Jardiance Cardiovascular Impact Long-Term: What the Evidence Actually Shows

What the long-term evidence covers

The cardiovascular case for empagliflozin comes from four large outcome programs, not from a single trial. EMPA-REG OUTCOME tested adults with type 2 diabetes at high cardiovascular risk [1]. EMPEROR-Reduced tested adults with heart failure and an ejection fraction of 40% or less [2]. EMPEROR-Preserved tested adults with heart failure and an ejection fraction above 40% [3]. EMPA-KIDNEY tested adults with chronic kidney disease [4]. The heart failure and kidney trials enrolled people with and without diabetes [5].

The current Jardiance label lists three cardiovascular or kidney indications: reducing cardiovascular death and heart failure hospitalization in adults with heart failure; reducing sustained eGFR decline, end-stage kidney disease, cardiovascular death and hospitalization in adults with chronic kidney disease at risk of progression; and reducing cardiovascular death in adults with type 2 diabetes and established cardiovascular disease [5]. The heart failure indication is not restricted by ejection fraction in the label [5].

EMPA-REG OUTCOME: cardiovascular death and heart failure hospitalization

EMPA-REG OUTCOME treated 7,020 adults with type 2 diabetes at high cardiovascular risk with empagliflozin 10 mg, empagliflozin 25 mg, or placebo, and followed them for a median of 3.1 years [1]. The primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 10.5% of the pooled empagliflozin group and 12.1% of the placebo group (hazard ratio 0.86, 95% CI 0.74 to 0.99; P=0.04 for superiority) [1].

The components moved differently. Cardiovascular death occurred in 3.7% versus 5.9%, a 38% relative risk reduction [1]. Hospitalization for heart failure occurred in 2.7% versus 4.1%, a 35% relative risk reduction [1]. Death from any cause occurred in 5.7% versus 8.3%, a 32% relative risk reduction [1]. There were no significant between-group differences in myocardial infarction or stroke when each was considered alone [1].

That pattern matters for how the result is described. The trial supports a reduction in cardiovascular death and heart failure hospitalization in this population; it did not show a significant reduction in heart attacks or strokes [1]. The label indication for type 2 diabetes is to reduce the risk of cardiovascular death in adults with established cardiovascular disease, not a general claim of reducing all major cardiovascular events [5].

EMPEROR-Reduced: heart failure with reduced ejection fraction

EMPEROR-Reduced randomized 3,730 adults with class II, III or IV heart failure and an ejection fraction of 40% or less to empagliflozin 10 mg once daily or placebo, on top of recommended therapy [2]. Over a median of 16 months, the primary composite of cardiovascular death or hospitalization for worsening heart failure occurred in 19.4% of the empagliflozin group and 24.7% of the placebo group (hazard ratio 0.75, 95% CI 0.65 to 0.86; P<0.001) [2].

Total hospitalizations for heart failure were lower with empagliflozin (hazard ratio 0.70, 95% CI 0.58 to 0.85; P<0.001) [2]. The annual decline in estimated glomerular filtration rate was slower with empagliflozin, -0.55 versus -2.28 mL per minute per 1.73 m2 [2]. The effect on the primary outcome was consistent in patients with or without diabetes [2].

EMPEROR-Preserved: heart failure with preserved ejection fraction

EMPEROR-Preserved randomized 5,988 adults with class II to IV heart failure and an ejection fraction above 40% to empagliflozin 10 mg once daily or placebo [3]. Over a median of 26.2 months, the primary composite of cardiovascular death or hospitalization for heart failure occurred in 13.8% of the empagliflozin group and 17.1% of the placebo group (hazard ratio 0.79, 95% CI 0.69 to 0.90; P<0.001) [3].

The result was mainly related to a lower risk of hospitalization for heart failure [3]. Total heart failure hospitalizations were 407 with empagliflozin versus 541 with placebo (hazard ratio 0.73, 95% CI 0.61 to 0.88; P<0.001) [3]. Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin [3]. The effects appeared consistent in patients with or without diabetes [3].

EMPA-KIDNEY: chronic kidney disease

EMPA-KIDNEY enrolled 6,609 adults with chronic kidney disease: an eGFR of at least 20 but less than 45 mL/min/1.73 m2, or an eGFR of at least 45 but less than 90 with a urinary albumin-to-creatinine ratio of at least 200 mg/g [4]. Participants received empagliflozin 10 mg once daily or placebo and were followed for a median of 2.0 years [4].

The primary composite of kidney disease progression or cardiovascular death occurred in 13.1% of the empagliflozin group and 16.9% of the placebo group (hazard ratio 0.72, 95% CI 0.64 to 0.82; P<0.001) [4]. Results were consistent among patients with or without diabetes [4]. Hospitalization for any cause was lower with empagliflozin (hazard ratio 0.86) [4]. The trial did not show a significant difference in all-cause death (4.5% versus 5.1%) or in the composite of heart failure hospitalization or cardiovascular death [4].

What the label says about dose and monitoring

The Jardiance label gives 10 mg once daily in the morning for all indications, with or without food [5]. For additional glycemic control in type 2 diabetes, the dose may be increased to 25 mg once daily [5]. The label says to assess renal function and volume status before starting and to correct volume depletion first [5]. It also says to withhold empagliflozin for at least 3 days, if possible, before surgery or procedures with prolonged fasting [5].

For glycemic control, the label does not recommend use at an eGFR under 30 mL/min/1.73 m2 [5]. It lists ketoacidosis as a warning, including cases with blood glucose under 250 mg/dL, and states that empagliflozin is not recommended for glycemic control in type 1 diabetes, which may increase ketoacidosis risk [5]. It also warns about volume depletion and acute kidney injury, genitourinary infections including urosepsis, pyelonephritis and Fournier's gangrene, hypoglycemia with insulin or sulfonylureas, lower limb amputation, and serious hypersensitivity including angioedema [5].

The label reports amputation rates across four Jardiance outcome trials of 5.0 versus 4.3 events per 1,000 patient-years (hazard ratio 1.05, 95% CI 0.81 to 1.36), and in the long-term kidney trial 4.3 versus 2.9 per 1,000 patient-years [5]. The label advises foot care and monitoring in patients at highest risk, including those with diabetic foot, peripheral artery disease or prior amputation [5].

How the cardiovascular benefit is thought to work

Empagliflozin blocks SGLT2 in the kidney, so more glucose leaves in urine and blood glucose falls independently of insulin [5]. The effect depends on kidney filtration, and glucose-lowering is likely ineffective at low eGFR [5]. The heart failure trials found the primary effect consistent in patients with or without diabetes [2][3].

A 2018 review described proposed cardiovascular mechanisms including diuresis and natriuresis, lower afterload, improved vascular function, and changes in myocardial substrate use [6]. A 2021 analysis of EMPEROR-Reduced found that patients with recent volume overload did not have larger benefits, and that changes in weight, hematocrit and natriuretic peptides did not track closely; the authors concluded that the findings do not support a dominant role of diuresis [7].

How it compares with other SGLT2 inhibitors

In DECLARE-TIMI 58, dapagliflozin did not lower major adverse cardiovascular events (8.8% versus 9.4%; hazard ratio 0.93, 95% CI 0.84 to 1.03) but did lower cardiovascular death or heart failure hospitalization (4.9% versus 5.8%; hazard ratio 0.83, 95% CI 0.73 to 0.95) [8]. In CANVAS, canagliflozin lowered major adverse cardiovascular events (hazard ratio 0.86, 95% CI 0.75 to 0.97) but increased amputation (6.3 versus 3.4 participants per 1,000 patient-years; hazard ratio 1.97, 95% CI 1.41 to 2.75) [9].

For heart failure, dapagliflozin reduced worsening heart failure or cardiovascular death in DAPA-HF (16.3% versus 21.2%; hazard ratio 0.74, 95% CI 0.65 to 0.85) and in DELIVER (16.4% versus 19.5%; hazard ratio 0.82, 95% CI 0.73 to 0.92) [10][11]. These are separate trials with different populations and designs, not head-to-head comparisons with empagliflozin.