Combination of a aldosterone synthase inhibitor (ASI) and a sodium-glucose co-transporter 2 inhibitor (SGLT2i) for use in methods of reducing the risk of cardiovascular and heart failure events in a subject

Abstract

The disclosure provides methods of reducing the risk of cardiovascular events and heart failure events in patients at risk of heart failure, the methods comprising administering to the patient a combination comprising an aldosterone synthase inhibitor (ASi) and a sodium-glucose co-transporter 2 inhibitor (SGLT2i).

Description

METHODS OF REDUCING THE RISK OF CARDIOVASCULAR AND HEART FAILURE EVENTS IN A SUBJECTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 715,731, filed November 4, 2024, the disclosure of which is incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure provides methods of reducing the risk of cardiovascular events and heart failure events in patients at risk of heart failure, and compounds for use in such methods.BACKGROUND

[0003] Heart failure (HF) is a serious and progressive condition associated with frequent hospitalisations and high mortality rates. The aetiology of HF is complex, with multiple risk factors contributing to its development, including type 2 diabetes mellitus (T2DM), hypertension (HTN), atherosclerotic cardiovascular disease (CVD), older age, and obesity (Virani SS et al. Circulation. 2021;143(8):e254-e743).

[0004] Lifestyle factors such as diet and smoking also play a role in HF development. Risk factors vary between HF subtypes; myocardial infarction (MI) and ischaemic heart disease are common causes of heart failure with reduced ejection fraction, while heart failure with preserved ejection fraction is more common in older, female patients with hypertension and obesity. Heart failure is more prevalent in patients with diabetes or prediabetes compared to those with normal blood sugar levels (Kristensen SL et al. Circulation Heart failure.2016;9(l):e002560). There is significant overlap between HF and kidney impairment, and the combination of HF and chronic kidney disease (CKD) is further accentuated by T2DM (Zelniker TA, Braunwald E. Journal of the American College of Cardiology.2018;72(15): 1845-55).

[0005] When prevention fails, HF becomes a serious, progressive condition characterised by frequent hospitalisations and high mortality. Approximately 50% of patients die within 5 years of diagnosis. Moreover, HF is the leading cause of hospitalisations inindividuals over 65 years (Savarese G et al. Cardiovascular research. 2023; 118(17):3272-87). Symptoms such as fatigue, dyspnoea, and fluid retention are severe and debilitating, significantly impacting patients’ quality of life (McDonagh TA et al. European heart journal. 2021;42(36):3599-726). An estimated 64 million people worldwide are affected by HF (Groenewegen et al. European journal of heart failure. 2020;22(8): 1342-56; Lippi G, Sanchis- Gomar F. AME Medical Journal. 2020;5), with a prevalence of approximately 1.0% to 2.0% in the general US adult population (Groenewegen et al. European journal of heart failure. 2020;22(8): 1342-56) and ranging from 1.0% to 3.9% across European countries (Savarese G et al. Cardiovascular research. 2023;l 18(17):3272-87; Seferovic PM et al. European journal of heart failure. 2021;23(6):906-14). The lifetime risk of HF has increased, with approximately 1 in 4 individuals expected to develop HF in their lifetime (Bozkurt et al. Journal of Cardiac Failure. 2023;29(10): 1412-51). Moreover, recent data has indicated that HF related mortality in the US is on the rise (Martin et al. Circulation. 2024;149(8):e347- e913).

[0006] The recent 2022 American Heart Association (AHA) / American College of Cardiology (ACC) / Heart Failure Society of America (HF SA) guideline highlights the evolving role of biomarkers and structural changes in identifying patients at risk of developing HF, enabling targeted treatment strategies for prevention. Heart failure is classified into four stages (Stages A to D) by the ACC / AHA, with Stages A (at risk for HF) and B (pre-HF) being asymptomatic stages. Therapeutic treatments in Stage A aim to modify risk factors, while treatments in Stage B aim to address risk and structural heart disease to prevent HF (Heidenreich et al. Circulation. 2022;145(18):e895-el032).

[0007] Patients with T2DM, HTN, and CVD have increased risks of morbidity and mortality. Current treatments for these conditions are focused on treating the underlying diseases. Treatments like renin-angiotensin system inhibitors, GLP-1 receptor agonists, betablockers, and sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) were primarily aimed at protecting the patients from atherothrombotic events, such as MI, stroke, and microvascular complications to T2DM. Although T2DM, HTN, and CVD are recognised risk factors of HF, the risk of leading to HF development is often overlooked until an event of hospitalisation for HF has occurred, a stage after which it may be considered too late for effective treatments and having poor prognosis.

[0008] The improvement in treatment of HF with SGLT2i is significant regardless of underlying LVEF, with relative risk reduction in hospitalisation for HF / HF events and CV death ranging between 18% and 26% in the dapagliflozin and empagliflozin studies (Anker etal. The New England journal of medicine. 2021 ;385(16): 1451 -61 ; McMurray et al. European journal of heart failure. 2019;21(5):665-75; Packer et al. Circulation. 2021;144(16): 1284-94; Solomon et al. The New Engl and journal of medicine. 2022;387(12): 1089-98). However, the residual risk in this patient population is substantial, necessitating the need for upstream treatments that can prevent the development of HF.

[0009] The methods described herein which utilize the combination of an aldosterone synthase inhibitor (ASi) and an SGLT2i may provide benefits in reducing cardiovascular risk, preserving kidney function, and lowering the composite of cardiovascular death and HF events in populations at increased risk of cardiorenal events. The methods described herein address the substantial medical need to prevent HF in individuals at increased risk of its development, considering the high burden of concomitant diseases and the persistently high morbidity and mortality associated with an HF diagnosis.SUMMARY

[0010] The disclosure provides a method of reducing the risk of cardiovascular death or a heart failure (HF) event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an aldosterone synthase inhibitor (ASi) and an amount of a sodium-glucose co-transporter 2 inhibitor (SGLT2i), wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0011] Also provided is a method of reducing the risk of a HF event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0012] Also provided is a method of reducing the risk of cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0013] Also provided is a method of reducing the risk of all-cause mortality in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0014] Also provided is a method of reducing the risk of atrial fibrillation or cardiovascular death in a patient with one or more risk factors for developing HF, and no previous history of atrial fibrillation, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0015] Also provided is a method of reducing the risk of myocardial infarction or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0016] Also provided is a method of reducing the risk of MACE (myocardial infarction, stroke or cardiovascular death) in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0017] Also provided is a method of reducing the risk of stroke or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0018] Also provided is a method of preventing or delaying an event selected from:(a) a composite of cardiovascular death or a HF event;(b) a HF event;(c) a composite of hospitalisation for HF, HF without hospitalisation, or cardiovascular death;(d) a composite of hospitalisation for HF or cardiovascular death;(e) a composite of hospitalisation for HF or HF without hospitalisation;(f) cardiovascular death;(g) all -cause death;(h) a composite of stroke or cardiovascular death;(i) a composite of a new diagnosis of atrial fibrillation or cardiovascular death;(j) a composite of myocardial infarction or cardiovascular death; and(k) a composite of myocardial infarction, stroke or cardiovascular death; in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount ofan SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0019] Also provided is a method of preventing or delaying HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0020] Also provided is a method of preventing or delaying HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0021] Also provided is a method of preventing or delaying symptomatic HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0022] Also provided is a method of preventing or delaying symptomatic HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

[0023] In any of the methods described herein, the ASi may be baxdrostat or a pharmaceutically acceptable salt thereof.

[0024] In any of the methods described herein, the SGLT2i may be dapagliflozin.

[0025] Also provided is an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) for use in any of the methods described herein.

[0026] Also provided is an SGLT2i (such as dapagliflozin) for use in any of the methods described herein.

[0027] Also provided is a combination of an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and an SGLT2i (such as dapagliflozin) for use in any of the methods described herein.

[0028] Also provided is the use of an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for use in any of the methods described herein.

[0029] Also provided is the use of an SGLT2i (such as dapagliflozin) in the manufacture of a medicament for use in any of the methods described herein.

[0030] Also provided is the use of a combination of an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and an SGLT2i (such as dapagliflozin) in the manufacture of a medicament for use in any of the methods described herein.

[0031] Also provided is a kit comprising: (a) an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and / or an SGLT2i (such as dapagliflozin), and (b) instructions for use of the ASi and / or an SGLT2i in any of the methods described herein.

[0032] Further aspects of the disclosure will be apparent to one skilled in the art from reading this specification.BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 depicts the study design of Study 1 (A Phase III, Randomised, Doubleblind, Placebo-controlled, Event-driven Study to Evaluate the Effect of Baxdrostat in Combination with Dapagliflozin Compared with Dapagliflozin Alone on the Risk of Incident Heart Failure and Cardiovascular Death in Participants with Increased Risk of Developing Heart Failure).DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0034] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed methods, compounds for use, and uses which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed methods, compounds for use, and uses that are, for brevity, described in the context of a single aspect, may also be provided separately or in any sub combination. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.Definitions

[0035] The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted.

[0036] In the disclosure, the singular forms “a,” “an,” and “the” include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise.

[0037] The term "and / or" as used in a phrase such as "A and / or B" herein is intended to include the following embodiments: "A and B," "A or B," "A," and "B."

[0038] Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0039] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0040] When a value is expressed as an approximation by use of the descriptor “about” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.

[0041] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is deemed to be combinable with any other embodiment s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. It is further noted that the claims may bedrafted to exclude an optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0042] As used herein, the terms “treatment,” “treating,” and the like, refer to measures (e.g., administration of a medicament(s) to a subject) that cure, lessen symptoms of, slow progression of, and / or halt progression of a diagnosed pathologic condition or disorder.

[0043] Prophylactic or preventative measures refer to measures (e.g., administration of the combination as described herein, to a subject) that prevent and / or delay the development of a targeted pathologic condition or disorder. Thus, those in need of prophylactic or preventative measures include those prone to have the disorder and those in whom the disorder is to be prevented.

[0044] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that may be used to enable delivery of a drug, e.g., an ASi and / or an SGLT2i, to a patient, as described herein.

[0045] An “effective amount” refers to an amount of one or more compounds of the present disclosure that, when administered to a patient, either as a single dose or as part of a series of doses, is effective to produce the described therapeutic or prophylactic effect. The dose may depend upon the body mass, weight, and / or blood volume of the patient. Patients may generally be monitored for therapeutic or prophylactic effectiveness using assays suitable for the disease, disorder, and / or condition being treated or prevented. The level of a compound that is administered to a patient may be monitored by determining the level of the compound (or a metabolite of the compound) in a biological fluid, for example, in the blood, blood fraction (e.g., serum), and / or in the urine, and / or other biological sample from the patient. Any method practiced in the art to detect the compound, or metabolite thereof, may be used to measure the level of the compound during the course of a therapeutic regimen.

[0046] The dose of a compound described herein may depend upon the patient’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person of ordinary skill in the medical art.

[0047] The terms “subject” and “patient” are used interchangeably and typically refer to mammals. In some embodiments, the patient or subject is a human. In some embodiments, the subject or patient is at least 18 years of age, i.e., an adult.

[0048] The term “combination” as used herein with respect to an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and an SGLT2i (such asdapagliflozin), may include, for example, fixed and non-fixed (e.g. free) forms (including kits or other administration or dosage forms) and uses, such as the simultaneous, sequential or separate use of an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and an SGLT2i (such as dapagliflozin).

[0049] As used herein, “standard of care agents for any of T2DM, hypertension and CVD” include at least one standard of care agent, for example, at least two or at least three or more medications or medication classes that are used to treat T2DM, hypertension and / or CVD. The standard of care agents, as described herein, may be used prior to and / or during administration of the combination described herein. Standard of care medications for T2DM, hypertension and CVD and their dosages are well-known to cardiologists and other medical practitioners who examine and treat patients with such conditions.

[0050] The term “cardiovascular (CV) death” refers to a death of a patient wherein the primary cause of death is due to acute myocardial infarction (MI), sudden cardiac death, heart failure, stroke, cardiovascular procedures, cardiovascular hemorrhage, or other cardiovascular causes. “Other cardiovascular causes” refers to a CV death not included in the above categories but with a specific, known cause (e.g., pulmonary embolism or peripheral arterial disease). In some embodiments, CV death may also include the death of a patient wherein the underlying cause of death is unknown.Methods

[0051] In one embodiment, there is provided a method of reducing the risk of cardiovascular death or a heart failure (HF) event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an aldosterone synthase inhibitor (ASi) and an amount of a sodiumglucose co-transporter 2 inhibitor (SGLT2i), wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of cardiovascular death or a HF event. In some embodiments, the patient has type 2 diabetes mellitus (T2DM), hypertension and cardiovascular disease (CVD), and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of cardiovascular death or a HF event (such as a composite of cardiovascular death or a HF event) relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of cardiovascular death or a HF event (such as a composite of cardiovascular death or a HF event) relative to a patient who was administered only anSGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of cardiovascular death or a HF event (such as a composite of cardiovascular death or a HF event) relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of cardiovascular death or a HF event is measured by time to the first occurrence of cardiovascular death or a HF event.

[0052] In one embodiment, there is provided a method of reducing the risk of cardiovascular death or a heart failure (HF) event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of cardiovascular death or a HF event. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of cardiovascular death or a HF event (such as a composite of cardiovascular death or a HF event) relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of cardiovascular death or a HF event (such as a composite of cardiovascular death or a HF event) relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of cardiovascular death or a HF event (such as a composite of cardiovascular death or a HF event) relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of cardiovascular death or a HF event is measured by time to the first occurrence of cardiovascular death or a HF event.

[0053] In one embodiment, there is provided a method of reducing the risk of a HF event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments,the method reduces the risk of a HF event relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of a HF event relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of a HF event relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of a HF event is measured by time to the first occurrence of a HF event.

[0054] In one embodiment, there is provided a method of reducing the risk of a HF event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of a HF event relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of a HF event relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of a HF event relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of a HF event is measured by time to the first occurrence of a HF event.

[0055] In one embodiment, there is provided a method of reducing the risk of cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of cardiovascular death relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of cardiovascular death relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In someembodiments, the method reduces the risk of cardiovascular death relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of cardiovascular death is measured by time to cardiovascular death.

[0056] In one embodiment, there is provided a method of reducing the risk of cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of cardiovascular death relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of cardiovascular death relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of cardiovascular death relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of cardiovascular death is measured by time to cardiovascular death.

[0057] In one embodiment, there is provided a method of reducing the risk of all-cause mortality in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of all-cause mortality relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of all-cause mortality relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of all-cause mortality relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertensionand CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of all-cause mortality is measured by time to all-cause mortality.

[0058] In one embodiment, there is provided a method of reducing the risk of all-cause mortality in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of all-cause mortality relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of all-cause mortality relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of all-cause mortality relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of all-cause mortality is measured by time to all-cause mortality.

[0059] In one embodiment, there is provided a method of reducing the risk of atrial fibrillation or cardiovascular death in a patient with one or more risk factors for developing HF, and no previous history of atrial fibrillation, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of atrial fibrillation or cardiovascular death. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of atrial fibrillation or cardiovascular death (such as a composite of atrial fibrillation or cardiovascular death) relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of atrial fibrillation or cardiovascular death (such as a composite of atrial fibrillation or cardiovascular death) relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of atrial fibrillation or cardiovascular death (such as a composite of atrial fibrillation or cardiovascular death) relative to a patient who was administered with only anSGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of atrial fibrillation or cardiovascular death is measured by time to the first occurrence of atrial fibrillation or cardiovascular death.

[0060] In one embodiment, there is provided a method of reducing the risk of atrial fibrillation or cardiovascular death in a patient with one or more risk factors for developing HF, and no previous history of atrial fibrillation, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of atrial fibrillation or cardiovascular death. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of atrial fibrillation or cardiovascular death (such as a composite of atrial fibrillation or cardiovascular death) relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of atrial fibrillation or cardiovascular death (such as a composite of atrial fibrillation or cardiovascular death) relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of atrial fibrillation or cardiovascular death (such as a composite of atrial fibrillation or cardiovascular death) relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of atrial fibrillation or cardiovascular death is measured by time to the first occurrence of atrial fibrillation or cardiovascular death.

[0061] In one embodiment, there is provided a method of reducing the risk of myocardial infarction or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of myocardial infarction or cardiovascular death. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reducesthe risk of myocardial infarction or cardiovascular death (such as a composite of myocardial infarction or cardiovascular death) relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of myocardial infarction or cardiovascular death (such as a composite of myocardial infarction or cardiovascular death) relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of myocardial infarction or cardiovascular death (such as a composite of myocardial infarction or cardiovascular death) relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of myocardial infarction or cardiovascular death is measured by time to the first occurrence of myocardial infarction or cardiovascular death.

[0062] In one embodiment, there is provided a method of reducing the risk of myocardial infarction or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of myocardial infarction or cardiovascular death. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of myocardial infarction or cardiovascular death (such as a composite of myocardial infarction or cardiovascular death) relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of myocardial infarction or cardiovascular death (such as a composite of myocardial infarction or cardiovascular death) relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of myocardial infarction or cardiovascular death (such as a composite of myocardial infarction or cardiovascular death) relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of myocardial infarction or cardiovascular death is measured by time to the first occurrence of myocardial infarction or cardiovascular death.

[0063] In one embodiment, there is provided a method of reducing the risk of MACE (myocardial infarction, stroke or cardiovascular death) in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of MACE relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of MACE relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of MACE relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of MACE is measured by time to the first occurrence of myocardial infarction, stroke or cardiovascular death.

[0064] In one embodiment, there is provided a method of reducing the risk of MACE (myocardial infarction, stroke or cardiovascular death) in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of MACE relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of MACE relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of MACE relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of MACE is measured by time to the first occurrence of myocardial infarction, stroke or cardiovascular death.

[0065] In one embodiment, there is provided a method of reducing the risk of stroke or cardiovascular death in a patient with one or more risk factors for developing HF, the methodcomprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of stroke or cardiovascular death. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of stroke or cardiovascular death (such as a composite of stroke or cardiovascular death) relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of stroke or cardiovascular death (such as a composite of stroke or cardiovascular death) relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of stroke or cardiovascular death (such as a composite of stroke or cardiovascular death) relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the reduction of the risk of stroke or cardiovascular death is measured by time to the first occurrence of stroke or cardiovascular death.

[0066] In one embodiment, there is provided a method of reducing the risk of stroke or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the method reduces the risk of a composite of stroke or cardiovascular death. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method reduces the risk of stroke or cardiovascular death (such as a composite of stroke or cardiovascular death) relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of stroke or cardiovascular death (such as a composite of stroke or cardiovascular death) relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method reduces the risk of stroke or cardiovascular death (such as a composite of stroke or cardiovascular death) relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio< 1). In some embodiments, the reduction of the risk of stroke or cardiovascular death is measured by time to the first occurrence of stroke or cardiovascular death.

[0067] In one embodiment, there is provided a method of preventing or delaying an event selected from:(a) a composite of cardiovascular death or a HF event;(b) a HF event;(c) a composite of hospitalisation for HF, HF without hospitalisation, or cardiovascular death;(d) a composite of hospitalisation for HF or cardiovascular death;(e) a composite of hospitalisation for HF or HF without hospitalisation;(f) cardiovascular death;(g) all -cause death;(h) a composite of stroke or cardiovascular death;(i) a composite of a new diagnosis of atrial fibrillation or cardiovascular death;(j) a composite of myocardial infarction or cardiovascular death; and(k) a composite of myocardial infarction, stroke or cardiovascular death; in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays the event relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays the event relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays the event relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of the event is measured by time to the first occurrence of the event or a component within the composite event.

[0068] In one embodiment, there is provided a method of preventing or delaying an event selected from:(a) a composite of cardiovascular death or a HF event;(b) a HF event;(c) a composite of hospitalisation for HF, HF without hospitalisation, or cardiovascular death;(d) a composite of hospitalisation for HF or cardiovascular death;(e) a composite of hospitalisation for HF or HF without hospitalisation;(f) cardiovascular death;(g) all -cause death;(h) a composite of stroke or cardiovascular death;(i) a composite of a new diagnosis of atrial fibrillation or cardiovascular death;(j) a composite of myocardial infarction or cardiovascular death; and(k) a composite of myocardial infarction, stroke or cardiovascular death; in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays the event relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays the event relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays the event relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of the event is measured by time to the first occurrence of the event or a component within the composite event.

[0069] In one embodiment, there is provided a method of preventing or delaying HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays HF and / or cardiovascular death relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF and / or cardiovascular death relative to a patient who was administered only an SGLT2i (forexample, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF and / or cardiovascular death relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of HF and / or cardiovascular death is measured by time to the first occurrence of HF or cardiovascular death.

[0070] In one embodiment, there is provided a method of preventing or delaying HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays HF and / or cardiovascular death relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF and / or cardiovascular death relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF and / or cardiovascular death relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of HF and / or cardiovascular death is measured by time to the first occurrence of HF or cardiovascular death.

[0071] In one embodiment, there is provided a method of preventing or delaying HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays HF relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF relative to apatient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of HF is measured by time to the first occurrence of HF.

[0072] In one embodiment, there is provided a method of preventing or delaying HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays HF relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays HF relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of HF is measured by time to the first occurrence of HF.

[0073] In one embodiment, there is provided a method of preventing or delaying symptomatic HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays symptomatic HF and / or cardiovascular death relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF and / or cardiovascular death relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF and / or cardiovascular death relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in ahazard ratio < 1). In some embodiments, the preventing or delaying of symptomatic HF and / or cardiovascular death is measured by time to the first occurrence of symptomatic HF or cardiovascular death.

[0074] In one embodiment, there is provided a method of preventing or delaying symptomatic HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays symptomatic HF and / or cardiovascular death relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF and / or cardiovascular death relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF and / or cardiovascular death relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of symptomatic HF and / or cardiovascular death is measured by time to the first occurrence of symptomatic HF or cardiovascular death.

[0075] In one embodiment, there is provided a method of preventing or delaying symptomatic HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays symptomatic HF relative to a patient who was not administered the ASi (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF relative to a patient who was administered only an SGLT2i (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF relative to a patient who was administered with only an SGLT2i and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In someembodiments, the preventing or delaying of symptomatic HF is measured by time to the first occurrence of symptomatic HF.

[0076] In one embodiment, there is provided a method of preventing or delaying symptomatic HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of baxdrostat or a pharmaceutically acceptable salt thereof and an amount of dapagliflozin, wherein the amount of the baxdrostat or a pharmaceutically acceptable salt thereof and the amount of the dapagliflozin together comprise an effective amount. In some embodiments, the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the method prevents or delays symptomatic HF relative to a patient who was not administered the baxdrostat or a pharmaceutically acceptable salt thereof (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF relative to a patient who was administered only dapagliflozin (for example, resulting in a hazard ratio < 1). In some embodiments, the method prevents or delays symptomatic HF relative to a patient who was administered with only dapagliflozin and optionally one or more standard of care agents for any of T2DM, hypertension and CVD (for example, resulting in a hazard ratio < 1). In some embodiments, the preventing or delaying of symptomatic HF is measured by time to the first occurrence of symptomatic HF.

[0077] In embodiments herein, a hazard ratio is used to indicate the risk reduction, prevention or delay provided by the methods described herein. In some embodiments, the hazard ratio is < 1. In some embodiments, the hazard ratio is < 0.9. In some embodiments, the hazard ratio is < 0.86. In some embodiments, the hazard ratio is < 1 and the entirety of the 95% confidence interval (CI) of the hazard ratio is < 1. In some embodiments, the hazard ratio is < 0.9 and the entirety of the 95% CI of the hazard ratio is < 0.9. In some embodiments, the hazard ratio is < 0.86 and the entirety of the 95% CI of the hazard ratio is < 0.86.Heart failure (HF) events

[0078] In some embodiments, a “heart failure event” (HF event) is a hospitalization for HF or HF without hospitalisation.

[0079] In some embodiments, an “HF event” is a hospitalization for HF.

[0080] In some embodiments, the hospitalization for HF comprises a hospital admission lasting at least 24 hours or as measured by a change in calendar date, and the patient has objective evidence of new or worsening HF.

[0081] In some embodiments, the hospitalization for HF meets one or more of the following criteria: (i) admission to the hospital with a primary cause of HF; and / or (ii) new or worsening symptoms due to HF exhibited by the patient; and / or (iii) objective evidence of new or worsening HF; and / or (iv) initiation or intensification of treatment specifically for HF. In some embodiments, the hospitalization for HF meets all of the above criteria. In some embodiments, new or worsening symptoms due to HF exhibited by the patient comprises at least one of the following: dyspnoea (such as dyspnoea with exertion, dyspnoea at rest, orthopnoea, and / or paroxysmal nocturnal dyspnoea); decreased exercise tolerance; fatigue; and other symptoms of worsened end-organ perfusion or volume overload. In some embodiments, objective evidence of new or worsening HF comprises physical examination findings considered to be due to HF, laboratory evidence of new or worsening HF and / or invasive evidence of new or worsening HF. In some embodiments, the physical examination findings considered to be due to HF comprises at least one of the following findings: peripheral oedema; increasing abdominal distention or ascites (such as in the absence of primary hepatic disease); pulmonary rales / crackles / crepitations; increased jugular venous pressure and / or hepatojugular reflux; third heart sound (S3) gallop; and clinically significant or rapid weight gain related to fluid retention. In some embodiments, laboratory evidence of new or worsening HF comprises at least one of the following findings: increased B-type natriuretic peptide (BNP) / NT -proBNP concentrations consistent with decompensation of heart failure; radiological, ultrasonographic, or implantable monitor evidence of pulmonary congestion; and non-invasive or implantable diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure or low cardiac output. In some embodiments, invasive evidence of new or worsening HF comprises at least one of the following findings: right heart catheterization showing elevated pulmonary capillary wedge pressure (pulmonary artery occlusion pressure), elevated central venous pressure, and / or depressed cardiac index; and left heart catheterization showing elevated left ventricular end- diastolic pressure consistent with decompensation of HF. In some embodiments, the initiation or intensification of treatment specifically for HF comprises at least one of the following: initiation of maintenance diuretic therapy; augmentation in oral diuretic therapy (such as increasing, for example doubling, diuretic dose or initiation of combination diuretic therapy); initiation of intravenous administration of a diuretic; initiation of intravenous administrationof a vasoactive agent (such as catecholamine, phosphodiesterase-3 inhibitor, or other vasopressor or vasodilator); mechanical or surgical intervention (such as mechanical circulatory support); and mechanical fluid removal (such as ultrafiltration, haemofiltration and haemodialysis).

[0082] In some embodiments, the HF without hospitalisation comprises an outpatient visit in an emergency department or ambulatory setting, and the patient has objective evidence of new or worsening HF.

[0083] In some embodiments, the HF without hospitalisation meets one or more of the following criteria: (i) new or worsening symptoms due to HF exhibited by the patient; and / or (ii) objective evidence of new or worsening HF; and / or (iii) initiation or intensification of treatment specifically for HF. In some embodiments, the HF without hospitalisation meets all of the above criteria. In some embodiments, new or worsening symptoms due to HF exhibited by the patient comprises at least one of the following: dyspnoea (such as dyspnoea with exertion, dyspnoea at rest, orthopnoea, and / or paroxysmal nocturnal dyspnoea); decreased exercise tolerance; fatigue; and other symptoms of worsened end-organ perfusion or volume overload. In some embodiments, objective evidence of new or worsening HF comprises physical examination findings considered to be due to HF, imaging evidence of structural or functional cardiac disease consistent with a diagnosis of HF, laboratory evidence of new or worsening HF and / or invasive evidence of new or worsening HF. In some embodiments, the physical examination findings considered to be due to HF comprises at least one of the following findings: peripheral oedema; increasing abdominal distention or ascites (such as in the absence of primary hepatic disease); pulmonary rales / crackles / crepitations; increased jugular venous pressure and / or hepatojugular reflux; third heart sound (S3) gallop; and clinically significant or rapid weight gain related to fluid retention. In some embodiments, imaging evidence of structural or functional cardiac disease consistent with a diagnosis of HF comprises at least one of the following findings: left ventricular systolic dysfunction; left atrial enlargement; left ventricular diastolic dysfunction; increased pulmonary pressure; and left ventricular hypertrophy. In some embodiments, laboratory evidence of new or worsening HF comprises at least one of the following findings: increased B-type natriuretic peptide (BNP) / NT-proBNP concentrations; radiological, ultrasonographic, or implantable monitor evidence of pulmonary congestion; and non-invasive or implantable diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure or low cardiac output. In some embodiments, invasive evidence of new or worsening HF comprises at least one of the following findings: right heart catheterization showing elevated pulmonarycapillary wedge pressure (pulmonary artery occlusion pressure), elevated central venous pressure, and / or depressed cardiac index; and left heart catheterization showing elevated left ventricular end-diastolic pressure consistent with decompensation of HF. In some embodiments, the initiation or intensification of treatment specifically for HF comprises at least one of the following: initiation of oral administration of at least one new oral diuretic therapy, SGLT2i treatment, renin-angiotensin system inhibitor, angiotensin receptor neprilysin inhibitors, beta-blocker, MRA, ivabradine, digoxin, vericiguat or hydralazine / isosorbide dinitrate prescribed as a treatment for HF; augmentation in oral diuretic therapy (such as increasing, for example doubling, diuretic dose or initiation of combination diuretic therapy); initiation of intravenous administration of a diuretic; initiation of intravenous administration of a vasoactive agent (such as catecholamine, phosphodiesterase-3 inhibitor, or other vasopressor or vasodilator); mechanical or surgical intervention (such as mechanical circulatory support); and mechanical fluid removal (such as ultrafiltration, haemofiltration and haemodialysis).

[0084] In some embodiments, HF without hospitalisation is an urgent HF medical visit.

[0085] In some embodiments, an urgent HF medical visit is an emergency room visit for a new or worsening HF but does not require hospitalization. In some embodiments, an urgent HF medical visit is an urgent unscheduled visit to a physician’s office for new or worsening HF.

[0086] In some embodiments, the HF event is development of symptomatic HF. In some embodiments, the symptomatic HF is Stage C based on the American College of Cardiology (ACC) / American Heart Association (AHA) classification of heart failure (Heidenreich et al. Circulation. 2022;145(18):e895-el032).

[0087] In some embodiments, the HF event is development of incident HF. In some embodiments, incident HF is the first clinical diagnosis of HF in a patient. In some embodiments, incident HF is the first clinical diagnosis of Stage C HF or Stage D HF in a patient, as described in the American College of Cardiology (ACC) / American Heart Association (AHA) classification of heart failure (Heidenreich et al. Circulation. 2022;145(18):e895-el032). In some embodiments, incident HF is the first clinical diagnosis of Stage C HF in a patient.Patient characteristics

[0088] The patient in the methods described herein has one or more risk factors for developing HF. Such risk factors for developing HF are known to clinicians skilled in the art, for example the risk factors described in Virani SS et al. Circulation. 2021;143(8):e254-e743.

[0089] In some embodiments, the patient has multiple risk factors for developing HF. In some embodiments, the patient has two or more risk factors for developing HF. In some embodiments, the patient has three or more risk factors for developing HF. In some embodiments, the patient has four or more risk factors for developing HF.

[0090] Type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) are recognized risk factors for developing HF. Accordingly, in some embodiments, the one or more risk factors for developing HF are selected from T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the one or more additional risk factors for developing HF are selected from one or more of (1) age > 70 years, (2) UACR > 20 mg / g, (3) eGFR < 60 mL / min / 1.73 m2, (4) history of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease, (5) history of atrial fibrillation or atrial flutter and (6) NT-proBNP > 125 ng / L.

[0091] In some embodiments, the one or more risk factors for developing HF are selected from T2DM, hypertension and CVD, and optionally one or more of (1) age > 70 years, (2) UACR > 20 mg / g, (3) eGFR < 60 mL / min / 1.73 m2, (4) history of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease, (5) history of atrial fibrillation or atrial flutter and (6) NT-proBNP > 125 ng / L.

[0092] In some embodiments, the patient in the methods described herein has T2DM, hypertension and CVD. In some embodiments, the patient in the methods described herein has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF. In some embodiments, the patient in the methods described herein has T2DM, hypertension, CVD, and one or more additional risk factors for developing HF.

[0093] In some embodiments, the one or more additional risk factors for developing HF are selected from (1) age > 70 years, (2) UACR > 20 mg / g, (3) eGFR < 60 mL / min / 1.73 m2, (4) history of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease, (5) history of atrial fibrillation or atrial flutter and (6) NT-proBNP > 125 ng / L. In some embodiments, the patient has an age > 70 years. In some embodiments, the patient has a UACR > 20 mg / g. In some embodiments, the patient has an eGFR < 60 mL / min / 1.73 m2. In some embodiments, the patient has ahistory of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease. In some embodiments, the patient has a history of atrial fibrillation or atrial flutter. In some embodiments, the patient has NT- proBNP > 125 ng / L.

[0094] In some embodiments, the patient has T2DM. In some embodiments, the patient requires treatment for T2DM. In some embodiments, the patient is receiving treatment for T2DM, such as an anti-hyperglycaemic medication. In some embodiments, the patient has one or more of: fasting plasma glucose > 126 mg / dl (7.0 mmol / L), HbAlc > 6.5%, 2-hour plasma glucose > 200 mg / dl (11.1 mmol / L) during an oral glucose tolerance test, and a random plasma glucose > 200 mg / dL (11.1 mmol / L) in patients with classic symptoms of hyperglycaemia or hyperglycaemic crisis.

[0095] In some embodiments, the T2DM is controlled. In some embodiments, the T2DM is controlled with HbAlc < 10.5% (< 91 mmol / mol). In some embodiments, the patient does not have uncontrolled T2DM. In some embodiments, the patient does not have uncontrolled T2DM with HbAlc > 10.5% (> 91 mmol / mol).

[0096] In some embodiments, the patient does not have type 1 diabetes mellitus.

[0097] In some embodiments, the patient has hypertension. In some embodiments, the patient has hypertension when the combination described herein is first administered to the patient.

[0098] The severity of hypertension may be classified into categories, as shown in the table below:SBP = Systolic blood pressure; DBP = Diastolic blood pressure

[0099] In some embodiments, the hypertension is Stage 1 hypertension or Stage 2 hypertension. In some embodiments, the hypertension is Stage 1 hypertension. In someembodiments, the hypertension is Stage 2 hypertension. In some embodiments, the hypertension is not hypertensive crisis.

[0100] In some embodiments, the patient has a systolic blood pressure (SBP) > 120 mmHg. In some embodiments, the patient has a SBP > 130 mmHg. In some embodiments, the patient has a SBP > 140 mmHg.

[0101] In some embodiments, the SBP is mean seated SBP.

[0102] In some embodiments, the SBP is the SBP of the patient when the combination described herein is first administered to the patient.

[0103] In some embodiments, the patient has a diastolic blood pressure (DBP) > 80 mmHg. In some embodiments, the patient has a DBP > 90 mmHg. In some embodiments, the patient has a DBP < 110 mmHg. In some embodiments, the patient has a DBP < 120 mmHg. In some embodiments, the DBP is mean seated DBP.

[0104] In some embodiments, the DBP is the DBP of the patient when the combination described herein is first administered to the patient.

[0105] In some embodiments, the patient has a SBP > 120 mmHg and a DBP < 80 mmHg. In some embodiments, the patient has a SBP > 130 mmHg and a DBP > 80 mmHg. In some embodiments, the patient has a SBP > 140 mmHg and a DBP > 90 mmHg.

[0106] In some embodiments, the patient has CVD. In some embodiments, the CVD is established CVD.

[0107] In some embodiments, the CVD is atherosclerotic cardiovascular disease.

[0108] In some embodiments, the CVD is selected from one or more of ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease.

[0109] In some embodiments, the patient has normal serum potassium. In some embodiments, the patient does not have hyperkalemia. In some embodiments, the patient has serum potassium > 3.0 mmol / L. In some embodiments, the patient has serum potassium < 4.8 mmol / L. In some embodiments, the patient has serum potassium < 5.5 mmol / L. In some embodiments, the patient has serum potassium > 3.0 and < 4.8 mmol / L. In some embodiments, the patient has serum potassium > 3.0 and < 5.5 mmol / L.

[0110] In some embodiments, the serum potassium is the serum potassium of the patient when the combination described herein is first administered to the patient.

[0111] In some embodiments, the patient has serum potassium > 3.0 and < 4.8 mmol / L and the method comprises administering about 1 mg or about 2 mg of baxdrostat to the patient, once daily.

[0112] In some embodiments, the patient has serum potassium > 4.8 and < 5.5 mmol / L and the method comprises administering about 1 mg of baxdrostat to the patient, once daily.

[0113] In some embodiments, the patient has serum sodium of < 135 mmol / L.

[0114] In some embodiments, the serum sodium is the serum sodium of the patient when the combination described herein is first administered to the patient.

[0115] In some embodiments, the patient does not have an established heart failure diagnosis.

[0116] In some embodiments, the patient is at Stage A (at risk for heart failure) or Stage B (pre-heart failure) based on the American College of Cardiology (ACC) / American Heart Association (AHA) classification of heart failure (Heidenreich et al. Circulation. 2022;145(18):e895-el032). The American College of Cardiology (ACC) / American Heart Association (AHA) classification of heart failure classifies heart failure into four stages: Stage A (at risk for heart failure), Stage B (pre-heart failure), Stage C (symptomatic heart failure) and Stage D (advanced heart failure).

[0117] In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2.

[0118] In some embodiments, the patient has not received a mineralocorticoid receptor antagonist (MRA) (such as spironolactone, eplerenone, or finerenone) in the four weeks prior to the first administration of the combination. In some embodiments, a mineralocorticoid receptor antagonist (MRA) (such as spironolactone, eplerenone, or finerenone) is not administered to the patient. In some embodiments, a mineralocorticoid receptor antagonist (MRA) (such as spironolactone, eplerenone, or finerenone) is not administered to the patient after first administration of the combination described herein.

[0119] In some embodiments, the patient has not received a potassium-sparing diuretic (such as triamterene or amiloride) in the four weeks prior to first administration of the combination. In some embodiments, the patient is not treated with a potassium-sparing diuretic (such as triamterene or amiloride) during treatment with the combination.

[0120] In some embodiments, the patient has not received a direct renin inhibitor (such as aliskiren) in the four weeks prior to first administration of the combination. In some embodiments, the patient is not treated with a direct renin inhibitor (such as aliskiren) during treatment with the combination.Aldosterone synthase inhibitor

[0121] In some embodiments, the aldosterone synthase inhibitor (ASi) is chosen from those disclosed in WO2013 / 041591, US2017 / 0044115, US2023 / 0365513, WO2014 / 179186, WO20 16 / 089800, WO2016 / 123275, W02016 / 061161, WO2016 / 014736, WO2018 / 005177, WO2023 / 114170, WO2016 / 109492, WO2018 / 125799, WO2020 / 146532, W02018 / 125800 and WO2018 / 078049, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the ASi is selected from those disclosed in W02016 / 061161 and WO2016 / 014736, or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the ASi is selected from baxdrostat, BI 690517, lorundrostat and dexfadrostat, or a pharmaceutically acceptable salt thereof. In some embodiments, the ASi is selected from baxdrostat, BI 690517, lorundrostat and dexfadrostat phosphate.

[0124] In some embodiments, the ASi is baxdrostat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASi is baxdrostat.

[0125] The chemical structure of baxdrostat is:

[0126] Baxdrostat may be prepared by the methods disclosed in the International Patent Application published as WO2013 / 041591.

[0127] In some embodiments, baxdrostat or pharmaceutically acceptable salt thereof is in a form suitable for oral administration. In some embodiments, the baxdrostat or pharmaceutically acceptable salt thereof is in the form of a tablet.

[0128] In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 0.5 mg / day, about 1 mg / day or about 2 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 1 mg / day or about 2 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 0.5 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 1 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 2 mg / day.

[0129] In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg / day, 1 mg / day or 2 mg / day. In someembodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg / day or 2 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of 2 mg / day.

[0130] In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is selected such that the patient does not exhibit hyperkalemia. In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is selected from about 0.5 mg / day, about 1 mg / day and about 2 mg / day such that the patient does not exhibit hyperkalemia. In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is selected from about 1 mg / day and about 2 mg / day such that the patient does not exhibit hyperkalemia. In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is selected from about 0.5 mg / day and about 1 mg / day such that the patient does not exhibit hyperkalemia. In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is about 0.5 mg / day such that the patient does not exhibit hyperkalemia. In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is about 1 mg / day such that the patient does not exhibit hyperkalemia.

[0131] In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered initially at a dosage of about 1 mg / day and then up-titrated to about 2 mg / day. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered initially at a dosage of about 1 mg / day and then up-titrated to about 2 mg / day provided that the patient does not have hyperkalemia. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered initially at a dosage of about 1 mg / day and then up-titrated to about 2 mg / day provided that serum potassium is < 4.8 mmol / L.

[0132] In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is down-titrated to about 1 mg / day if the patient has hyperkalemia. In some embodiments, the dosage of baxdrostat or a pharmaceutically acceptable salt thereof is down-titrated to about 1 mg / day if serum potassium is > 5.5 mmol / L.

[0133] Embodiments describing a mass of baxdrostat or a pharmaceutically acceptable salt thereof refer to the specified mass of baxdrostat or an equivalent molar amount of a pharmaceutically acceptable salt of baxdrostat. For example, 2 mg / day of a pharmaceuticallyacceptable salt of baxdrostat refers to the dosage of the pharmaceutically acceptable salt of baxdrostat required to deliver 2 mg / day of baxdrostat.

[0134] In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered orally once daily.SGLT2 inhibitor

[0135] In some embodiments, the SGLT2 inhibitor (SGLT2i) is chosen from those disclosed in U.S. Pat. No. 6,515,177, WO / 2003 / 099836, U.S. PG Pub. No. 2006 / 0194809, U.S. PG Pub. No. 2006 / 0063722 Al, WG / 2002 / 083066, U.S. PG Pub. No. 2003 / 0064935, U.S. Pat. No. 6,774,112, U.S. PG Pub. No. 2005 / 0209166, U.S. PG Pub. No. 2006 / 0074031, U.S. PG Pub. No. 2006 / 0035841, U.S. PG Pub. No. 2006 / 0009400, U.S. PG Pub. No. 2006 / 0025349, U.S. PG Pub. No. 2006 / 0122126, U.S. PG Pub. No. 2006 / 0019948, U.S. PG Pub. No. 2006 / 0194809, U.S. Pat. No. 6,908,905, U.S. Pat. No. 6,815,428, U.S. Pat. No. 6,555,519, U.S. Pat. No. 6,683,056, EP 598359 Al, JP 035988, U.S. Pat. No. 5,731,292, EP 0850948 Al, U.S. Pat. No. 6,048,842, JP 09188625 A, JP 09124685 A, JP 09124684, EP 773226 Al, U.S. Pat. No. 5,767,094, JP 08027006 A, EP 684254 Al, JP 10245391 (Dainippon), U.S. PG Pub. No. 2005 / 0233982 (Boehringer Ingelheim Corp.), U.S. PG Pub. No. 2005 / 0119192 (Kissei Pharmaceutical Co.), WO / 2006 / 035796 (Kissei Pharmaceutical Co.), JP 2006 / 117651 (Taisho Pharmaceutical Co.), JP 2004 / 4359630 (Yamanouchi Pharmaceutical Co.), WO / 2006 / 080421 (Chugai Seiyaku Kabushiki Kaishi), U.S. PG Pub. No. 2005 / 0233988 (Tanabe Seiyaku Co.), WO / 2005 / 012321 (Tanabe Seiyaku Co.), U.S. Pat. No. 7,015,201 (Ajinomoto Co.), WO 2006 / 058597 (Merck Patent GmbH), WO 2006 / 011469 (Chugai Seiyaku Kabushiki Kaisha), U.S. PG Pub. No. 2003 / 0195235 (Johnson & Johnson), and WO 2006 / 037537 (Boehringer Ingelheim).

[0136] In some embodiments, the SGLT2i is chosen from those disclosed in Tsujihara, K. et al., Chem. Pharm. Bull., 44: 1174-1180 (1996); Hongu, M. et al., Chem. Pharm. Bull., 46:22-33 (1998); Hongu, M. et al., Chem. Pharm. Bull., 46: 1545-1555 (1998); and Oku, A. et al., Diabetes, 48: 1794-1800 (1999).

[0137] In some embodiments, the SGLT2i may be dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, sotagliflozin, ipragliflozin, tofogliflozin, or luseogliflozin, or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the SGLT2i is dapagliflozin such as described in U.S. Patent Nos. 6,414,126 and 6,515,117, which are incorporated by reference in their entireties.

[0139] The chemical structure of dapagliflozin is:

[0140] In some embodiments, dapagliflozin is in the form of a (S)-propylene glycol((S)-PG) solvate, which has the structure:

[0141] Methods for preparing a (S)-PG solvate of dapagliflozin, including a crystalline (S)-PG solvate, are provided in U.S. Pat. No. 7,919,598.

[0142] In some embodiments, the SGLT2i, such as dapagliflozin, is in a form suitable for oral administration. In some embodiments, the SGLT2i, such as dapagliflozin, is in the form of a tablet.

[0143] In some embodiments, the dapagliflozin is administered at a dosage of about 10 mg / day. In some embodiments, the dapagliflozin is administered at a dosage of 10 mg / day.

[0144] In some embodiments, the dapagliflozin is administered once daily. In some embodiments, the dapagliflozin is administered orally once daily.Pharmaceutically acceptable salts

[0145] The ASi and SGLT2i utilized in the methods described herein may be in the form of a pharmaceutically acceptable salt.

[0146] “Pharmaceutically acceptable” refers to properties and / or substances that are acceptable to the patient from a pharmacological / toxicological vantage, and to the manufacturing pharmaceutical chemist from a phy si cal / chemi cal vantage regarding composition, formulation, stability, patient acceptance, and bioavailability.

[0147] A pharmaceutically acceptable salt of baxdrostat includes salts with a pharmaceutically acceptable acid or base, e.g., inorganic acids, e.g., hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, hydroiodic, nitric, and phosphoric acid and organic acids, ie., adipic, citric, fumaric, maleic, malic, malonic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic, cyclohexylsulfamic (cyclamic), edisylate, glutaric, or p-toluenesulfonic acid. Pharmaceutically acceptable bases include alkali metal, e.g., sodium or potassium, and alkali earth metal, e.g., calcium or magnesium, hydroxides, and organic bases, e.g., alkyl amines, arylalkyl amines and heterocyclic amines.Particular combinations of ASi and SGLT2i

[0148] In some embodiments, about 0.5 mg, about 1 mg or about 2 mg of baxdrostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 1 mg or about 2 mg of baxdrostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 0.5 mg of baxdrostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 1 mg of baxdrostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 2 mg of baxdrostat or a pharmaceutically acceptable salt thereof is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily.

[0149] In some embodiments, about 0.5 mg, about 1 mg or about 2 mg of baxdrostat is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 1 mg or about 2 mg of baxdrostat is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 0.5 mg of baxdrostat is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient oncedaily. In some embodiments, about 1 mg of baxdrostat is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily. In some embodiments, about 2 mg of baxdrostat is administered to the patient once daily, and about 10 mg of dapagliflozin is administered to the patient once daily.

[0150] In some embodiments, about 0.5 mg, about 1 mg or about 2 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily. In some embodiments, about 1 mg or about 2 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily. In some embodiments, about 0.5 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily. In some embodiments, about 1 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily. In some embodiments, about 2 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily.

[0151] In some embodiments, the ASi (such as baxdrostat or pharmaceutically acceptable salt thereof) is administered before, after, or concurrently with the SGLT2i (such as dapagliflozin). In some embodiments, the ASi (such as baxdrostat or pharmaceutically acceptable salt thereof) is administered concurrently with the SGLT2i (such as dapagliflozin).

[0152] In some embodiments, about 0.5 mg, about 1 mg or about 2 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily, wherein the baxdrostat and dapagliflozin are administered concurrently. In some embodiments, about 1 mg or about 2 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily, wherein the baxdrostat and dapagliflozin are administered concurrently. In some embodiments, about 0.5 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily, wherein the baxdrostat and dapagliflozin are administered concurrently. In some embodiments, about 1 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily, whereinthe baxdrostat and dapagliflozin are administered concurrently. In some embodiments, about 2 mg of baxdrostat in the form of a tablet is administered to the patient orally once daily, and about 10 mg of dapagliflozin in the form of a tablet is administered to the patient orally once daily, wherein the baxdrostat and dapagliflozin are administered concurrently.

[0153] In some embodiments, the ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and the SGLT2i (such as dapagliflozin), are administered to the patient with one or more standard of care agents for any of T2DM, hypertension and CVD.

[0154] Exemplary standard of care agents include antiplatelets, beta-blockers, cholesterol lowering medications, ACE inhibitors / ARBs and anti-hyperglycaemic treatments other than SGLT2i. Such standard of care agents and their dosages are well-known to medical practitioners who examine and treat patients with T2DM, hypertension and CVD. Representative examples of antiplatelets are aspirin, cangrelor, clopidogrel, ticagrelor, prasugrel and dipyridamole. Representative examples of beta-blockers are acebutolol, atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, nebivolol, propranolol and sotalol. Representative examples of cholesterol lowering medications are statins such as atorvastatin and rosuvastatin, ezetimibe, bile acid sequestrants such as cholestyramine, colestipol and colesevelam, fibrates such as gemfibrozil, fenofibrate and fenofibric acid, bempedoic acid, and PCSK9 inhibitors such as alirocumab, evolocumab and inclisiran. Representative examples of ACE inhibitors include captopril, enalapril, and lisinopril. Representative examples of ARBs include valsartan, losartan, and irbesartan. Representative examples of anti-hyperglycaemic treatments include metformin, sulfonylureas such as gliclazide, glimepiride and glipizide, meglitinides such as repaglinide and nateglinide, thiazolidinediones such as rosiglitazone and pioglitazone, a-glucosidase inhibitors such as acarbose, miglitol and voglibose, and DPP -4 inhibitors such as alogliptin, saxagliptin, sitagliptin, linagliptin and vildagliptin.

[0155] In one embodiment, the standard of care agent does not include an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof).

[0156] The standard of care agents for T2DM, hypertension and / or CVD, as described herein, may be used prior to and / or during administration of the combination comprising the ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and the SGLT2i (such as dapagliflozin). In some embodiments, the standard of care agents for T2DM, hypertension and / or CVD and the ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and the SGLT2i (such as dapagliflozin), are administered together, at the same or at different times.Compounds for use in the methods described herein

[0157] In some embodiments, there is provided an ASi for use in any of the methods described herein. In some embodiments, there is provided baxdrostat or a pharmaceutically acceptable salt thereof for use in any of the methods described herein. In some embodiments, there is provided baxdrostat for use in any of the methods described herein.

[0158] In some embodiments, there is provided an SGLT2i for use in any of the methods described herein. In some embodiments, there is provided dapagliflozin for use in any of the methods described herein. In some embodiments, there is provided (S)-PG solvate of dapagliflozin for use in any of the methods described herein.

[0159] In some embodiments, there is provided a combination comprising an ASi and an SGLT2i for use in any of the methods described herein. In some embodiments, there is provided a combination comprising baxdrostat or a pharmaceutically acceptable salt thereof and an SGLT2i for use in any of the methods described herein. In some embodiments, there is provided a combination comprising baxdrostat and dapagliflozin for use in any of the methods described herein. In some embodiments, there is provided a combination comprising baxdrostat and (S)-PG solvate of dapagliflozin for use in any of the methods described herein.

[0160] In some embodiments, there is provided the use of an ASi in the manufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of baxdrostat or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of baxdrostat in the manufacture of a medicament for use in any of the methods described herein.

[0161] In some embodiments, there is provided the use of an SGLT2i in the manufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of dapagliflozin in the manufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of (S)-PG solvate of dapagliflozin in the manufacture of a medicament for use in any of the methods described herein.

[0162] In some embodiments, there is provided the use of a combination comprising an ASi and an SGLT2i in the manufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of a combination comprising baxdrostat or a pharmaceutically acceptable salt thereof and an SGLT2i in themanufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of a combination comprising baxdrostat and dapagliflozin in the manufacture of a medicament for use in any of the methods described herein. In some embodiments, there is provided the use of a combination comprising baxdrostat and (S)-PG solvate of dapagliflozin in the manufacture of a medicament for use in any of the methods described herein.

[0163] In some embodiments, there is provided a kit comprising: (a) an ASi and / or an SGLT2i, and (b) instructions for use of the ASi and / or an SGLT2i in any of the methods described herein.

[0164] In some embodiments, there is provided a kit comprising: (a) baxdrostat or a pharmaceutically acceptable salt thereof and / or an SGLT2i, and (b) instructions for use of the baxdrostat or a pharmaceutically acceptable salt thereof and / or an SGLT2i in any of the methods described herein.

[0165] In some embodiments, there is provided a kit comprising: (a) baxdrostat and / or dapagliflozin, and (b) instructions for use of the baxdrostat and / or dapagliflozin in any of the methods described herein.

[0166] In some embodiments, there is provided a kit comprising: (a) baxdrostat and / or (S)-PG solvate of dapagliflozin, and (b) instructions for use of the baxdrostat and / or (S)-PG solvate of dapagliflozin in any of the methods described herein.

[0167] All documents cited herein are each entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited documents.Further EmbodimentsEmbodiment Al . An aldosterone synthase inhibitor (ASi) for use in a method of reducing the risk of cardiovascular death or a heart failure (HF) event in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with a sodium-glucose co-transporter 2 inhibitor (SGLT2i).Embodiment A2. An ASi for use in a method of reducing the risk of a HF event in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A3. An ASi for use in a method of reducing the risk of cardiovascular death in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A4. An ASi for use in a method of reducing the risk of all-cause mortality in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A5. An ASi for use in a method of reducing the risk of atrial fibrillation or cardiovascular death in a patient with one or more risk factors for developing HF, and no previous history of atrial fibrillation, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A6. An ASi for use in a method of reducing the risk of myocardial infarction or cardiovascular death in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A7. An ASi for use in a method of reducing the risk of MACE (myocardial infarction, stroke or cardiovascular death) in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A8. An ASi for use in a method of reducing the risk of stroke or cardiovascular death in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A9. An ASi for use in a method of preventing or delaying an event selected from:(a) a composite of cardiovascular death or a HF event;(b) a HF event;(c) a composite of hospitalisation for HF, HF without hospitalisation, or cardiovascular death;(d) a composite of hospitalisation for HF or cardiovascular death;(e) a composite of hospitalisation for HF or HF without hospitalisation;(f) cardiovascular death;(g) all -cause death;(h) a composite of stroke or cardiovascular death;(i) a composite of a new diagnosis of atrial fibrillation or cardiovascular death;(j) a composite of myocardial infarction or cardiovascular death; and(k) a composite of myocardial infarction, stroke or cardiovascular death; in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A10. The ASi for use according to any one of embodiments Al, A2 and A9, wherein the HF event is hospitalisation for HF or HF without hospitalisation.Embodiment Al 1. The ASi for use according to any one of embodiments Al, A2 and A9, wherein the HF event is hospitalisation for HF.Embodiment A12. The ASi for use according to any one of embodiments Al, A2, A9, A10 and Al l, wherein hospitalisation for HF comprises a hospital admission lasting at least 24 hours or as measured by a change in calendar date, and the patient has objective evidence of new or worsening HF.Embodiment Al 3. The ASi for use according to any one of embodiments Al, A2, A9 and A10, wherein HF without hospitalisation comprises an outpatient visit in an emergency department or ambulatory setting, and the patient has objective evidence of new or worsening HF.Embodiment A14. The ASi for use according to any one of embodiments Al, A2 and A9, wherein the HF event is development of symptomatic HF.Embodiment Al 5. The ASi for use according to any one of embodiments Al, A2 and A9, wherein the HF event is incident HF.Embodiment Al 6. An ASi for use in a method of preventing or delaying HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment Al 7. An ASi for use in a method of preventing or delaying HF in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment Al 8. An ASi for use in a method of preventing or delaying symptomatic HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment Al 9. An ASi for use in a method of preventing or delaying symptomatic HF in a patient with one or more risk factors for developing HF, wherein the ASi is administered to the patient in combination with an SGLT2i.Embodiment A20. The ASi for use according to any one of embodiments Al to Al 9, wherein the one or more risk factors for developing HF are selected from type 2 diabetes mellitus (T2DM), hypertension and cardiovascular disease (CVD), and optionally one or more of (1) age > 70 years, (2) UACR > 20 mg / g, (3) eGFR < 60 mL / min / 1.73 m2, (4) history of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease, (5) history of atrial fibrillation or atrial flutter and (6) NT-proBNP > 125 ng / L.Embodiment A21. The ASi for use according to any one of embodiments Al to A20, wherein the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF.Embodiment A22. The ASi for use according to embodiment A21, wherein the one or more additional risk factors for developing HF are selected from (1) age > 70 years, (2) UACR > 20 mg / g, (3) eGFR < 60 mL / min / 1.73 m2, (4) history of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease, (5) history of atrial fibrillation or atrial flutter and (6) NT-proBNP > 125 ng / L.Embodiment A23. The ASi for use according to any one of embodiments Al to A22, wherein the ASi is baxdrostat or a pharmaceutically acceptable salt thereof.Embodiment A24. The ASi for use according to embodiment A23, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 0.5 mg / day, about 1 mg / day or about 2 mg / day.Embodiment A25. The ASi for use according to embodiment A23, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 1 mg / day or about 2 mg / day.Embodiment A26. The ASi for use according to any one of embodiments A23 to A25, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered once daily.Embodiment A27. The ASi for use according to any one of embodiments A23 to A26, wherein the baxdrostat or pharmaceutically acceptable salt thereof is in a form suitable for oral administration, such as a tablet.Embodiment A28. The ASi for use according to any one of embodiments A23 to A27 , wherein the baxdrostat or pharmaceutically acceptable salt thereof is baxdrostat.Embodiment A29. The ASi for use according to any one of embodiments Al to A28, wherein the SGLT2i is selected from dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, ertugliflozin, tofogliflozin, and luseogliflozin, or a pharmaceutically acceptable salt thereof.Embodiment A30. The ASi for use according to any one of embodiments Al to A29, wherein the SGLT2i is dapagliflozin.Embodiment A31. The ASi for use according to embodiment A30, wherein the dapagliflozin is administered at a dosage of about 10 mg / day.Embodiment A32. The ASi for use according to embodiment A30 or embodiment A31, wherein the dapagliflozin is administered once daily.Embodiment A33. The ASi for use according to any one of embodiments A30 to A32, wherein the dapagliflozin is in a form suitable for oral administration, such as a tablet.Embodiment A34. The ASi for use according to any one of embodiments Al to A33, the method comprising administering to the patient a combination comprising about 0.5 mg, about 1 mg or about 2 mg, once daily, of baxdrostat and about 10 mg, once daily, of dapagliflozin.Embodiment A35. The ASi for use according to any one of embodiments Al to A34, the method comprising administering to the patient a combination comprising about 1 mg or about 2 mg, once daily, of baxdrostat and about 10 mg, once daily, of dapagliflozin.Embodiment A36. The ASi for use according to any one of embodiments A30 to A35, wherein the dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate which has the structureEmbodiment A37. The ASi for use according to any one of embodiments Al to A36, wherein the ASi, such as baxdrostat or a pharmaceutically acceptable salt thereof, is administered before, after, or concurrently with the SGLT2i, such as dapagliflozin.Embodiment A38. The ASi for use according to any one of embodiments Al to A37, wherein the patient has a systolic blood pressure (SBP) > 120 mmHg.Embodiment A39. The ASi for use according to any one of embodiments Al to A38, wherein the patient has a SBP > 130 mmHg.Embodiment A40. The ASi for use according to any one of embodiments Al to A39, wherein the patient has a SBP > 140 mmHg.Embodiment A41. The ASi for use according to any one of embodiments Al to A40, wherein the patient has CVD, and the CVD is selected from one or more of ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease.Embodiment A42. The ASi for use according to any one of embodiments Al to A41, wherein the patient has serum potassium > 3.0 and < 4.8 mmol / L.Embodiment A43. The ASi for use according to any one of embodiments Al to A41, wherein the patient has serum potassium > 3.0 and < 5.5 mmol / L.Embodiment A44. The ASi for use according to any one of embodiments Al to A41, wherein the patient has serum potassium > 3.0 and < 4.8 mmol / L and the method comprises administering about 1 mg or about 2 mg of baxdrostat to the patient, once daily.Embodiment A45. The ASi for use according to any one of embodiments Al to A41, wherein the patient has serum potassium > 4.8 and < 5.5 mmol / L and the method comprises administering about 1 mg of baxdrostat to the patient, once daily.Embodiment A46. The ASi for use according to any one of embodiments Al to A45, wherein the patient does not have an established heart failure diagnosis.Embodiment A47. The ASi for use according to any one of embodiments Al to A46, wherein the patient is at Stage A (at risk for heart failure) or Stage B (pre-heart failure) based on the American College of Cardiology / American Heart Association classification of heart failure.Embodiment A48. The ASi for use according to any one of embodiments Al to A47, wherein the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2.Embodiment A49. The ASi for use according to any one of embodiments Al to A48, wherein a mineralocorticoid receptor antagonist (MRA) is not administered to the patient.Embodiment A50. The ASi for use according to any one of embodiments Al to A49, wherein the method comprises administering one or more standard of care agents for any of T2DM, hypertension and CVD to the patient.ABBREVIATIONS AND DEFINITION OF TERMS

[0168] The following Examples are provided to illustrate some concepts described within this disclosure. While the Examples are considered to provide specific individual embodiments of formulations, methods of preparation and use, the Examples should not be considered to limit the more general embodiments described herein.Study 1: A Phase III, Randomised, Double-blind, Placebo-controlled, Event-driven Study to Evaluate the Effect of Baxdrostat in Combination with Dapagliflozin Compared with Dapagliflozin Alone on the Risk of Incident Heart Failure and Cardiovascular Death in Participants with Increased Risk of Developing Heart Failure

[0169] A. Study Design

[0170] This is a Phase III, multicentre, event-driven, randomised, double-blind, placebo-controlled, parallel-group study to evaluate whether baxdrostat / dapagliflozin is superior to placebo / dapagliflozin in reducing HF events and CV deaths in participants at increased risk of developing HF. The study design is illustrated in Figure 1.

[0171] Approximately 11,300 participants will be randomised to study intervention in this study.

[0172] Run-in period: Participants who meet all screening inclusion / exclusion criteria but are not treated with SGLT2i or are treated for less than 4 weeks, will enter a run-in period with dapagliflozin 10 mg once daily for at least 4 weeks (and not more than 6 weeks) before randomisation (Visit 2).

[0173] Double-blind period: Eligible participants will be randomised in a 1 : 1 ratio to receive either baxdrostat / dapagliflozin or placebo / dapagliflozin once daily:• Baxdrostat 1 mg + dapagliflozin 10 mg• Placebo matching baxdrostat 1 mg + dapagliflozin 10 mg

[0174] At Visit 5, baxdrostat or matching placebo will be up-titrated to 2 mg provided that the potassium concentration (based on local laboratory value) is < 4.8 mmol / L at each Visits 3, 4, and 5.

[0175] Study Closure Visit: The study closure procedures will be initiated when the predetermined number of the first secondary endpoint events (i.e., the composite of hospitalisation for HF or CV death) is predicted to have occurred (N = 722), i.e., the PACD. All potential endpoint events will be adjudicated by an independent CEA Committee who is blinded to the treatment allocation. All randomised participants, including any participants who have prematurely discontinued study intervention, will be scheduled for an SCV within 6 weeks of the PACD.

[0176] End-of-Study definition: A participant is considered to have completed the study if they have completed all phases of the study including the last scheduled procedure, i.e., the SCV.

[0177] The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure for the last participant in the study globally, whichever occurs last.

[0178] B. Study Population

[0179] (i) Principal Inclusion Criteria

[0180] Participants are eligible to be included in the study only if all the following criteria apply:1 Participants of any sex and gender must be > 40 years old at the time of signing the informed consent2 Diagnosed with T2DM and requiring treatment3 Established CV disease (ischaemic heart disease, cerebrovascular disease, peripheral arterial disease)4 History of HTN and an SBP > 130 mmHg at screening and > 120 mmHg at the Randomisation Visit.5 Central laboratory serum potassium > 3.0 to < 4.8 mmol / L at screening6 At least one additional risk factor for HF : o Age > 70 years o UACR > 20 mg / g o eGFR < 60 mL / min / 1.73 m2o History of polyvascular disease (at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease)o History of atrial fibrillation or atrial flutter o NT -proBNP > 125 ng / L

[0181] (ii) Principal Exclusion Criteria

[0182] Participants are excluded from the study if any of the following criteria apply:1 Established heart failure diagnosis2 An eGFR < 30 mL / min / 1 ,73m2at screening3 Known hyperkalaemia, defined as potassium > 5.5 mmol / L within 3 months prior to screening4 Type 1 diabetes mellitus or uncontrolled T2DM with HbAlc > 10.5% (> 91 mmol / mol) at screening5 Serum sodium < 135 mmol / L at screening, determined as per central laboratory assessment6 Stroke, transient ischaemic cerebral attack, valve implantation or valve replacement, carotid surgery, carotid angioplasty, or cardiac surgery, within 3 months prior to randomisation7 Myocardial infarction within 3 months prior to randomisation, or within 1 month prior to randomisation when there is no further planned revascularisation8 Percutaneous coronary intervention within 1 month prior to randomisation9 Known severe hepatic impairment, defined as Child-Pugh Class C, based on records that confirm documented medical history10 Documented history of adrenal insufficiency11 Any dialysis (including for acute kidney injury) within 3 months prior to screening12 Any acute kidney injury within 3 months prior to screening13 History or known allergy / hypersensitivity to the study treatment, as judged by the Investigator (eg, SGLT2i or active substance or excipients)14 History of organ transplant or bone marrow transplant, or planned organ transplant within 6 months following randomisation (including kidney transplant)15 Any clinical condition requiring systemic immunosuppression therapy other than maintenance therapy (stable for at least 3 months prior to screening)16 Drug or alcohol abuse that in the Investigator’ s judgement makes the participant a poor candidate for the study17 Any use of mineralocorticoid receptor antagonists (such as spironolactone, eplerenone, or finerenone) or aldosterone synthase inhibitor within 4 weeks prior to screening and / or during the study18 Concomitant therapy with strong inducers of cytochrome P450 (CYP) 3 A (eg, apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John’s wort)18 Use of potassium-sparing diuretics (such as triamterene or amiloride) and direct renin inhibitor (eg, aliskiren) at the time of screening19 Use of potassium binders (such as sodium zirconium cyclosilicate, patiromer, or sodium polystyrene sulfonate) within 4 weeks prior to screening

[0183] Participant eGFR for the determination of eligibility will be calculated according to the CKD-EPI 2021 equation, based on serum creatinine concentration alone (Inker et al. N Engl J Med. 2021;385(19): 1737-49)

[0184] The UACR is calculated as follows:UACR(mg / g = urine albumin [mg / dL] / urine creatinine [g / dL])

[0185] C. Study Intervention and Concomitant Therapy

[0186] (i) Study Intervention Administered

[0187] Dapagliflozin will be provided as an IMP to all participants. Participants who enter the run-in period will receive dapagliflozin 10 mg, to be administered orally once daily. During the double-blind treatment period, participants will receive either baxdrostat / dapagliflozin or placebo / dapagliflozin. To ensure blinding to treatment, the baxdrostat 1 mg, baxdrostat 2 mg, and placebo to match baxdrostat tablets are identical in appearance (matching and indistinguishable). Study interventions to be administered and investigated in this study are described in the table below:

[0188] All participants who meet all the eligibility criteria will be centrally assigned to randomised, blinded study intervention using an automated IRT / RTSM that will allocate participants, at a 1 : 1 ratio, into one of the 2 treatment arms (ie, either baxdrostat / dapagliflozin or placebo / dapagliflozin arm).

[0189] (ii) Dose Modification

[0190] Up-titration: On Day 1 (Visit 2), participants randomised to the baxdrostat / dapagliflozin arm will initially receive a dose of baxdrostat 1 mg and dapagliflozin 10 mg. Participants randomised to the placebo / dapagliflozin arm will receive placebo matching baxdrostat 1 mg and dapagliflozin 10 mg. At Visit 5, baxdrostat or matching placebo will be up-titrated to 2 mg provided that the potassium concentration (based on local laboratory value) is < 4.8 mmol / L at each Visits 3, 4, and 5.

[0191] Up-titration of the baxdrostat dose should occur within 7 days and preferably as soon as possible after the serum / plasma potassium concentration is confirmed from the local laboratory assessment.

[0192] Serum / plasma potassium concentration must be assessed at the local and central laboratories at 14 (±5) days after up-titration. In addition, for participants with eGFR value < 45 mL / min / 1.73 m2who are up-titrated to 2 mg dose, potassium concentration should also be checked at the local and central laboratories at 4 weeks after up-titration.

[0193] Participants who experience potassium concentration > 5.5 mmol / L, or sodium concentration < 130 mmol / L, or symptomatic hypotension with SBP < 90 mmHg at any point during the study should not be up-titrated and should remain on 1 mg dose.

[0194] Down-titration: For participants whose baxdrostat doses are previously up- titrated, down-titration can be considered at any point throughout the study, for example based on the potassium level, SBP, sodium level, or for other safety or tolerability concerns. These decisions should be reviewed with the Sponsor’s representative when possible.Following down-titration, an unscheduled safety visit may be performed within 2 weeks, at the Investigator’s discretion. Participants who are down-titrated from 2 mg to 1 mg during the study should remain at 1 mg for the rest of the study.

[0195] (iii) Potassium Monitoring Measurements

[0196] Serum potassium levels will be monitored systemically throughout the study. Instructions for management of serum potassium measurements are described below:

[0197] Serum potassium < 4.8 mmol / L:

[0198] If participant is on 1 mg baxdrostat / placebo, up-titrate to 2 mg.

[0199] If participant is on 2 mg baxdrostat / placebo, continue on the same dose.

[0200] Serum potassium 4.9 to 5.5 mmol / L: continue on the same dose.

[0201] Serum potassium > 5.5 mmol / L: withhold baxdrostat / placebo, manage hyperkalaemia as per clinical judgment (e.g. potassium binders), and re-check potassium. If subsequent sample is < 4.8 mmol / L, re-start baxdrostat / placebo at 1 mg. Serum potassium should be re-checked within 2 weeks (+ / - 5 days) following resumption of baxdrostat / placebo in an unscheduled visit.

[0202] If subsequent sample is > 4.8 mmol / L: continue to withhold baxdrostat / placebo; continue to monitor serum potassium and restart baxdrostat / placebo at 1 mg when potassium is < 4.8 mmol / L. Serum potassium should be re-checked within 2 weeks (+ / - 5 days) in an unscheduled visit.

[0203] NOTE: participants who experienced serum potassium > 5.5 mmol / L should not be up-titrated during the course of the study.

[0204] (iv) Prohibited Concomitant Medications

[0205] The medications and supplements listed below are prohibited during this study.• Potassium-sparing diuretics (eg, amiloride, triamterene) and direct renin inhibitor (eg, aliskiren).• Mineralocorticoid receptor antagonists or aldosterone antagonists (eg, eplerenone, finerenone, spironolactone) or aldosterone synthetase inhibitors.• Strong CYP3A4 inducers (eg, apalutamide, avasimibe, carbamazepine, enzalutamide, lumacaftor, mitotane, phenytoin, rifampin, rifapentine, St. John’s wort).• Long-term concomitant medication with NS AID should, if possible, be avoided during the study. Use of low-dose aspirin is permitted.• Concomitant treatment with SGLT2i other than the dapagliflozin• Treatment with potassium supplements are not prohibited but should only be prescribed to individuals for whom the Investigator considers these agents to be required to avoid hypokalaemia.• Potassium binders may be used at any point in the study following randomisation, at the discretion of the Investigator and the participant’s treating physician(s), per local standard of care.(v) Standard of Care TreatmentParticipants are expected to be on standard of care treatment according to local guidelines for treatment of atherosclerotic CV / cerebrovascular disease, T2DM, HTN as well as for CV risk factors and comorbidities (American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes- 2021. Diabetes Care. 2021;44 (Suppl 1):S15-S33; Byrne RA et al. Eur Heart J. 2023 Oct 12;44(38):3720-3826. Erratum in: Eur Heart J. 2024 Apr 1;45(13): 1145; Mancia G et al. J Hypertens. 2023;41(12): 1874-2071. Erratum in: J Hypertens. 2024 Jan 1 ;42(1): 194). Consequently, common background treatments are expected to be antiplatelets, beta-blockers, cholesterol lowering medications, ACER ARB and anti- hyperglycaemic treatments other than SGLT2i.

[0206] C. Objectives / Endpoints

[0207] All potential endpoint events will be adjudicated by an independent CEA Committee who is blinded to the treatment allocation.

[0208] Primary estimand definition

[0209] The estimand is described by the following attributes:

[0210] Treatment: Baxdrostat / dapagliflozin or placebo / dapagliflozin regardless of discontinuation of investigational intervention (treatment policy strategy), and irrespective of initiation or change in concomitant medications (treatment policy strategy).

[0211] Population: Patients at increased risk of developing HF, defined through inclusion and exclusion criteria.

[0212] Variable: Time from randomisation to first occurrence of any component in the composite of HF with or without hospitalisation or CV death (including undetermined cause of death).

[0213] Intercurrent event strategies: Non-CV death will be handled using a hypothetical strategy, by assuming participants cannot die from non-CV death, implemented by censoring at time of death and not imputing data after death. All other intercurrent events will be handled using treatment policy.

[0214] Population-level summary for the variable: Hazard ratio between treatment arms.

[0215] This estimand requires that, to the extent possible, randomised participants are followed up regardless of study intervention compliance and adherence to the protocol.Disease Definitions

[0216] Established Cardiovascular Disease:• Ischaemic heart disease (any of the following): o Documented Myocardial Infarction o Percutaneous Coronary Intervention o Coronary Artery Bypass Grafting o Objective Findings of Coronary Stenosis (> 50%) in at least 2 coronary artery territories (ie, left anterior descending, ramus intermedius, left circumflex, right coronary artery) involving the main vessel, a major branch, or a bypass graft• Cerebrovascular disease (any of the following): o Documented ischaemic stroke o Known transient ischaemic attack, primary intracerebral haemorrhage or subarachnoid haemorrhage do not qualify o Carotid stenting or endarterectomyPlease note, transient ischaemic attack, primary intracerebral haemorrhage or subarachnoid haemorrhage do not qualify.• Peripheral Arterial Disease (any of the following): o Peripheral arterial intervention, stenting or surgical revascularisation o Lower extremity amputation as a result of peripheral arterial obstructive disease o Current symptoms of intermittent claudication AND ankle / brachial index < 0.90 documented within last 12 months

[0217] Polyvascular Disease: At least two of: Ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease (for definition see above).

[0218] Type 2 Diabetes Mellitus (T2DM): Prior documentation of type 2 diabetes AND treatment with anti -hyperglycaemic medications. Definition of T2DM according to ADA criteria: fasting > 126 mg / dl (7.0 mmol / L) or HbAlc > 6.5% or 2-hour plasma glucose> 200 mg / dl (11.1 mmol / L) during an oral glucose tolerance test, or a random plasma glucose> 200 mg / dL (11.1 mmol / L) in patients with classic symptoms of hyperglycaemia or hyperglycaemic crisis. In the absence of unequivocal hyperglycaemia, results should be confirmed by repeat testing.Endpoint DefinitionsHospitalisation for Heart Failure:

[0219] An admission to the hospital where a participant’s length of stay extends for at least 24 hours or as measured by a change in calendar date, which meets all the criteria below (i-iv): i. The participant is admitted to the hospital with a primary cause of HF. ii. The participant exhibits documented new or worsening symptoms due to HF on presentation, including at least one of the following: dyspnoea (dyspnoea with exertion, dyspnoea at rest, orthopnoea, paroxysmal nocturnal dyspnoea); decreased exercise tolerance; fatigue; or other symptoms of worsened endorgan perfusion or volume overload. iii. The participant has objective evidence of new or worsening HF, consisting of either at least one physical examination finding or one laboratory or invasively measured criterion, including: a. Physical examination finding considered to be due to HF include new or worsened: peripheral oedema; increasing abdominal distention or ascites (in the absence of primary hepatic disease); pulmonaryrales / crackles / crepitations; increased jugular venous pressure and / or hepatojugular reflux; third heart sound (S3) gallop; clinically significant or rapid weight gain thought to be related to fluid retention. b. Laboratory evidence of new or worsening HF, if obtained within 24 hours of presentation, include: increased B-type natriuretic peptide (BNP) / NT- proBNP concentrations consistent with decompensation of HF (in participants with chronically elevated natriuretic peptides, a significant increase should be noted above baseline); radiological, ultrasonographic, or implantable monitor evidence of pulmonary congestion; non-invasive or implantable diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure, or low cardiac output. c. Invasive evidence of new or worsening HF including right heart catheterization showing elevated pulmonary capillary wedge pressure (pulmonary artery occlusion pressure), elevated central venous pressure, depressed cardiac index, or left heart catheterization showing elevated left ventricular end-diastolic pressure consistent with decompensation of HF. iv. The participant receives at least one of the following treatments specifically for HF : a. In participants presenting with a new diagnosis of HF, initiation of maintenance diuretic therapy. In participants with a confirmed diagnosis of HF during follow-up and a further episode of worsening HF, significant augmentation in oral diuretic therapy (at least a doubling of diuretic dose or initiation of combination diuretic therapy). b. Initiation of intravenous diuretic (even a single dose). c. Initiation of an intravenous vasoactive agent (catecholamine, phosphodiesterase-3 inhibitor, other vasopressor, vasodilator). d. Mechanical or surgical intervention, including mechanical circulatory support (intra-aortic balloon pump, temporary or durable ventricular assist device including both percutaneous and surgically placed devices, extracorporeal membrane oxygenation, or total artificial heart). e. Mechanical fluid removal (ultrafiltration, haemofiltration, haemodialysis).

[0220] For every event corresponding to new onset HF, either in an inpatient or outpatient setting, information about LVEF will be collected in conjunction with the event, where available.Heart Failure Without Hospitalisation:

[0221] An outpatient visit in an emergency department or ambulatory setting, which meets all criteria below (i-iii): i. The participant exhibits documented new or worsening symptoms due to HFon presentation, including at least one of the following: dyspnoea (dyspnoea with exertion, dyspnoea at rest, orthopnoea, paroxysmal nocturnal dyspnoea); decreased exercise tolerance; fatigue; or other symptoms of worsened endorgan perfusion or volume overload. ii. The participant has objective evidence of new onset or worsening HF, consisting of at least one physical examination finding or one imaging or one laboratory or invasively measured criterion, including: a. Physical examination finding considered to be due to HF include new onset or worsened: peripheral oedema; increasing abdominal distention or ascites (in the absence of primary hepatic disease); pulmonary rales / crackles / crepitations; increased jugular venous pressure and / or hepatojugular reflux; S3 gallop; clinically significant or rapid weight gain thought to be related to fluid retention. b. Imaging evidence of structural or functional cardiac disease consistent with a diagnosis of HF, eg, left ventricular systolic dysfunction; left atrial enlargement; left ventricular diastolic dysfunction; increased pulmonary pressure or left ventricular hypertrophy. c. Laboratory evidence of new or worsening HF including: increased BNP / NT -proBNP concentrations (in participants with chronically elevated natriuretic peptides, a significant increase should be noted above baseline); radiological, ultrasonographic, or implantable monitor evidence of pulmonary congestion; non-invasive or implantable diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure or low cardiac output. d. Invasive evidence of new or worsening HF including right heart catheterization showing elevated pulmonary capillary wedge pressure (pulmonary artery occlusion pressure), elevated central venous pressure, depressed cardiac index, or left heart catheterization showing elevated left ventricular end-diastolic pressure consistent with decompensation of HF. iii. The participant receives at least one of the following treatments specifically for HF : a. In participants with a new diagnosis of HF, initiation of at least one of new oral diuretic therapy, SGLT2i treatment, renin-angiotensin system inhibitor, angiotensin receptor neprilysin inhibitors, beta-blocker, MRA, ivabradine, digoxin, vericiguat or hydralazine / isosorbide dinitrate prescribed as a treatment for HF. ALL newly prescribed drugs for HF will be documented from the time of diagnosis to the end of the study. Cardiac device implantation during the course of the study will also be documented. b. In participants with a confirmed diagnosis of HF during follow-up and a further episode of worsening HF, significant augmentation in oral diuretic therapy (including at least a doubling of diuretic dose, initiation of diuretictherapy, or initiation of combination diuretic therapy). c. Initiation of intravenous diuretic (even a single dose). d. In the emergency department or hospital, initiation of an intravenous vasoactive agent (catecholamine, phosphodiesterase- 3 inhibitor, other vasopressor, vasodilator). e. In the emergency department or hospital, mechanical fluid removal (ultrafiltration, haemofiltration, initiation of dialysis for what is felt to be a primary cardiac rather than renal cause).

[0222] For every event corresponding to new onset HF, either in an inpatient or outpatient setting, information about LVEF will be collected in conjunction with the event, where available.Measurement of vital signs

[0223] Vital signs will include heart rate and BP measurements.

[0224] Participants should not exercise, smoke, or consume alcohol, caffeine- containing food or beverages 30 minutes prior to BP measurements. On study visits, when study intervention is administered on-site, BP will be assessed predose. Blood pressure measurements should be obtained prior to performing ECG measurements and blood sampling.

[0225] Pulse and BP will be measured 3 times per timepoint, and all measurements will be recorded in the eCRF, the average of the measurements is calculated. The measurements should be taken using a standardised calibrated cuff adapted to the size of the participant’s arm after the participant has been sitting and resting for least 5 minutes in a quiet setting.

[0226] The same arm and the appropriate size cuff should be used for measurements at each visit.

Claims

Claims1. A method of reducing the risk of cardiovascular death or a heart failure (HF) event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an aldosterone synthase inhibitor (ASi) and an amount of a sodium-glucose co-transporter 2 inhibitor (SGLT2i), wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

2. A method of reducing the risk of a HF event in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

3. A method of reducing the risk of cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

4. A method of reducing the risk of all-cause mortality in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

5. A method of reducing the risk of atrial fibrillation or cardiovascular death in a patient with one or more risk factors for developing HF, and no previous history of atrial fibrillation, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

6. A method of reducing the risk of myocardial infarction or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

7. A method of reducing the risk of MACE (myocardial infarction, stroke or cardiovascular death) in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

8. A method of reducing the risk of stroke or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

9. A method of preventing or delaying an event selected from:(a) a composite of cardiovascular death or a HF event;(b) a HF event;(c) a composite of hospitalisation for HF, HF without hospitalisation, or cardiovascular death;(d) a composite of hospitalisation for HF or cardiovascular death;(e) a composite of hospitalisation for HF or HF without hospitalisation;(f) cardiovascular death;(g) all -cause death;(h) a composite of stroke or cardiovascular death;(i) a composite of a new diagnosis of atrial fibrillation or cardiovascular death;(j) a composite of myocardial infarction or cardiovascular death; and(k) a composite of myocardial infarction, stroke or cardiovascular death; in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

10. The method according to any one of claims 1, 2 and 9, wherein the HF event is hospitalisation for HF or HF without hospitalisation.

11. The method according to any one of claims 1, 2 and 9, wherein the HF event is hospitalisation for HF.

12. The method according to any one of claims 1, 2, 9, 10 and 11, wherein hospitalisation for HF comprises a hospital admission lasting at least 24 hours or as measured by a change in calendar date, and the patient has objective evidence of new or worsening HF.

13. The method according to any one of claims 1, 2, 9 and 10, wherein HF without hospitalisation comprises an outpatient visit in an emergency department or ambulatory setting, and the patient has objective evidence of new or worsening HF.

14. The method according to any one of claims 1, 2 and 9, wherein the HF event is development of symptomatic HF.

15. The method according to any one of claims 1, 2 and 9, wherein the HF event is incident HF.

16. A method of preventing or delaying HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

17. A method of preventing or delaying HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

18. A method of preventing or delaying symptomatic HF and / or cardiovascular death in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

19. A method of preventing or delaying symptomatic HF in a patient with one or more risk factors for developing HF, the method comprising administering to the patient a combination comprising an amount of an ASi and an amount of an SGLT2i, wherein the amount of the ASi and the amount of the SGLT2i together comprise an effective amount.

20. The method according to any one of the preceding claims, wherein the one or more risk factors for developing HF are selected from type 2 diabetes mellitus (T2DM), hypertension and cardiovascular disease (CVD), and optionally one or more of (1) age > 70 years, (2) UACR > 20 mg / g, (3) eGFR < 60 mL / min / 1.73 m2, (4) history of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease, (5) history of atrial fibrillation or atrial flutter and (6) NT-proBNP > 125 ng / L.

21. The method according to any one of the preceding claims, wherein the patient has T2DM, hypertension and CVD, and optionally one or more additional risk factors for developing HF.

22. The method according to claim 21, wherein the one or more additional risk factors for developing HF are selected from (1) age > 70 years, (2) UACR > 20 mg / g, (3) eGFR < 60 mL / min / 1.73 m2, (4) history of polyvascular disease, for example at least two of: ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease, (5) history of atrial fibrillation or atrial flutter and (6) NT-proBNP > 125 ng / L.

23. The method according to any one of the preceding claims, wherein the ASi is baxdrostat or a pharmaceutically acceptable salt thereof.

24. The method according to claim 23, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 0.5 mg / day, about 1 mg / day or about 2 mg / day.

25. The method according to claim 23, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 1 mg / day or about 2 mg / day.

26. The method according to any one of claims 23 to 25, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered once daily.

27. The method according to any one of claims 23 to 26, wherein the baxdrostat or pharmaceutically acceptable salt thereof is in a form suitable for oral administration, such as a tablet.

28. The method according to any one of claims 23 to 27, wherein the baxdrostat or pharmaceutically acceptable salt thereof is baxdrostat.

29. The method according to any one of the preceding claims, wherein the SGLT2i is selected from dapagliflozin, canagliflozin, empagliflozin, sotagliflozin, ipragliflozin, ertugliflozin, tofogliflozin, and luseogliflozin, or a pharmaceutically acceptable salt thereof.

30. The method according to any one of the preceding claims, wherein the SGLT2i is dapagliflozin.

31. The method according to claim 30, wherein the dapagliflozin is administered at a dosage of about 10 mg / day.

32. The method according to claim 30 or claim 31, wherein the dapagliflozin is administered once daily.

33. The method according to any one of claims 30 to 32, wherein the dapagliflozin is in a form suitable for oral administration, such as a tablet.

34. The method according to any one of the preceding claims, the method comprising administering to the patient a combination comprising about 0.5 mg, about 1 mg or about 2 mg, once daily, of baxdrostat and about 10 mg, once daily, of dapagliflozin.

35. The method according to any one of the preceding claims, the method comprising administering to the patient a combination comprising about 1 mg or about 2 mg, once daily, of baxdrostat and about 10 mg, once daily, of dapagliflozin.

36. The method according to any one of claims 30 to 35, wherein the dapagliflozin is in the form of a (S)-propylene glycol ((S)-PG) solvate which has the structure37. The method according to any one of the preceding claims, wherein the ASi, such as baxdrostat or a pharmaceutically acceptable salt thereof, is administered before, after, or concurrently with the SGLT2i, such as dapagliflozin.

38. The method according to any one of the preceding claims, wherein the patient has a systolic blood pressure (SBP) > 120 mmHg.

39. The method according to any one of the preceding claims, wherein the patient has a SBP > 130 mmHg.

40. The method according to any one of the preceding claims, wherein the patient has a SBP > 140 mmHg.

41. The method according to any one of the preceding claims, wherein the patient has CVD, and the CVD is selected from one or more of ischaemic heart disease, cerebrovascular disease, and peripheral arterial disease.

42. The method according to any one of the preceding claims, wherein the patient has serum potassium > 3.0 and < 4.8 mmol / L.

43. The method according to any one of claims 1 to 41, wherein the patient has serum potassium > 3.0 and < 5.5 mmol / L.

44. The method according to any one of claims 1 to 41, wherein the patient has serum potassium > 3.0 and < 4.8 mmol / L and the method comprises administering about 1 mg or about 2 mg of baxdrostat to the patient, once daily.

45. The method according to any one of claims 1 to 41, wherein the patient has serum potassium > 4.8 and < 5.5 mmol / L and the method comprises administering about 1 mg of baxdrostat to the patient, once daily.

46. The method according to any one of the preceding claims, wherein the patient does not have an established heart failure diagnosis.

47. The method according to any one of the preceding claims, wherein the patient is at Stage A (at risk for heart failure) or Stage B (pre-heart failure) based on the American College of Cardiology / American Heart Association classification of heart failure.

48. The method according to any one of the preceding claims, wherein the patient has an estimated glomerular filtration rate (eGFR) > 30 mL / min / 1.73 m2.

49. The method according to any one of the preceding claims, wherein a mineralocorticoid receptor antagonist (MRA) is not administered to the patient.

50. The method according to any one of the preceding claims, wherein the method comprises administering one or more standard of care agents for any of T2DM, hypertension and CVD to the patient.

51. An ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) for use in the method of any one of the preceding claims.

52. An SGLT2i (such as dapagliflozin) for use in the method of any one of claims 1 to 50.

53. A combination of an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and an SGLT2i (such as dapagliflozin) for use in any one of claims 1 to 50.

54. Use of an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for use in the method of any one of claims 1 to 50.

55. Use of an SGLT2i (such as dapagliflozin) in the manufacture of a medicament for use in the method of any one of claims 1 to 50.

56. A kit comprising: (a) an ASi (such as baxdrostat or a pharmaceutically acceptable salt thereof) and / or an SGLT2i (such as dapagliflozin), and (b) instructions for use of the ASi and / or an SGLT2i in the method of any one of claims 1 to 50.

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