The Shared Molecular Axes Driving DKD and HFpEF

Diabetic kidney disease (DKD) and heart failure with preserved ejection fraction (HFpEF) converge on two dominant molecular axes: the renin-angiotensin-aldosterone system (RAAS) and mineralocorticoid receptor (MR) pathway, and the renal sodium-glucose cotransporter 2 (SGLT2) expressed in the proximal tubule. Both conditions share pathophysiological drivers — aldosterone excess, RAAS activation, and sodium-glucose dysregulation — making them a clinically overlapping cardiorenal syndrome with high unmet therapeutic need.

In DKD, albuminuria and estimated glomerular filtration rate (eGFR) decline are the primary clinical endpoints used to evaluate therapeutic benefit, as consistently identified across retrieved patent and literature records. A literature record from Xuzhou Medical University identifies FTO-mediated N6-methyladenosine (m6A) modification of SOCS1 mRNA as a mechanistic contributor to DKD progression, proposing FTO as a novel molecular target distinct from current pharmacological approaches.

The causal relationship between heart failure and CKD is not simply correlative. A pending patent from Chongqing Medical University employs Mendelian randomization analysis on GWAS datasets to identify shared differentially expressed genes and confirm bidirectional cardiorenal causality — providing genomic-level evidence for the mechanistic overlap that drives both conditions simultaneously.

For HFpEF specifically, HDAC6 has emerged as an intracellular therapeutic target distinct from the neurohormonal approaches dominating the broader pipeline. A Tenaya Therapeutics patent claims oral HDAC6 inhibitors for metabolic disease and HFpEF treatment through epigenetic and cytoskeletal mechanisms. Additionally, a literature record from the Cardiovascular Research Institute of Wuhan University implicates right heart disease and pulmonary vascular remodelling as mechanistically relevant contexts for SGLT2 intervention in heart failure settings — broadening the mechanistic rationale beyond glycaemic control.

SGLT2 Inhibitors vs. MRAs: What the Patent and Clinical Evidence Shows

SGLT2 inhibitors are the dominant pharmacological modality in the current cardiorenal patent dataset, with dapagliflozin (AstraZeneca) carrying the largest volume of active IP filings. These agents block glucose reabsorption in the renal proximal tubule, reducing eGFR decline, improving urinary albumin-creatinine ratio (UACR), reducing vascular stiffness, and providing hemodynamic benefits including preload and afterload reduction — effects that extend well beyond glycaemic control.

Phase 3 data from DAPA-HF explicitly cited in AstraZeneca’s Canadian and Australian patents (2021) shows dapagliflozin reduces the composite of worsening heart failure or cardiovascular death in HFrEF patients, with efficacy maintained in the 55% of patients without type 2 diabetes. The DAPA-CKD Phase 3 trial, cited in AstraZeneca’s Israeli patents, establishes efficacy across IgA nephropathy, non-diabetic CKD, and diabetic CKD populations. A 2021 meta-analysis from the First Affiliated Hospital of Yangtze University, drawing on both the EMPEROR-Reduced and DAPA-HF trials, evaluated SGLT2 inhibitor effects on fatal and non-fatal heart failure events across 10 clinically important subgroups including renal endpoints.

Mineralocorticoid receptor antagonists (MRAs) present a more complex picture. Steroidal agents — spironolactone and eplerenone — appear primarily in literature records evaluating clinical outcomes in CKD and HF settings. A 2018 Karolinska Institutet study examining the SWEDEHEART registry (2005–2014) assessed real-world MRA outcomes in myocardial infarction patients with heart failure stratified by ejection fraction and CKD presence (eGFR <60 mL/min/1.73 m²). Clinical evidence for aldosterone blockade in CKD progression comes from Hospital General Universitario Gregorio Marañón (Madrid), where spironolactone reduced annual eGFR decline to −2.1 ± 4.8 mL/min/1.73 m² compared to furosemide at −3.2 ± 5.6 mL/min/1.73 m² (p <0.01) in resistant hypertension patients with CKD.

“A post-hoc analysis of DAPA-CKD (4,304 patients, 229 on MRA at baseline) found no significant moderating effect of baseline MRA use on dapagliflozin’s cardiorenal benefit — P interaction = 0.59 — though wide confidence intervals among MRA users were noted.”

The most significant clinical interaction question — whether MRA use attenuates dapagliflozin benefit — was addressed by a 2022 Veterans Administration post-hoc analysis of DAPA-CKD. The finding of no significant interaction (P interaction = 0.59) suggests the two drug classes can co-exist pharmacologically, though the wide confidence intervals in the MRA-user subgroup leave open the question of possible benefit attenuation. This ambiguity is precisely the clinical gap that AstraZeneca’s fixed-dose AZD9977 plus dapagliflozin combination is designed to address with a purpose-built, pharmacologically optimised pairing.

Real-world evidence extends beyond clinical trials. A 2022 study using UK primary care electronic health records (N=12,978 SGLT2 inhibitor users; N=44,286 matched comparators) provides population-level replication of cardiovascular and renal outcome benefits outside trial settings, according to data published in peer-reviewed literature and indexed by NEJM Evidence. This real-world validation is increasingly cited in regulatory submissions and patent claim substantiation.

Six Combination Strategies Reshaping the Cardiorenal Pipeline

The most consequential signal in the current patent landscape is not any single agent but the rapid proliferation of mechanistically complementary combination strategies — each targeting distinct nodes in cardiorenal pathophysiology. Six distinct approaches have been identified across retrieved patent filings.

1. MR Modulator (AZD9977) + Dapagliflozin — Fixed-Dose Combination

The most advanced combination signal in the dataset. Multiple AstraZeneca patents (CN 2025, ID 2025, JP 2023, JP 2022) specify a fixed-dose pharmaceutical composition with pellet-in-pellet architecture delivering AZD9977 (10–50 mg) and dapagliflozin (10 mg) co-formulated for CKD and heart failure. Patent claims explicitly address reduction of UACR, hyperkalemia risk mitigation — positioning the SGLT2 inhibitor as a potassium-sparing facilitator enabling MRA use — and cardiorenal dual endpoints. The defined target population is patients with eGFR 15–89 mL/min/1.73 m².

2. Aldosterone Synthase Inhibitor (CYP11B2) + SGLT2 Inhibitor

Boehringer Ingelheim International GmbH and Mineralys Therapeutics, Inc. hold separate patent positions combining upstream aldosterone suppression with SGLT2 inhibition. Boehringer Ingelheim’s pending filings in Chile and Brazil claim CYP11B2 inhibitor compounds of Formula (I) for CKD with explicit combination intent. Mineralys Therapeutics holds a 2025 Taiwan patent for lorundrostat — a clinical-stage aldosterone synthase inhibitor — alone or combined with an SGLT2 inhibitor for CKD with or without hypertension. This approach may circumvent the hyperkalemia liability of traditional steroidal MRAs while preserving aldosterone pathway blockade.

3. Endothelin Receptor Antagonist (ERA) + SGLT2 Inhibitor

AstraZeneca (zibotentan + dapagliflozin, 2025, Israel) and Chinook Therapeutics — now part of Novartis — (atrasentan + SGLT2 inhibitor, 2023, Mexico) both claim this combination for proteinuric and diabetic CKD. Idorsia Pharmaceuticals Ltd holds patents for aprocitentan (dual endothelin receptor antagonist) plus SGLT2 inhibitors for diabetic nephropathy and glomerulonephritis. Endothelin-1-driven renal vasoconstriction combined with SGLT2-mediated tubuloglomerular feedback modulation represents a mechanistically complementary approach in high-proteinuria CKD not addressed by MRAs or SGLT2 monotherapy alone.

4. BET Bromodomain Inhibitor (Apabetalone/RVX-208) + SGLT2 Inhibitor

Resverlogix Corp. holds multiple international patents (WO, US, NZ, AU, MX) for apabetalone (RVX-208) combined with SGLT2 inhibitors for renal function improvement. Patent data specifically reports that the RVX-208 plus SGLT2 inhibitor combination increased eGFR from a median of 114 mL/min at baseline to 120 mL/min at last visit on treatment — exceeding the additive single-agent effects and signalling an unexpected superadditive synergy potentially reflecting complementary epigenomic and hemodynamic mechanisms.

5. SLC6A19 + SGLT2 Inhibitor

Jnana Therapeutics, Inc. holds a WO 2025 patent proposing dual tubular transporter blockade — neutral amino acid transporter B0AT1 (SLC6A19) combined with SGLT2 — for CKD across all stages. The patent argues that the distinct mechanisms of SLC6A19 and SGLT2 transporters provide additive-to-synergistic renoprotection. This constitutes an early-stage but mechanistically differentiated entry point in the CKD pipeline, according to WIPO patent filings.

6. RXFP1 Modulator + SGLT2 Inhibitor

A 2025 AstraZeneca Brazil patent for combinations of relaxin family peptide receptor 1 (RXFP1) modulators and SGLT2 inhibitors represents the most recently filed novel combination signal in the dataset. This pairing potentially targets myocardial fibrosis — a key HFpEF substrate — combined with hemodynamic and renal SGLT2 effects, and may represent an early signal of AstraZeneca’s next-generation HFpEF strategy.

Assignee Landscape: Who Holds the IP and Where

Patent-driven commercial IP activity in the cardiorenal space is heavily concentrated in AstraZeneca AB, which accounts for the largest volume of retrieved filings across multiple jurisdictions for both dapagliflozin in HFrEF and CKD indications and for the AZD9977 plus dapagliflozin combination. AstraZeneca’s IP position spans active filings in the US, AU, JP, SG, IL, MX, CA, KR, PE, ID, BR, TW, and CN — a global multi-jurisdictional filing strategy consistent with a late-stage commercial asset.

Boehringer Ingelheim International GmbH holds two distinct patent threads: aldosterone synthase inhibitors for CKD in combination with SGLT2 inhibitors (CL, BR), and veterinary SGLT2 inhibitor applications (CN, TW) — the latter representing a separately filed commercial IP track. Resverlogix Corp. holds multiple international patents for apabetalone across WO, US, NZ, AU, and MX jurisdictions, constituting a differentiated mechanistic patent cluster. Academic literature in this dataset derives primarily from Brigham and Women’s Hospital/Harvard Medical School, Karolinska Institutet, Northwestern Medicine, Veterans Affairs San Diego, and multiple Asian academic medical centres — predominantly observational, registry-based, or meta-analytic in character, consistent with translational validation of established clinical signals. The NIH and affiliated academic networks continue to support the investigator-initiated studies that underpin this translational evidence base.

HFpEF’s Thin Pipeline and the Emerging Targets Filling the Gap

HFpEF represents the highest unmet-need indication with the thinnest pipeline in the cardiorenal dataset analysed. Diuretics remain the most common pharmacological approach for HFpEF, and only HDAC6 inhibitors — specifically Tenaya Therapeutics’ 2-fluoroalkyl-1,3,4-oxadiazol-5-yl-thiazole scaffold compounds — specifically claim HFpEF as a primary indication in the retrieved patent literature. SGLT2 inhibitor patent filings in this dataset predominantly cover HFrEF and CKD rather than HFpEF.

The mechanistic basis for HDAC6 inhibition in HFpEF involves cytoskeletal protein deacetylation and metabolic pathway modulation — a fundamentally different approach from the neurohormonal and hemodynamic strategies dominating the broader pipeline. This is consistent with the emerging scientific understanding that HFpEF is driven by microvascular inflammation, metabolic dysfunction, and cardiomyocyte stiffness rather than the neurohormonal activation that characterises HFrEF, as documented in cardiovascular research published by the American Heart Association.

“HFpEF-specific mechanisms — HDAC6, RXFP1, and potentially MPO inhibition — constitute emerging but as-yet unvalidated clinical directions in a field where diuretics remain the dominant pharmacological approach.”

Three additional HFpEF-relevant signals appear in the dataset. First, AstraZeneca’s 2025 Brazil patent for RXFP1 modulator plus SGLT2 inhibitor combinations targets myocardial fibrosis — a key HFpEF substrate — combined with hemodynamic SGLT2 effects. Second, a 2022 retrospective study from Wenxian People’s Hospital (247 maintenance hemodialysis patients) assessed sacubitril/valsartan in HFpEF patients on maintenance hemodialysis — a population with extreme cardiorenal overlap — providing an adjacent clinical signal for neprilysin inhibition in end-stage cardiorenal disease. Third, HDAC6 as a target class has not yet produced Phase 3 data; no clinical trial data for HDAC6 inhibitors in HFpEF was identified in the retrieved dataset.

The strategic implication is clear: the HFpEF IP landscape is sparsely populated relative to HFrEF and CKD, and the emerging mechanistic directions — HDAC6, RXFP1, and dual SGLT2-plus-fibrosis targets — represent genuine white-space opportunities for entrants willing to invest in the clinical validation work that the current patent holders have not yet completed. Regulatory guidance from the European Medicines Agency on HFpEF endpoint design continues to evolve, potentially accelerating the path to approval for novel mechanisms in this indication.

For the cardiorenal overlap population specifically — patients with both CKD and HFpEF — the pipeline gap is most acute. The AZD9977 plus dapagliflozin combination addresses the cardiorenal overlap from the HFrEF and CKD angle; no currently retrieved patent specifically claims a fixed-dose combination for the CKD-plus-HFpEF phenotype, representing a potential unoccupied IP position in the dataset. Explore the PatSnap Life Sciences intelligence platform for a broader view of the HFpEF pipeline and related cardiorenal indications.

The SLC6A19 plus SGLT2 inhibitor and BET bromodomain plus SGLT2 inhibitor combination strategies are early-stage but mechanistically differentiated, potentially offering IP freedom to operate for entrants seeking to combine SGLT2 inhibition with non-RAAS, non-MR targets. However, clinical validation of these combinations is not yet evidenced in retrieved data, and the PatSnap innovation intelligence resources provide ongoing monitoring of this evolving landscape.