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Toxicological and Lactological Monograph: ATC A10AE – Insulins and Analogues for Injection, Long-Acting

1. ATC Classification and Pharmacological Profile

ATC Code: A10AE ATC Classification: Alimentary Tract and Metabolism → Drugs Used in Diabetes → Insulins and Analogues → Insulins and Analogues for Injection, Long-Acting Pharmacotherapeutic Group: Long-acting and ultra-long-acting insulin preparations Principal Therapeutic Indication: Diabetes mellitus requiring basal insulin replacement or supplementation.

The ATC A10AE group comprises long-acting insulin preparations and insulin analogues designed to provide sustained basal insulin activity and maintain glycaemic stability over extended periods. These agents are fundamental components of insulin replacement therapy in type 1 diabetes mellitus and are widely used in type 2 diabetes mellitus when endogenous insulin secretion is insufficient to achieve adequate metabolic control.

The group includes modified human insulin analogues and prolonged-action insulin formulations with pharmacokinetic characteristics intended to reduce fluctuations in circulating insulin concentrations. Their extended duration of action is achieved through formulation-dependent mechanisms, including altered subcutaneous solubility, reversible albumin binding, and the formation of subcutaneous multihexameric or depot structures.

Following subcutaneous administration, these preparations provide a relatively sustained insulin supply, suppressing hepatic glucose production, promoting peripheral glucose uptake, inhibiting lipolysis, and regulating protein and carbohydrate metabolism. Although their pharmacodynamic profiles differ, the common therapeutic objective is to reproduce physiological basal insulin secretion while limiting glycaemic variability.

From a toxicological and lactological perspective, the defining characteristic of this class is its peptide-based molecular structure. Insulin and its analogues are large, hydrophilic molecules that are susceptible to proteolytic degradation in the gastrointestinal tract. These properties are central to assessing their potential transfer into human breast milk and the likelihood of systemic exposure in breastfed infants.

The pharmacological activity of long-acting insulin preparations is mediated through interaction with insulin receptors and subsequent activation of intracellular signalling pathways involved in glucose transport, glycogen synthesis, lipid metabolism, and cellular growth regulation. Some insulin analogues demonstrate modified receptor-binding kinetics; however, the clinical significance of these differences depends on the specific molecular structure, systemic exposure, and therapeutic context.

During the postpartum period, insulin requirements may change substantially as pregnancy-associated insulin resistance decreases. Lactating women with pre-existing diabetes therefore require individualised insulin dose adjustment to maintain maternal metabolic stability and prevent hypoglycaemic episodes.

2. Toxicological Profile

The toxicological profile of ATC A10AE preparations is primarily determined by their intrinsic insulin activity rather than by conventional organ-specific chemical toxicity. At therapeutic concentrations, long-acting insulins are generally well tolerated, with adverse reactions arising predominantly from excessive pharmacodynamic effects, local administration-related complications, or immunological responses.

Hypoglycaemia is the principal dose-dependent toxicological risk associated with this pharmacological group. Excessive insulin exposure, whether caused by dosing errors, altered insulin sensitivity, inadequate carbohydrate intake, increased physical activity, or impaired insulin clearance, may produce clinically significant reductions in blood glucose concentrations.

Severe hypoglycaemia can result in neuroglycopenia, confusion, seizures, loss of consciousness, and, in exceptional circumstances, irreversible neurological injury. The prolonged pharmacodynamic activity of certain basal insulin formulations may complicate the management of overdose because recurrent hypoglycaemia can persist beyond the period expected with shorter-acting preparations.

Additional class-related adverse effects include weight gain, peripheral oedema, hypokalaemia, injection-site reactions, and lipodystrophic changes associated with repeated subcutaneous administration. Allergic reactions are uncommon but may range from local hypersensitivity to rare systemic reactions.

Insulin-mediated intracellular potassium redistribution may produce clinically relevant hypokalaemia in susceptible individuals, particularly following excessive administration or in the presence of additional potassium-lowering factors.

Experimental toxicological evaluations of insulin analogues have included assessments of receptor selectivity, mitogenic potential, reproductive toxicity, and long-term systemic safety. Although molecular modifications can influence interactions with insulin and insulin-like growth factor receptors, available clinical evidence does not establish a uniform clinically meaningful carcinogenic risk attributable to therapeutic use of the A10AE class. Any analogue-specific toxicological findings require separate evaluation and should not be extrapolated indiscriminately across the group.

Long-acting insulin preparations are not generally associated with direct hepatotoxicity, nephrotoxicity, or genotoxicity at therapeutic exposure levels. Nevertheless, hepatic and renal dysfunction may alter insulin requirements and increase susceptibility to hypoglycaemia.

In lactating women, maternal hypoglycaemia represents an important indirect safety concern. Severe episodes may impair consciousness, judgement, and the ability to provide safe infant care. Consequently, postpartum insulin treatment should incorporate appropriate glucose monitoring, nutritional planning, and individualised dose adjustment.

The toxicological assessment of this class must distinguish between maternal systemic toxicity, which is well characterised, and potential infant toxicity resulting from breast-milk exposure, for which the available evidence indicates substantially lower biological plausibility.

3. Lactation Pharmacology and Breast-Milk Exposure

The lactation pharmacology of ATC A10AE preparations is characterised by limited expected systemic exposure of the breastfed infant, based on the physicochemical properties of insulin molecules, their peptide structure, and their susceptibility to gastrointestinal degradation.

Transfer into Human Breast Milk

Insulin is a naturally occurring constituent of human breast milk and participates in the complex biological environment of mammary secretions. Endogenous milk insulin originates from maternal circulation and may also reflect local mammary regulatory processes.

Exogenous insulin preparations may contribute to the insulin content of breast milk, although the extent of transfer and the relative contributions of endogenous and administered insulin are not consistently distinguishable in available studies.

The molecular size, hydrophilicity, and protein interactions of insulin analogues generally limit passive diffusion across the mammary epithelium. Nevertheless, the presence of endogenous insulin in milk demonstrates that mammary insulin transport cannot be explained solely by passive diffusion principles.

For long-acting insulin analogues, quantitative human lactation pharmacokinetic data remain limited. Robust comparative measurements of milk concentrations, milk-to-plasma ratios, and infant exposure are unavailable for several members of the group.

Accordingly, the absence of extensive quantitative milk-transfer data should not be interpreted as proof of complete exclusion from breast milk. Rather, the expected exposure is considered clinically low on the basis of molecular characteristics, available observations, and the established physiological presence of insulin in human milk.

Oral Bioavailability in the Breastfed Infant

Insulin is a peptide hormone that undergoes degradation by gastrointestinal proteases. Consequently, orally ingested insulin generally exhibits very low systemic bioavailability.

This characteristic is particularly important in evaluating the clinical relevance of insulin potentially transferred into breast milk. Even when insulin molecules are present in milk, their capacity to produce systemic hypoglycaemic effects following normal oral ingestion is expected to be minimal.

However, gastrointestinal digestion and intestinal permeability differ according to developmental maturity. Premature infants and neonates may exhibit less mature digestive and mucosal barrier functions, introducing theoretical uncertainty regarding the handling of orally ingested peptide hormones.

Although these physiological differences warrant consideration, clinically significant systemic absorption of therapeutic insulin analogues from breast milk has not been established.

Relative Infant Dose and Pharmacokinetic Uncertainty

The relative infant dose (RID) is conventionally calculated by comparing the estimated infant dose received through milk with the maternal weight-adjusted dose.

For ATC A10AE preparations, reliable class-wide RID estimates cannot be established because adequately characterised human milk concentration–time data are lacking for multiple agents.

Furthermore, RID calculations alone may be of limited interpretive value for peptide therapeutics with negligible oral bioavailability. A measurable concentration in breast milk does not necessarily indicate meaningful systemic exposure or pharmacological activity in the infant.

Therefore, lactological assessment should integrate molecular properties, oral absorption, biological activity, infant maturity, and observed clinical outcomes rather than relying exclusively on theoretical milk-transfer estimates.

4. Effects in the Breastfed Infant and on Lactation

Effects on the Breastfed Infant

Available clinical evidence and established pharmacological principles indicate that maternal treatment with long-acting insulin preparations is unlikely to produce clinically significant adverse effects in breastfed infants.

Insulin is naturally present in human milk, and exogenous insulin, including several long-acting analogues, has been detected in breast milk. Nevertheless, the oral route of exposure substantially limits the likelihood of systemic insulin activity in the infant.

The LactMed database considers breastfeeding compatible with maternal insulin therapy, including treatment with modern biosynthetic insulin analogues. This assessment is supported by the physiological presence of insulin in milk, its limited oral bioavailability, and the absence of an established clinically significant infant toxicity signal.

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The principal theoretical concern is infant hypoglycaemia resulting from systemic absorption of biologically active insulin. However, clinically meaningful hypoglycaemia attributable specifically to maternal long-acting insulin exposure through breast milk has not been established.

Other potential adverse outcomes, including disturbances of glucose homeostasis, abnormal weight gain, gastrointestinal intolerance, or alterations in endocrine development, have not been consistently associated with therapeutic maternal use of this pharmacological group.

Importantly, the available evidence is not equally extensive for all long-acting insulin formulations. Newer preparations with prolonged or ultra-prolonged pharmacodynamic activity may have limited direct lactation outcome data. Consequently, class-wide reassurance should be interpreted alongside formulation-specific evidence rather than as definitive proof of identical safety profiles.

Potential Biological Effects of Milk Insulin

Beyond its metabolic function, insulin in human milk may contribute to gastrointestinal maturation, intestinal epithelial development, and metabolic signalling during early infancy.

Experimental and observational research suggests that milk-derived insulin may participate in local intestinal regulatory processes, although its precise contribution to infant metabolic programming and long-term health remains incompletely understood.

The physiological presence of insulin in breast milk should not be regarded as evidence of toxicity. Equally, potential developmental benefits associated with endogenous milk insulin should not be automatically extrapolated to exogenous insulin analogues.

The biological significance of differences in milk insulin concentrations among women receiving insulin therapy remains uncertain.

Effects on Milk Production and Breastfeeding Performance

Long-acting insulin preparations are not recognised as direct inhibitors of prolactin secretion, oxytocin-mediated milk ejection, or mammary milk synthesis.

Adequate insulin signalling is important for normal mammary metabolic function, and maternal diabetes may influence lactogenesis through mechanisms involving insulin resistance, metabolic dysregulation, and associated obstetric factors.

Women with diabetes may experience delayed onset of lactogenesis II, particularly when glycaemic control is suboptimal or when additional maternal complications are present. This association should not be interpreted as a direct adverse pharmacological effect of prescribed insulin.

Rather, effective insulin treatment supports maternal metabolic regulation and may indirectly facilitate successful lactation.

Breastfeeding itself increases maternal energy expenditure and may influence glucose utilisation and insulin sensitivity. Although postpartum insulin requirements are frequently lower than during late pregnancy, the additional effect of breastfeeding on insulin requirements varies between individuals and clinical settings.

Current evidence does not establish that breastfeeding universally produces substantially lower insulin requirements than those observed in non-breastfeeding postpartum women with diabetes.

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Consequently, adjustments in basal insulin therapy should be guided by observed glucose concentrations, dietary intake, clinical symptoms, and individual metabolic requirements.

5. Lactological Safety Assessment and Clinical Recommendations

Overall Lactological Risk Assessment

Lactological compatibility: Generally compatible with breastfeeding for insulin-only preparations.

The overall lactological safety profile of ATC A10AE insulin preparations is favourable. The principal determinants of this assessment include their peptide structure, limited expected systemic bioavailability following oral ingestion, physiological occurrence in human milk, and reassuring clinical experience with maternal insulin therapy.

Importantly, the A10AE classification also includes fixed-dose combinations of long-acting insulin with non-insulin antidiabetic agents.

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The favourable lactation assessment of insulin itself cannot automatically be extended to these combinations, because the additional active components may have different milk-transfer characteristics, oral bioavailability, and infant safety profiles.

For this reason, the general compatibility conclusion applies primarily to long-acting insulin preparations administered without additional pharmacologically distinct antidiabetic agents. Combination products require separate assessment of every active ingredient.

Clinical Recommendations

Continuation of maternal therapy. Long-acting insulin treatment should generally be continued during breastfeeding when clinically indicated. Discontinuation solely because of lactation is not justified by current evidence and may expose the mother to significant metabolic instability.

Individualisation of postpartum dosing. Maternal insulin requirements should be reassessed after delivery because the rapid decline in pregnancy-associated insulin resistance may substantially reduce basal insulin needs. Subsequent dose adjustments should be based on glucose monitoring and clinical response.

Prevention of maternal hypoglycaemia. Particular attention should be given to adequate nutritional intake, recognition of hypoglycaemic symptoms, and appropriate glucose monitoring. Women experiencing recurrent nocturnal hypoglycaemia may require reassessment of basal insulin dosing and administration schedules.

Infant monitoring. Routine biochemical monitoring of infant glucose concentrations is not generally required solely because the mother receives long-acting insulin. Standard paediatric assessment of feeding effectiveness, weight gain, hydration, and developmental progress is appropriate.

Additional evaluation may be warranted in premature infants, medically vulnerable neonates, or infants exhibiting unexplained lethargy, poor feeding, abnormal weight progression, or symptoms suggestive of hypoglycaemia. Such findings should prompt a broad clinical assessment rather than an assumption of insulin toxicity through breast milk.

Breastfeeding management. Routine interruption of breastfeeding, timed feeding intervals relative to maternal insulin administration, or expression and disposal of breast milk are not considered necessary for insulin-only preparations.

The prolonged absorption and systemic action of basal insulin formulations also make attempts to minimise infant exposure through temporary feeding schedules pharmacologically unnecessary in most circumstances.

Selection of insulin preparations. When initiating or modifying basal insulin treatment during lactation, clinicians should consider maternal glycaemic requirements, previous therapeutic response, hypoglycaemia risk, availability of clinical lactation data, and the characteristics of the selected formulation.

Established clinical experience may support the use of familiar insulin preparations, but a lack of extensive breastfeeding studies for newer analogues does not independently establish that they are unsafe.

Combination therapy. Fixed-dose preparations containing additional antidiabetic agents should not be assessed according to the insulin component alone. The pharmacological and lactological properties of the accompanying substance must be considered separately.

Evidence Limitations and Research Priorities

Despite the favourable overall safety assessment, important limitations remain in the evidence supporting the lactological evaluation of ATC A10AE.

Published data are heterogeneous with respect to insulin formulation, maternal diabetes type, postpartum interval, breastfeeding intensity, and analytical methods used to measure insulin in milk.

For several long-acting preparations, direct measurements of milk concentrations and detailed infant pharmacokinetic assessments are limited or unavailable. Furthermore, studies specifically designed to evaluate infant clinical outcomes following exposure to individual long-acting insulin analogues remain relatively scarce.

Future research should prioritise standardised human milk pharmacokinetic studies, differentiation between endogenous and exogenous insulin, evaluation of biologically active insulin metabolites, and prospective monitoring of infant growth and metabolic outcomes.

Particular attention should be directed towards newer ultra-long-acting formulations, premature infants, and fixed-dose combination products, where extrapolation from conventional insulin therapy may be insufficient.

Nevertheless, these evidence limitations should be interpreted in the context of the established clinical importance of insulin therapy and the absence of a demonstrated significant breastfeeding-related toxicity signal.

6. Conclusion

Long-acting insulin preparations classified under ATC A10AE constitute an essential pharmacotherapeutic group for maintaining basal glycaemic control in patients with diabetes mellitus. Their toxicological profile is dominated by insulin-mediated hypoglycaemia and other predictable pharmacodynamic effects rather than by direct systemic organ toxicity.

From a lactological perspective, insulin-only preparations within this class are generally considered compatible with breastfeeding. Although exogenous insulin may be present in human milk, its peptide structure, susceptibility to gastrointestinal degradation, and very low expected oral bioavailability substantially limit the potential for clinically significant systemic exposure in breastfed infants.

Available clinical experience does not indicate that therapeutic maternal use of long-acting insulin produces clinically relevant hypoglycaemia or other consistent adverse effects in breastfed infants. Furthermore, insulin therapy is not recognised as a direct suppressor of lactation and may support breastfeeding indirectly by maintaining adequate maternal metabolic control.

The principal clinical consideration during lactation is therefore the optimisation of maternal insulin therapy, particularly in the early postpartum period when insulin sensitivity and therapeutic requirements may change rapidly.

Although direct lactation data remain incomplete for certain newer formulations, current pharmacological evidence supports the continued use of clinically indicated long-acting insulin during breastfeeding, with individualised maternal monitoring and routine infant clinical surveillance.

Overall, the benefit–risk balance of long-acting insulin monotherapy during lactation is strongly favourable, and breastfeeding should generally be encouraged and maintained. Fixed-dose combinations containing additional antidiabetic agents require separate evaluation and should not automatically inherit the lactological safety classification of insulin alone.