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

What does dapagliflozin do to the heart and kidneys?

Dapagliflozin blocks SGLT2 in the kidney so more glucose is excreted in urine, which produces an osmotic diuresis [4]. The Farxiga label states that the heart and kidney benefits occur with or without diabetes, while glucose lowering depends on kidney function and fades at low eGFR [4].

The current label carries three cardiovascular or kidney indications plus glycemic control: reducing sustained eGFR decline, end-stage kidney disease, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease at risk of progression; reducing cardiovascular death, hospitalization for heart failure and urgent heart failure visits in adults with heart failure; and reducing hospitalization for heart failure in adults with type 2 diabetes who have established cardiovascular disease or multiple risk factors [4]. The heart failure indication is not limited by ejection fraction [4].

What did DAPA-HF show?

The trial randomized 4,744 adults with NYHA class II to IV heart failure and an ejection fraction of 40% or less to dapagliflozin 10 mg daily or placebo on top of recommended therapy [1]. Over a median of 18.2 months, the primary composite of worsening heart failure or cardiovascular death occurred in 16.3% of the dapagliflozin group versus 21.2% of the placebo group (HR 0.74, 95% CI 0.65 to 0.85) [1].

A first worsening heart failure event occurred in 10.0% versus 13.7% (HR 0.70, 0.59 to 0.83), cardiovascular death in 9.6% versus 11.5% (HR 0.82), and death from any cause in 11.6% versus 13.9% (HR 0.83) [1]. Results were similar in people with and without diabetes [1].

What did DELIVER show at higher ejection fractions?

DELIVER randomized 6,263 adults with heart failure and an ejection fraction above 40% [2]. Over a median of 2.3 years, the primary composite of worsening heart failure or cardiovascular death occurred in 16.4% versus 19.5% (HR 0.82, 0.73 to 0.92) [2]. Worsening heart failure was 11.8% versus 14.5% (HR 0.79, 0.69 to 0.91) [2].

Cardiovascular death on its own was 7.4% versus 8.3% (HR 0.88, 0.74 to 1.05), a difference that did not reach statistical significance [2]. Benefit was similar with and without diabetes [2].

What did DECLARE-TIMI 58 show in type 2 diabetes?

DECLARE-TIMI 58 enrolled 17,160 adults with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, including 10,186 without established disease, and followed them for a median of 4.2 years [3].

On major adverse cardiovascular events (cardiovascular death, heart attack or ischemic stroke) the rates were 8.8% versus 9.4% (HR 0.93, 0.84 to 1.03). Dapagliflozin met the criterion for noninferiority but did not show superiority [3]. The cardiovascular death or heart failure hospitalization composite was 4.9% versus 5.8% (HR 0.83, 0.73 to 0.95), driven mainly by heart failure hospitalization (HR 0.73); cardiovascular death alone had an HR of 0.98 [3]. The renal composite occurred in 4.3% versus 5.6% (HR 0.76), and diabetic ketoacidosis in 0.3% versus 0.1% [3].

What did DAPA-CKD show?

DAPA-CKD randomized 4,304 adults with chronic kidney disease (eGFR 25 to 75 and a urine albumin-to-creatinine ratio of 200 to 5000), with or without type 2 diabetes, and stopped early for efficacy [5]. Over a median of 2.4 years, the primary composite of a sustained eGFR decline of at least 50%, end-stage kidney disease, or kidney or cardiovascular death occurred in 9.2% versus 14.5% (HR 0.61, 0.51 to 0.72), with a number needed to treat of 19 [5]. Death from any cause was 4.7% versus 6.8% (HR 0.69) [5], and the composite of cardiovascular death or heart failure hospitalization had an HR of 0.71 [5].

Is there real-world evidence?

One population-level signal comes from Brazil, where dapagliflozin became publicly funded in 2021. A nationwide time-series analysis reported that cardiovascular mortality rates fell 4.7% in 2022, 11.4% in 2023 and 19.1% in 2024 compared with 2017, with a steeper downward trend after funding began [6]. That is an observational analysis of population trends, not a randomized comparison.

What does the Farxiga label say to watch for?

The label lists no boxed warning [4]. Its warnings cover ketoacidosis, which can present with blood glucose below 250 mg/dL and has been reported fatally in type 2 diabetes; volume depletion and acute kidney injury, with higher risk at eGFR under 60, in older adults and in people on loop diuretics; and genitourinary infections, including urosepsis, pyelonephritis, necrotizing fasciitis of the perineum (Fournier gangrene) and genital yeast infections [4]. Hypoglycemia risk rises when dapagliflozin is combined with insulin or an insulin secretagogue such as a sulfonylurea [4].

The label directs that dapagliflozin be withheld for at least 3 days, if possible, before surgery or procedures with prolonged fasting [4]. The only contraindication is a history of a serious hypersensitivity reaction to dapagliflozin or an excipient, as anaphylaxis and angioedema have occurred [4]. The current label text contains no bladder cancer or lower limb amputation warning [4].

In DECLARE-TIMI 58 specifically, volume depletion events were 2.5% on dapagliflozin versus 2.4% on placebo, and in the loop-diuretic subgroup 6.6% versus 6.1% [4]. In the pooled 12-week to 24-week glycemic trials, female genital yeast infections occurred in 6.9% on 10 mg versus 1.5% on placebo, male genital yeast infections in 2.7% versus 0.3%, and urinary tract infections in 4.3% versus 3.7% [4].

What the evidence does not support

The label has no weight-loss indication [4]. It is not recommended for glycemic control when eGFR is below 45, and for the heart and kidney indications the usual 10 mg dose is used down to eGFR 25, with no new starts below that level [4]. It is also not recommended for glycemic control in type 1 diabetes [4].

When was Farxiga approved?

Drugs@FDA records the original approval of Farxiga (NDA 202293) on 8 January 2014. Later efficacy supplements for new indications are listed on 18 October 2019, 5 May 2020, 30 April 2021 and 8 May 2023, and a new patient population on 12 June 2024 [7]. Combination products, such as dapagliflozin with metformin or with saxagliptin, have separate labels with their own warnings [7].