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MyDeficiencies

Insulin degludec

Ultra-Long-Acting Basal Insulin Analogue

Also sold as Tresiba.

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Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Insulin degludec is a recombinant human-insulin analogue, extended with a fatty-diacid side chain, given by once-daily subcutaneous injection. It is not a substrate of hepatic CYP450 enzymes, does not induce or inhibit any CYP enzyme, and is not orally absorbed, so the classical small-molecule drug-nutrient depletion machinery, chelation, gastric-pH change, CYP-driven catabolism, GI mucosal injury, bile-acid sequestration, does not apply to it. Its own FDA label states directly, by name, that "all insulins, including TRESIBA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia." This is real and drug-attributable, but it is a redistribution, not a dietary deficiency, and the label frames it as a monitoring issue for at-risk patients rather than a routine effect of stable, once-daily maintenance dosing.

ultra-long-acting basal insulin analogue · ATC A10AE06 · also sold as Tresiba; also in Xultophy (insulin degludec/liraglutide) · reviewed 2026-09-20. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Insulin degludec in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
severe: at least two independent Tier A sources with this drug in the studied cohort, nutrient directly measured, consistent direction and clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
moderate: at least one Tier A source with this drug in the cohort showing a real but bounded deficit (exposure window, subgroup, low frequency, or functional rather than circulating deficit).
Yellow — Low
low/theoretical: mechanistic plausibility only (Tier B), or class-level extrapolation (Tier C); also used for context flags and for reverse-direction findings where the drug's own chemistry appears protective rather than depleting.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: evidence gap: no Tier B/C evidence exists to support even a yellow grade, and no circulating claim exists to rebut as white. A genuine gap in the literature or in what this review could access, not a finding of safety.

What the research found

Potassium

Orange — Moderate

See study details

Insulin degludec, named specifically in its own FDA label, drives potassium from outside to inside cells. Degludec is given subcutaneously only — section 2.1 of the TRESIBA label states it must not be administered intravenously — and the section 5.6 hypokalemia warning directs potassium monitoring in at-risk patients without restricting the risk to acute, correction-phase or high-dose use. The only degludec-specific quantitative data located come from an acute-correction study, which bounds what has been measured, not where the labeled risk applies.

Full detail and limits

What the grade means here: moderate: at least one Tier A source with this drug in the cohort showing a real but bounded deficit (exposure window, subgroup, low frequency, or functional rather than circulating deficit). ORANGE

Limits on what this shows

  • Key negative/null findings: In the degludec DKA RCT, adding subcutaneous degludec on top of standard IV insulin infusion did not significantly increase hypokalaemia frequency compared with IV infusion alone, an active-comparator finding: both arms received insulin, so this does not test degludec against no insulin, only against a different insulin-dosing strategy. [2]
  • At-risk subgroups: Patients undergoing rapid correction of severe hyperglycemia or diabetic ketoacidosis; patients on intravenous or high-dose insulin protocols using other insulins (degludec itself is not given intravenously); patients also taking other potassium-lowering drugs (diuretics, beta-agonists); malnourished or refeeding patients; insulin overdose.
  • Counter-evidence: No Tier A source located shows clinically significant hypokalemia from routine, stable, once-daily degludec maintenance dosing in outpatients; the only degludec-specific quantitative hypokalemia data come from the acute DKA-correction setting, where the effect was not distinguishable between degludec-augmented and standard insulin protocols.

Regulatory status

FDA labeling for TRESIBA states directly: "All insulins, including TRESIBA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia," and directs potassium monitoring in at-risk patients. [1]

Population evidence

Randomized controlled trial, 80 adults with diabetic ketoacidosis (67.5% type 2 diabetes), comparing early subcutaneous insulin degludec added to a standard continuous intravenous infusion of a separate short-acting insulin, versus that infusion alone. Degludec was given subcutaneously in both descriptions of this protocol; no arm received intravenous degludec, which its label prohibits. DKA resolved 3.25 hours faster and 72-hour glucose was lower in the early-degludec arm, but rates of hypokalaemia (along with rebound hyperglycaemia, rebound DKA, hypoglycaemia, length of stay, and in-hospital mortality) were not significantly different between groups. [2]

Mechanism

Named at the class level in the label: insulin receptor activation drives cellular potassium uptake (via Na⁺/K⁺-ATPase stimulation), shifting potassium from extracellular to intracellular space independent of its glucose-lowering action. [1]

Counter-evidence held on record

This is an intracellular shift/retention-direction risk, not a dietary deficiency, and it must never be framed as a reason to increase potassium intake. Potassium management in a patient on insulin degludec should be directed by a clinician monitoring labs; unsupervised potassium supplementation carries its own hyperkalemia risk.

Phosphate

Yellow — Low

See study details

Insulin administration is a recognized contributor to the intracellular phosphate shift seen in refeeding syndrome and DKA correction, a class-level, mechanism-only finding for degludec, not a demonstrated effect of steady-state basal dosing.

Full detail and limits

What the grade means here: low/theoretical: mechanistic plausibility only (Tier B), or class-level extrapolation (Tier C); also used for context flags and for reverse-direction findings where the drug's own chemistry appears protective rather than depleting. YELLOW

Limits on what this shows

  • Key negative/null findings: None located specific to insulin degludec or to basal (non-IV, non-correction) insulin dosing.
  • At-risk subgroups: Patients being treated for DKA or severe hyperglycemia; malnourished/refeeding patients started on insulin as part of nutritional rehabilitation.
  • Counter-evidence: No cohort study isolating insulin degludec's phosphate effect from concurrent glucose or nutrition administration was located; the DKA RCT that measured hypokalaemia for degludec specifically did not report phosphate as an outcome. [2]

Regulatory status

Not mentioned in the TRESIBA label's warnings (unlike potassium). [1]

Population evidence

Narrative review confirms refeeding syndrome as "potentially fatal shifts in fluids and electrolytes" occurring in malnourished patients receiving artificial refeeding; this is a general, class-level (not insulin-degludec-specific, not insulin-specific by name) clinical review. Full text describing insulin's quantitative or mechanistic role in the phosphate shift was not accessible this session (subscription-gated beyond the abstract), so the detailed mechanism below reflects the well-established general pharmacology of insulin-stimulated cellular glucose uptake rather than a passage directly read from this source. [4]

Mechanism

Proposed, not directly confirmed in an opened full-text source this session: insulin-stimulated glycolysis in cells consumes phosphate to form phosphorylated glycolytic intermediates and ATP, and insulin's activation of Na⁺/K⁺-ATPase promotes cellular phosphate uptake alongside potassium. This is the same category of disturbance (intracellular ion shift) already confirmed at Tier A for potassium specifically with TRESIBA. [1][4]

Counter-evidence held on record

This is a redistribution effect tied to acute correction and refeeding contexts, not a chronic dietary depletion from routine degludec use. No phosphate supplementation is implied for typical stable basal-insulin patients; this entry should be re-verified against full-text mechanistic sources in a future revision.

Magnesium

Yellow — Low

See study details

Magnesium is carried forward on the same intracellular-shift mechanism family implicated for potassium and phosphate, but no insulin-degludec-specific or fully-verified general-insulin mechanistic source was accessible this session.

Full detail and limits

What the grade means here: low/theoretical: mechanistic plausibility only (Tier B), or class-level extrapolation (Tier C); also used for context flags and for reverse-direction findings where the drug's own chemistry appears protective rather than depleting. YELLOW

Limits on what this shows

  • Key negative/null findings: None located.
  • At-risk subgroups: Same acute-correction/refeeding populations as phosphate, above, by analogy only.
  • Counter-evidence: Of the three electrolytes screened (potassium, phosphate, magnesium), magnesium has the thinnest evidence base located this session; this entry rests on mechanistic analogy rather than a directly confirmed source.

Regulatory status

Not mentioned in the TRESIBA label. [1]

Population evidence

No insulin-degludec-specific study of magnesium was located despite targeted Crossref queries combining insulin degludec with magnesium. The refeeding syndrome literature this review could access confirms the general phenomenon of electrolyte shifts with artificial refeeding but its abstract did not itemize magnesium specifically, and full text was not reachable this session. [4]

Mechanism

Proposed only, by analogy to the potassium and phosphate shift mechanisms (insulin-stimulated cellular uptake via Na⁺/K⁺-ATPase activation and increased anabolic/glycolytic demand), not independently confirmed for magnesium in a source opened this session.

Counter-evidence held on record

This is the weakest-evidenced entry in the dossier. Do not present it to consumers as an established effect of insulin degludec; it should be re-verified against a directly-opened, drug- or class-specific source before any stronger claim is made.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden

Not graded — disclosed evidence gap

See study details

No evidence was found, in either the harm or benefit direction, that insulin degludec directly affects mitochondrial structure, membrane integrity, electron transport, or biogenesis.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Dual condition met. (1) A targeted Crossref bibliographic search ("insulin degludec mitochondrial function ATP") returned ten results, all concerning degludec's clinical efficacy, hypoglycemia risk, or pharmacokinetics, with none addressing mitochondrial function; a follow-up search for insulin signaling and mitochondrial biogenesis in skeletal muscle surfaced studies about endogenous insulin-resistance physiology and unrelated interventions (vitamin K2, myoblast transplantation), not about exogenous insulin therapy as the studied variable, so no usable Tier B/C evidence was found. (2) No circulating consumer claim specific to insulin degludec and mitochondrial harm was identified.
  • Tooling limitation: This session's WebSearch tool budget was already exhausted before this medication's turn in a 25-drug batch run, which removed the primary channel for locating consumer-facing claims. Europe PMC and Semantic Scholar API queries for this category were also blocked by repeated HTTP 429 responses despite waits of 60-120 seconds between attempts. A future revision with fresh search access should re-run this category before treating the gap as final.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress

Yellow — Low

See study details

A randomized crossover pilot comparing insulin degludec with insulin glargine U300 measured redox markers directly and found no significant difference between the two insulins, in a study the authors describe as likely underpowered.

Full detail and limits

What the grade means here: low/theoretical: mechanistic plausibility only (Tier B), or class-level extrapolation (Tier C); also used for context flags and for reverse-direction findings where the drug's own chemistry appears protective rather than depleting. YELLOW

Limits on what this shows

  • Key negative/null findings: No significant between-insulin difference in glycemic variability or the panel of oxidative-stress markers over 12 weeks per arm; the authors attribute this to insufficient statistical power at standard clinical dosing rather than to a confirmed absence of effect. [3]
  • At-risk subgroups: None established; this is a small, underpowered pilot in insulin-naive type 2 diabetes patients, not a subgroup-stratified study.
  • Counter-evidence: This is an active-comparator design (degludec versus glargine U300, not versus no insulin or placebo), so it cannot show whether either insulin changes oxidative stress relative to an untreated state, only that the two did not differ meaningfully from each other at n=25.

Regulatory status

Not addressed in the TRESIBA label. [1]

Population evidence

Randomized crossover pilot study, 25 insulin-naive adults with type 2 diabetes, each receiving insulin degludec U100 and insulin glargine U300 for 12 weeks apiece, with glycemic variability and oxidative-stress markers (thiols, hydroperoxides, among others) measured on each regimen. Degludec was associated with a small increase in thiols (about 0.15 μmol/L) and an increase in hydroperoxides, but there was no significant difference in oxidative-stress markers between the two insulins overall. The authors state a larger study with higher insulin doses would be needed to detect a meaningful effect. [3]

Mechanism

Not established by this pilot; the study was designed to detect a difference in redox status between two insulin analogues rather than to test a specific biochemical mechanism, and no significant difference was found to explain. [3]

Counter-evidence held on record

This is a genuinely inconclusive pilot result, not evidence of either harm or protection. It must not be presented to consumers as proof that insulin degludec raises or lowers oxidative stress, and it does not support an antioxidant-supplementation recommendation.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper

Not graded — disclosed evidence gap

See study details

No evidence was found, in either the depletion or retention direction, that insulin degludec or insulin as a class affects copper status.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Dual condition met. (1) A targeted Crossref search ("insulin degludec copper zinc trace element") and a follow-up search ("insulin degludec copper ceruloplasmin") returned no insulin-degludec-specific results; the one tangentially relevant hit found, a study of copper and ceruloplasmin in insulin-resistant subjects, concerns endogenous insulin resistance as a disease state, not exogenous insulin therapy as the studied variable, and does not support even a class-level extrapolation. (2) No circulating consumer claim that insulin depletes copper was identified.
  • Tooling limitation: WebSearch budget exhausted for this session; Europe PMC REST API queries for copper/iron together were blocked by repeated 429 responses. A revision should re-try PubMed and Europe PMC directly for this category.

Iron

Not graded — disclosed evidence gap

See study details

No evidence was found that insulin degludec affects iron status, ferritin, or hemoglobin synthesis via an iron-specific pathway.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Dual condition met. (1) A targeted Crossref search ("insulin degludec iron anemia hemoglobin") returned insulin-degludec studies unrelated to iron or hemoglobin (Ramadan fasting experience, general efficacy reviews) and separately returned iron/anemia studies unrelated to insulin degludec (infantile anemia, iron supplementation), with no overlap. (2) No circulating consumer claim that insulin degludec depletes iron or causes anemia was identified.
  • Tooling limitation: WebSearch budget exhausted for this session; direct Europe PMC queries combining insulin degludec with iron were attempted but blocked by repeated 429 rate-limiting. Copper and Iron are graded as fully independent entries per this protocol's hard rule, even though the same search attempt covered both.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk

Not graded — disclosed evidence gap

See study details

No evidence was found that insulin degludec, or exogenous insulin therapy generally, alters gut microbiome composition or diversity.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Dual condition met. (1) A targeted Crossref search ("insulin degludec gut microbiome microbiota") returned no insulin-degludec-specific or insulin-therapy-specific results; the one topically adjacent hit found concerned endogenous insulin homeostasis and the gut microbiome in menopause, not a drug-therapy effect, and does not support even a class-level extrapolation. (2) No circulating consumer claim that insulin degludec disrupts the gut microbiome was identified.
  • Tooling limitation: WebSearch budget exhausted for this session; Europe PMC REST API queries for this category returned repeated HTTP 429 responses even after multi-minute waits between attempts. As a subcutaneously injected peptide with no GI-tract exposure, a direct gut-luminal mechanism is pharmacologically implausible on its face, but this review could not independently confirm or rule out an indirect (e.g., glycemic-control-mediated) pathway in the literature this session, so the gap is disclosed rather than resolved.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

ATP production

Not graded — disclosed evidence gap

See study details

No evidence was found that insulin degludec directly affects mitochondrial ATP synthesis or cellular energy output.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Dual condition met. (1) The same Crossref search used for mitochondrial burden ("insulin degludec mitochondrial function ATP") covered this category jointly and returned no relevant results; no separate ATP-specific source was located. (2) No circulating "low energy" or ATP-depletion claim specific to insulin degludec was identified.
  • Tooling limitation: Same as Mitochondrial burden above: WebSearch budget exhausted for this session, and Europe PMC/Semantic Scholar access was rate-limited throughout. Because this category and Mitochondrial burden were checked with a single combined query, see the Overlap map below for the shared search basis.

Oxygen delivery/utilization

Not graded — disclosed evidence gap

See study details

No evidence was found that insulin degludec affects hemoglobin, hematocrit, red-cell mass, arterial oxygenation, or tissue oxygen delivery.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. UNGRADED

Limits on what this shows

  • Why no grade: Dual condition met. (1) The Crossref search combining insulin degludec with iron, anemia, and hemoglobin (used for the Iron entry above) also covered this category and returned no relevant results. (2) No circulating consumer claim that insulin degludec impairs oxygen delivery or utilization was identified. Per this protocol's hard rules, the drug's own intended pharmacodynamic effects (glucose lowering, weight gain listed as an adverse reaction in the label) are not filed here as an oxygen-delivery finding, since neither hemoglobin nor hematocrit was directly measured in any source located. [1]
  • Tooling limitation: WebSearch budget exhausted for this session; Europe PMC and Semantic Scholar access was rate-limited throughout. Oxygen delivery/utilization and ATP production are graded as fully independent entries per this protocol's hard rule, despite being conceptually adjacent and both currently ungraded.
All references used above
  1. TRESIBA (insulin degludec) injection, solution — FDA-approved prescribing information (Novo Nordisk) — Regulatory label. Accessed via DailyMed, SPL setid 456c5e87-3dfd-46fa-8ac0-c6128d4c97c6.
  2. Thammakosol K, Jantarapootirat M, Traiwanatham S, Sriphrapradang C. Early insulin degludec with continuous intravenous insulin infusion in the management of diabetic ketoacidosis: a randomized controlled trial. Diabetes Obes Metab. 2025 (online 3 Sep 2025). — Randomized controlled trial, n=80 adults with DKA (67.5% type 2 diabetes). DOI 10.1111/dom.70101.
  3. Vrebalov Cindro P, Krnić M, Modun D, Vuković J, Tičinović Kurir T, Kardum G, Rušić D, Šešelja Perišin A, Bukić J. Comparison of the Impact of Insulin Degludec U100 and Insulin Glargine U300 on Glycemic Variability and Oxidative Stress in Insulin-Naive Patients With Type 2 Diabetes Mellitus: Pilot Study for a Randomized Trial. JMIR Form Res. 2022. — Randomized crossover pilot trial, n=25, 12 weeks per arm. DOI 10.2196/35655 (preprint DOI 10.2196/preprints.35655). Active-comparator design (degludec vs. glargine U300, not vs. no insulin or placebo).
  4. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to prevent and treat it. BMJ. 2008;336(7659):1495-1498. — Narrative review, class-level (general refeeding-syndrome pathophysiology, not insulin-degludec-specific and not insulin-specific by name). DOI 10.1136/bmj.a301.Cohort excludes insulin degludec (general narrative review). Full text was paywalled; only the abstract could be accessed this session.
  5. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index, code A10AE06, insulin degludec. — Regulatory classification reference. DDD listed as 40 units, parenteral route.