LACTOLOGY FOUNDATION

Drugs Used in Diabetes

ATC code: A10
ATC designation: Drugs used in diabetes
Anatomical main group: A — Alimentary tract and metabolism
Pharmacological/therapeutic group: Antidiabetic medicines

1. ATC Classification and Pharmacological Profile

ATC A10 — Drugs used in diabetes is a broad therapeutic group comprising pharmacologically diverse medicines used to control hyperglycemia and other metabolic abnormalities associated with diabetes mellitus. In the current WHO Anatomical Therapeutic Chemical (ATC) classification, the principal subdivisions are A10A — Insulins and analogues; A10B — Blood glucose lowering drugs, excl. insulins; and A10X — Other drugs used in diabetes. WHO assigns a Defined Daily Dose (DDD) of 40 units to insulins, whereas DDDs for non-insulin agents are substance- and formulation-specific.

The class is highly heterogeneous and cannot be described by a single mechanism of action or pharmacokinetic profile.

Insulins and insulin analogues (A10A) replace or supplement endogenous insulin. They bind to insulin receptors and promote glucose uptake and utilization while suppressing hepatic glucose production, lipolysis and ketogenesis. Individual preparations differ principally in absorption characteristics and duration of action, allowing rapid-, intermediate-, long-acting and combination therapeutic strategies. WHO accordingly classifies insulin preparations partly according to onset and duration of action.

Non-insulin glucose-lowering drugs (A10B) encompass several mechanistically distinct families. Current WHO categories include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl-peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, sodium-glucose cotransporter-2 (SGLT2) inhibitors, other glucose-lowering drugs and numerous fixed combinations.

Their pharmacological targets include reduction of hepatic glucose production, stimulation of pancreatic insulin secretion, improvement of insulin sensitivity, inhibition of intestinal carbohydrate digestion, enhancement or prolongation of incretin activity, slowing of gastric emptying, modulation of appetite and inhibition of renal glucose reabsorption. Combination products exploit complementary mechanisms but also combine the toxicological and lactational considerations of their constituent agents.

The pharmacokinetic diversity within A10 is equally substantial. Insulins and peptide-based incretin therapies are large molecules administered predominantly parenterally and are susceptible to gastrointestinal proteolysis. By contrast, most traditional non-insulin agents are small molecules administered orally, with variable protein binding, volume of distribution, metabolism, renal elimination and half-life.

These differences are particularly important during lactation because ATC membership alone does not predict transfer into human milk or oral exposure of the breastfed infant. Molecular size, maternal plasma concentrations, protein binding, elimination, active metabolites and—critically—infant gastrointestinal bioavailability must be considered for the individual drug.

The therapeutic objective of maternal treatment is itself relevant to lactation. Inadequately controlled diabetes carries clinically important maternal risks; therefore, withholding effective treatment merely to eliminate theoretical medication exposure through breast milk may itself be harmful.

2. Toxicological Profile

The toxicological profile of A10 is dominated by the pharmacological diversity of its constituent groups. There is no single A10 poisoning syndrome.

Hypoglycemia

Hypoglycemia is the principal acute pharmacodynamic toxicity of insulin and insulin-secretagogue therapy. Excess insulin activity relative to glucose availability may produce adrenergic and neuroglycopenic manifestations including sweating, tremor, palpitations, hunger, behavioral disturbance, confusion, seizures, loss of consciousness and, in severe untreated cases, neurological injury or death.

Insulin overdose may produce prolonged or recurrent hypoglycemia depending on formulation, dose and injection depot characteristics. Potassium may shift intracellularly during substantial insulin exposure, producing hypokalemia.

Sulfonylureas and related insulin secretagogues may similarly produce clinically significant and sometimes prolonged hypoglycemia. Toxicity can be particularly important after overdose and in patients with impaired renal or hepatic elimination.

Other A10 classes have substantially lower intrinsic hypoglycemic potential when used alone because their effects are partly glucose-dependent or do not directly stimulate insulin secretion. Hypoglycemia may nevertheless emerge when such agents are combined with insulin or secretagogues.

Gastrointestinal and metabolic toxicity

Gastrointestinal adverse effects are prominent with several non-insulin classes. Nausea, vomiting, diarrhea, abdominal discomfort or altered gastrointestinal motility may occur, although the mechanisms differ considerably between drug groups.

Biguanide toxicity deserves particular distinction. Therapeutic use is usually not associated with hypoglycemia when used alone, but severe accumulation—especially in the presence of marked renal dysfunction or overdose—may be associated with lactic acidosis, a potentially life-threatening metabolic toxicity.

Alpha-glucosidase inhibitors act primarily within the intestinal lumen and commonly produce gastrointestinal effects related to carbohydrate fermentation, including flatulence, abdominal discomfort and diarrhea. Systemic exposure to some members is very low; for example, less than 2% of an acarbose dose is absorbed as active drug.

GLP-1 receptor agonist therapy is frequently associated with gastrointestinal intolerance, particularly nausea, vomiting, diarrhea or constipation. Clinically significant dehydration may occur secondarily in susceptible patients. Other uncommon but clinically relevant adverse events require evaluation at the individual-drug level rather than extrapolation to the entire A10 class.

Renal, cardiovascular and other class-specific toxicities

SGLT2 inhibition increases urinary glucose excretion. Important toxicological and safety considerations include genital and urinary infections, volume depletion and ketoacidosis, which may occasionally occur without extreme hyperglycemia. The renal mechanism of action also has particular relevance when assessing exposure of a developing breastfed infant.

Thiazolidinediones can cause fluid retention and may exacerbate heart failure in susceptible patients. Other adverse effects are agent-specific and should be addressed in individual monographs.

The newer incretin-based therapies, DPP-4 inhibitors and other modern glucose-lowering agents likewise possess distinct adverse-effect profiles that cannot be scientifically collapsed into a single class-wide toxicity statement.

Overdose management

No class-wide antidote or universal management strategy exists for A10 poisoning.

Management depends on the pharmacological mechanism involved. Severe hypoglycemia requires prompt glucose restoration and continued surveillance for recurrence; insulin-secretagogue poisoning may require prolonged observation and additional pharmacologically targeted treatment. Severe biguanide toxicity requires correction of metabolic and circulatory disturbances and may require extracorporeal elimination in appropriate circumstances.

Accordingly, significant A10 overdose should be managed according to the specific agent, formulation, dose and clinical syndrome, rather than according to the broad ATC classification.

3. Lactation Pharmacology and Breast-Milk Exposure

Lactation evidence within A10 is markedly uneven. Insulin and metformin have comparatively reassuring clinical experience; several older secretagogues have limited human milk-transfer data; emerging evidence is available for some newer peptide therapies; while direct lactation data remain absent or very limited for many contemporary oral glucose-lowering agents.

A recent systematic review of type 2 diabetes pharmacotherapy found human plasma-to-milk transfer data for only a minority of evaluated drugs, emphasizing the substantial evidence gap across modern antidiabetic pharmacotherapy.

Consequently, no meaningful class-wide milk-to-plasma ratio or Relative Infant Dose can be assigned to A10.

Insulin

Insulin represents a special lactological case.

Insulin is a physiological component of human milk, and exogenous insulin—including modern biosynthetic insulin analogues—can also be present in breast milk. LactMed considers maternal insulin therapy compatible with breastfeeding.

The presence of insulin in milk does not imply clinically significant systemic pharmacological exposure of the infant. Insulin is a peptide that undergoes gastrointestinal digestion and has extremely poor oral bioavailability. Indeed, oral exposure to insulin through breast milk is fundamentally different from parenteral therapeutic administration.

Thus, even where exogenous insulin contributes to milk insulin concentrations, clinically important systemic insulin exposure of the breastfed infant is not expected.

This is a particularly important example of why milk concentration alone cannot determine lactational risk.

Metformin

Among oral glucose-lowering agents, metformin has one of the strongest lactation evidence bases.

Well-conducted studies demonstrate low concentrations in human milk. LactMed estimates infant exposure at less than approximately 0.5% of the maternal weight-adjusted dose. Milk concentrations remain relatively stable over the dosing interval, making dose–feed timing of little practical value. Low concentrations can occasionally be detected in infant serum, but prospective clinical observations have not demonstrated adverse developmental or clinical effects attributable to exposure through milk.

These data represent direct pharmacokinetic and clinical evidence rather than purely mechanistic reassurance.

Insulin secretagogues

Human data for selected sulfonylureas suggest that milk transfer can be very low. Glyburide was undetectable in milk after studied maternal doses, with conservative estimates of maximum infant exposure below approximately 1.5% of the maternal weight-adjusted dose in a single-dose study. Glipizide has likewise been undetectable or present at very low levels in the limited available studies.

Nevertheless, because the pharmacological consequence of systemic exposure would be infant hypoglycemia, greater clinical vigilance is appropriate than might be inferred solely from low measured milk concentrations.

These limited data cannot be generalized to all sulfonylureas or other secretagogues, particularly agents with long half-lives or active metabolites.

Poorly absorbed intestinal agents

For drugs whose therapeutic activity occurs predominantly in the maternal gastrointestinal tract, very low maternal systemic bioavailability may markedly restrict transfer into milk.

Acarbose provides a representative example: less than 2% of an oral dose is absorbed as active drug, and LactMed therefore considers clinically relevant passage into breast milk unlikely, although direct maternal milk and infant-level studies are unavailable.

This is primarily a mechanistic exposure assessment, not direct demonstration of absence from milk.

Incretin-based therapies

Peptide-based incretin therapies have physicochemical characteristics that may restrict clinically important infant exposure: they are relatively large molecules and generally have poor oral bioavailability. However, individual formulations differ and direct lactation evidence cannot be assumed across the group.

Importantly, human evidence has begun to emerge. For subcutaneous semaglutide, LactMed reports that the drug was not detectable in serial milk samples from eight lactating women receiving 0.25–1 mg weekly. Using the assay detection limit, investigators calculated a hypothetical upper-bound RID of approximately 1.12%; actual exposure was presumably lower because the drug was not detected, and oral bioavailability is very low. The studied infants, aged 4–23 months and mixed-fed, had no reported adverse growth or developmental effects during the observation period.

These results are reassuring for the studied subcutaneous formulation, but should not be generalized automatically to other GLP-1 therapies, younger exclusively breastfed infants or oral formulations containing absorption-enhancing excipients. LactMed specifically distinguishes oral semaglutide formulations containing salcaprozate sodium from the injectable product.

SGLT2 inhibitors and other insufficiently studied agents

Direct human lactation evidence for SGLT2 inhibitors remains very limited. Physicochemical characteristics may predict limited milk transfer for some individual agents, but this does not resolve the principal theoretical concern: pharmacological exposure during postnatal renal development.

For empagliflozin, for example, LactMed notes limited clinical information and cites the manufacturer's recommendation against breastfeeding use because of theoretical risk to the developing kidney; an alternative is particularly preferred for newborn or premature infants.

This illustrates another central lactological principle: a low predicted milk concentration does not necessarily establish safety when the infant pharmacological target itself raises developmental concern.

For DPP-4 inhibitors, thiazolidinediones and several other newer or less commonly used agents, human milk and infant outcome data are generally insufficient for a confident class-wide assessment.

4. Effects in the Breastfed Infant and on Lactation

Clinical effects in breastfed infants

The available evidence does not suggest a common adverse-effect syndrome among infants exposed to A10 drugs through breast milk. Instead, potential effects depend on the maternal drug and its mechanism.

For insulin, clinically significant pharmacological exposure through breastfeeding is not expected despite the physiological presence of insulin in human milk. LactMed explicitly supports breastfeeding during maternal insulin therapy.

Metformin has comparatively substantial reassuring evidence. Milk exposure is low, and a prospective study cited by LactMed found no adverse effects in breastfed infants.

Limited studies of glyburide and glipizide found no detectable drug in milk under the studied conditions and no hypoglycemia in the small number of fully breastfed infants evaluated. However, the number of exposed infants was small, and these findings should not be interpreted as proof of safety for the entire secretagogue class.

For subcutaneous semaglutide, the available small study found no measurable milk concentrations and no reported adverse effects among eight mixed-fed infants; importantly, these infants were 4–23 months old rather than neonates.

For many other A10 drugs, no adequate published infant outcome data are available.

Potential infant hypoglycemia

Hypoglycemia is the most clinically intuitive infant concern when maternal therapy involves an insulin secretagogue capable of reaching the infant systemically.

Possible manifestations include jitteriness, excessive sleepiness, poor feeding, hypothermia, cyanosis, apnea or seizures. LactMed recommends observation for such manifestations with glyburide and glipizide and suggests measurement of infant blood glucose when clinically indicated.

Routine glucose testing is not justified for every infant whose mother receives any A10 drug. Monitoring should be proportional to the specific medicine, milk-transfer evidence, infant age and clinical condition.

Effects on lactation

Diabetes itself and the postpartum metabolic state may influence breastfeeding physiology and management independently of medication exposure.

No evidence suggests that insulin therapy impairs lactation. Rather, adequate insulin availability is physiologically important for normal mammary metabolism. Maternal insulin requirements commonly decrease after delivery, and the American Diabetes Association emphasizes reassessment of postpartum insulin dosing. Lactation can increase maternal susceptibility to hypoglycemia, particularly overnight, so maternal treatment may require adjustment.

Metformin has been investigated as a possible galactogogue in women with low milk supply associated with metabolic dysfunction, but current evidence does not establish it as an effective treatment for increasing milk production.

For most other A10 subclasses, adequate evidence regarding prolactin, oxytocin-mediated milk ejection, lactogenesis or established milk volume is lacking.

Therapies producing substantial nausea, vomiting, appetite suppression, dehydration or excessive maternal weight loss could theoretically impair maternal nutritional status and thereby affect lactation indirectly. This consideration is particularly relevant when glucose-lowering medicines with major gastrointestinal or weight-reducing effects are used postpartum, although such indirect effects should not be misrepresented as established inhibition of lactation.

The ADA recommends supporting breastfeeding in individuals with diabetes and specifically notes its maternal and infant health benefits.

5. Lactological Safety Assessment and Clinical Recommendations

A single breastfeeding recommendation for the entire A10 group would be scientifically inappropriate because lactational evidence and pharmacological risk differ markedly between subclasses.

The practical approach should distinguish well-characterized compatible therapies, drugs with limited but reassuring evidence, and agents for which substantial uncertainty or developmental concern remains.

Breastfeeding compatibility

Insulin therapy is compatible with breastfeeding. Exogenous insulin may occur in milk, but insulin is also a physiological milk constituent and clinically important systemic exposure of the infant after oral ingestion is not expected.

Metformin has reassuring direct human lactation data, with low milk transfer, very low relative infant exposure and no adverse effects demonstrated in the available prospective infant data.

These two therapeutic approaches therefore have substantially stronger lactation support than most other members of A10. UK Specialist Pharmacy Service guidance similarly identifies insulin and metformin as preferred antidiabetic choices during breastfeeding in healthy term infants.

Some sulfonylureas have limited but reassuring milk-transfer data, although observation for infant hypoglycemia remains appropriate.

Poorly systemically absorbed intestinal agents may produce negligible milk exposure on mechanistic grounds, but the absence of direct milk studies should be acknowledged.

For newer drug groups, recommendations must evolve with the evidence. Subcutaneous semaglutide now has limited direct human milk data that are reassuring for the studied circumstances, but these findings cannot establish a class-wide conclusion for all incretin therapies or formulations.

By contrast, SGLT2 inhibitors generally warrant greater caution during breastfeeding because of limited direct evidence and theoretical developmental renal concerns.

Infant monitoring

Infant monitoring should be drug-specific rather than routinely imposed for all antidiabetic treatment.

For insulin and metformin in a healthy term infant, special laboratory surveillance is generally unnecessary solely because of breastfeeding exposure.

Where a maternal insulin secretagogue is used, caregivers should be aware of possible manifestations of infant hypoglycemia. Blood glucose measurement is appropriate when symptoms or other clinical circumstances create concern.

For therapies with limited evidence, attention to feeding, hydration, gastrointestinal tolerance, growth and general clinical status may be reasonable, particularly in neonates and premature or medically fragile infants.

Neonates and premature infants

Greater caution is justified during the neonatal period and in premature infants.

Immature renal elimination, hepatic metabolism and gastrointestinal physiology can increase susceptibility to drug exposure. Furthermore, developmental toxicity may depend on pharmacodynamic targets rather than merely systemic dose.

For example, theoretical renal developmental concerns with SGLT2 inhibition have particular relevance to young infants.

Metformin should also be used more cautiously when breastfeeding newborn, premature or renally impaired infants despite its generally low milk exposure.

Dose–feed timing

Routine separation of antidiabetic dosing from breastfeeding is generally not an appropriate class-wide strategy.

For insulin, such timing is unnecessary from the standpoint of milk exposure.

Metformin concentrations in milk remain relatively stable, so attempting to breastfeed around maternal dosing provides little exposure reduction.

Long half-lives and sustained pharmacological exposure similarly make dose–feed timing ineffective for many modern agents.

Timing strategies should therefore be recommended only where individual pharmacokinetic evidence demonstrates a meaningful reduction in infant exposure.

Pumping and discarding milk

Routine “pump and dump” is not justified merely because a mother requires pharmacological treatment for diabetes.

For compatible therapies such as insulin and metformin, interruption would expose mother and infant to the disadvantages of unnecessary breastfeeding disruption without a corresponding pharmacological benefit.

For insufficiently studied or potentially unsuitable drugs, the preferred strategy is usually selection of an appropriately studied alternative when clinically possible rather than intermittent milk disposal based on an arbitrary dosing interval.

Combination therapy

Fixed-dose combinations require particular care.

A favourable lactation assessment of one constituent cannot be extrapolated to the complete product. Each pharmacologically active component must be assessed separately, and the least well-characterized or most clinically concerning constituent may determine the practical recommendation.

Overall lactological assessment

6. Conclusion

ATC A10 encompasses a broad and pharmacologically heterogeneous range of drugs used in diabetes, including insulins and analogues, non-insulin glucose-lowering medicines and other diabetes therapies.

Because these agents differ profoundly in molecular size, systemic bioavailability, protein binding, metabolism, elimination, mechanism of action and infant oral bioavailability, there is no scientifically valid class-wide estimate of milk transfer, milk-to-plasma ratio or Relative Infant Dose.

The strongest lactation evidence exists for established therapies. Insulin is compatible with breastfeeding: insulin is naturally present in human milk, and orally ingested peptide insulin is not expected to produce clinically significant systemic exposure in the infant. Metformin also has reassuring direct pharmacokinetic evidence, with infant exposure generally below 0.5% of the maternal weight-adjusted dose and no adverse effects identified in the principal prospective infant study.

Limited direct evidence is also reassuring for selected older oral agents, including glyburide and glipizide, although infant hypoglycemia remains an appropriate pharmacodynamic consideration. Drugs with negligible maternal gastrointestinal absorption may present low milk exposure on mechanistic grounds.

For newer antidiabetic therapies, the evidence is evolving and should not be generalized across subclasses. Direct human data now provide some reassurance for specific injectable incretin-based therapy under studied conditions, whereas other drugs remain poorly characterized. SGLT2 inhibitors merit particular caution because limited lactation evidence is accompanied by theoretical concern regarding the developing infant kidney.

The principal maternal toxicological hazards across A10 include hypoglycemia from insulin and insulin secretagogues, severe metabolic toxicity such as biguanide-associated lactic acidosis under appropriate predisposing conditions, gastrointestinal toxicity, and several mechanism-specific adverse effects associated with newer agents. No single toxicological profile applies to the entire group.

Importantly, maternal diabetes itself requires effective treatment during lactation. Breastfeeding is recommended and should be supported in women with diabetes; pharmacotherapy should therefore be selected to achieve adequate maternal metabolic control while minimizing clinically meaningful infant exposure. The postpartum reduction in insulin requirements and increased susceptibility to maternal hypoglycemia during lactation should also be considered.

Overall, ATC A10 should not be classified simply as either “safe” or “unsafe” during breastfeeding. Insulin and metformin provide the strongest evidence-supported options; several other agents may also be compatible depending on their individual pharmacokinetics and available clinical evidence, whereas some newer or insufficiently studied therapies warrant greater caution. Final lactological assessment must therefore be performed at the level of the individual medicine and formulation, particularly for newborn, premature or medically fragile infants.