Finerenone and GLP-1 medicines and their effects on heart and kidney health in type 2 diabetes

Over the past few decades, the prevalence of type 2 diabetes mellitus (T2DM) has risen dramatically worldwide, and approximately 537 million adults are living with diabetes [1], resulting in an elevated risk of cardiovascular and renal diseases. As the prevalence of T2DM increases, it has become one of the leading causes of the substantial increase in end-stage renal disease (ESRD) globally. Even with the current treatment options available, people with T2DM still face a considerable risk of developing cardiovascular and renal events such as myocardial infarction, stroke and ESRD [2]. Therefore, the prevention of cardiovascular diseases (CVD) and DKD progression is critical for the management of patients with T2DM.

Recently, trials on two new classes of antidiabetic agents, finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA), have shown cardiovascular and kidney benefits in patients with T2DM. Notably, in clinical trials of renin-angiotensin system (RAS) inhibitors therapy in people with type 2 diabetes, lowering albuminuria to levels < 300 mg/g creatinine or by > 30% from baseline has been related to improved renal and cardiovascular outcomes, leading to the ADA’s clinical practice recommendation that RAS inhibitors should be the first-line drug therapy in diabetes [3]. Therefore, it should be mentioned that the benefit of these two new classes of glucose-lowering medications was on background RAS inhibitors therapy in > 80% of the participants. Finerenone is a novel selective and nonsteroidal mineralocorticoid receptor antagonist. Compared with steroidal mineralocorticoid receptor antagonists, finerenone has shown more potent anti-inflammatory and anti-fibrotic effects in rodent models [4–6]. Two large-scale randomized placebo-controlled trials targeted at patients with T2DM and chronic kidney disease (CKD) have shown that finerenone significantly lowers the occurrences of composite cardiovascular outcome (defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and composite renal outcome (defined as a composite of a sustained decrease of at least 40% in the estimated glomerular filtration rate (eGFR) from the baseline, kidney failure, or death from renal causes), irrespective of history of CVD [7, 8].

There is good evidence to support the use of GLP1-RA. Several sizable randomized placebo-controlled trials (RCTs) have shown cardiovascular and renal benefits in patients with T2DM and/or CKD. In addition, the ADA recommended a GLP1-RA or sodium-glucose co-transporter-2 (SGLT2) inhibitors for individuals with T2DM who have established atherosclerotic cardiovascular disease or indicators of high cardiovascular risk, CKD, or heart failure to reduce the risk of MACE [9].

A recently published meta-analysis reported a significant reduction in MACE with the use of GLP1-RA in patients with T2DM [10, 11]. However, to date, the impact of finerenone and GLP1-RA on MACE in patients with or without established atherosclerotic cardiovascular disease (ASCVD) has not been confirmed. As such, we designed the present meta-analysis based on RCTs to compare the clinical benefit of finerenone and GLP1-RA in patients with T2DM with and without established ASCVD and to update their overall cardiovascular and renal effects.

Finerenone and GLP1-RA are antidiabetic medications that have been demonstrated to lower the risk of cardiovascular and renal events in patients with T2DM [33, 34]. However, the relative benefits of these drugs between patients with or without pre-existing ASCVD remain uncertain. The present meta-analysis confirms the benefits of finerenone and GLP1-RA in reducing the risk of MACE by approximately 14% in patients with pre-existing ASCVD. In addition, our meta-analysis reveals that these drugs have a significant impact on overall cardiovascular and renal events.

Finerenone is the first non-steroidal mineralocorticoid receptor antagonist that has high affinity and selectivity for the mineralocorticoid receptor (MR) and differs from steroidal mineralocorticoid receptor antagonists (MRAs) and between each other in terms of important physiochemical, pharmacodynamic, and pharmacokinetic properties [35]. Similar to steroidal MRAs, evidence supports a protective role of finerenone in anti-inflammatory, anti-fibrotic and anti-remodeling in both kidney and cardiac tissues, as well as reducing renal and myocardial hypertrophy, BNP, and proteinuria in rodent models, which may be associated with its benefits in renal outcomes [4, 36, 37]. There is evidence from a previous publication that finerenone did not show a significant difference in reduced incidence of MACE based on pre-existing cardiovascular disease status [38]. However, with recently updated trials of finerenone, the present meta-analysis shows that finerenone is likely to reduce the risk of MACE by 15% in patients with established ASCVD (HR, 0.85; 95% CI, 0.78–0.94).

Heart failure is a major cause of hospitalization and is responsible for approximately 7% of cardiovascular deaths, which worsens the prognosis of T2DM patients [39]. Patients with a history of HF at baseline studied in finerenone and GLP1-RA trials have asymptomatic HFrEF (LVEF < 40%) or HFrEF with NYHA class I, HFpEF (LVEF ≥ 50%), or HFmrEF (LVEF 40–49%). Finerenone reduced HHF risk by 22%, whereas there was only a nonsignificant 9% relative risk reduction with GLP1-RA. In addition, a history of HF did not appear to modify the effect of finerenone versus placebo on HHF in the presence of optimized RAS blockade, which might be explained by the special potency of finerenone, such as controlling blood pressure, anti-cardiac remodeling and fibrosis [37]. A newly published meta-analysis has highlighted that the effects of GLP-RA are modified by HF status. Treatment with GLP1-RA did not reduce the risk of HHF in T2DM patients with HF history, particularly HFrEF, but may prevent new-onset HF in T2DM patients without HF [30, 40, 41]. The mechanisms for the different effects of GLP1-RA on HHF prevention among patient with or without HF remains uncertain but, notably, the outcomes showed the reductions in myocardial infarction among the GLP1-RA trials (Figure S3). This finding raises the possibility that GLP1-RA may lower the risk of HHF by reducing the risk of myocardial damage by either reducing body weight, preventing coronary occlusion and myocardial small vessel disease, or ameliorating myocardial muscle damage caused by inflammation or other processes [41, 42]. Meanwhile, GLP1-RA are known to increase heart rate, which may be deleterious to patients with HF. It has reported that GLP1-RA can reduce epicardial fat, which leads to decreased risk of atherosclerotic cardiovascular disease, may explain why GLP1-RA may possibly reduce HHF [43, 44]. Furthermore, the GLP1 receptor, which plays an important role in cardiomyocytes and sinoatrial node cells through a cyclic adenosine monophosphate–dependent pathway, may induce intracellular calcium overload and increase the risk of ventricular ectopy in high-risk patients, such as those with severely depressed left ventricular ejection fraction (LVEF) [30, 40].

With regard to kidney outcomes, the present meta-analysis revealed that GLP1-RA has a similar effect as finerenone on reducing the risk of renal events, even excluding macroalbuminuria, which is in contrast to the findings of another meta-analysis [10]. One of the reasons could be that the REWIND data were not included, because the results were not published at the time of submission. The REWIND data showed the greatest relative risk reductions in renal outcomes among the GLP1-RA trials. Dulaglutide significantly lowered all three components of the composite renal outcome (the development of new macroalbuminuria, a sustained 30% or greater decline in eGFR, or new chronic renal replacement therapy), the largest effect was noted for the development of new macroalbuminuria [27]. The US Food and Drug Administration product label states that liraglutide is at increased risk of renal impairment [45]. Meanwhile, patients with HFrEF and recent hospitalization for acute HF have a greater risk of adverse renal outcomes compared with patients without these conditions. However, a post hoc analysis of FIGHT suggests that liraglutide was not associated with worsening renal function among patients with HFrEF and a recent hospitalization for HF [46]. In addition, the possibility of the benefit of GLP1-RA on renal outcomes will come with the results of the ongoing FLOW (NCT03819153↗), which specifically tests the kidney benefits of this class [3, 47]. The mechanism underlying the beneficial effects remains unclear but could be, at least in part, due to a combination of GLP-1 receptor agonist-induced weight loss, blood pressure lowering and glycaemia improvements [42]. Interestingly, human GLP-1 analogues such as liraglutide and semaglutide show a favorable risk–benefit profile for MACE and renal outcomes compared with exendin-4-based drugs, including exenatide and lixisenatide. Mechanisms linking the actions of GLP-1 analogues to cardiovascular and renal outcomes are not well understood. It was reported that GLP-1 analogues enhance sodium and water excretion, reduce albumin excretion and have anti-inflammatory effects, which might play a protective role in cardiovascular and renal events. Furthermore, they are resistant to renal elimination due to their large molecular weight or noncovalent binding to albumin, whereas exendin-4 based drugs are eliminated by the kidneys. In addition, exendin-4 analogues are resistant to degradation by dipeptidyl peptidase-4 (DPP-4), which might explain the greater cardiovascular and renal protective effects of GLP-1 analogues than exendin-4 analogues [48, 49].

The major strengths of this meta-analysis are as follows: first, this is the first study to investigate the benefits of finerenone and GLP1-RA between patients with or without established ASCVD. Second, the trials included in this meta-analysis were large, and the statistics were reliable, which provided high-quality evidence to minimize the risk of bias and heterogeneity. Several limitations should be noted in this meta-analysis. We performed this meta-analysis using aggregate trial-level data, and as a result, the observed differences in treatment effects between subgroups were limited. In addition, the included studies were slightly different in the exact inclusion/exclusion criteria and endpoint definitions, which is particularly evident for the definitions of renal outcomes. Randomized trials with head-to-head comparisons would be necessary to demonstrate the possible superiority of a drug class over the other within finerenone and GLP1-RA. Third, there were differences in drug doses, patient characteristics, and background therapy. Finally, the present meta-analysis is not able to assess potential incremental or additive treatment effects when both drug classes are used in combination.

In conclusion, finerenone and GLP1-RA lead to a risk reduction in MACE to a similar extent in patients with established ASCVD. In patients with T2DM, finerenone has significant effects on reducing the risk of progression of kidney disease and HHF, whereas GLP1-RA is associated with a lower risk of renal events but has no effect on HHF. Therefore, the prevention of HHF potentially by finerenone over GLP1-RA should be considered for decision makers in adults with T2DM.

Below is the link to the electronic supplementary material.

This work was supported by grants from the National High Level Hospital Clinical Research Funding (2023-NHLHCRF-YS-01) and National Natural Science Foundation of China (82300815).

XG and WL designed and monitored the whole analysis. XG and SJ contributed to study selection. GX, SJ and YY contributed to data extraction. SJ and YY provided the methodological support. GX and SJ contributed to the data analysis and paper writing. SJ and WL were responsible for the data review. All authors provided critical review. All authors reviewed the manuscript.

The author Wenge Li received a fund from the National High Level Hospital Clinical Research Funding and National Natural Science Foundation of China. The funding agency had no role in designing the study, conducting the analysis, interpreting the data or writing the manuscript.

All data generated or analyzed during this study are included in this published article.

Shimin Jiang, Email: minjiang101@163.com.

Wenge Li, Email: wenge_lee2002@126.com.