Novel treatments deliver positive results for populations with substantial cardiovascular morbidity and mortality
Presenters: Gerasimos Filippatos, MD and Robert Rosenson, MD
In separate clinical trials, investigational therapies for the treatment of patients with chronic kidney disease (CKD) and type 2 diabetes mellitus and patients with refractory hypercholesterolemia showed the potential to reduce cardiovascular risk in these populations.
Finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist that inhibits inflammation and fibrosis, reduced the risk of a composite cardiovascular outcome irrespective of a history of cardiovascular disease, with a low incidence of hyperkalemia-related treatment discontinuation, in patients with CKD and type 2 diabetes in the phase III clinical trial Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD),1 announced Gerasimos Filippatos, MD, professor of cardiology, the National and Kapodistrian University of Athens, Greece.
“In patients with CKD and type 2 diabetes treated with optimized renin-angiotensin system therapy, finerenone significantly reduced the overall risk of cardiovascular events by 14% compared with placebo, and we found this effect to be similar between patients with a history of cardiovascular disease and those without, demonstrating the benefit of finerenone for both primary and secondary cardiovascular prevention,” he said.
In FIDELIO-DKD, conducted at 913 sites in 48 countries, 5,734 patients with type 2 diabetes, moderately or severely elevated levels of albumin, and an estimated glomerular filtration rate (eGFR) ≥ 25 to < 75 mL/min/1.73 m2 were randomized to finerenone at titrated dosages of 10 or 20 mg once daily or placebo. All patients were on maximally tolerated doses of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 4 weeks prior to randomization; 45.9% of patients had a history of cardiovascular disease at entry.
As reported previously, the primary outcome, a composite of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes, occurred in 17.8% of the finerenone group and in 21.1% of the placebo group over a median of 2.6 years of follow-up, corresponding to an 18% relative risk reduction (hazard ratio [HR] 0.82; P = .001).2
A key secondary end point, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure, was reduced by 14% (HR 0.86; P = .034) in the finerenone arm compared with placebo. The relative reduction in the risk of a composite outcome event with finerenone was 15% (HR, 0.85; 95% confidence interval 0.71–1.02) in patients with a history of cardiovascular disease, similar to the 14% reduction (HR, 0.86; 95% confidence interval 0.68–1.08) in those without a history of cardiovascular disease (P for interaction = .85).1
Overall, the rates of treatment-emergent adverse events were similar between the two arms, with a manageable increase in the rate of hyperkalemia in the finerenone arm. The mean increase in serum potassium was 0.2 mEq/L in the active-treatment arm vs placebo. Any hyperkalemia occurred in 18.3% of patients randomized to finerenone and in 9.0% of those randomized to placebo, and the incidence of hyperkalemia leading to permanent discontinuation was 2.3% and 0.9%, respectively.
Additional phase III trials of finerenone are in progress.
In a second study, evinacumab, an investigational fully human monoclonal antibody inhibitor of angiopoietin-like 3, significantly reduced levels of low-density lipoprotein cholesterol (LDL-C) vs placebo when administered subcutaneously or intravenously to patients with refractory primary hypercholesterolemia.3
“The addition of evinacumab to standard-of-care lipid-lowering therapy in patients with refractory hypercholesterolemia may potentially facilitate more patients attaining guideline-defined LDL-C goals and in doing so, the potential to reduce the risk of cardiovascular disease events and overall mortality,” said lead investigator Robert Rosenson, MD, professor of medicine, Mount Sinai Icahn School of Medicine, New York City.
Eligible patients for the phase II study were those with a diagnosis of primary hypercholesterolemia. Heterozygous familial hypercholesterolemia was diagnosed by genotyping or by clinical diagnosis and represented 72.5% of participants in the study of subcutaneous evinacumab and 81.1% of those in the study of the intravenous form. All participants had LDL-C levels at least 70 mg/dL if they had cardiovascular disease or at least 100 mg/dL if they did not have cardiovascular disease.
At the screening visit, patients had to be receiving a stable maximally tolerated dose of a statin, with or without ezetimibe, for at least 4 weeks, and all had to be receiving a proprotein convertase subtilisin/kexin type 9 inhibitor for at least 8 weeks.
In the study of the subcutaneous regimen (n = 160), patients were randomized 1:1:1:1 to placebo or evinacumab 450 mg every week, 300 mg every week, 300 mg every 2 weeks. The mean baseline LDL-C in this group was 150.0 mg/dL. The reductions in LDL-C from baseline to week 16 in the evinacumab arms compared with placebo were 56.0% with 450 mg weekly (P < .0001), 44.0% with 300 mg weekly (P < .0001), and 29.7% with 300 mg every 2 weeks (P < .0001).
In the study of the intravenous regimen (n = 106), patients were randomized 1:1:1 to placebo or evinacumab 5 or 15 mg/kg every 4 weeks. The mean baseline LDL-C in this study was 144.5 mg/dL. Reductions in LDL-C from baseline to week 16 in the evinacumab arms compared with placebo were 50.5% in the 15-mg/kg arm (P < .0001) and 24.2% in the 5-mg/kg arm (P = .0109).
There were favorable changes in other atherogenic lipoproteins with both subcutaneous and intravenous evinacumab compared with placebo.
References
- https://www.abstractsonline.com/pp8/?#!/9144/presentation/40168
- Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med, October 23, 2020. doi:10.1056/NEJMoa2025845
- https://www.abstractsonline.com/pp8/?#!/9144/presentation/40160
Dr. Filippatos has disclosed financial relationships (grant, research support, advisor, or review panel member) with Bayer, Vifor, Medtronic, Boehringer Ingelheim, Novartis, and Sanofi. Dr. Rosenson has disclosed the following: honoraria from 89Bio, Amgen, Corvidia, CVS Caremark, Kowa, Medicines Company, Regeneron, and UpToDate; stock shareholder with MediMergent; research grants with Amgen, Medicines Company, Regeneron, and Novartis (all paid to institution).