Insulin Degludec (Tresiba)

Insulin degludec reaches an ultra-long, once-daily profile through a genuinely different trick than this site's other engineered insulin, insulin icodec: instead of albumin binding the intact molecule, it forms a slow-dissolving chain of hexamers right at the injection site. It's also a real case study in a drug nearly derailed by its own numbers — a cardiovascular signal in a pooled meta-analysis triggered a 2013 FDA rejection and a dedicated 7,637-patient outcomes trial, and a Danish regulator later fined its maker for how slowly it told the market the rejection had happened at all.

A third way to make insulin last longer

Insulin degludec (Tresiba, Novo Nordisk) is an engineered insulin analog built to last far longer than the daily basal insulins that came before it, using a mechanism unrelated to insulin icodec, this site's once-weekly insulin. Degludec is made by removing the terminal amino acid from the insulin B-chain (des-B30 human insulin) and attaching a 16-carbon fatty diacid (hexadecanedioic acid) to the remaining chain's LysB29 position through a short gamma-L-glutamyl spacer.³ Formulated with zinc and phenol, the drug exists in the vial as stable di-hexamers; once injected, the phenol diffuses away and the di-hexamers link into long, soluble multi-hexamer chains that form a physical depot under the skin. Individual insulin monomers slowly and continuously break off that depot into circulation, giving degludec a measured half-life of about 25 hours and a duration of action beyond 42 hours — long enough that its label allows dosing at any time of day, including some flexibility in exact timing from one day to the next, rather than a fixed daily clock. That's a different piece of chemistry than icodec's reversible albumin binding, though both are examples of the same broader strategy: modifying an old hormone's release kinetics rather than its core biological activity.

The FDA's 2013 rejection: a real cardiovascular signal

In November 2012, an FDA advisory committee voted 8-4 to recommend approval of degludec and a co-formulated degludec/aspart product (Ryzodeg) for type 1 and type 2 diabetes — but voted unanimously to require a dedicated cardiovascular outcomes trial first, after FDA reviewers flagged a signal in a pooled meta-analysis of the Phase 3 program: 70 major adverse cardiovascular events (MACE) among 5,794 patients on degludec versus 21 among 3,461 patients on active comparators (relative risk 1.67, 95% CI 1.01-2.75) — a difference that, while based on relatively few events, cleared the threshold the FDA had used since 2008 to require dedicated cardiovascular safety trials for new diabetes drugs. Separately, and not specific to degludec itself, the FDA had also sent Novo Nordisk a warning letter, dated 12 December 2012 and made public in February 2013, over sterile-manufacturing procedure violations found during a March 2012 inspection of its Bagsværd, Denmark, filling plant — a compliance issue the agency required resolved before any approval at a related facility could proceed. On 8 February 2013, the FDA sent Novo Nordisk a Complete Response Letter for both Tresiba and Ryzodeg, citing the outstanding cardiovascular question and the unresolved warning letter; Novo Nordisk announced the rejection to the public two days later, on 10 February.

The DEVOTE trial

Novo Nordisk launched DEVOTE within months of the rejection: a randomized, double-blind, active-controlled trial enrolling 7,637 adults with type 2 diabetes at high cardiovascular risk across 20 countries, comparing once-daily degludec to insulin glargine U100, with a pre-specified noninferiority margin on the primary MACE endpoint (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) of a hazard ratio below 1.3 (Marso SP, McGuire DK, Zinman B, et al., for the DEVOTE Study Group, "Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes," N Engl J Med 2017;377(8):723-732, PMID 28605603, DOI 10.1056/NEJMoa1615692). The primary outcome occurred in 8.5% of the degludec group versus 9.3% of the glargine group — a hazard ratio of 0.91 (95% CI 0.78-1.06, p<0.001 for noninferiority), comfortably clearing the noninferiority bar the FDA had required. Severe hypoglycemia, a prespecified secondary outcome, was 40% less frequent with degludec than glargine (rate ratio 0.60, p<0.001) — a real, statistically significant safety advantage layered on top of the noninferiority finding the trial was designed to test.

A stalled disclosure, and a Danish fine

That fine is a genuinely separate story from the drug's clinical or regulatory record: it's a finding about how promptly a public company disclosed material bad news to its shareholders, not a finding about degludec's safety or efficacy. It's worth knowing alongside the FDA rejection specifically because the two episodes are easy to conflate — one is a securities-law violation about timing of disclosure, the other a genuine, since-resolved cardiovascular safety question the DEVOTE trial went on to answer.

Current status

Degludec reached patients well before the US had access to it: the European Commission approved Tresiba and Ryzodeg on 21 January 2013 — three weeks before the FDA's rejection letter — and Japan's PMDA had approved it even earlier, in September 2012. The FDA approved Tresiba on 25 September 2015, for adults with type 1 and type 2 diabetes, based on the BEGIN Phase 3a trial program plus an interim DEVOTE analysis; a supplemental approval announced 19 December 2016 extended the indication down to age 1, based on the BEGIN Young 1 pediatric trial. The FDA approved a label update incorporating DEVOTE's completed cardiovascular and hypoglycemia data on 26 March 2018. Tresiba remains actively marketed by Novo Nordisk and, as of 2025-2026, is one of the insulins named in the manufacturer pricing agreements described on this site's Insulin page.