: The head-to-head randomized controlled InRange trial." Diabetes Obes Metab, 2023;25(2):545-555. PMID: 36263928.
- [pubmed] Lingvay I, et al. "Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial." JAMA, 2023;330(3):228-237. PMID: 37354562.
- [pubmed] Wysham C, et al. "Insulin Efsitora versus Degludec in Type 2 Diabetes without Previous Insulin Treatment." N Engl J Med, 2024;391(23):2201-2211. PMID: 39254740.
- [pubmed] Gastaldelli A, et al. "Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial." Lancet Diabetes Endocrinol, 2022;10(6):393-406. PMID: 35468325.
- [pubmed] Jonassen I, et al. "Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin." Pharm Res, 2012;29(8):2104-14. PMID: 22485010.
Sources & Citations
Studies were read from their PubMed records (October 6, 2026); the label and Drugs@FDA are listed below with their read dates.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.