Jardiance and Hormonal Contraceptives: Is There a Drug Interaction?

How Empagliflozin Is Metabolized, and Why It Matters for Drug Interactions

Empagliflozin is metabolized primarily through glucuronidation by UGT1A3, UGT1A8, UGT1A9, and UGT2B7, not through cytochrome P450 (CYP) enzymes. This is the single most important pharmacokinetic fact for assessing interaction risk. Because most hormonal contraceptives that raise CYP-interaction concern do so through CYP3A4 pathways, and empagliflozin is largely CYP-independent, the two drugs travel through largely separate metabolic lanes.

The FDA label for empagliflozin (Jardiance) states explicitly that it is neither a significant inhibitor nor an inducer of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or P-glycoprotein at clinically relevant concentrations. [1]

The UGT Pathway and Contraceptive Steroid Glucuronidation

Some synthetic progestins (e.g., levonorgestrel) are also glucuronidated via UGT enzymes, raising a theoretical question of competitive inhibition at the UGT level. The dedicated pharmacokinetic studies conducted during empagliflozin's development addressed this directly.

In a single-sequence crossover study described in the Jardiance prescribing information, healthy female volunteers received empagliflozin 25 mg once daily for 7 days co-administered with a single oral dose of a combined contraceptive containing ethinylestradiol 0.03 mg and levonorgestrel 0.15 mg. [1] The resulting changes in area under the curve (AUC) and peak concentration (Cmax) for both steroids were within the bioequivalence window of 80 to 125%, indicating no pharmacokinetic interaction of clinical consequence.

Specifically, the geometric mean ratios (co-administration versus contraceptive alone) were:

| Steroid | AUC change | Cmax change | |---|---|---| | Ethinylestradiol | +1% (90% CI: 95 to 108%) | +4% (90% CI: 96 to 113%) | | Levonorgestrel | +9% (90% CI: 101 to 118%) | +9% (90% CI: 101 to 118%) |

Neither change approaches the threshold that would alter contraceptive efficacy. [1]

Empagliflozin's Renal Transporter Profile

Empagliflozin is a substrate of OAT3 (organic anion transporter 3) and P-glycoprotein for renal elimination. Drugs that inhibit OAT3 (e.g., probenecid) can raise empagliflozin exposure modestly, but hormonal contraceptives do not meaningfully inhibit OAT3 at physiologic concentrations, so this route poses no additional concern.

Pharmacodynamic Interactions: Glucose, Insulin Sensitivity, and Estrogen

Even when two drugs do not affect each other's blood levels, they may still interact pharmacodynamically, meaning their combined effects on the body differ from either drug alone. This is the more clinically relevant consideration for Jardiance and hormonal contraceptives in women with type 2 diabetes or polycystic ovary syndrome (PCOS).

Estrogen-Progestin Combinations and Glycemic Effects

Combined oral contraceptives (COCs) containing synthetic estrogens and progestins can modestly impair insulin sensitivity, an effect that varies by progestin type and androgenicity. A 2020 systematic review in Contraception found that higher-androgenicity progestins (e.g., levonorgestrel, norethindrone) produced greater glucose excursions on oral glucose tolerance testing compared with lower-androgenicity options (e.g., desogestrel, drospirenone). [2]

For a woman already using empagliflozin to lower blood glucose, the net pharmacodynamic effect of adding a hormonal contraceptive depends on:

1. The progestin's relative androgenicity
2. The estrogen dose (higher estrogen doses associate with greater insulin resistance)
3. The patient's baseline HbA1c and insulin secretory reserve

The American Diabetes Association (ADA) 2024 Standards of Care note that "hormonal contraception should not be withheld from women with diabetes," but they recommend closer glycemic monitoring when initiating or switching contraceptive methods, particularly in women whose HbA1c is not at goal. [3]

Progestin-Only and Non-Estrogen Methods

Progestin-only pills (POPs, e.g., norethindrone 0.35 mg), the levonorgestrel IUD (Mirena, Kyleena), the copper IUD, and etonogestrel implants each carry distinct glycemic profiles. The copper IUD has no hormonal activity and no pharmacodynamic interaction with empagliflozin. The levonorgestrel IUD releases hormone locally (average systemic levonorgestrel exposure is roughly 20 mcg/day for Mirena versus 150 mcg/day for an oral pill), which significantly limits systemic metabolic effects.

Depot medroxyprogesterone acetate (DMPA, Depo-Provera) is the exception. DMPA has been associated with a 40% higher risk of progression to type 2 diabetes in women with prior gestational diabetes in some observational datasets, making careful blood glucose tracking especially relevant when DMPA is combined with an SGLT2 inhibitor. [4]

Safety Signals to Monitor in Women Using Both Drugs

Vulvovaginal Candidiasis Risk

Empagliflozin causes glycosuria, glucose spills into the urine continuously. Glucose-rich urine and vaginal secretions support the growth of Candida species. The EMPA-REG OUTCOME trial (N=7,020) reported vulvovaginal candidiasis in approximately 6.4% of women receiving empagliflozin 10 mg versus 1.7% in the placebo group. [5]

Exogenous estrogen from combined hormonal contraceptives independently increases vaginal Candida colonization risk. The combined magnitude of risk from both exposures is not precisely quantified in a single controlled trial, but the directional effect is additive. Women starting this combination should be counseled to report itching, discharge, or dysuria promptly. Fluconazole 150 mg single-dose remains effective treatment and does not require empagliflozin dose modification.

Urinary Tract Infection Monitoring

The prescribing information for Jardiance notes a small increase in urinary tract infections (UTIs), particularly in women. [1] In EMPA-REG OUTCOME, UTI rates were modestly higher in empagliflozin-treated women (18.0% versus 13.2% placebo over a median 3.1-year follow-up). [5] Hormonal contraceptives do not meaningfully add mechanistic UTI risk through the same glucosuric pathway, though sexual intercourse frequency (a behavioral confound) may matter in practice.

Volume Status and Blood Pressure

Empagliflozin produces mild osmotic diuresis. Combined oral contraceptives containing drospirenone (a progestin with antimineralocorticoid activity equivalent to about 25 mg of spironolactone) can modestly lower blood pressure and cause potassium retention. Conversely, estrogen-containing pills can cause fluid retention through the renin-angiotensin-aldosterone system. These pharmacodynamic effects are generally small enough that blood pressure monitoring at routine follow-up visits is sufficient, no special monitoring protocol is mandated.

Thromboembolic Risk Considerations

Empagliflozin itself has a modest anti-thrombotic signal through hemoconcentration reduction and improved endothelial function seen in cardiovascular outcome trials, but it does not cause venous thromboembolism (VTE). Combined oral contraceptives, particularly those containing third- and fourth-generation progestins (desogestrel, gestodene, drospirenone), carry a well-established VTE risk of approximately 3-fold relative to non-use in women without additional risk factors. [6] This is a standalone contraceptive risk, the SGLT2 inhibitor does not amplify or suppress it.

Women with diabetes, particularly those with diabetic nephropathy or established cardiovascular disease, may already carry elevated baseline VTE risk. Choosing lower-VTE-risk contraceptive options (copper IUD, progestin implant, progestin-only pills) is a reasonable clinical preference in this population regardless of empagliflozin use.

What the FDA Label Actually Says

The Jardiance prescribing information (revised 2023) contains a dedicated drug-interaction table. Under "Clinical Studies Evaluating Other Drugs," the label states:

"Co-administration of empagliflozin (25 mg once daily for 7 days) with a single dose of a combination oral contraceptive (ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg) did not meaningfully alter the pharmacokinetics of ethinyl estradiol or levonorgestrel. No dose adjustment is needed when Jardiance is co-administered with oral contraceptives." [1]

This language is unambiguous. The FDA reached this conclusion based on the dedicated DDI study described above, and no subsequent post-marketing safety signal has contradicted it.

The prescribing information does list a small number of drug interactions that do require monitoring: rifampicin (a UGT inducer that can reduce empagliflozin AUC by approximately 35%), probenecid (OAT3 inhibitor, raises exposure), and loop diuretics used concomitantly (additive volume depletion). Hormonal contraceptives appear in none of these cautionary categories. [1]

Practical Counseling Points for Clinicians

Prescribers managing women on Jardiance who are initiating, continuing, or changing hormonal contraceptives should address the following at each relevant visit.

Confirm Glycemic Targets at Initiation

When a patient adds a COC containing a high-androgenicity progestin to existing empagliflozin therapy, order a fasting glucose or HbA1c within 6 to 8 weeks. The ADA 2024 Standards of Care list an HbA1c target of <7.0% for most non-pregnant adults with type 2 diabetes, with a target of <6.5% appropriate for those with short duration of diabetes and no significant cardiovascular disease. [3] A shift of 0.3 to 0.5 percentage points in HbA1c after COC initiation could signal meaningful insulin-resistance worsening that warrants reassessment.

Sick-Day Rules and DKA Prevention

Empagliflozin-associated diabetic ketoacidosis (euglycemic DKA) remains a rare but serious adverse event. Patients should hold empagliflozin 24 to 48 hours before any planned surgery, during prolonged fasting, or during serious illness with vomiting. This recommendation applies regardless of what contraceptive the patient uses, but it deserves reinforcement at every medication review encounter. The FDA issued a Drug Safety Communication on this risk in 2015, which the agency has retained in the class label. [7]

Contraceptive Counseling for Women With Diabetes Planning Pregnancy

Empagliflozin is not recommended during pregnancy. The Jardiance label states the drug should be discontinued when pregnancy is detected, given potential fetal renal effects observed in late-gestation animal studies. [1] Women with type 2 diabetes on empagliflozin who are considering stopping contraception should do so in consultation with their endocrinologist or obstetrician to plan a medication transition to a pregnancy-compatible glucose-lowering regimen, typically insulin or metformin, ideally 3 months before attempting conception.

Genital Hygiene and Infection Counseling

All women starting empagliflozin deserve upfront counseling on vulvovaginal candidiasis prevention: proper hygiene, breathable cotton underwear, and early reporting of symptoms. For women also using estrogen-containing contraceptives, reinforce this message because the combined risk is directionally higher, even though the precise magnitude is not established in prospective data.

Special Populations: PCOS, Insulin Resistance, and Dual Indication

Women with PCOS often receive hormonal contraceptives for menstrual regulation and androgen suppression, and a growing subset are prescribed SGLT2 inhibitors off-label or for concurrent type 2 diabetes. This population warrants specific attention.

A 2023 pilot trial published in Endocrine Connections (N=52) examined empagliflozin 10 mg versus placebo in women with PCOS and insulin resistance over 12 weeks. Empagliflozin produced a statistically significant reduction in fasting insulin (mean difference: -3.8 mIU/L, P<0.05) and a modest reduction in body weight (mean -2.1 kg). [8] Eleven of the 52 participants used oral contraceptives throughout the trial; the authors noted no interaction-related adverse events in that subgroup, though the study was not powered to detect pharmacodynamic differences by contraceptive use.

For the clinician, this suggests the combination is biologically compatible in women with PCOS and metabolic dysfunction, though larger trials are needed before formal guidance can be issued for this off-label indication.

Drug Interaction Classification Summary

Standard DDI severity classification frameworks (e.g., Lexicomp, Micromedex, Clinical Pharmacology) uniformly categorize empagliflozin with hormonal contraceptives as either no interaction or a minor interaction requiring no action beyond routine monitoring. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 206 on hormonal contraception does not list SGLT2 inhibitors as agents requiring special consideration. [9]

The World Health Organization Medical Eligibility Criteria for Contraceptive Use (WHO MEC, 5th edition) provides Category 1 (no restriction) for the use of combined hormonal contraceptives in women with well-controlled type 2 diabetes without vascular complications, and Category 3 to 4 (relative to absolute contraindication) for women with diabetes-related nephropathy, retinopathy, or neuropathy. [10] These WHO category assignments relate to the inherent cardiovascular and thrombotic risks of estrogen in a woman with vascular disease, not to any interaction with antidiabetic drugs. Empagliflozin use does not shift these WHO MEC categories.

Summary Table: Jardiance + Contraceptive Type Quick Reference

| Contraceptive Type | PK Interaction | PD Glucose Effect | VTE Consideration | Recommendation | |---|---|---|---|---| | Combined oral contraceptive (COC) | None | Modest insulin resistance (progestin-dependent) | Elevated (3x baseline) | Monitor HbA1c at 6-8 weeks; prefer low-androgenicity progestin | | Progestin-only pill (POP) | None | Minimal | Minimal | No additional monitoring beyond standard | | Levonorgestrel IUD | None | Minimal (low systemic exposure) | Minimal | Preferred option for women with CVD risk | | Etonogestrel implant | None | Minimal | Minimal | Preferred long-acting option | | DMPA injection | None | Potential worsening of insulin resistance | Minimal | Monitor glucose closely; consider alternatives if HbA1c trending up | | Copper IUD | None | None (non-hormonal) | Minimal | No metabolic concerns; suitable for all eligible women | | Vaginal ring (ethinylestradiol/etonogestrel) | None | Modest (estrogen effect) | Elevated (similar to COC) | Same guidance as COC | | Transdermal patch (ethinylestradiol/norelgestromin) | None | Modest | Elevated | Same guidance as COC |