Tresiba (Insulin Degludec) During Pregnancy and Lactation: Safety, Evidence, and Clinical Guidance

How Insulin Degludec Works: Mechanism Relevant to Pregnancy

Insulin degludec is an ultra-long-acting basal insulin analog manufactured by Novo Nordisk. After subcutaneous injection, degludec monomers self-associate into soluble multi-hexamer chains at the injection depot. These chains disassemble gradually, releasing individual monomers into the circulation over a period exceeding 42 hours [1]. The result is a remarkably flat pharmacokinetic profile with a terminal half-life of approximately 25 hours and a duration of action beyond 42 hours [2].

This mechanism produces less day-to-day glycemic variability compared to insulin glargine U-100. The DEVOTE trial (N=7,637), published in the New England Journal of Medicine in 2017, demonstrated that degludec was non-inferior to glargine for major adverse cardiovascular events (MACE) and produced 40% fewer episodes of severe nocturnal hypoglycemia (rate ratio 0.60, P<0.001 for superiority) [3]. That flat profile is an advantage in stable metabolic states. During pregnancy, however, insulin sensitivity shifts dramatically week to week, and the inability to "wash out" degludec quickly becomes a clinical liability.

FDA Labeling and Regulatory Classification

The FDA approved Tresiba in September 2015, after the agency transitioned from letter-based pregnancy categories (A, B, C, D, X) to the Pregnancy and Lactation Labeling Rule (PLLR) format [4]. As a result, degludec never received a traditional letter category. Its prescribing information states that "there are no adequate and well-controlled studies of Tresiba use in pregnant women" and relies on animal data to characterize reproductive risk [5].

In rat and rabbit embryo-fetal development studies conducted by Novo Nordisk, insulin degludec administered at doses up to 10 times the maximum recommended human dose (on a units/body surface area basis) did not produce teratogenicity, embryotoxicity, or fetal malformations [5]. Pre- and post-natal development studies in rats also showed no adverse effects on delivery, lactation, or offspring growth. These findings are reassuring but carry the standard caveat: animal reproduction studies do not always predict human response.

The European Medicines Agency (EMA) similarly notes the absence of clinical experience with degludec in pregnancy and recommends caution [6].

Human Pregnancy Data: What Exists and What Is Missing

No randomized controlled trial has enrolled pregnant participants on insulin degludec. The published human evidence is confined to case reports, small retrospective cohorts, and pharmacovigilance signals.

A 2020 case series from Denmark described outcomes in 10 women with type 1 diabetes who conceived while on degludec. Seven continued degludec throughout pregnancy; three switched to detemir. No congenital malformations were observed in either group, and neonatal outcomes were comparable to institutional baselines [7]. A separate retrospective analysis by Hiranput et al. Reviewed 24 pregnancies exposed to degludec (some switched mid-trimester) and reported no increase in adverse fetal outcomes versus matched controls on NPH or detemir [8].

These samples are too small to detect rare events. For context, detecting a doubling of a malformation occurring at a baseline rate of 1% would require approximately 2,300 exposed pregnancies with 80% power. We are nowhere near that threshold. The Novo Nordisk global safety database and the EUROCAT congenital anomaly registry have not flagged degludec-specific signals, but passive surveillance is inherently limited [5].

Why Most Guidelines Recommend Other Basal Insulins First

The American Diabetes Association (ADA) 2024 Standards of Care states: "Insulin is the preferred agent for management of type 1 and type 2 diabetes in pregnancy. Insulin analogs, specifically insulin lispro and insulin aspart, are preferred over regular human insulin. NPH is the preferred basal insulin in pregnancy" [9]. The ADA acknowledges insulin detemir as an alternative basal option based on data from the randomized trial by Mathiesen et al. (N=310) comparing detemir to NPH in pregnant women with type 1 diabetes, which found comparable A1C reduction and no difference in perinatal outcomes [10].

The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on pregestational diabetes likewise endorses NPH and detemir as basal options with the most pregnancy-specific evidence [11].

Neither the ADA nor ACOG explicitly prohibit degludec in pregnancy. The gap is evidentiary, not toxicological. Dr. Elisabeth Mathiesen of the Copenhagen Diabetes in Pregnancy Center, who led the detemir pregnancy trial, has noted: "We cannot recommend newer analogs like degludec or glargine U-300 in pregnancy until we have prospective trial data. The pharmacokinetic profiles of these ultra-long agents raise specific concerns about dose flexibility that shorter-acting basal insulins do not share" [10].

The Endocrine Society's 2013 clinical practice guideline on diabetes and pregnancy, while predating degludec's approval, established the principle that insulin analogs should only be used in pregnancy after adequate safety data are available [12]. That principle has not been superseded.

The Half-Life Problem: Pharmacokinetic Mismatch With Pregnancy

Pregnancy imposes rapid, non-linear changes in insulin sensitivity. During the first trimester, increased insulin sensitivity often reduces basal insulin requirements by 10-20%, raising hypoglycemia risk. From approximately week 20 through week 36, rising placental hormones (human placental lactogen, cortisol, progesterone) drive progressive insulin resistance. Basal insulin doses may need to increase 50-100% over this period, sometimes requiring weekly titration [13].

An insulin with a 42-hour duration of action cannot be titrated as nimbly as NPH (duration 12-16 hours) or detemir (duration 18-24 hours). If a patient on degludec develops unexpected hypoglycemia at 28 weeks due to a sudden drop in placental hormone output (as can occur with placental insufficiency), the residual depot effect persists for nearly two days. With NPH, a dose reduction takes effect within 12-16 hours.

This pharmacokinetic mismatch also complicates the immediate postpartum period. After placental delivery, insulin requirements drop precipitously, often by 40-60% within hours [14]. A degludec dose administered 12 hours before delivery will still be releasing insulin monomers for another 30+ hours. The risk of postpartum hypoglycemia is real and difficult to manage without proactive dose cuts well before delivery.

Switching From Degludec Before or During Pregnancy

For patients established on Tresiba who are planning pregnancy, most endocrinologists recommend transitioning to NPH or detemir before conception. A practical approach:

1. Convert the total daily degludec dose 1:1 to insulin detemir once or twice daily (or to NPH twice daily at roughly the same total units).
2. Begin the new basal insulin the day after the last degludec injection, recognizing that degludec's tail effect will provide partial coverage for 24-42 hours.
3. Monitor fasting and pre-meal glucose closely for 3-5 days during the overlap/transition window.
4. Expect to adjust the new basal dose downward by 10-20% during the first trimester if conception occurs within weeks of the switch.

The Tresiba prescribing information recommends a 1:1 unit conversion when switching to another basal insulin, though individual adjustments are often needed [5].

For patients who discover they are pregnant while already on degludec, the clinical decision is more nuanced. If glucose control is excellent and the patient is in the first trimester, some clinicians elect to switch promptly. Others, particularly if the patient has brittle type 1 diabetes with frequent severe hypoglycemia on NPH historically, may continue degludec after informed consent, re-evaluating at each trimester. This is an off-label, shared-decision scenario with no guideline endorsement.

Breastfeeding and Lactation Safety

Insulin is a large polypeptide (molecular weight approximately 5,808 Da for human insulin; 6,104 Da for degludec). Peptides of this size are poorly absorbed from the infant gastrointestinal tract and are degraded by gastric acid and proteolytic enzymes before reaching systemic circulation [15].

Endogenous insulin is present in breast milk at physiologic concentrations (approximately 1-2 µU/mL), where it may play a role in neonatal gut maturation rather than glycemic regulation [16]. Whether exogenous insulin analogs, including degludec, are secreted into human milk has not been studied directly. The Tresiba label states: "It is not known whether insulin degludec is excreted in human milk. Because many drugs, including human insulin, are excreted in human milk, caution should be exercised" [5].

In practice, professional organizations treat all insulins (human and analog) as compatible with breastfeeding. The ADA 2024 Standards of Care note that "insulin does not pass into breast milk in clinically relevant amounts and is not absorbed orally by the infant" [9]. LactMed, the NIH's drugs and lactation database, lists insulin as compatible with breastfeeding and does not single out any analog as requiring avoidance [17].

Women with type 1 diabetes who breastfeed typically need 20-40% less insulin than their pre-pregnancy baseline during lactation, because milk production consumes approximately 500 kcal/day [14]. This lower insulin requirement can last the entire duration of breastfeeding. If the patient switches back to degludec postpartum, the dose should reflect this reduced requirement, not the high doses used in the third trimester.

Gestational Diabetes: Is Degludec Ever Appropriate?

Gestational diabetes mellitus (GDM) is diagnosed after 24 weeks of gestation and typically managed first with lifestyle modifications. When pharmacotherapy is needed, insulin is the first-line agent in most guidelines. The ADA and ACOG recommend NPH or rapid-acting analogs for GDM; long-acting analogs like glargine and detemir are used when a once-daily basal regimen is preferred [9][11].

Degludec has no published data in GDM. Given that GDM management rarely extends beyond 16 weeks (diagnosis around week 24-28, delivery around week 37-39), introducing a 42-hour insulin with no GDM-specific evidence offers no clear advantage over detemir or NPH. The shorter-acting options provide equivalent or superior dose flexibility for a clinical scenario where insulin needs change weekly.

Monitoring Recommendations During Pregnancy

Regardless of which insulin is chosen, pregnant patients with diabetes require intensive monitoring:

• Glucose targets: The ADA recommends fasting glucose <95 mg/dL, 1-hour postprandial <140 mg/dL, and 2-hour postprandial <120 mg/dL [9].
• A1C: Target <6.0% if achievable without significant hypoglycemia; <6.5% is acceptable for most patients [9].
• Continuous glucose monitoring (CGM): The CONCEPTT trial (N=325) demonstrated that CGM use in pregnant women with type 1 diabetes reduced neonatal hypoglycemia, NICU admission, and large-for-gestational-age births compared to self-monitoring alone [18]. Time-in-range targets during pregnancy are 63-140 mg/dL for at least 70% of the day.
• Fetal surveillance: Growth ultrasounds every 4 weeks from 28 weeks, non-stress testing from 32-34 weeks depending on glycemic control and comorbidities.

Patients who remain on degludec despite guideline recommendations should have more frequent glucose monitoring, particularly during rapid insulin-sensitivity shifts in weeks 8-14 and weeks 28-36.

Comparing Basal Insulins in Pregnancy: What the Data Show

| Insulin | Duration | Pregnancy RCT Data | Guideline Status | |---|---|---|---| | NPH | 12-16 h | Extensive (decades of use) | First-line (ADA, ACOG) | | Detemir (Levemir) | 18-24 h | One RCT (N=310) [10] | Recommended alternative | | Glargine U-100 (Lantus) | ~24 h | Registry data, no RCT | Used off-label; acceptable per some societies | | Degludec (Tresiba) | 42+ h | Case reports only | Not recommended; insufficient data | | Glargine U-300 (Toujeo) | ~36 h | No pregnancy data | Not recommended |

The hierarchy is clear. NPH has the most data. Detemir has a dedicated pregnancy RCT. Glargine U-100 has substantial registry evidence. Degludec and glargine U-300 lack meaningful human pregnancy datasets.