SGLT‐2 inhibitors for cardiac amyloidosis: Hype or hope?

Cardiac amyloidosis (CA), resulting either from misfolded immunoglobulin light-chain (light-chain amyloidosis [AL]) or transthyretin (transthyretin amyloidosis [ATTR]) proteins, is responsible for a progressive impairment of cardiac function causing heart failure (HF).1 Despite the approval of disease-modifying treatments (DMTs) for ATTR-CA (tafamidis and acoramidis) and other drugs in the pipeline,2 a number of patients cannot access currently approved DMTs due to economic reasons, advanced stage of disease, or specific aetiology (i.e., AL), and supportive care remains the cornerstone for HF management.3 Furthermore, patients with CA were excluded from large clinical trials testing guideline-directed medical treatments (GDMTs) in patients with HF. A retrospective analysis of ATTR-CA patients, however, showed benefits of low-dose β-blockers (in those with left ventricular ejection fraction [LVEF] ≤40%) and mineralocorticoid receptor antagonists (MRAs) on all-cause mortality reduction (in all patients, and particularly in those with LVEF >40%).4 Similarly, hitherto sparse evidence reported positive effects on the reduction of HF hospitalization as well as on cardiovascular (CV) and all-cause mortality for sodium-glucose cotransporter-2 (SGLT-2) inhibitors.5, 6 Karakasis et al. recently reported in the European Journal of Clinical Investigation the results of a systematic review and meta-analysis about the use of SGLT-2 inhibitors in patients with CA.7 By considering 9766 participants from five observational studies, SGLT-2 inhibitors reduced all-cause and CV mortality, major adverse CV events, and hospitalizations for HF and were associated with a reduced occurrence of cardiac arrhythmias (atrial fibrillation, ventricular tachycardia and cardiac arrest).7 Irrespective of a number of limitations deriving from the observational design of the studies considered, which were correctly acknowledged by the Authors, this meta-analysis clearly suggests that SGLT-2 inhibitors are effective drugs that can improve the prognosis of CA patients. Patients with CA present with a peculiar impairment in hemodynamics. Indeed, they show increased pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP) and mean arterial pulmonary artery pressure (mPAP) as well as reduced cardiac index (CI) and stroke volume index (SVI) at rest.8 Importantly, a reduced CI was found as the strongest factor associated with a combination of cardiac transplantation, need for left ventricle assist device, or all-cause mortality and HF hospitalization.8 During exercise, a drastic worsening of pulmonary hypertension is observed in these patients along with a net reduction in pulmonary arterial compliance and an unchanged pulmonary vascular resistance.9 These modifications are responsible for a marked right-sided congestion in CA patients as well as for increased right ventricle (RV) afterload because of the disease of the left heart, the presence of RV stiffness caused by amyloid deposition, and right-sided ventriculo-arterial uncoupling.9 The presence of elevated filling pressures and pulmonary hypertension (combined pre- and post-capillary), which are worsened during exercise, are inevitably responsible for classic signs and symptoms of HF, and especially for their recurrence throughout the natural history of the underlying disease. It appears, then, plausible that prescription of drugs able to tackle such hemodynamic impairment should be instituted, especially, but not only, among those who cannot be prescribed DMTs. While CA patients were excluded from HF clinical trials of GDMTs, beneficial effects were reported in patients with ATTR-CA with low-dose β-blockers (in patients with HF and reduced ejection fraction [HFrEF]) and MRAs.4 Definitely, any drugs targeting the kidney-heart axis and systemic hemodynamics could better suit the management of CA patients with HF. To this end, the approval of SGLT-2 inhibitors as cardio-kidney-metabolic drugs represented a paradigm shift, especially, but not only, for patients with HF and preserved ejection fraction (HFpEF), whose phenotype is frequently encountered among CA patients at the time of diagnosis. Indeed, SGLT-2 inhibitors were tested in observational studies and provided encouraging results in terms of functional status, reduced diuretic agent requirement, decreased risk for HF hospitalization, CV and all-cause mortality, ischemic stroke and major adverse CV events5, 10, 11 with limited side effects that are not different from those reported in other populations of HF patients. Some mechanistic explanations for the success of SGLT-2 inhibitors in patients with HFpEF could be found by looking at the results of the CAMEO-DAPA trial, where dapagliflozin was able to decrease PCWP both at rest and during maximal exercise, exertional right atrial and pulmonary artery pressures, and also plasma volume and body weight,12 thus improving essential, pathophysiological abnormalities of HFpEF. Last but not least, it is important to consider that ATTR-CA and AL-CA are two different entities and are indeed treated differently. While therapies for the latter include chemotherapy (daratumumab, cyclophosphamide, bortezomib and dexamethasone) that causes immunosuppression,13 DMTs for ATTR-CA include amyloid stabilizers (tafamidis and acoramidis)2 which have a neutral impact on the immune system. Whether these therapeutic differences might reflect on the effects of SGLT-2 inhibitors is worthy of remark. However, SGLT-2 inhibitors have shown both cardioprotective effects and anticancer properties14 and an improvement in outcomes, such as acute HF, all-cause mortality, all-cause hospitalizations, atrial fibrillation/flutter and acute kidney injury,15, 16 thus portending a net benefit for cardio-oncology patients. Importantly, myocardial inflammation is encountered in a portion of patients with ATTR-CA and may be associated with a higher risk of death and HF hospitalizations.17 SGLT-2 inhibitors were shown to possess anti-inflammatory effects, mediated by a reduction in pro-inflammatory mediators, inflammasome activation and reduced recruitment of immune cells in the kidney and the heart18 (Figure 1). Accordingly, they could be used to target such aspects and improve the prognosis of CA patients. All of the aforementioned findings and the meta-analysis by Karakasis et al.7 do support additional research with SGLT-2 inhibitors in the field of CA. Vericiguat, a soluble guanylate cyclase (sGC) stimulator, is now approved for HFrEF patients with LVEF <45%. Based on the stimulation of the nitric oxide (NO)-sGC-cyclic guanosine monophosphate (cGMP) pathway, vericiguat provided positive results in terms of reduced hospitalizations for HF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial.19 Based on its mechanism of action, vericiguat improves the regulation of the vascular tone and similarly to SGLT-2 inhibitors might be considered in CA patients with reduced LVEF. In pre-clinical models, sGC stimulation exhibited vasodilatory properties, antifibrotic effects, improvement of myocardial remodelling and attenuation of renal dysfunction.20 A general improvement of hemodynamic parameters of left and right heart were observed in a sub-analysis of the VICTORIA trial21 and in small real-life experiences.22, 23 However, patients with CA were excluded from the VICTORIA trial19 and no evidence from case reports is available for vericiguat in CA patients. Since vericiguat is approved for HFrEF patients with LVEF <45%, this excludes a priori patients with CA, as in most cases they present with HFpEF. With this regard, it is important to remember that in the VITALITY-HFpEF (Effect of Vericiguat vs. Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction) trial, vericiguat was not able to improve the physical limitation score of the Kansas City Cardiomyopathy Questionnaire after 24 weeks of treatment.24 However, patients with CA display an LVEF which is preserved only apparently since they have smaller ventricular cavities due to the accumulation of amyloid fibrils that causes reduced and fixed SVI and a decreased CI.25 The equivalent of such impairment is the clinical picture of a patient who is hypoperfused and congested, that is, “cold & wet” according to Stevenson diagram. Accordingly, HF in the context of CA might be considered as a functional HFrEF, and vericiguat could fit in this context. Since right HF is likely to respond to NO stimulation following the administration of NO donors (nitrates, sodium nitroprusside) or vasodilators (levosimendan), the stimulation of the NO-sGC-cGMP pathway through vericiguat may represent an important therapeutic strategy for managing such patients in the long term. As a proof of the beneficial hemodynamic effects of vericiguat, the positive experience in a patient with Fabry disease, a genetic, storage disease with a restrictive phenotype responsible for HF,26 could serve as an example to further study this drug in CA. Although a single experience does not support the routine use of vericiguat in that context, we feel that some pathophysiological aspects may overlap with CA, supporting the cautious use of vericiguat on a case-by-case basis. However, for the sake of truth, this hypothesis needs to be formally tested in adequately designed studies and no randomized trials with vericiguat have been conducted to date nor have been registered on ClinicalTrials.gov. In conclusion, observational studies reported SGLT-2 inhibitors as an effective therapeutic strategy in patients with CA amyloidosis, and this was confirmed by the meta-analysis by Karakasis et al.7 We believe that SGLT-2 inhibitors should be routinely prescribed to CA patients as they were found beneficial to improve outcomes, including HF hospitalization and CV mortality. SGLT-2 inhibitors also provide a cardio-renal protection, which is an important aspect in CA patients, who could experience the involvement of both heart and kidney. Finally, SGLT-2 inhibitors have a good safety profile. In the future, randomized clinical trials are definitely needed to confirm the preliminary, encouraging findings recently reported by Karakasis et al.7 All authors contributed to the second revision of the manuscript. All authors approved the final version of the manuscript. Open access publishing facilitated by Aziende Socio Sanitarie Territoriale dei Sette Laghi, as part of the Wiley – SBBL agreement. None. The present manuscript does not contain any original data.