Jardiance for Renal Protection: What the Trials Show

What EMPA-KIDNEY found

EMPA-KIDNEY is the trial behind the kidney indication. It enrolled 6,609 adults with chronic kidney disease, defined as an eGFR of at least 20 but under 45 mL/min/1.73 m2, or an eGFR of 45 to under 90 with a urinary albumin-to-creatinine ratio of at least 200 mg/g, and assigned them empagliflozin 10 mg once daily or placebo [1].

Over a median of 2.0 years, the primary composite outcome (end-stage kidney disease, a sustained eGFR below 10, a sustained eGFR fall of 40% or more, death from renal causes, or death from cardiovascular causes) occurred in 432 of 3,304 people on empagliflozin (13.1%) and 558 of 3,305 on placebo (16.9%), a hazard ratio of 0.72 (95% CI 0.64 to 0.82) [1]. Results were consistent among patients with or without diabetes [1].

Not every endpoint moved. The trial found no significant difference in all-cause death (4.5% vs 5.1%) or in the composite of heart failure hospitalization or cardiovascular death [1]. Hospitalization for any cause was lower on empagliflozin (HR 0.86) [1].

EMPA-REG OUTCOME was a cardiovascular trial

EMPA-REG OUTCOME is often cited for kidney protection, but it was designed as a cardiovascular trial. It treated 7,020 adults with type 2 diabetes at high cardiovascular risk with empagliflozin 10 mg, 25 mg or placebo for a median of 3.1 years [3]. The primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke fell from 12.1% to 10.5% (HR 0.86, 95% CI 0.74 to 0.99), with significantly lower cardiovascular death (3.7% vs 5.9%), heart failure hospitalization (2.7% vs 4.1%) and all-cause death (5.7% vs 8.3%), and no significant between-group difference in myocardial infarction or stroke alone; genital infections increased [3].

That trial supports the label indication to reduce cardiovascular death in adults with type 2 diabetes and established cardiovascular disease [2]. The kidney-specific outcome numbers come from EMPA-KIDNEY, which enrolled people selected for chronic kidney disease rather than for cardiovascular risk [1].

What happens to eGFR at the start

Empagliflozin blocks SGLT2 in the kidney so that more glucose leaves in the urine, and because this effect depends on kidney filtration, glucose-lowering is likely ineffective at low eGFR [2].

The label describes what happens to kidney numbers: eGFR dips and creatinine rises within weeks and then stabilizes, generally by no more than 0.1 mg/dL in creatinine and -9.0 mL/min/1.73 m2 in eGFR at week 4 in the cardiovascular outcomes trial [2].

One small mechanistic study measured this directly. Forty adults with type 1 diabetes received empagliflozin 25 mg daily for 8 weeks, with glomerular filtration rate measured by inulin clearance [4]. In the 27 people with hyperfiltration at baseline, GFR fell by 33 mL/min/1.73 m2 (from 172 ± 23 to 139 ± 25); in the 13 with normal GFR at baseline it did not change. The authors attributed the effect to tubuloglomerular feedback mechanisms [4]. That study is small and was done in type 1 diabetes, not in the chronic kidney disease population the kidney indication covers.

Who the label covers, and what it excludes

The Jardiance label indicates the drug to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death and hospitalization in adults with chronic kidney disease at risk of progression, at 10 mg once daily [2]. It states limitations of use: the drug is not recommended to treat chronic kidney disease in polycystic kidney disease, or in patients who need or recently received intravenous immunosuppression, or more than 45 mg/day prednisone-equivalent, for kidney disease [2]. Use for glycemic control is not recommended when eGFR is under 30 mL/min/1.73 m2, and the drug is not recommended for glycemic control in type 1 diabetes because it may increase the risk of diabetic ketoacidosis [2].

Kidney failure is not a listed contraindication. The only contraindication on the label is hypersensitivity to empagliflozin or any excipient, with angioedema reported [2].

What the label says to watch for

Volume depletion and acute kidney injury. Empagliflozin can cause intravascular volume depletion, which may show up as symptomatic hypotension or acute transient creatinine changes, and there are postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis [2]. The label names impaired renal function (eGFR under 60 mL/min/1.73 m2), older age and loop diuretic use as risk factors, and says to assess volume status and renal function before starting and to monitor after [2]. In adults aged 75 and older, volume-depletion reactions were reported in 2.1% on placebo, 2.3% on 10 mg and 4.4% on 25 mg, and urinary tract infection in 10.5%, 15.7% and 15.1% [2].

Genitourinary infections. In the label's pooled 24-week placebo-controlled trials in type 2 diabetes (placebo N=995, 10 mg N=999, 25 mg N=977), urinary tract infection occurred in 7.6%, 9.3% and 7.6%; female genital mycotic infections in 1.5%, 5.4% and 6.4% of women; and male genital mycotic infections in 0.4%, 3.1% and 1.6% of men [2]. Serious cases including urosepsis, pyelonephritis and necrotizing fasciitis of the perineum (Fournier's gangrene) are listed as warnings, and patients with chronic or recurrent genitourinary infections are more likely to develop them on the drug [2].

Lower limb amputation is a labeled warning. Across four Jardiance outcome trials, amputation rates were 5.0 versus 4.3 events per 1,000 patient-years on Jardiance versus placebo (HR 1.05, 95% CI 0.81 to 1.36); in the long-term CKD trial, 4.3 on Jardiance 10 mg versus 2.9 on placebo per 1,000 patient-years [2]. Risk is highest with diabetic foot disease, peripheral artery disease or prior amputation, and the label advises foot care and monitoring [2].

Ketoacidosis can occur in type 2 as well as type 1 diabetes, can present with blood glucose below 250 mg/dL, and glucosuria or ketoacidosis may last beyond 6 days after stopping [2]. The label says to withhold Jardiance for at least 3 days, if possible, before surgery or procedures with prolonged fasting [2].

Lithium. The label says SGLT2 inhibitors may decrease serum lithium and to monitor lithium concentration more frequently at initiation and after dose changes [2].

Heart failure trials

The heart failure trials add kidney and outcome data. In EMPEROR-Reduced (3,730 adults with ejection fraction 40% or less, median 16 months), the annual eGFR decline was -0.55 on empagliflozin versus -2.28 on placebo [5]. In EMPEROR-Preserved (5,988 adults with ejection fraction over 40%, median 26.2 months), cardiovascular death or heart failure hospitalization fell from 17.1% to 13.8% (HR 0.79), mainly through fewer heart failure hospitalizations, with more genital and urinary tract infections and hypotension on empagliflozin [6].

How it compares with other SGLT2 inhibitors

Comparisons across agents come from indirect network meta-analysis rather than direct trials. A 2026 network meta-analysis pooled 20 randomized trials with 80,670 participants with type 2 diabetes and chronic kidney disease: dapagliflozin 10 mg showed the largest reduction in composite renal outcomes (OR 0.55, 95% CI 0.42 to 0.72, high-certainty evidence), followed by canagliflozin, empagliflozin and others; canagliflozin reduced the urinary albumin-to-creatinine ratio while dapagliflozin did not; and certainty was low or very low for the indirect estimates [7].

For context on the individual trials: CREDENCE enrolled 4,401 adults with type 2 diabetes and albuminuric CKD on renin-angiotensin system blockade and found a primary-outcome hazard ratio of 0.70 (43.2 vs 61.2 events per 1,000 patient-years), with the renal-specific composite 34% lower (HR 0.66) [8]. DAPA-CKD enrolled 4,304 adults with eGFR 25 to 75 and albuminuria, and the primary composite occurred in 9.2% on dapagliflozin versus 14.5% on placebo (HR 0.61) [9]. These populations and eGFR entry criteria differ from EMPA-KIDNEY, so the percentages should not be read as a ranking.