Finerenone, Sotagliflozin Benefit HF Despite Renal Dysfunction

Mitchel L. Zoler, PhD

November 15, 2021

New analyses of trial results for the cardiorenal agents finerenone and sotagliflozin continued the pattern showing that they exert consistent heart failure benefits in patients who span a broad spectrum of renal function, further disproving the notion that more severe stages of chronic kidney disease preclude aggressive medical management.

Analysis of combined data from two pivotal trials of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (Kerendia), which together enrolled more than 13,000 patients with type 2 diabetes and chronic kidney disease, showed in greater detail that finerenone treatment reduced the incidence of hospitalizations for heart failure and cardiovascular death "across the spectrum" of chronic kidney disease (CKD) stages 1-4.

That spectrum included patients with estimated glomerular filtration rates (eGFR) as low as 25 mL/min per 1.73m2 and patients with micro- or macroalbuminuria, as well as those with normal urinary albumin levels, Gerasimos Filippatos, MD, reported at the American Heart Association scientific sessions.

And in a separate, unrelated report, combined data from the two pivotal trials, with a total of nearly 12,000 patients with type 2 diabetes, for sotagliflozin (Zynquista), a novel and still unapproved agent that inhibits both the sodium-glucose cotransporter (SGLT) 1 and 2 enzymes, showed a consistent effect significantly reducing cardiovascular death, hospitalization for heart failure, or urgent heart failure outpatient events in patients with eGFR rates as low as 25 mL/min per 1.73m2, Deepak L. Bhatt, MD, reported at the meeting.

These two reports follow a third, presented just a week earlier during Kidney Week, that showed the benefit from the SGLT2 inhibitor empagliflozin (Jardiance) for preventing heart failure hospitalizations or cardiovascular death in patients with heart failure with preserved ejection fraction remained consistent even in patients with an eGFR as low as 20 mL/min/1.73m2 in results from the EMPEROR-Preserved trial. Similar findings for empagliflozin in patients with heart failure with reduced ejection fraction in the EMPEROR-Reduced trial came out nearly a year ago.

A message to clinicians from these reports is, "don't wait for patients to develop heart failure" to start these drugs, according to Dipti Itchhaporia, MD, director of disease management for the Hoag Heart and Vascular Institute in Newport Beach, Calif. "It's time to start using these drugs upstream to have fewer patients with heart failure downstream," she said in an interview.

Finerenone Works Differently Than Spironolactone

The new finerenone analysis included 5,734 patients enrolled in the FIDELIO-DKD trial, and 7,437 in the FIGARO-DKD trial, two very similar trials that differed by transposing the primary endpoint of one to the secondary endpoint of the other, and vice versa. The combined analysis is known as FIDELITY.

Expanding on a report that he first gave at the European Society of Cardiology annual congress in August 2021, Filippatos provided a few additional details on the analysis that showed a consistent effect of finerenone on preventing hospitalizations for heart failure, and on preventing a combined endpoint of hospitalizations for heart failure and cardiovascular death regardless of the severity of chronic kidney disease down to 25 mL/min per 1.73 m. Statistical analysis showed no hint of an interaction between finerenone's effect on these outcomes in patients with an eGFR of 60 mL/min per 1.73 m2 or greater and those with reduced renal function. Analyses also showed no interaction based on urinary albumin-to-creatinine ratio, be it more or less than 300 mg/g, reported Filippatos, professor and director of the heart failure unit at Attikon University Hospital in Athens.

"We use MRAs [such as spironolactone] in heart failure patients, but it's difficult to use because of the risk of patients developing hyperkalemia," noted Itchhaporia, who added that reluctance to use spironolactone is especially high for patients with depressed renal function, which could exacerbate a hyperkalemic effect. Evidence shows that finerenone poses a substantially reduced risk for raising serum potassium levels, making finerenone a more attractive agent to use in patients with CKD who have an elevated risk for heart failure events as well as an increased risk for hyperkalemia, like those enrolled in the two finerenone trials, she said.

Sotagliflozin Uniquely Inhibits SGLT1 and SGLT2

The new sotagliflozin analyses reported by Bhatt combined data for more than 11,800 patients randomized into either of two trials, SCORED, which randomized more than 10,000 patients with type 2 diabetes and chronic kidney disease, and SOLOIST, which randomized more than 1,000 patients with type 2 diabetes who were recently hospitalized for worsening heart failure.

looked at the impact of sotagliflozin treatment on the combined outcome of cardiovascular death, hospitalization for heart failure, or an urgent outpatient visit because of heart failure based on kidney function at baseline. The analysis showed that sotagliflozin was at least as effective in the 8% of study patients who at baseline had an eGFR of 25-29 mL/min per 1.73 m2 as it was in patients with more preserved renal function.

Benefit from sotagliflozin treatment "was consistent across the full range of eGFR," said Bhatt, professor at Harvard Medical School in Boston and executive director of interventional cardiovascular programs at Brigham and Women's Hospital in Boston.

Results from a second analysis that he reported also showed a consistent effect of sotagliflozin on reducing hemoglobin A1c levels in the enrolled patients, even those with the lowest levels of renal function, an effect not previously seen with the related class of SGLT2 inhibitors (which includes empagliflozin, canagliflozin [Invokana], and dapagliflozin [Farxiga]). Bhatt suggested that, while SGLT2 inhibitors act entirely in the kidneys and hence their effect on glycemic control is blunted by renal dysfunction, sotagliflozin also inhibits the SGLT1 enzyme, which functions in the gut to transport glucose out of the digestive tract and into the blood, a glycemic control pathway that's independent of renal function.

FIDELIO-DKD, FIGARO-DKD, and FIDELITY were sponsored by Bayer, the company that markets finerenone (Kerendia). SCORED and SOLOIST were sponsored by Sanofi, and later by Lexicon, the companies developing sotagliflozin (Zynquista). EMPEROR-Preserved and EMPEROR-Reduced were sponsored by Boehringer-Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). Filippatos has had financial relationships with Bayer and Boehringer-Ingelheim, as well as with Amgen, Medtronic, Novartis, Servier, and Vifor. Bhatt has received research funding from Sanofi, Lexicon, Bayer, and Boehringer-Ingelheim, Lilly, and numerous other companies, and he has been an adviser to Boehringer-Ingelheim and several other companies.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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