Efficacy of dapagliflozin and empagliflozin not influenced by diabetes status

A pooled meta-analysis of 2 large studies on sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure (HF) treatment evaluated subgroups results. Adding an SGLT2 inhibitor to treatment was advantageous in cardiovascular (CV) outcomes irrespective of diabetic status.

EMPEROR-Reduced (NCT03057977) and DAPA-HF (NCT03036124) investigated the effects of adding SGLT2 inhibition with empagliflozin or dapagliflozin to recommended therapy in HF patients with reduced ejection fraction (HFrEF), including both subjects with and without diabetes. The 2 studies were similar in design and demonstrated positive results on CV death and hospitalisation for HF [1,2]. “The only difference was the higher event rate in EMPEROR-Reduced because we enriched it with more history about HF hospitalisation and higher levels of NT-proBNP as entry criteria,” Prof. Faiez Zannad (University of Lorraine, France) pointed out. He presented a pre-specified meta-analysis of the 2 trials that was powered to assess CV and renal outcomes in subgroups of special interest [1].

The pooled hazard ratio for the primary outcome of first hospitalisation for HF or CV death for both trials was 0.74 (95% CI 0.68–0.82), with HR 0.75 (95% CI 0.65–0.86) for EMPEROR-Reduced and HR 0.74 (95% CI 0.65–0.85) for DAPA-HF. A test for heterogeneity of the effect was non-significant (P=0.89). “Because we had a wealth of data, we could look deeper into subgroups,” Prof. Zannad introduced further results. When stratifying according to diabetes status, the treatment benefit was very similar in patients with and without diabetes: with diabetes, the HR was 0.74 (95% CI 0.65–0.84) and without 0.75 (95% CI 0.65–0.87) for both trials.

Also of interest were the results for renal outcomes. Assessing the first renal composite, defined as ≥50% sustained decline in estimated glomerular filtration rate (eGFR), end-stage renal disease, or renal death, revealed a decrease of about 40% in those with SGLT2 inhibitor treatment (HR 0.62; 95% CI 0.43–0.90). This benefit was consistent in patients with and without diabetes. “Contrary to the conventional therapy group, there was a slowing of the decline in eGFR in patients with and without diabetes,” said Prof. Zannad.

Further evidence on renal outcomes is provided by DAPA-CKD (NCT03036150), a study that enrolled only patients with an eGFR between 25–75 mL/minute/1.73 m² of body surface area and a urinary albumin-to-creatinine ratio between 200 and 5,000 mg/g [1,3]. The primary composite outcome was a lasting deterioration in eGFR of ≥50%, end-stage kidney disease, or death (renal or CV). Focusing on subgroups with and without diabetes, the hazard ratio for patients with diabetes was 0.64 (95% CI 0.52–0.79) and 0.50 (95% CI 0.35- 0.72) for non-diabetic patients. EMPA-Kidney (NCT03594110), a similar trial to DAPA-CKD but evaluating empagliflozin, is currently underway [1].

In view of these results for SGLT2 inhibition in HF, Prof. Zannad stressed that “benefits are not related to glucose-lowering. Patients with HFrEF and/or chronic kidney disease should be given an SGLT2 inhibitor whether they have or do not have type 2 diabetes.” However, as trial-based evidence is only available for these 2 agents at present, he considered it premature to talk about a class effect.

1. 
   
   1. Zannad F. Role of SGLT2 inhibitors in patients without DM: is it a class effect? Heart Failure and World Congress on Acute Heart Failure 2021, 29 June–1 July.
   2. Zannad F, et al. Lancet. 2020;396(10254):819–29.
   3. Heerspink HJL, et al. New Engl J Med. 2020;383(15):1436–46.

 

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Posted on 19 August, 202122 February, 2024