Jardiance Label Updates 2020 to 2026

Empagliflozin Before 2020: The Foundation for Expansion

Jardiance received its initial FDA approval on August 1, 2014, as an adjunct to diet and exercise for glycemic control in adults with type 2 diabetes [1]. Two years later, the label gained a cardiovascular (CV) indication that changed the trajectory of SGLT2 inhibitor prescribing across every specialty touching cardiometabolic disease.

The EMPA-REG OUTCOME trial (N=7,020) demonstrated a 38% relative risk reduction in CV death among T2D patients with established cardiovascular disease treated with empagliflozin versus placebo (3.7% vs. 5.9%; hazard ratio 0.62 to 95% CI 0.49, 0.77) [2]. That result led the FDA to add, in December 2016, an indication to reduce the risk of cardiovascular death in adults with T2D and established CV disease [3]. No other glucose-lowering agent had earned a CV death reduction claim at the time.

The 2016 label also included updated Warnings and Precautions language for hypotension in patients on diuretics or with renal impairment and a reminder that the drug was not recommended when eGFR fell below 30 mL/min/1.73 m² [3]. By the end of 2019, prescribers viewed Jardiance primarily through an endocrinology lens. That was about to change.

2021: Heart Failure With Reduced Ejection Fraction

The first major post-2020 label expansion arrived on August 18, 2021, when the FDA approved empagliflozin 10 mg to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure and reduced ejection fraction (HFrEF), regardless of diabetes status [4]. This was new territory. For the first time, an SGLT2 inhibitor carried an HF indication decoupled from glycemic control.

The approval rested on EMPEROR-Reduced (N=3,730), which showed a 25% relative risk reduction in the composite of CV death or first HF hospitalization (19.4% vs. 24.7%; HR 0.75 to 95% CI 0.65, 0.86; P<0.001) [5]. The benefit was consistent across subgroups defined by diabetes status, baseline ejection fraction, and background therapy including sacubitril/valsartan.

Dr. Milton Packer, principal investigator of the EMPEROR trials, noted: "The magnitude of the effect on heart failure hospitalization was striking and appeared within the first 12 days of treatment" [5]. The 2021 label specified the 10 mg dose only for the HF indication and did not require A1C monitoring or a diabetes diagnosis. The eGFR threshold for initiation in the HF population was set at 20 mL/min/1.73 m², lower than the diabetes indication's cutoff at the time [4].

2022: Heart Failure Across the Ejection Fraction Spectrum

On February 24, 2022, the FDA broadened the heart failure indication to include adults with heart failure regardless of ejection fraction [6]. This update removed the "reduced" qualifier. Jardiance became the first SGLT2 inhibitor approved for heart failure across the full ejection fraction spectrum in the United States.

EMPEROR-Preserved (N=5,988) provided the evidence. Patients with heart failure and an ejection fraction above 40% treated with empagliflozin 10 mg experienced a 21% relative risk reduction in the composite of CV death or HF hospitalization compared with placebo (13.8% vs. 17.1%; HR 0.79 to 95% CI 0.69, 0.90; P<0.001) [7]. The treatment effect was driven primarily by a reduction in HF hospitalizations.

The 2022 label revision also removed the eGFR lower limit for HF initiation, a practical change that allowed nephrologists and cardiologists to prescribe empagliflozin for HF patients with more advanced kidney dysfunction. The Dosage and Administration section was restructured to distinguish between the diabetes indication (10 mg or 25 mg) and the HF indication (10 mg only) [6].

A pooled analysis of both EMPEROR trials published in Nature Medicine reported that empagliflozin reduced the combined risk of CV death or HF hospitalization by 23% across 9,718 patients, with a number needed to treat of 19 over a median follow-up of 16 months [8].

2023: Chronic Kidney Disease Enters the Label

On June 20, 2023, the FDA approved empagliflozin to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression [9]. The CKD indication was the third major expansion in three years.

EMPA-KIDNEY (N=6,609) randomized adults with CKD (eGFR 20 to 45 mL/min/1.73 m², or eGFR 45, 90 with a urine albumin-to-creatinine ratio of at least 200 mg/g) to empagliflozin 10 mg or placebo. The trial was stopped early for efficacy at a planned interim analysis. The primary composite endpoint of kidney disease progression or CV death occurred in 13.1% of the empagliflozin group versus 16.9% of the placebo group (HR 0.72 to 95% CI 0.64, 0.82; P<0.001) [10].

The EMPA-KIDNEY Collaborative Group stated: "Empagliflozin reduced the risk of kidney disease progression by 28%, a benefit that was consistent regardless of the presence or absence of diabetes" [10]. This finding mirrored the diabetes-agnostic pattern seen in the HF trials and cemented SGLT2 inhibitors as a class with organ-protective properties independent of glucose lowering.

The 2023 label set the CKD initiation threshold at eGFR 20 mL/min/1.73 m² and noted that patients already on empagliflozin could continue the drug even if eGFR fell below 20, provided they remained on dialysis-free care [9]. The Dosage and Administration section grew to three distinct blocks: diabetes, heart failure, and chronic kidney disease.

Safety Label Revisions: Ketoacidosis, Fournier Gangrene, and Amputation Signals

Between 2020 and 2026, the FDA made several safety-focused changes to the Jardiance label. These updates reflected ongoing pharmacovigilance signals from the FDA Adverse Event Reporting System (FAERS) and class-wide post-marketing data across all approved SGLT2 inhibitors.

Ketoacidosis (updated 2020 to 2022). The Warnings and Precautions section was strengthened in 2020 to clarify that euglycemic diabetic ketoacidosis (eDKA) can occur with blood glucose levels below 250 mg/dL. The 2022 revision added guidance to withhold empagliflozin for at least 3 days before scheduled surgery, aligning with the American College of Endocrinology recommendation [11]. FAERS data through 2022 identified approximately 200 eDKA reports per year among SGLT2 inhibitor users, with empagliflozin accounting for roughly 25% of cases [12].

Fournier Gangrene (updated 2020). The necrotizing fasciitis of the perineum warning, first added to the class label in 2018, was expanded with additional post-marketing case detail. Between 2013 and 2019, the FDA identified 55 cases of Fournier gangrene across all SGLT2 inhibitors, compared with 19 cases across all other diabetes drug classes combined over the same period [13]. The 2020 update reinforced the instruction to discontinue the drug and initiate broad-spectrum antibiotics immediately upon suspicion.

Urosepsis and Pyelonephritis (updated 2021). The urinary tract infection warning was updated to include reports of urosepsis and pyelonephritis requiring hospitalization. The label now advises monitoring for signs of UTI and treating promptly [4].

Lower Limb Amputation Signal (class-level monitoring, no label change for Jardiance). While canagliflozin carries a boxed warning for lower limb amputation based on CANVAS trial data, empagliflozin has not received a similar warning. A meta-analysis of five cardiovascular outcome trials (N=46,969) found no statistically significant increase in amputation risk with empagliflozin (OR 1.01 to 95% CI 0.83, 1.23) [14]. The FDA continues to monitor this signal class-wide through Sentinel.

Dosing and Renal Threshold Changes: A Moving Target

One of the most clinically impactful label changes between 2020 and 2026 involved shifting eGFR thresholds. The original 2014 label prohibited initiation below eGFR 45 mL/min/1.73 m² for the diabetes indication. By 2023, the label allowed initiation at eGFR 20 for heart failure and CKD, with continuation permitted below 20 in certain circumstances.

The practical effect is significant. Approximately 37 million adults in the United States have CKD, and roughly 40% of them have an eGFR between 20 and 45 [15]. Before the threshold changes, these patients were largely excluded from SGLT2 inhibitor therapy. The EMPA-KIDNEY data showed that even patients with eGFR 20, 29 at baseline experienced a 30% reduction in the primary composite endpoint [10].

For the diabetes indication, the label was updated in 2023 to permit initiation down to eGFR 30 mL/min/1.73 m² (previously 45), reflecting evidence from EMPA-REG OUTCOME renal subgroup analyses and consensus guidance from the American Diabetes Association's Standards of Care [16]. The 25 mg dose remains restricted to the diabetes indication and is not approved for HF or CKD.

How Jardiance's Label Compares to Other SGLT2 Inhibitors

Dapagliflozin (Farxiga) followed a similar trajectory. It earned an HFrEF indication in May 2020 based on DAPA-HF and a CKD indication in April 2021 based on DAPA-CKD [17]. Canagliflozin (Invokana) carries a CKD indication based on CREDENCE but lacks a dedicated HF indication and retains its boxed amputation warning [18].

As of mid-2026, empagliflozin is the only SGLT2 inhibitor with a single-agent indication spanning type 2 diabetes, heart failure across all ejection fractions, and chronic kidney disease. The label differences matter at the formulary level: payers and PBMs use FDA-approved indications to determine coverage, and an indication gap can mean a prior authorization barrier for patients.

The European Medicines Agency (EMA) has approved empagliflozin for comparable indications through its EPAR process, though the specific wording of the heart failure indication references NYHA Class II, IV rather than the ejection fraction framework used by the FDA [19].

What Prescribers Should Watch for in 2026 and Beyond

Boehringer Ingelheim's pipeline includes ongoing studies of empagliflozin in acute heart failure (EMPACT-MI, already reported) and in patients with preserved kidney function but high CV risk. The EMPACT-MI trial (N=6,522) evaluated empagliflozin initiated within 14 days of acute myocardial infarction and found a non-significant 5% reduction in HF hospitalization or all-cause death (HR 0.95 to 95% CI 0.84, 1.07) [20]. This did not lead to a label expansion, but subgroup data are under FDA review.

The 2025 ADA Standards of Care now recommend SGLT2 inhibitors as first-line add-on therapy for T2D patients with heart failure, CKD (eGFR 20, 60), or established atherosclerotic CVD, independent of A1C [16]. Prescribers writing empagliflozin for HF or CKD should use the 10 mg dose, monitor serum creatinine and potassium within 1 to 2 weeks of initiation, and counsel patients on symptoms of ketoacidosis and genital mycotic infections.