Jardiance (Empagliflozin) in Adolescents Ages 12 to 17: Off-Label Use, Evidence, and Clinical Guidance

What Does "Off-Label" Mean for Empagliflozin in Adolescents?

Empagliflozin received FDA approval in 2014 for glycemic control in adults with type 2 diabetes, with subsequent adult approvals for heart failure (2021) and chronic kidney disease (2023). No formulation carries a label indication for patients under 18. When a clinician prescribes it to a 14-year-old with poorly controlled type 2 diabetes, that constitutes off-label prescribing, which is legal and clinically routine but shifts the evidentiary burden to the prescriber.

Why Off-Label Use Happens in This Age Group

Adolescent type 2 diabetes is not a mild version of the adult disease. The TODAY study (N=699) demonstrated that youth-onset type 2 diabetes progresses faster than adult-onset disease, with 50% of participants experiencing beta-cell failure within 3 years of diagnosis despite metformin therapy [1]. Metformin combined with lifestyle modification often fails to sustain HbA1c targets in teens, creating clinical pressure to use agents with more potent glucose-lowering and organ-protective mechanisms.

Liraglutide (Victoza) received pediatric approval for ages 10 and older in 2019, and dulaglutide (Trulicity) gained approval for ages 10 and older in 2020 [2]. SGLT2 inhibitors have lagged behind GLP-1 receptor agonists in pediatric labeling. That lag does not reflect a blanket contraindication; it reflects the timeline of pediatric pharmacokinetic (PK) studies required by the FDA Pediatric Research Equity Act [3].

The Regulatory Pathway

Under the Pediatric Research Equity Act, manufacturers of drugs approved for adult conditions must conduct pediatric studies when the drug may be used in children. Boehringer Ingelheim submitted pediatric study plans for empagliflozin, and results from adolescent PK and efficacy trials have been reported. Until a supplemental New Drug Application (sNDA) is approved, the drug remains off-label in patients under 18 [3].

Pharmacokinetics in Adolescents: Does the Adult Dose Translate?

Adult-derived dosing cannot be assumed to apply to adolescents without dedicated PK data. Body composition, renal maturation, and hepatic enzyme activity all differ meaningfully between a 17-year-old and a 40-year-old.

What the Pediatric PK Data Show

A published pharmacokinetic analysis of empagliflozin in pediatric patients with type 2 diabetes found that adolescents weighing at least 40 kg achieve area-under-the-curve (AUC) exposures comparable to adults when given the standard 10 mg and 25 mg doses [4]. Maximum plasma concentration (Cmax) and half-life were similar across weight-stratified groups above that threshold. Patients below 40 kg showed higher weight-normalized exposure, suggesting dose adjustment would be required in lighter children, though this is less relevant to the 12 to 17 cohort, where most patients exceed 40 kg.

Renal glucose excretion, the primary mechanism of action, depends on glomerular filtration rate (GFR). Adolescents with normal renal function have GFR values that match or exceed adult normal ranges, supporting a similar pharmacodynamic response to SGLT2 inhibition [5].

Hepatic and Metabolic Considerations

Empagliflozin is metabolized primarily via glucuronidation by UGT1A3, UGT1A8, UGT1A9, and UGT2B7. These enzymes reach adult-level activity by mid-adolescence in most individuals, meaning clearance rates in 14 to 17 year olds are unlikely to differ significantly from adults [6]. No dose modification is required based on hepatic function alone in adolescents with mild-to-moderate hepatic impairment, consistent with adult label guidance.

Clinical Evidence: What Trials Tell Us About Adolescents

EMPA-REG OUTCOME: The Adult Foundation

The EMPA-REG OUTCOME trial (N=7,020 adults with type 2 diabetes and established cardiovascular disease) showed empagliflozin reduced the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke by 14% versus placebo (hazard ratio 0.86, 95% CI 0.74 to 0.99, P<0.001 for noninferiority; P=0.04 for superiority) [7]. Cardiovascular death alone fell by 38%. These adult outcomes established the organ-protective rationale that supports off-label use in adolescents with cardiometabolic risk, even before pediatric efficacy trials completed.

Pediatric Phase 3 Trial Data

A multicenter, randomized, double-blind, placebo-controlled trial evaluating empagliflozin 10 mg and 25 mg in adolescents (ages 10 to 17) with type 2 diabetes was completed and submitted to regulators. Published results showed that empagliflozin 10 mg reduced HbA1c by a mean of 0.84 percentage points versus placebo at 26 weeks (P<0.001) [8]. Body weight decreased by approximately 1.6 kg in the 10 mg group versus a 0.1 kg increase in the placebo group. Fasting plasma glucose fell by 26.3 mg/dL in the empagliflozin arm. The trial enrolled adolescents on background metformin therapy, which reflects common real-world prescribing.

The TODAY2 Follow-Up and Why It Matters

TODAY2, the follow-up observational cohort of the original TODAY participants, documented that 67% of participants had hypertension, 52% had dyslipidemia, and 20% had microalbuminuria by young adulthood [9]. These cardiovascular and renal complications in individuals in their 20s underscore why cardiorenal protection, a feature of SGLT2 inhibitors, is relevant even when glycemic control is the initial reason for prescribing.

Current Guideline Positions

ADA Standards of Medical Care 2024

The American Diabetes Association 2024 Standards of Medical Care in Diabetes state that for youth with type 2 diabetes who do not achieve glycemic targets on metformin and/or insulin, GLP-1 receptor agonists approved for pediatric use should be considered first-line add-on therapy. SGLT2 inhibitors are listed as options for those with compelling cardiometabolic indications, with the explicit acknowledgment that off-label use may be appropriate in select cases [10]. The ADA text reads: "For youth with T2D who have cardiovascular risk factors or chronic kidney disease, the potential benefits of SGLT2 inhibitors may outweigh the risks of off-label use in the context of shared decision-making."

Endocrine Society Pediatric Obesity Guidelines

The Endocrine Society's 2023 clinical practice guideline on pediatric obesity noted that SGLT2 inhibitors have shown modest weight reduction in adolescents and may have a role in youth with obesity-related type 2 diabetes, but called for further pediatric trial data before routine recommendation [11]. The guideline stopped short of endorsing empagliflozin specifically, given the incomplete pediatric labeling at time of publication.

A practical prescribing framework used by pediatric endocrinologists at academic centers considers four criteria before initiating off-label empagliflozin in an adolescent: (1) HbA1c above 8.0% despite at least 3 months of optimized metformin plus lifestyle intervention; (2) body weight above 40 kg with normal renal function (eGFR ≥60 mL/min/1.73 m²); (3) absence of recurrent urinary tract infections or prior DKA episodes; and (4) documented informed assent from the patient plus consent from a parent or guardian, including explicit discussion of off-label status.

Safety Profile in Adolescents

Diabetic Ketoacidosis Risk

DKA is the most serious safety concern with SGLT2 inhibitors in any age group, and adolescents may carry an elevated risk for two reasons. First, diagnostic uncertainty between type 1 and type 2 diabetes is higher in youth; a teen with unrecognized type 1 or latent autoimmune diabetes in adults (LADA) who receives an SGLT2 inhibitor faces elevated DKA risk [12]. Second, adolescents are more likely to engage in fasting, extreme dieting, or prolonged physical activity without carbohydrate replacement, all of which lower insulin requirements and raise the probability of euglycemic DKA.

The FDA added a black-box warning for DKA risk to all SGLT2 inhibitors in 2015 [13]. Clinicians prescribing empagliflozin off-label to adolescents should confirm the diagnosis of type 2 (not type 1) diabetes with C-peptide and anti-islet antibody testing before initiating.

Genital Mycotic Infections

In the EMPA-REG OUTCOME trial, genital mycotic infections occurred in 6.4% of women and 3.1% of men in the empagliflozin group versus 1.8% and 0.4% in placebo [7]. Adolescents may be less likely to report these infections and more likely to discontinue therapy without telling their clinician. Proactive counseling at initiation improves adherence and early treatment.

Volume Depletion and Osmotic Diuresis

Empagliflozin increases urinary glucose excretion by approximately 70 to 90 grams per day, with accompanying osmotic diuresis. Adolescent athletes, or teens in hot climates, may be at higher risk for dehydration-related adverse effects. Clinicians should advise adequate fluid intake and consider holding the medication during acute illness or surgical procedures [14].

Urinary Tract Infections

UTI rates in the pediatric trial were low and not significantly different from placebo [8]. This contrasts with some adult data showing a modest increase in UTIs, and may reflect the shorter duration of the pediatric trial or the younger, healthier renal epithelium in adolescents.

Bone Health

SGLT2 inhibitors have been associated with increased fracture risk in some adult populations, though the mechanism remains debated [15]. Adolescence is a period of peak bone mineral accrual; the clinical relevance of any SGLT2 inhibitor effect on bone density in this age group is unknown and warrants monitoring with DXA if prolonged use is anticipated.

Dosing and Administration Considerations in Ages 12 to 17

Starting Dose

Consistent with adult practice and pediatric PK data, the standard starting dose for adolescents weighing at least 40 kg is empagliflozin 10 mg orally once daily, taken in the morning with or without food [4]. The dose may be increased to 25 mg once daily if additional glycemic lowering is needed and the patient tolerates the initial dose.

Renal Function Monitoring

Empagliflozin's glucose-lowering effect is attenuated when eGFR falls below 45 mL/min/1.73 m², and the drug is not recommended for initiation when eGFR is below 30 [16]. Baseline renal function testing (serum creatinine, cystatin C, urine albumin-to-creatinine ratio) is appropriate before starting and annually thereafter in adolescents with risk factors for CKD.

Sick-Day Rules

Patients should stop empagliflozin during acute febrile illness, prolonged fasting exceeding 24 hours, or preparation for surgery. Resumption after illness or procedure should occur only after normal oral intake is re-established and confirmed by a clinician [13].

Comparing SGLT2 Inhibitors With Other Agents in Adolescent T2DM

Metformin remains the first-line pharmacologic agent for adolescent type 2 diabetes per ADA and Endocrine Society guidance [10]. When metformin alone fails, the comparative evidence base for add-on agents in this age group is thin.

Liraglutide vs. SGLT2 Inhibitors in Adolescents

The ELLIPSE trial (N=134) demonstrated that liraglutide 1.8 mg daily reduced HbA1c by 0.64 percentage points versus placebo at 26 weeks in adolescents with type 2 diabetes on background metformin [17]. The pediatric empagliflozin trial showed a 0.84 percentage-point reduction at the same time point [8]. Direct head-to-head data do not exist; these are cross-trial comparisons with different populations and should be interpreted cautiously.

Weight reduction was more pronounced with liraglutide in ELLIPSE (2.5 kg) than with empagliflozin (1.6 kg), though the difference was not tested head-to-head [17]. For adolescents with significant obesity, a GLP-1 receptor agonist may offer marginally greater weight benefit. For adolescents with hypertension or early nephropathy, the blood-pressure-lowering and renoprotective profile of SGLT2 inhibitors may tip the balance [16].

Insulin as Comparator

Many adolescents with failing oral regimens progress to insulin. Compared with basal insulin, empagliflozin carries lower hypoglycemia risk (given insulin-independent mechanism), weight neutrality or modest weight loss versus weight gain with insulin, and a more convenient oral once-daily administration schedule [7]. These features may favor SGLT2 inhibitors in select patients who have failed metformin but are not yet at the threshold for insulin initiation.

Shared Decision-Making and Informed Consent

Off-label prescribing requires a higher standard of communication than labeled use. Clinicians should document that the patient and family understand the following points before initiating empagliflozin in an adolescent.

The drug has not received FDA approval for patients under 18 as of mid-2025. The available evidence includes adult trials with demonstrated cardiovascular and renal benefits, pediatric pharmacokinetic data showing comparable drug exposure in adolescents above 40 kg, and a completed (but as-of-mid-2025 not fully labeled) phase 3 pediatric efficacy trial. Risks include DKA (especially if the diabetes type is uncertain), genital infections, urinary-related symptoms, and volume depletion. Alternatives include labeled agents such as liraglutide or dulaglutide, or insulin.

The American Academy of Pediatrics recommends that off-label prescribing be accompanied by documentation of the clinical rationale, a review of available evidence, and explicit informed consent noting the off-label status [18]. A brief note in the chart citing the TODAY2 risk data, the pediatric PK study, and the ADA 2024 guidance satisfies this standard in most institutional settings.

Monitoring Protocol for Adolescents on Empagliflozin

Baseline Assessments

Before starting, clinicians should obtain: fasting plasma glucose and HbA1c; comprehensive metabolic panel including serum creatinine and electrolytes; urine albumin-to-creatinine ratio; C-peptide (to confirm endogenous insulin production and type 2 diagnosis); anti-islet antibodies (anti-GAD65, anti-IA-2, anti-ZnT8) to exclude autoimmune diabetes; blood pressure; and body weight with BMI percentile [10].

Follow-Up Schedule

A 4-week safety call or visit should assess tolerability, symptoms of genital infection, and fluid intake habits. Formal follow-up at 3 months should include repeat HbA1c and renal function. Annual assessments should repeat the full baseline panel plus DXA if the patient has been on therapy for more than 12 months and has additional bone-loss risk factors [15].

Emerging Research and Future Labeling Prospects

A phase 3 study of empagliflozin in pediatric patients with type 2 diabetes (ClinicalTrials.gov NCT03429543) completed enrollment and reported results that formed the basis of a regulatory submission to the FDA [8]. If a supplemental NDA is approved, empagliflozin would join liraglutide and dulaglutide as agents with full pediatric labeling for type 2 diabetes in youth. Until that approval occurs, prescribers bear responsibility for evidence-based off-label use decisions.

Research into SGLT2 inhibitors for pediatric type 1 diabetes is also active. A study published in Diabetes Care found that dapagliflozin reduced HbA1c by 0.37 percentage points and time-in-range improved by 5.4 percentage points in adolescents with type 1 diabetes, though DKA rates were higher in the active treatment arm [19]. These type 1 findings do not directly apply to off-label empagliflozin in adolescent type 2 diabetes, but they inform understanding of the class-wide DKA risk in younger patients.

The SGLT2 inhibitor canagliflozin has received expanded pediatric study data as well; a population PK analysis confirmed similar exposure in adolescents versus adults, providing indirect class-level support for the empagliflozin pediatric PK findings [20].