Targeting metabolism to protect fertility and healthy pregnancy with SGLT2 inhibitors and GLP-1RAs

Abstract

Metabolic disease is a global health epidemic with detrimental effects on reproduction. The rising use of sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have introduced new treatment options, however there is little data examining their impact on reproductive safety and efficacy during pregnancy. This review summarizes how these medications may impact hormonal regulation, limit pregnancy complications, and prevent the progression of gestational diabetes into type II diabetes post-partum. Due to safety concerns, clinical data on the use of these medications during pregnancy is limited to retrospective studies of inadvertent exposure, and the limited data on possible teratogenic effects warrants further analysis, especially considering the promising results observed in pre-clinical studies.

Metabolic Disease and Reproductive Health

Obesity and type II diabetes, herein referred to collectively as metabolic disease, are global health epidemics that are increasingly prevalent in people of reproductive age.¹ Obesity, insulin resistance, and diabetes all disrupt reproductive physiology and cardiometabolic health of both mothers and their offspring. Specifically for reproduction, these conditions alter hypothalamic-pituitary signaling, impair ovarian function, and shift sex-steroid balance, leading to impaired ovulation and reduced fertility.² Concurrently, the systemic inflammation and vascular endothelial dysfunction that accompany poor metabolic health confer cardiovascular instability, further complicate conception and pregnancy outcomes, and predispose offspring for metabolic dysfunction later in life.^3,4 Individuals with metabolic disease experience higher rates of infertility, pregnancy loss, gestational diabetes (GDM), and hypertensive disorders of pregnancy.^5–7 As metabolic disease becomes increasingly common in people of reproductive age, there is a growing motivation to identify therapies that can mitigate the underlying metabolic dysfunction while improving fertility and pregnancy outcomes and limiting adverse effects to the child.

Non-Insulin Mediated Medications for Metabolic Control

The current recommendation to mitigate the development and progression of metabolic disease in people of reproductive age is lifestyle intervention, primarily via changes in diet and exercise.⁸ Many patients, however, struggle to achieve significant results with diet and exercise alone, and thus, pharmaceutical intervention is pursued as an alternative option. Two common classes of non-insulin mediated therapies are sodium glucose co-transporter (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs). Due to limited data on their potential impact on the developing fetus, neither of these medications are recommended during pregnancy, and thus, there is very little information regarding the effects of these drugs on pregnancy.

While lifestyle modifications are the first-line treatment recommendation in people with GDM, 15–30% of patients require additional pharmacological intervention through insulin therapy.⁸ Insulin is preferred over other anti-diabetic medications since it does not cross the placenta, and GDM patients on insulin have improved glycemic control, reduced fetal overgrowth, and decreased rates of fetal hypoglycemia.^8,9 Insulin therapy, however, is associated with excess gestational weight gain of the pregnant person and decreased infant weight gain post-delivery when compared with metformin, another anti-diabetic medication.¹⁰ While insulin does not cross the placenta, excess insulin binding to its receptors alters nutrient flux across the placenta, potentially inhibiting placental and fetal vascularization.⁹ Therefore, traditional insulin therapy is not sufficient to prevent the deleterious consequences of GDM for both the pregnant person and the fetus, and there is a demonstrated need to explore alternative therapies, such as SGLT2 inhibitors and GLP-1RAs.

SGLT2 inhibitors include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, and these medications lower blood glucose levels by limiting renal glucose reuptake in the proximal tubule. Patients on these medications experience attenuated hyperglycemia in addition to improved cardiovascular outcomes, notably reduced heart failure-associated mortality and morbidity, but the mechanisms behind this cardioprotection are not fully understood.¹¹ Despite these benefits, SGLT2 inhibitors are currently contraindicated during pregnancy due to concerns about potential effects on fetal renal development, postnatal kidney function, and skeletal development.¹² Treatments for obesity and diabetes prior to and during pregnancy are crucially needed. Obese pregnant people have increased risk of miscarrying, and both diabetes and obesity confer increased risk of congenital heart defects for the fetus.^6,13 Additionally, offspring exposed to gestational obesity in utero have significantly higher rates of childhood obesity that persists into adolescence and adulthood.¹⁴ SGLT2 inhibitors could mitigate some of the risks to the pregnant person and the offspring, and thus, a more nuanced understanding of these inhibitors is necessary since preclinical data on potential risks is sparse. As the prevalence of diabetes and cardiometabolic disease rises in people of reproductive age, carefully designed studies are warranted to clarify whether SGLT2 inhibitors are safe for therapeutic use in pregnant people and their offspring.

GLP-1RAs include exenatide, liraglutide, dulaglutide, and semaglutide. These medications act more diffusely than SGLT2 inhibitors by modifying the metabolic function of several tissues, including the brain.¹⁵ GLP-1RAs achieve supraphysiologic and prolonged activation of the GLP-1 receptor (GLP-1R), exceeding both the potency and duration of signaling elicited by endogenous GLP-1. This activation leads to an increase in insulin secretion and a decrease in glucagon release by the pancreas, delayed gastric emptying, and modified hypothalamic-pituitary signaling.¹⁵ The potent effects of GLP-1RAs in the brain reduce appetite and promote satiety, leading to weight loss and attenuated hypertension in obese, type II diabetic patients.¹⁶ Both obesity and hypertension are associated with poor fertility and pregnancy outcomes.^5,17 Therefore, GLP-1RAs have the potential to improve fertility in people with obesity and/or diabetes of reproductive age. Despite these potential benefits, GLP-1RAs, like SGLT2 inhibitors, are not recommended during pregnancy due to limited data on their safety for the pregnant person and developing fetus.¹² Given their potent metabolic effects and the reproductive risks associated with obesity and diabetes, these therapies warrant further investigation for their potential to improve fertility and pregnancy outcomes in diabetic people who are also overweight or obese.

GLP-1 RAs and SGLT2 Inhibitors may Improve Infertility due to Metabolic Dysfunction

Metabolic dysfunction confers an increased risk of infertility, and the current recommendation for obese patients seeking pregnancy is weight loss through lifestyle interventions.^5,18 Obesity alone, independent of diabetes or cardiovascular disease, is a risk factor for female infertility.¹⁷ Obese patients also often have other comorbidities such as insulin resistance, hyperinsulinemia, and hyperandrogenemia that make weight loss without pharmacological intervention difficult.^2,17 Therefore, use of weight loss and anti-diabetic medications, like GLP-1 RAs and SGLT2 inhibitors, is becoming increasingly common in patients who are attempting to become pregnant.¹⁹ Beyond improving glycemic control and promoting weight loss, these medications may exert additional benefits relevant to reproductive health. For example, GLP-1 RAs and SGLT2 inhibitors have been shown to restore hormonal balance and mitigate several pathophysiological mechanisms that underlie infertility in nondiabetic, obese people with polycystic ovary syndrome (PCOS).²⁰

Female fertility is regulated, in part, through the hypothalamic-pituitary-gonadal axis. Primary signaling in the hypothalamus triggers release of gonadotropins in the pituitary, resulting in the subsequent germ cell maturation and sex hormone generation in the gonads (Fig. 1A). In obese people, increased visceral adiposity is associated with increased androgen aromatization and catabolism, which can disrupt estrogen levels.²¹ Obesity is also associated with impaired hypothalamic-pituitary-gonadal axis signaling, manifesting in reduced follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol secretion and pulsatility in premenopausal women.^22–24 In female rats, GLP-1R is expressed in the hypothalamus, pituitary, and ovaries, and exogenous GLP-1 administration confers increased LH, FSH, and progesterone release (Fig. 1A).²⁵ Preclinical mouse studies have demonstrated that the downstream release of LH and FSH is in part regulated by interaction of GLP-1-producing and kisspeptin neurons in the arcuate nucleus of the hypothalamus.²⁶ This interaction is inhibited by prolonged fasting and/or caloric restriction conditions. While GLP-1R activity stimulates the release of LH in ovariectomized mice, liraglutide treatment is not sufficient to rescue the fasting-mediated inhibition of LH release (Fig. 1A).²⁶ The beneficial effects of GLP-1RAs on fertility have also been observed in the clinic, particularly with PCOS patients. Obese PCOS patients on liraglutide experience weight loss that is paired with increased insulin sensitivity and more regular menstrual cycles compared to those on a placebo treatment; however, ovarian morphology is not improved.²⁷ Additionally, obese PCOS patients who have been previously unsuccessful with in vitro fertilization have improved pregnancy rates when placed on a combination of metformin and liraglutide compared to those on metformin alone.²⁸ The beneficial effects of GLP-1RAs appear to not be solely due to weight loss, as the increased pregnancy rates are not observed with other weight loss medications such as lipase inhibitors like Orlistat.²⁹

Figure 1. SGLT2 inhibitors and GLP-1RAs may improve infertility due to diabetes and obesity.

A. Fertility is in part regulated by the hypothalamic-pituitary-gonadal axis. Glucagon-like peptide-1 (GLP-1) neurons under fed conditions activate kisspeptin neuron signaling, triggering gonadotropin-releasing hormone (GnRH) release, and subsequent pituitary activation, resulting in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) pulsatility. Both GLP-1RAs and SGLT2 inhibitors may improve this signaling with GLP-1RAs acting directly through GLP-1 neurons and SGLT2 inhibitors indirectly through reducing hyperglycemia, both of which increase the activity of kisspeptin neurons. B. In the ovary, SGLT2 inhibitors inhibit inflammation resulting in improved mitochondrial and endoplasmic reticulum (ER) function, manifesting in increased follicular reserve and decreased fibrosis.

SGLT2 inhibitors offer complementary metabolic mechanisms that could also improve hormonal regulation and fertility outcomes. People with type II diabetes, regardless of whether they are obese or not, have increased risk of infertility.⁶ Like in obesity, rodent studies suggest that the hypothalamic-pituitary-gonadal axis is disturbed by diabetes. In a rat model of type I diabetes, hyperglycemia without hyperinsulinemia or weight gain induces reduced kisspeptin expression in hypothalamic neurons, resulting in perturbed estrous cycles (Fig. 1A).³⁰ Additionally, female mice with diet-induced metabolic dysfunction, characterized by obesity, hyperglycemia, hyperinsulinemia, and insulin resistance, have perturbed estrous cycles, increased serum testosterone, and reduced folliculogenesis.³¹ Importantly, preclinical rodent studies suggest that SGLT2 inhibition with dapagliflozin or canagliflozin can attenuate diabetic and PCOS-associated metabolic disturbances (Fig. 1A).^32–34 While both metformin and dapagliflozin improve metabolism in a mouse model of PCOS paired with obesity, only dapagliflozin could prevent adipocyte remodeling and rescue systemic lipid profile levels.³² In mouse models of PCOS, dapagliflozin and canagliflozin improve estrous cycle pulsatility, hypothalamus-dependent hormone secretion, and ovarian morphology (Fig. 1A, B).^33–35 Potential mechanisms of this improvement could be due to alterations in systemic metabolism and attenuation of pro-inflammatory signaling.^32,34,35 Preclinical mouse studies also suggest that SGLT2 inhibition could slow reproductive aging. In breeding-age healthy mice, canagliflozin improves ovarian mitochondrial and endoplasmic reticulum function, and the treatment is paired with reduced ovarian fibrosis, increased follicular reserve, attenuated ovarian inflammation as the mice age (Fig. 1B).³⁶ Similar to these preliminary results in rodents, dapagliflozin and canagliflozin have been shown to improve metabolism and hyperandrogenemia in PCOS patients.^20,37 However, whether these improvements confer improved fertility has yet to be established, and while informative, these preclinical results should not obscure the substantial physiological differences between rodent and human reproduction.

GLP-1RA and SGLT2 Inhibitor Use during Pregnancy is an Underexplored Research Area with Unknown Consequences

Maternal metabolic health plays a major role in shaping pregnancy outcomes. Maternal obesity and impaired glucose regulation increase the risk of GDM, hypertensive disorders like preeclampsia, and congenital heart defects in the child.^7,13 In addition, maternal obesity and GDM also impose long-term health consequences on the child, including increased susceptibility to develop type II diabetes, obesity, cardiovascular disease, and neurological dysfunction.³⁸ Patients are encouraged to control undue weight gain and prevent (or attenuate the progression of) GDM through lifestyle interventions like diet and exercise.¹⁸ When pharmacological therapy is required, insulin is preferred, but the growing use of GLP-1RAs and SGLT2 inhibitors in people of reproductive age raises important questions regarding their potential to improve pregnancy outcomes.^8,39

Insulin remains the first-line therapy for GDM.⁸ While maternal insulin does not cross the placenta and enter fetal circulation, insulin plays an important role in placental development.⁴⁰ In contrast, other antidiabetic medications like metformin freely enter fetal circulation. This transplacental transfer of metformin during GDM alters both the pregnant person’s and fetus’s metabolism, contributing to changes in human mesenchymal stem cell metabolism and increased infant weight gain within the first 18 months of life compared to treatment with insulin.^41,42 Preclinical rodent studies have suggested that SGLT2 inhibition may confer benefits during pregnancy. In mouse models of preeclampsia, empagliflozin and dapagliflozin reduce blood pressure, limit hypertension-mediated renal injury, and improve long-term cardiovascular outcomes in comparison to untreated preeclamptic dams (Fig. 2A, Fig. 3B, C).^43,44 These studies did not, however, assess if the SGLT2 inhibitors affected the long-term health of the pups. While these mouse models present promising results, an ex vivo perfusion study indicates that empagliflozin, dapagliflozin, and canagliflozin all readily cross the human placenta and reduce placental leptin secretion, raising concerns that while perinatal health may improve, fetal metabolism could be adversely affected in the long-term (Fig. 2B).⁴⁵

Figure 2. Pregnant people may benefit from SGLT2 inhibitors and GLP-1RAs.

A. Both SGLT2 inhibitors and GLP-1RAs reduce the risk of gestational hypertension in rodent models. B. SGLT2 inhibitors fully cross the placental barrier, and their presence reduces placental leptin secretion. GLP-1RAs do not cross the placental barrier, but they may bind to their receptor and alter placental nutrient flux. C. GLP-1RAs are associated with reduced rates of congenital heart defects, however they may also alter birth weight. Acronyms: SGLT2i (sodium glucose co-transporter 2 inhibitor), GLP-1RA (glucagon-like peptide-1 receptor agonist), GLP-1R (glucagon-like peptide-1 receptor).

Figure 3. Use of either SGLT2 inhibitors or GLP-1RAs post-partum may protect against metabolic disease development associated with previous GDM or preeclampsia.

A. GLP-1RAs act through the hypothalamus by increasing satiety and decreasing food intake. B. The cardioprotective effects of SGLT2 inhibitors extend to post-partum by protecting against left ventricular functional decline due to previous preeclampsia. C. In addition to cardio-protection, SGLT2 inhibitors have the potential to also protect against hypertension-mediated renal damage due to previous preeclampsia. D. Only SGLT2 inhibitors, not GLP-1RAs, are secreted in human breast milk. E. GLP-1RA use during pregnancy is associated with increased offspring anxiety-like behaviors, but F. its use post-partum is associated with decreased intrahepatic fat accumulation. Acronyms: SGLT2i (sodium glucose co-transporter 2 inhibitor), GLP-1RA (glucagon-like peptide-1 receptor agonist).

Like insulin, GLP-1RAs do not cross the human placenta.⁴⁶ GLP-1R is however expressed in the mouse placenta, and semaglutide alters nutrient transporter expression and murine placenta vascular development (Fig. 2B).⁴⁷ The effect on fetal birth weight is controversial; some rodent studies report reduced birth weights while others report increased birth weights.^47–49 In lean mice, exenatide increased pup birth weights and anxiety-like behaviors, whereas semaglutide decreased pup weights in a glucose-independent manner (Fig. 2, Fig. 3E).^47,48 In a rat model of preeclampsia, liraglutide lowered blood pressure, improved renal function, and decreased pup weights (Fig. 2A, C).⁴⁹ The differing effects on pup birth weight likely reflects differences in the pharmacokinetic and pharmacodynamic properties of individual GLP-1RAs and the details of the rodent disease models, highlighting the possibility that the potency and degradation rate of specific agents may differentially affect rodent fetal development facing distinct in utero metabolic stresses.

Human data remains very limited on the use of either GLP-1 RAs or SGLT2 inhibitors during pregnancy, but several observational studies offer some initial insight. Neither GLP-1RA nor SGLT2 inhibitor exposure during the first trimester increases the incidence of major congenital malformations relative to pregnancies in individuals with type II diabetes. However, these treatments do not correct the elevated rates of congenital malformations relative to healthy pregnancies.¹⁹ Additionally, GLP-1RA use during the first trimester of pregnancy is associated with reduced rates of congenital heart defects without significantly affecting birth weight or rates of preterm birth (Fig. 2A, C).⁵⁰ Interestingly, a separate meta-analysis study including public insurance status and delivery hospital location in the cohort matching criteria found that pre-pregnancy GLP-1RA use is instead associated with higher gestational weight gain, increased birth weight, and greater rates of preterm delivery.³⁹ Taken together, these conflicting findings underscore the need for deeper investigation into the safety and metabolic consequences of GLP-1RAs and SGLT2 inhibitors during pregnancy. As these medications become increasingly common in people of reproductive age, clarifying their short- and long-term effects on both the pregnant person and child is essential for guiding evidence-based clinical care.

Lactation May Confound the Benefits of SGLT2 Inhibitors and GLP-1RAs During Post-Partum

GDM confers health risks to the pregnant person even after delivery. People with a history of GDM are at higher risk of developing type II diabetes within 10 years of the pregnancy.⁵¹ Both lifestyle interventions and pharmacological interventions have been found to reduce the risk of developing type II diabetes in these patients with glucose-lowering medications being the most effective.⁵² Following parturition, insulin therapy may be continued, and metformin, which is not recommended to be used during pregnancy in the U.S., can be introduced as an additional treatment option.⁸ SGLT2 inhibitors and GLP-1RAs may confer additional benefits such as cardiovascular protection and weight loss following delivery, potentially making them more beneficial to patients, but clinical data supporting these agents is sparse.^53,54

The hyperglycemia associated with GDM usually resolves quickly post-delivery, but in some cases, additional interventions are needed.⁸ Lactation, despite being a major metabolic stressor, aids in glucose excretion, improves glucose sensitivity, and lowers insulin resistance in post-partum people.⁵⁵ Furthermore, the duration of lactation has a significant negative correlation with the development of type II diabetes later in life, but this effect is negated if the person was previously diagnosed with GDM.⁵⁶ In such patients, lactation is not sufficient to decrease the risk of further metabolic decline, and therefore, more intensive interventions may be required. Animal studies have demonstrated that canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are all excreted in breast milk, but semaglutide and liraglutide are not present at detectable concentrations (Fig. 3D).^12,57 Like in utero, offspring exposure to metabolism-altering medications must be limited during lactation. Thus, GLP-1RAs are more likely candidates than SGLT2 inhibitors to manage post-partum metabolic dysfunction in patients currently breastfeeding. Given the high maternal energy demand during the lactation period, the weight loss effect of GLP-1RAs warrant thorough investigation as they may have an effect on milk production and quality, potentially eliciting a long-lasting impact of offspring metabolic health (Fig. 3A).

In addition to lactation, GLP-1RAs or SGLT2 inhibitors can also be used to reduce body weight and improve glycemic regulation, although concerns about SGLT2 inhibitors being secreted into the milk may limit their utility in breast feeding people. GDM represents a significant stress on insulin production and signaling which preconditions people to develop type II diabetes, and this effect could outweigh the therapeutic benefits of GLP-1RA and SGLT2 inhibitor use.⁵¹ In patients who had GDM, empagliflozin treatment within 36 months postpartum did not significantly improve insulin secretion nor other beta-cell functionality metrics compared to placebo.⁵⁴ Interestingly, the empagliflozin-receiving patients had increased progression of pre-diabetes compared to the placebo group, however this cohort of people had significantly worse metabolic statuses at baseline, limiting the interpretability of these results.⁵⁴ Given the modest and inconclusive post-partum effects of SGLT2 inhibitors, attention has increasingly shifted toward GLP-1RAs, especially due to their superior effects on weight management. In overweight and obese people with previous GDM, liraglutide significantly lowers body weight and improves glucose tolerance but not insulin resistance.^58,59 All of the benefits conferred by liraglutide are reversed after these patients ceased using the medications, suggesting that the underlying metabolic machinery does not recover function but instead depends on GLP-1RA activity.^58,59 Accumulation of fat in the liver is associated with previous GDM, and while liraglutide does reduce intrahepatic fat, these patients do not have significantly reduced rates of metabolically-associated fatty liver disease compared to those receiving a placebo (Fig. 3F).⁶⁰ Collectively, these data underscore that although liraglutide provides beneficial metabolic support following GDM, more durable strategies that can also mitigate the underlying metabolic dysfunction are needed to address the long-term cardiometabolic risk that persists beyond pregnancy.

Clinical Implications and Future Directions in Integrating GLP-1RAs and SGLT2 Inhibitors into Reproductive Care

Both GLP-1RAs and SGLT2 inhibitors may offer promising metabolic benefits for people of reproductive age, including improved glycemic control, weight management, and cardiovascular protection.^11,15,16 Data on their safety and efficacy during pregnancy and lactation remain extremely limited, especially in humans. Preclinical and initial clinical studies suggest potential benefits, but these studies also highlight significant uncertainties about fetal exposure, postnatal development, and durability of metabolic improvements following cessation of treatment.^{37,39,58,59,61–63} Carefully designed pre-clinical animal studies and clinical trials are critically needed to determine whether these therapies can be safely integrated into reproductive care. It will be particularly important to define their potential to mitigate pregnancy-related cardiovascular complications while ensuring exposure is safe for the pregnant person and fetus. Additionally, long-term observational studies will be essential to establish whether there are long-term impacts on offspring metabolism associated with maternal use of either GLP-1RAs or SGLT2 inhibitors during gestation. Critically, the current clinical guidance does not recommend the use of GLP-1RAs or SGLT2 inhibitors during pregnancy; therefore, their safety, efficacy, and long-term effects must be clearly established before considering potential metabolic benefits.⁸