Jardiance Global Regulatory Status: FDA Approvals, Label Updates, and Safety Profile

What Is the FDA Approval History for Jardiance?

Jardiance has accumulated four distinct FDA-approved indications over nine years, making it one of the most label-expanded oral cardio-metabolic drugs on the market today. Each expansion followed a large randomized controlled trial with pre-specified cardiovascular or renal endpoints, and each triggered a formal supplemental NDA review under priority or standard designation.

Initial 2014 Type 2 Diabetes Approval

The FDA approved empagliflozin 10 mg and 25 mg on August 2, 2014, under NDA 204629, to improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise. [1] The approval relied on Phase 3 glycemic data from the EMPA-REG MONO and combination trials, which showed A1C reductions of 0.7 to 0.9 percentage points versus placebo over 24 weeks at the 10 mg dose. The drug belongs to the sodium-glucose cotransporter-2 (SGLT2) inhibitor class and works by blocking glucose reabsorption in the proximal renal tubule, producing glycosuria and modest caloric deficit.

2016 Cardiovascular Risk-Reduction Expansion

The 2016 label expansion was driven by EMPA-REG OUTCOME, a placebo-controlled trial in 7,020 adults with type 2 diabetes and established cardiovascular disease. Published in the New England Journal of Medicine, the trial showed that empagliflozin reduced the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke by 14% (hazard ratio 0.86; 95% CI 0.74 to 0.99; P<0.001 for non-inferiority, P=0.04 for superiority). [2] Cardiovascular mortality fell by 38% (HR 0.62; 95% CI 0.49 to 0.77). On December 2, 2016, the FDA updated the label to state that Jardiance reduces the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease. This made empagliflozin the first SGLT2 inhibitor to carry an active CV risk-reduction claim on its U.S. Prescribing information.

2021 Heart Failure Approvals

The EMPEROR-Reduced trial (N=3,730) evaluated empagliflozin 10 mg versus placebo in patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction 40% or below), regardless of diabetes status. Empagliflozin reduced the primary composite of cardiovascular death or hospitalization for heart failure by 25% (HR 0.75; 95% CI 0.65 to 0.86; P<0.001). [3] The FDA approved the HFrEF indication on August 18, 2021.

EMPEROR-Preserved (N=5,988) extended the evidence to heart failure with preserved ejection fraction (LVEF above 40%). Empagliflozin reduced cardiovascular death or HF hospitalization by 21% (HR 0.79; 95% CI 0.69 to 0.90; P<0.001). [4] The FDA approved the HFpEF and HFmrEF indication in May 2022, making Jardiance the first drug with FDA approval specifically for HFpEF.

2023 Chronic Kidney Disease Approval

EMPA-KIDNEY (N=6,609) enrolled adults with CKD defined by either eGFR 20 to 44 mL/min/1.73 m² or eGFR 45 to 89 with elevated urine albumin-to-creatinine ratio. The trial was stopped early for efficacy: empagliflozin 10 mg reduced the composite of kidney disease progression or cardiovascular death by 28% (HR 0.72; 95% CI 0.64 to 0.82; P<0.001). [5] On February 22, 2023, the FDA approved empagliflozin for slowing the progression of CKD and reducing the risk of CV death in adults with CKD.

What Does the Current Jardiance Label Say?

The current prescribing information (PI) reflects all four indications and carries several specific safety communications that clinicians and patients must understand before initiating therapy.

Approved Indications as of 2025

Per the FDA-approved label, Jardiance is indicated for:

1. Glycemic control in adults with type 2 diabetes as adjunct to diet and exercise.
2. Reduction of cardiovascular death risk in adults with type 2 diabetes and established CV disease.
3. Reduction of risk of CV death and hospitalization for heart failure in adults with HFrEF, HFmrEF, or HFpEF.
4. Reducing the risk of sustained eGFR decline, end-stage kidney disease, CV death, and hospitalization for heart failure in adults with CKD at risk of progression.

The drug is not indicated for type 1 diabetes or for glycemic control in patients with an eGFR below 30 mL/min/1.73 m² (though CKD patients with eGFR as low as 20 may receive it specifically for renal and CV protection). [1]

Dosing and Administration

Standard dosing for glycemic control and CV risk reduction starts at 10 mg orally once daily in the morning, with or without food. The dose may be increased to 25 mg once daily for additional A1C lowering if tolerated. For heart failure and CKD indications, the approved dose is 10 mg once daily; the 25 mg dose provides no additional benefit in those populations per trial data.

Contraindications and Key Warnings

The label lists the following contraindications:

• History of serious hypersensitivity reaction to empagliflozin or any excipient.
• Dialysis-dependent end-stage renal disease (for the glycemic control and CV risk-reduction indications).

Boxed warnings are absent from the current empagliflozin label. A class-wide boxed warning for lower-limb amputation risk, first added to canagliflozin (Invokana) in 2017, was never added to empagliflozin because EMPA-REG OUTCOME and post-marketing surveillance did not show the same signal. [1]

The most clinically significant warnings in the label are:

Diabetic ketoacidosis (DKA). Cases have been reported in patients with type 2 diabetes. Many occurred with lower-than-expected blood glucose levels (euglycemic DKA). Clinicians should assess patients presenting with acidosis symptoms even when glucose appears normal.

Volume depletion. SGLT2-mediated osmotic diuresis can cause symptomatic hypotension, particularly in elderly patients, those on loop diuretics, or those with low systolic blood pressure.

Urinary tract and genital infections. Empagliflozin increases glucose concentration in urine. Genital mycotic infections affect approximately 6 to 7% of women and 3% of men in pooled trial data.

Urosepsis and pyelonephritis. Serious urinary tract infections requiring hospitalization have been reported post-market. The FDA issued a Drug Safety Communication on this topic for the entire SGLT2 class in 2015.

Fournier's gangrene. A rare but life-threatening necrotizing fasciitis of the perineum. The FDA issued a Drug Safety Communication in August 2018 covering the entire SGLT2 class after identifying 12 cases between 2013 and 2018 in the FDA Adverse Event Reporting System (FAERS). [6]

A practical clinical decision framework for initiating empagliflozin should screen for: baseline eGFR and urine ACR (to select the appropriate indication and starting dose), volume status and diuretic burden (to anticipate hypotension), history of recurrent genital mycotic infections, any prior DKA, and planned surgical procedures (the label recommends holding empagliflozin at least 3 days before elective surgery due to DKA risk).

EMA Authorization and European Label

The European Medicines Agency granted centralized marketing authorization for Jardiance on May 22, 2014, approximately ten weeks before the U.S. Approval. The EMA's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion in March 2014. The European Public Assessment Report (EPAR) documents the full benefit-risk review.

European Indications

The EMA label (as of 2024) covers adults with type 2 diabetes, symptomatic chronic heart failure (both HFrEF and HFpEF), and CKD. European labeling for the HFpEF indication was approved in September 2022, matching the U.S. Expansion closely. The CKD indication, based on EMPA-KIDNEY, was approved by the EMA in September 2023. [5]

Reimbursement and National Approvals

EMA central authorization applies across all EU member states, but national health technology assessment bodies independently decide on reimbursement. The National Institute for Health and Care Excellence (NICE) in England issued technology appraisal TA679 in 2021, recommending empagliflozin for HFrEF within its licensed indication when the manufacturer's patient access scheme price was met. NICE issued a subsequent appraisal for CKD (TA942, 2023), recommending empagliflozin for adults with CKD and either albuminuria or low eGFR.

In Canada, Health Canada approved empagliflozin in 2015 for T2DM. The Canadian label was updated to include CV risk reduction after EMPA-REG and later expanded for heart failure and CKD in alignment with the U.S. Timeline.

EMPA-REG OUTCOME: The Trial That Changed the Label

EMPA-REG OUTCOME remains the regulatory and clinical anchor for empagliflozin's cardiovascular claims. Understanding the trial design explains why the FDA granted the CV indication.

Trial Design and Population

The trial enrolled 7,020 adults with type 2 diabetes, BMI of 45 kg/m² or below, eGFR at or above 30 mL/min/1.73 m², and established CV disease defined as prior myocardial infarction, stroke, or peripheral artery disease. Patients were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo added to standard of care. Median follow-up was 3.1 years. [2]

Primary and Key Secondary Results

The three-point MACE (major adverse cardiovascular event) composite was the primary endpoint. As noted above, the pooled empagliflozin arms reduced MACE by 14% versus placebo. The renal secondary composite, defined as incident or worsening nephropathy, was reduced by 39% (HR 0.61; 95% CI 0.53 to 0.70; P<0.001). [2]

The FDA concluded that these data supported a risk-reduction claim rather than merely a glucose-lowering claim, a distinction that directly shaped the supplemental NDA review and the specific label language approved in December 2016.

Post-EMPA-REG Regulatory Guidance

The trial prompted the FDA to revise its 2008 guidance on CV outcome trials for anti-diabetic drugs. While the 2008 guidance required CV non-inferiority, EMPA-REG demonstrated superiority, setting a new benchmark. The American Diabetes Association's Standards of Care (2024 edition) specifically recommends empagliflozin for patients with T2DM and established ASCVD, citing EMPA-REG OUTCOME as supporting evidence (Level A recommendation). [7]

Post-Marketing Safety Surveillance

The FDA monitors Jardiance through FAERS, the Sentinel System (an active surveillance database covering more than 100 million patients' electronic health records), and periodic safety update reports required under the approved label.

Euglycemic DKA Signal

Post-market reports of euglycemic DKA led the FDA to update SGLT2 inhibitor labels in May 2015 with a new warning. Euglycemic DKA presents with blood glucose typically below 250 mg/dL, making diagnosis challenging. A 2020 meta-analysis of SGLT2 inhibitor trials (N=35,000+ pooled) found the absolute risk of DKA was low at approximately 0.3 events per 100 patient-years but significantly higher than placebo (RR approximately 2.5). [8]

Fournier's Gangrene

The 2018 FDA Drug Safety Communication identified cases of Fournier's gangrene across SGLT2 inhibitors in FAERS. A 2019 analysis by Bersoff-Matcha et al., published in Annals of Internal Medicine, identified 55 cases over 6 years in FAERS for SGLT2 inhibitors, compared with 19 cases over 30 years for other anti-diabetic drugs, supporting a class signal rather than drug-specific risk. [9]

Bone Fracture: No Signal for Empagliflozin

Unlike canagliflozin, which carries a bone fracture warning, empagliflozin has not demonstrated a consistent fracture signal in clinical trials or post-marketing data. EMPA-REG OUTCOME showed no statistically significant increase in fracture events (HR 1.02; 95% CI 0.77 to 1.35). The FDA label for empagliflozin does not include a bone fracture warning.

Bladder Cancer: No Causal Association

Early class-level concern about bladder cancer arose from pioglitazone data and was monitored for SGLT2 inhibitors. A 2022 Sentinel analysis of over 600,000 SGLT2 inhibitor users found no elevated risk of bladder cancer for empagliflozin compared with DPP-4 inhibitors (HR 0.94; 95% CI 0.76 to 1.16). [10]

Comparison with Other Approved SGLT2 Inhibitors

Four SGLT2 inhibitors are currently FDA-approved in the United States: empagliflozin (Jardiance), canagliflozin (Invokana), dapagliflozin (Farxiga), and ertugliflozin (Steglatro). Each has a distinct regulatory profile.

Approved Indications by Drug

| Drug | T2DM Glycemic | CV Risk Reduction | HFrEF | HFpEF | CKD | |---|---|---|---|---|---| | Empagliflozin | Yes (2014) | Yes (2016) | Yes (2021) | Yes (2022) | Yes (2023) | | Canagliflozin | Yes (2013) | Yes (2018) | No | No | Yes (2019) | | Dapagliflozin | Yes (2014) | No | Yes (2020) | Yes (2022) | Yes (2021) | | Ertugliflozin | Yes (2017) | No | No | No | No |

Empagliflozin and dapagliflozin are the only two drugs in the class with approved HFpEF indications. Empagliflozin is the only one with all five indications listed above. Canagliflozin carries a boxed warning for lower-limb amputation that is not present on the empagliflozin label.

Key Label Differences

The empagliflozin label explicitly permits use down to eGFR 20 mL/min/1.73 m² for the CKD and heart failure indications, reflecting the EMPA-KIDNEY enrollment criteria. Dapagliflozin's CKD label (based on DAPA-CKD) similarly allows use at low eGFR. Canagliflozin's renal use is restricted to eGFR 30 or above for glycemic benefit; the CKD indication permits use down to eGFR 15 based on CREDENCE trial data.

Pediatric and Special Population Regulatory Status

Pediatric Patients

The FDA has not approved empagliflozin for patients under 18 years of age for any indication. Under the Pediatric Research Equity Act, Boehringer Ingelheim submitted a Pediatric Study Plan. The FDA issued a Written Request for pediatric glycemic control studies. Results from the DINAMO trial, which enrolled children aged 10 to 17 with T2DM, were submitted to the FDA. The agency had not granted a pediatric T2DM approval as of the article's last review date. [1]

Pregnancy

The label assigns a pregnancy category consistent with the FDA's current descriptive system: animal data show adverse renal effects. Women of childbearing potential are advised to use empagliflozin only if the benefit outweighs risk, and the drug should be discontinued during the second and third trimesters given the known renal developmental concerns associated with RAAS-active drugs and osmotic diuretics. [1]

Renal Impairment Dosing

For the glycemic control indication, empagliflozin is not recommended when eGFR is persistently below 30 mL/min/1.73 m². For CV and HF indications, no dose adjustment is required for any level of renal function. For the CKD indication, treatment may be initiated or continued down to an eGFR of 20 mL/min/1.73 m² based on EMPA-KIDNEY data.

Drug Interactions and Concomitant Use

The empagliflozin label identifies several clinically relevant interactions:

Insulin and insulin secretagogues. Combination with insulin or sulfonylureas increases hypoglycemia risk. The label recommends a lower dose of the secretagogue or insulin when combining with empagliflozin.

Diuretics. Additive volume-depletion effects. The label notes that symptomatic hypotension is more common when empagliflozin is added to existing diuretic therapy, especially loop diuretics.

UGT inducers (rifampin, ritonavir, carbamazepine, phenytoin). These agents reduce empagliflozin plasma concentrations by inducing UGT1A3 and UGT2B7, the enzymes responsible for glucuronide conjugation. The clinical significance is uncertain; the label recommends monitoring glycemic response if strong UGT inducers are co-prescribed.

No dose adjustment is required based on renal or hepatic function for the standard 10 mg dose outside of the glycemic-control eGFR restriction noted above.

What Clinicians Should Know Before Prescribing in 2025

The 2024 ADA Standards of Care state: "For patients with T2D and established cardiovascular disease or indicators of high CV risk, heart failure, or CKD, an SGLT2 inhibitor with proven benefit should be used, independent of A1C." [7] Empagliflozin meets that criterion for all three comorbidity categories.

The 2022 AHA/ACC Heart Failure Guidelines (Heidenreich et al.) give empagliflozin a Class I, Level A recommendation for HFrEF, stating: "SGLT2 inhibitors are recommended in patients with symptomatic chronic HFrEF to reduce hospitalization for HF and CV mortality." [11]

Prescribers should check the current FDA label at Drugs@FDA (NDA 204629) before initiating, particularly given the eGFR thresholds that differ by indication. The FDA label was last updated in February 2023 to incorporate the CKD indication, and no further supplemental NDAs for new indications were approved as of the article's last review date. Boehringer Ingelheim and Lilly have ongoing trials evaluating empagliflozin in pediatric populations and in additional cardiorenal subgroups; label changes may follow pending trial results.

For patients starting empagliflozin for any indication, a baseline eGFR and urine ACR should be obtained, and eGFR should be rechecked at 3 months, given that SGLT2 inhibitors cause a small acute hemodynamic dip in GFR that typically reverses and is followed by long-term renoprotection per EMPA-KIDNEY data showing an average eGFR slope benefit of 1.4 mL/min/1.73 m² per year versus placebo over median 2-year follow-up. [5]