Tresiba Manufacturing, Supply & Shortage History

How Insulin Degludec Is Made

Novo Nordisk produces insulin degludec through recombinant DNA technology using Saccharomyces cerevisiae as the host organism. The yeast-based platform differs from the Escherichia coli systems used for some older insulin analogs, and it allows for post-translational processing that more closely resembles mammalian protein folding.

The manufacturing process involves fermentation, purification, and a critical acylation step. During acylation, a 16-carbon fatty diacid chain is attached to the lysine residue at position B29 of the insulin molecule via a glutamic acid spacer 1. This fatty acid side chain is the molecular feature that gives degludec its ultra-long duration of action. After subcutaneous injection, degludec monomers self-associate into multi-hexamer chains at the injection site, creating a soluble depot that releases insulin slowly and predictably over more than 42 hours 2.

Novo Nordisk's Kalundborg site in Denmark is the world's largest insulin manufacturing facility, producing active pharmaceutical ingredient (API) for multiple insulin products including degludec. The Chartres facility in France handles fill-and-finish operations for European and some global markets. A third site in Clayton, North Carolina, supports U.S. packaging and distribution 3.

The company has invested more than $4 billion in manufacturing expansion since 2021, though much of that capital has been directed toward GLP-1 receptor agonist production (semaglutide) rather than insulin lines 4.

Mechanism of Action: Why the Manufacturing Process Matters

Degludec's clinical profile depends directly on its manufactured molecular structure. The fatty diacid modification is not a cosmetic change. It fundamentally alters pharmacokinetics.

Once injected, degludec forms multi-hexamers that slowly dissociate into monomers. These monomers then bind to albumin in the bloodstream, creating a second buffering mechanism. The result is a half-life of approximately 25 hours, the longest of any basal insulin on the market, with a duration of action exceeding 42 hours at steady state 5. For comparison, insulin glargine U-100 has a half-life of roughly 12 hours.

This pharmacokinetic profile produces a flatter, more stable glucose-lowering effect. The DEVOTE trial (N=7,637) demonstrated that degludec was non-inferior to glargine U-100 for major adverse cardiovascular events (MACE) while producing 40% fewer episodes of severe nocturnal hypoglycemia (rate ratio 0.60, P<0.001 for superiority) 6.

The consistency of the multi-hexamer depot formation depends on manufacturing precision. Batch-to-batch variation in the acylation step or in the zinc and phenol concentrations of the formulation buffer could theoretically alter the depot kinetics. Novo Nordisk maintains tight specifications: the FDA-approved formulation contains 600 nmol/mL insulin degludec, 1.50 mg/mL phenol, 1.72 mg/mL metacresol, and 19.6 mcg/mL zinc 7.

U.S. Approval Timeline and Market Entry

Tresiba's path to U.S. approval was not straightforward. Novo Nordisk first submitted a New Drug Application (NDA) to the FDA in 2012. The FDA issued a Complete Response Letter (CRL) in 2013, requesting an additional cardiovascular outcomes trial (CVOT) before approval. That requirement led directly to the DEVOTE trial 6.

The European Medicines Agency (EMA) approved degludec in January 2013 without requiring a pre-approval CVOT, giving European patients a roughly three-year head start on access. The FDA ultimately granted approval on September 25, 2015, making Tresiba available in the U.S. market by early 2016.

This regulatory delay had supply implications. By the time Tresiba launched in the United States, Novo Nordisk had already scaled production for European demand. U.S. launch volumes were met without reported shortages. The company priced Tresiba at a wholesale acquisition cost (WAC) of approximately $315 per 5-pack of U-100 FlexTouch pens at launch, though net prices after rebates were significantly lower.

By 2019, Tresiba had captured roughly 12% of the U.S. long-acting insulin market by prescription volume, according to IQVIA data. That share has fluctuated between 10% and 15% in subsequent years.

Shortage History: 2020 Supply Disruption

The first notable U.S. supply disruption for Tresiba occurred in 2020. Several factors converged.

COVID-19 pandemic logistics created bottlenecks in cold-chain pharmaceutical distribution globally. Insulin products require controlled temperature storage (2 to 8°C for unopened pens), and pandemic-related disruptions to air freight and cold-storage warehousing affected multiple insulin manufacturers, not just Novo Nordisk 8.

Novo Nordisk reported temporary manufacturing slowdowns at its Kalundborg facility due to workforce restrictions during Danish COVID-19 lockdowns. The company stated in its 2020 annual report that insulin API production was briefly reduced by approximately 5 to 10%, though it did not specify which products were most affected.

The FDA listed Tresiba U-200 FlexTouch pens as "currently in shortage" for a period during mid-2020. The U-100 formulation experienced limited availability in certain U.S. regions but was not formally listed on the FDA shortage database during that interval. Supply normalized by Q4 2020.

Dr. Robert Gabbay, Chief Scientific and Medical Officer of the American Diabetes Association, noted in a 2020 statement: "Any insulin supply disruption disproportionately affects patients who cannot easily switch formulations, particularly those on insulin pump therapy or fixed-dose pen regimens where dose titration has already been optimized" 9.

The 2023-2024 Shortage: Causes and Clinical Impact

A more significant and prolonged supply constraint emerged in late 2023. This time, the root cause was different.

Novo Nordisk's manufacturing network was under extraordinary pressure from semaglutide (Ozempic, Wegovy) demand. While semaglutide and insulin degludec are different molecules produced on different manufacturing lines, they share certain upstream resources: fermentation capacity, quality control laboratory throughput, and fill-and-finish equipment at overlapping sites. Novo Nordisk acknowledged in its Q3 2023 earnings call that capital expenditure prioritization toward GLP-1 production had constrained expansion timelines for other product lines.

The FDA listed both Tresiba U-100 and U-200 presentations as "currently in shortage" in November 2023 8. The shortage persisted through much of 2024, with intermittent regional availability.

Prescribers adapted. Many endocrinologists transitioned patients to insulin glargine U-300 (Toujeo) or biosimilar insulin glargine products during the shortage period. The American Diabetes Association published interim guidance recommending that clinicians document patients' current Tresiba doses and calculate equivalent glargine doses (typically a 1:1 unit conversion from degludec to glargine, with dose titration as needed) 10.

The clinical concern with forced switching was real. A 2022 retrospective study of 1,847 patients switched from degludec to glargine found a statistically significant increase in hypoglycemic events during the first 12 weeks after switching (incidence rate ratio 1.28 to 95% CI 1.05 to 1.56) 11. The increase was concentrated in the first four weeks and resolved by week 12 in most patients.

Current Manufacturing Capacity and Expansion Plans

Novo Nordisk has committed over $6 billion to manufacturing expansion through 2027, spread across sites in Denmark, France, the United States, and a new facility in Odense, Denmark. The company broke ground in 2024 on a dedicated insulin finishing facility in Kalundborg designed to increase pen device output by an estimated 30%.

As of early 2026, the FDA shortage database no longer lists Tresiba in active shortage status 8. Novo Nordisk's Q4 2025 earnings report indicated that insulin degludec supply had returned to "full allocation" across all U.S. distribution channels.

The company has also expanded its contract with Catalent (now part of Novo Holdings) for supplemental fill-and-finish capacity. This diversification of finishing operations reduces single-site risk. Previously, a maintenance shutdown or regulatory inspection finding at one facility could cascade into regional shortages within 4 to 6 weeks.

Global demand for degludec continues to grow, particularly in Japan (where it holds the largest basal insulin market share at approximately 25%) and in Europe. Novo Nordisk projects mid-single-digit annual volume growth for Tresiba through 2028 in its long-range guidance.

Biosimilar Competition and Future Supply Dynamics

No biosimilar insulin degludec has been approved in the United States or Europe as of May 2026. Novo Nordisk's core patents on the degludec molecule and its formulation extend through 2029 in the U.S. and 2028 in Europe, though specific patent expiry dates depend on jurisdiction and any patent term extensions.

Several biosimilar developers have disclosed degludec programs. Biocon Biologics and Mylan (now Viatris) have both referenced insulin degludec biosimilar candidates in pipeline disclosures, though neither has filed for regulatory approval as of this writing.

The entry of biosimilar degludec products would meaningfully alter the supply picture. Biosimilar competition in the insulin glargine market (with products from Semglee, Rezvoglar, and others) increased available U.S. supply by an estimated 15 to 20% within two years of the first biosimilar launch, according to IQVIA tracking data. A similar dynamic could apply to degludec.

"Biosimilar insulin availability is not just a pricing story. It is a supply resilience story," noted Dr. Irl Hirsch, Professor of Medicine at the University of Washington, in a 2023 commentary in Diabetes Care. "Every additional manufacturer reduces the probability that a single production disruption leaves patients without their prescribed basal insulin" 12.

What Prescribers Should Know About Tresiba Supply Resilience

For clinicians managing patients on Tresiba, three practical steps reduce vulnerability to future shortages.

First, maintain an updated switching protocol. The ADA Standards of Care recommend documenting each patient's current degludec dose alongside a pre-calculated equivalent dose of an alternative basal insulin (typically glargine U-100 or U-300) so that transitions can happen within 24 to 48 hours if supply is interrupted 10.

Second, monitor the FDA Drug Shortage Database directly. The database at fda.gov/drugs/drug-safety-and-availability/drug-shortages provides manufacturer-reported shortage status with estimated resolution dates. Signing up for email alerts on specific NDC codes allows early awareness.

Third, for patients who have experienced nocturnal hypoglycemia on glargine (the primary clinical reason to prefer degludec, per DEVOTE data showing a rate ratio of 0.60 for severe nocturnal hypoglycemia 6), consider maintaining a small buffer supply during periods of stable availability. Most insurance formularies allow a 90-day mail-order supply, which provides a meaningful cushion against short-duration supply disruptions.