Jardiance FDA Approval History

Original NDA Approval: August 2014

The FDA approved empagliflozin (Jardiance) on August 1, 2014, under NDA 204629, granting Boehringer Ingelheim Pharmaceuticals a new sodium-glucose co-transporter 2 (SGLT2) inhibitor for adults with type 2 diabetes mellitus [1]. The approval covered two tablet strengths: 10 mg and 25 mg, both as adjuncts to diet and exercise.

The NDA relied on a Phase III program that enrolled over 14,500 patients across multiple registrational trials. Placebo-adjusted HbA1c reductions ranged from 0.7% to 0.8% at 24 weeks for the 25 mg dose. FDA reviewers noted modest weight loss (approximately 2 kg) and systolic blood pressure reductions (3-4 mmHg) as secondary pharmacologic effects, consistent with the SGLT2 mechanism of glucosuria-driven caloric loss and osmotic diuresis [2].

The approval made empagliflozin the third SGLT2 inhibitor to reach the U.S. market, following canagliflozin (March 2013) and dapagliflozin (January 2014). The original label carried warnings for hypotension, renal impairment, genital mycotic infections, and urinary tract infections. The original label restricted use to patients with eGFR ≥45 mL/min/1.73 m², a threshold that would later be revised downward as cardiovascular and renal data accumulated.

EMPA-REG OUTCOME and the Cardiovascular Indication (2016)

On December 2, 2016, the FDA approved a supplemental NDA adding reduction in the risk of cardiovascular death to the Jardiance label for adults with type 2 diabetes and established cardiovascular disease [3]. This made empagliflozin the first diabetes drug to receive a CV death indication.

The EMPA-REG OUTCOME trial (N=7,020) randomized patients with T2D and established atherosclerotic cardiovascular disease to empagliflozin 10 mg, 25 mg, or placebo. Over a median 3.1-year follow-up, empagliflozin produced a 38% relative risk reduction in cardiovascular death (HR 0.62, 95% CI 0.49-0.77, P<0.001) and a 35% relative risk reduction in hospitalization for heart failure (HR 0.65, 95% CI 0.50-0.85) [4]. All-cause mortality fell by 32%.

These results shifted clinical practice. The American Diabetes Association and the European Association for the Study of Diabetes subsequently recommended SGLT2 inhibitors as preferred second-line therapy for patients with T2D and established or high-risk cardiovascular disease [5]. The speed of the cardiovascular benefit, apparent within the first three months of treatment, suggested mechanisms beyond glucose lowering, likely involving hemodynamic unloading and natriuresis.

Heart Failure Indications: 2022-2023

The regulatory story expanded beyond diabetes management entirely when the FDA approved empagliflozin for heart failure with reduced ejection fraction (HFrEF, EF ≤40%) on February 24, 2022 [6]. This approval rested on the EMPEROR-Reduced trial (N=3,730), which demonstrated a 25% relative risk reduction in the composite of cardiovascular death or hospitalization for heart failure (HR 0.75, 95% CI 0.65-0.86, P<0.001) in patients with HFrEF regardless of diabetes status [7].

The benefit extended to patients without diabetes, a population that comprised approximately 50% of EMPEROR-Reduced enrollees. This represented a conceptual leap: a drug first approved for hyperglycemia now carried an indication for a structural cardiac condition independent of metabolic disease.

In February 2023, the FDA broadened the heart failure indication to include heart failure regardless of ejection fraction, based on the EMPEROR-Preserved trial (N=5,988). That trial showed a 21% relative risk reduction in the composite endpoint in HFpEF patients (HR 0.79, 95% CI 0.69-0.90, P<0.001) [8]. Dr. Norman Stockbridge, then-Director of the Division of Cardiology and Nephrology at CDER, noted that "this approval provides an important treatment option for a broader population of heart failure patients."

The combined EMPEROR program positioned empagliflozin as a therapy for the full spectrum of heart failure, a regulatory milestone that no other SGLT2 inhibitor had achieved at that time in the U.S.

Pediatric Approval and Type 2 Diabetes in Adolescents

In March 2023, the FDA approved Jardiance for pediatric patients aged 10 years and older with type 2 diabetes mellitus [9]. The approval was supported by the DINAMO trial, which enrolled 158 pediatric patients (ages 10-17) with inadequately controlled T2D. Empagliflozin 10 mg demonstrated a placebo-adjusted HbA1c reduction of 0.84% at 26 weeks.

This expansion acknowledged the rising prevalence of type 2 diabetes in adolescents, particularly among populations with higher metabolic risk. The pediatric label maintains the same safety warnings as the adult indication, with additional monitoring recommendations for bone health during skeletal maturation. No dose adjustment was required for patients weighing ≥20 kg.

Chronic Kidney Disease: Expanding Renal Indications

The EMPA-KIDNEY trial (N=6,609) evaluated empagliflozin in patients with chronic kidney disease with or without diabetes. Published in the New England Journal of Medicine in 2023, the trial showed a 28% relative risk reduction in the composite of kidney disease progression or cardiovascular death (HR 0.72, 95% CI 0.64-0.82, P<0.001) [10]. The trial enrolled patients with eGFR as low as 20 mL/min/1.73 m², substantially below the original 2014 label threshold.

Based on these data, the FDA approved empagliflozin for reducing the risk of kidney disease progression in adults with chronic kidney disease at risk of progression. The eGFR initiation threshold was revised to allow starting treatment at eGFR ≥20 mL/min/1.73 m², with continuation permitted even as eGFR declines below that point.

This renal indication aligned with the 2022 KDIGO Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease, which recommended SGLT2 inhibitors for all patients with T2D and CKD with eGFR ≥20 [11]. The guideline committee cited the class effect on tubuloglomerular feedback, reduction in intraglomerular pressure, and attenuation of tubulointerstitial fibrosis as plausible mechanisms.

Label Safety Updates and Post-Market Surveillance

The Jardiance label has undergone multiple safety-related revisions since 2014.

Euglycemic diabetic ketoacidosis (eDKA). In December 2015, the FDA issued a Drug Safety Communication warning that SGLT2 inhibitors, including empagliflozin, may cause ketoacidosis with blood glucose levels only mildly elevated or normal [12]. The mechanism involves insulin dose reduction, enhanced lipolysis, and shifted substrate utilization toward ketogenesis. The label now advises discontinuation in patients with suspected ketoacidosis and recommends withholding the drug at least 3 days before scheduled surgery.

Fournier gangrene (necrotizing fasciitis of the perineum). In August 2018, the FDA required a warning about this rare but serious adverse event across all SGLT2 inhibitors. A review identified 55 cases over a 5-year period across the class, compared to 19 cases over 35 years among other diabetes drugs [13]. Patients should seek immediate medical attention for pain, tenderness, erythema, or swelling in the genital or perineal area.

Urinary tract infections and urosepsis. The label carries warnings for complicated UTIs including pyelonephritis and urosepsis. Post-market case reports prompted strengthened language advising evaluation for urinary signs and symptoms and treatment initiation if infection is confirmed.

Lower limb amputation. Unlike canagliflozin, empagliflozin has not received a boxed warning for amputations. The EMPA-REG OUTCOME data did not show a statistically significant increase in amputation risk, and the FDA has not required this warning on the Jardiance label specifically.

Bone fractures. The label notes that bone mineral density changes have been observed with the SGLT2 class. The EMPA-REG OUTCOME trial reported fracture rates of 3.8% with empagliflozin versus 3.9% with placebo, providing no signal of increased fracture risk [4].

Regulatory Differentiation from Other SGLT2 Inhibitors

Empagliflozin was the first SGLT2 inhibitor to secure a cardiovascular death indication (December 2016). Dapagliflozin later received an HFrEF indication (May 2020) based on DAPA-HF, and canagliflozin received a renal indication (September 2019) based on CREDENCE. The regulatory trajectories of the three agents have converged, but the initial sequencing of approvals gave empagliflozin early market positioning in cardiology and heart failure clinics.

The combination product Synjardy (empagliflozin/metformin) received FDA approval on August 28, 2015, and Synjardy XR (extended-release metformin) followed in December 2016. Glyxambi (empagliflozin/linagliptin) was approved in January 2015. These fixed-dose combinations carry the same underlying safety warnings as empagliflozin monotherapy.

Current Approved Indications Summary

As of May 2026, the complete list of FDA-approved indications for Jardiance includes: (1) adjunct to diet and exercise for glycemic control in adults with type 2 diabetes, (2) reduction in the risk of cardiovascular death in adults with T2D and established cardiovascular disease, (3) reduction in the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure, (4) reduction in the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression, and (5) glycemic control in pediatric patients aged 10+ with type 2 diabetes [1][6][9][10].

The label recommends renal function assessment before initiation. The drug should not be used in type 1 diabetes or for treatment of diabetic ketoacidosis. Prescribers should assess volume status and correct hypovolemia before starting therapy, particularly in patients with eGFR <45, elderly patients, or those on loop diuretics.

Post-Market Real-World Evidence

FDA Sentinel System analyses and large observational databases have corroborated the trial findings in routine clinical practice. A 2021 CVD-REAL Nordic study (N=91,320) reported that SGLT2 inhibitor initiation versus DPP-4 inhibitor initiation was associated with lower rates of heart failure hospitalization (HR 0.62, 95% CI 0.50-0.77) and all-cause death (HR 0.56, 95% CI 0.44-0.70) [14]. While this was a class-level analysis, empagliflozin represented a substantial proportion of SGLT2 prescriptions in the Nordic cohorts.

The FDA's ongoing BEST (Biologics Effectiveness and Safety) initiative continues to monitor SGLT2 inhibitor outcomes in populations underrepresented in trials, including patients over age 75, those with advanced CKD stages 4-5, and patients with concurrent NYHA Class IV heart failure. No new unexpected safety signals have emerged from these surveillance activities through early 2026.