What Are SGLT2 Inhibitors?

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of oral medications used primarily for the management of type 2 diabetes. They work by inhibiting the SGLT2 protein in the proximal tubule of the kidneys, which normally reabsorbs up to 90% of filtered glucose. By blocking this transporter, these drugs increase urinary glucose excretion, thereby lowering blood glucose levels independently of insulin secretion. This mechanism also leads to a mild osmotic diuresis and caloric loss, which can contribute to modest weight reduction and slight decreases in blood pressure.

Commonly prescribed SGLT2 inhibitors include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Beyond glycemic control, large cardiovascular outcome trials have demonstrated additional benefits such as reductions in major adverse cardiovascular events and progression of chronic kidney disease in patients with or without diabetes. These advantages have made SGLT2 inhibitors a popular choice for many patients with type 2 diabetes, but their use is not recommended during pregnancy or breastfeeding.

Risks of SGLT2 Inhibitors During Pregnancy

Current evidence strongly advises against the use of SGLT2 inhibitors during pregnancy. Animal reproduction studies have raised concerns. For example, administration of canagliflozin to pregnant rats during organogenesis resulted in increased fetal visceral and skeletal malformations, as well as reduced fetal body weights. Similar findings were observed with empagliflozin and dapagliflozin in rodent models, including delayed ossification and renal pelvic dilation. These effects are often attributed to the pharmacological action of SGLT2 inhibition on fetal kidney development, as the sodium-glucose transporter is present in the developing kidney and may play a role in proper nephrogenesis.

Human data are limited to case reports and post-marketing surveillance, which cannot establish definitive risk. The U.S. Food and Drug Administration (FDA) has classified SGLT2 inhibitors as Pregnancy Category C (prior to 2015) or, under the current labeling rule, includes a warning that they are not recommended during the second and third trimesters based on animal data. The prescribing information for each drug explicitly states that they should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus — a threshold that is rarely met given the availability of safer alternatives. Because of these uncertainties, the American Diabetes Association (ADA) and the American College of Obstetricians and Gynecologists (ACOG) recommend against using SGLT2 inhibitors in pregnant women with diabetes.

Potential Effects on the Developing Fetus

Fetal exposure to SGLT2 inhibitors during critical windows of organ development may interfere with normal kidney maturation. The kidneys become functional around the 9th week of gestation, and SGLT2 expression increases as the nephrons develop. Inhibition could theoretically disrupt electrolyte balance and fluid homeostasis in the fetus. Additionally, the osmotic diuresis induced by these drugs may cause maternal volume depletion and hypotension, which could reduce placental perfusion and compromise fetal growth. While no specific congenital syndrome has been associated with SGLT2 inhibitors in humans, the animal data are sufficient to warrant caution.

Alternatives for Glycemic Control During Pregnancy

Insulin is the gold standard for managing diabetes during pregnancy. It does not cross the placenta in significant amounts, has a well-established safety record, and can be precisely titrated to achieve the tight glycemic targets required for optimal maternal and fetal outcomes. Metformin is sometimes used off-label for gestational diabetes, especially in women with polycystic ovary syndrome, but it is not as effective as insulin for achieving strict glucose control and may cross the placenta. However, metformin has been studied more extensively than SGLT2 inhibitors in pregnancy and is considered a second-line option when insulin is not feasible. Newer agents such as GLP-1 receptor agonists and DPP-4 inhibitors also lack adequate safety data and are generally avoided. Therefore, any woman with pre-existing type 2 diabetes who becomes pregnant while taking an SGLT2 inhibitor should be switched to insulin immediately under the guidance of an endocrinologist and obstetrician.

SGLT2 Inhibitors and Breastfeeding

The safety of SGLT2 inhibitors during breastfeeding has not been established. Published data on the transfer of these drugs into human breast milk are scarce. Animal studies show that canagliflozin and dapagliflozin are excreted into rat milk, and the drug concentration can reach levels similar to maternal plasma. In humans, it is likely that SGLT2 inhibitors and their active metabolites pass into breast milk, although the extent of transfer and the potential effects on the nursing infant are unknown.

Given that the kidneys of neonates and infants continue to develop after birth, exposure to an SGLT2 inhibitor through breast milk could theoretically interfere with renal function or cause dehydration and electrolyte imbalances. Infants have lower body weight and less efficient clearance of drugs, making them more vulnerable to pharmacological effects. Because of these unknowns, major health organizations — including the ADA, ACOG, and the Academy of Breastfeeding Medicine — recommend avoiding SGLT2 inhibitors while breastfeeding. The LactMed database (Drugs and Lactation Database) also flags these agents as having insufficient data to support safety during lactation.

Practical Guidance for Nursing Mothers

Women with type 2 diabetes who are breastfeeding and require pharmacotherapy should continue insulin or, in some cases, metformin if it was used during pregnancy. Insulin is considered safe because it is a large protein that is not secreted into breast milk in clinically relevant amounts. Metformin appears in low concentrations in breast milk and has not been associated with adverse effects in breastfed infants, though long-term data are limited. Women should not start an SGLT2 inhibitor while nursing, and those already on the medication should be transitioned to an appropriate alternative before initiating breastfeeding.

Safe Management Strategies for Diabetes During Pregnancy and Breastfeeding

Ensuring optimal glycemic control during pregnancy and the postpartum period requires a comprehensive, individualized approach. The following strategies are recommended by clinical practice guidelines and should be implemented with the help of a multidisciplinary team including an endocrinologist, obstetrician, diabetes educator, and dietitian.

Insulin Therapy

Insulin remains the first-line agent for both pre-existing diabetes and gestational diabetes during pregnancy. Multiple daily injections or continuous subcutaneous insulin infusion (insulin pump) can be used. Basal-bolus regimens with rapid-acting analogs (aspart, lispro, glulisine) and intermediate- or long-acting insulins (NPH, detemir, glargine) allow flexible dosing to match meals and activity levels. During breastfeeding, insulin requirements often decrease due to the glucose demands of milk production, so close monitoring and dose adjustments are essential to avoid hypoglycemia.

Blood Glucose Monitoring

Frequent self-monitoring of blood glucose is critical. Targets during pregnancy are stricter: fasting plasma glucose below 95 mg/dL, one-hour postprandial below 140 mg/dL, and two-hour postprandial below 120 mg/dL. Continuous glucose monitoring (CGM) can provide real-time trends and alarms, helping to prevent both hyperglycemia and hypoglycemia. Postpartum, targets can be relaxed slightly, but women should still aim for glycemic goals that reduce the risk of long-term complications.

Medical Nutrition Therapy and Physical Activity

A balanced diet with appropriate carbohydrate distribution is foundational. A registered dietitian can help plan meals that provide adequate nutrition for the mother and fetus while controlling blood sugar. Physical activity, such as walking or swimming for at least 30 minutes most days, improves insulin sensitivity and aids glucose management. However, exercise should be tailored to the individual’s pregnancy or postpartum status, with attention to avoiding falls or injury.

Medication Review and Planning

Before conception or as soon as pregnancy is confirmed, women with type 2 diabetes should undergo a medication review. Any oral hypoglycemic agents that lack safety data — including SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors — should be discontinued. Insulin or metformin should be substituted as appropriate. The same applies to breastfeeding women: only medications with well-established safety profiles should be used.

Multidisciplinary Care and Follow-Up

Coordinated care between obstetrics, endocrinology, and primary care is vital. Women with diabetes in pregnancy should have regular prenatal visits with maternal-fetal medicine specialists, as well as ongoing diabetes education. Postpartum follow-up should include a 75-gram oral glucose tolerance test at 4 to 12 weeks after delivery to reclassify diabetes status, along with long-term management planning.

Future Research Directions

Although SGLT2 inhibitors are currently contraindicated during pregnancy and breastfeeding, ongoing research may eventually clarify their safety. Some animal studies have been challenged for their dosing levels, which may have exceeded therapeutic human concentrations. Human pharmacokinetic studies during lactation are limited but possible using small sample sizes and sensitive assays. Pharmaceutical companies have pregnancy registries that collect data on inadvertent exposures; these registries may help identify any signals of harm. Until more robust evidence is available, the precautionary principle remains appropriate — avoid the drugs in these populations.

Investigators are also exploring the potential role of SGLT2 inhibition in preventing or treating gestational diabetes. Because of their weight-lowering and insulin-sparing effects, they could theoretically be beneficial. However, the lack of fetal safety data means such studies are unlikely to proceed unless animal studies demonstrate a wide margin of safety. In the meantime, clinicians should continue to rely on established therapies.

Conclusion

SGLT2 inhibitors are powerful tools for managing type 2 diabetes in non-pregnant adults, offering benefits that extend beyond glucose lowering. However, their use during pregnancy and breastfeeding is not recommended due to documented risks in animal studies and a lack of adequate human safety data. Fetal kidney development may be vulnerable to SGLT2 inhibition, and the potential for transmission through breast milk raises concerns for nursing infants. Women who become pregnant while taking an SGLT2 inhibitor should be switched to insulin or metformin under medical guidance. Those who are breastfeeding should continue using only medications with proven safety records. By adhering to these guidelines and working closely with healthcare providers, women with diabetes can achieve optimal outcomes for themselves and their children.

For further reading, consult the FDA information on SGLT2 inhibitors, the American Diabetes Association Standards of Medical Care in Diabetes, and the LactMed database entry for canagliflozin. Always discuss medication changes with your healthcare provider.