Dapagliflozin (Forxiga) in kidney disease

Overview

Heerspink HJL et al.. N Engl J Med 2020 · PMID 32970396 · DOI 10.1056/NEJMoa2024816

Forxiga reduced kidney failure and deaths; the trial was stopped early because the benefit was clear.

Does the study support the specific claim? No · Methodological quality: high

Original publication

Plain-language summary

Scientific in-depth review

1. Full reference

Authors

Heerspink HJL et al.

Journal

N Engl J Med

Year

2020

Identifier

PMID 32970396 DOI 10.1056/NEJMoa2024816

Verification

verified – PubMed efetch 2026-10-25 (this agent)

Retracted

no

Corrections

none

Extent checked

full text

Conflicts of interest and funding

Sponsored and funded by AstraZeneca (manufacturer); 4 of 14 authors AstraZeneca employees; executive committee of 9 academics plus 2 non-voting sponsor employees; sponsor analyses independently replicated at UMC Groningen; editorial assistance funded by AstraZeneca.

2. Research question

Dapagliflozin in CKD with/without diabetes

3. Study design and population

Study design

Randomised controlled trial – Randomised, double-blind, placebo-controlled, multicentre event-driven RCT (DAPA-CKD, NCT03036150), stopped early for efficacy on recommendation of the independent data monitoring committee

Population

Adults with CKD (eGFR 25-75 ml/min/1.73 m2, urinary albumin-to-creatinine ratio 200-5000 mg/g) on stable ACE inhibitor/ARB unless intolerant; 67.5% with type 2 diabetes; mean age 61.8 years; 33.1% female; mean eGFR 43.1; median UACR 949

Country

386 sites in 21 countries (including European sites, China, Latin America, North America)

Period

February 2017 to June 2020 (efficacy cut-off 3 April 2020); median follow-up 2.4 years (IQR 2.0-2.7)

Sample size

4,304 randomised (2,152 per group); 7,517 screened

Inclusion and exclusion criteria

Included: eGFR 25-75, UACR 200-5000, stable ACEi/ARB >=4 weeks (unless documented intolerance), with or without T2DM. Excluded: type 1 diabetes, polycystic kidney disease, lupus nephritis, ANCA-associated vasculitis, immunotherapy for kidney disease within 6 months. Stage 2 CKD capped at 10%.

4. Methods and endpoints

Exposure / intervention

Dapagliflozin 10 mg

Comparator

Placebo on top of standard care

Endpoints

eGFR decline >=50%, ESKD, renal/CV death

Statistical methods

ITT; Cox model stratified by T2DM and UACR, adjusted for baseline eGFR; closed hierarchical testing of primary and secondary outcomes; subgroups without multiplicity adjustment; planned interim analysis removed from protocol; analyses replicated by an independent academic group (UMC Groningen).

5. Actual results

Results

Primary composite: 197/2152 (9.2%) vs 312/2152 (14.5%), HR 0.61 (95% CI 0.51-0.72), NNT 19 (15-27). Kidney composite HR 0.56 (0.45-0.68); CV death or HF hospitalisation HR 0.71 (0.55-0.92); all-cause death 101 (4.7%) vs 146 (6.8%), HR 0.69 (0.53-0.88). CV death alone HR 0.81 (0.58-1.12). T2DM subgroup HR 0.64 (0.52-0.79); no T2DM HR 0.50 (0.35-0.72). Safety: serious AEs 29.5% vs 33.9%; amputation 35/2149 (1.6%) vs 39/2149 (1.8%); definite/probable DKA 0 vs 2; major hypoglycaemia 0.7% vs 1.3%; volume depletion 5.9% vs 4.2% (p=0.01); fractures 4.0% vs 3.2% (p=0.22).

Absolute risks

Primary outcome 4.6 vs 7.5 events/100 patient-years (absolute difference 5.3 percentage points over median 2.4 years); all-cause death 2.2 vs 3.1/100 patient-years (2.1 percentage points).

Authors' conclusion

Lower risk of kidney failure, CV death and death.

6. Strengths

• Large double-blind RCT with central IWRS randomisation and identical placebo
• Adjudicated hard kidney, cardiovascular and mortality outcomes
• 99.7% trial completion; vital status known for all but 5 participants
• Pre-specified hierarchical testing; independent academic replication of analyses
• Prespecified safety outcomes including amputation and adjudicated DKA

7. Weaknesses

• Stopped early for benefit (408 of planned 681 events), which can overestimate effect size and reduces power for secondary outcomes
• Industry sponsored with sponsor employees among authors
• Selected population (albuminuric CKD on RAS blockade); type 1 diabetes excluded
• Only selected adverse events collected
• Fournier's gangrene assessed by a sponsor internal safety group

8. Risk of bias

Orienting tool

RoB 2

Type of assessment

structured assessment based on the full text by a single reviewer (no formal double review)

Full formal assessment

no

Overall risk of bias

low

Rationale

Unchanged (low). Caveat: truncation for benefit may overstate effects; industry sponsorship mitigated by independent replication. Single-reviewer structured judgement; a formal RoB 2 needs two independent reviewers.

Full-text review (25 October 2026): Added full eligibility, 21 countries/386 sites, randomisation/blinding, component outcomes, subgroup HRs, safety table (amputation 1.6% vs 1.8%, DKA 0 vs 2, volume depletion 5.9% vs 4.2%), early stopping at 408/681 events, sponsor role and independent replication. Bias unchanged (low).

9. Assessment of the statistical interpretation

Effect sizes are large and precise with absolute benefits clinically meaningful; early stopping may inflate the point estimates somewhat, but CIs remain far from null. Safety data show no excess of amputation or DKA in this population, though rare harms cannot be excluded with 2.4 years of follow-up.

10. Relevance to the specific claim

Contradicts C-ODD-06 (Forxiga 'kills'); context for C-ODD-02.

11. Independent contrary findings

Adverse effects listed in archive studies.

12. Transferability to Germany and Europe

Multinational trial including European sites or directly applicable to EU practice.

13. Overall methodological judgement

High-quality evidence that dapagliflozin reduces kidney failure, cardiovascular events and death in albuminuric CKD with or without T2DM, with no excess amputations and no DKA cases in this population. Directly contradicts claims that dapagliflozin 'kills'; consistent with DKA being a rare, population-dependent risk rather than refuting it.

14. Open questions

Long-term (>2.4 years) safety; reversibility of the initial eGFR dip; effects in type 1 diabetes and non-albuminuric CKD.

15. Linked fact checks

• SGLT2 inhibitors such as dapagliflozin (Forxiga) can cause ketoacidosis, sometimes with normal or low blood glucose. – Studies contradicting or limiting the claim
• Every major class of glucose-lowering drug (metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 agonists) carries a documented signal of serious harm in the peer-reviewed literature. – Studies contradicting or limiting the claim
• Glucose-lowering drugs are net harmful and belong among the 'forbidden' items; dapagliflozin (Forxiga) is among the 'dirtiest' drugs and kills the brain; leg amputations happen only to people taking diabetes drugs and insulin. – Studies contradicting or limiting the claim