Finerenone and SGLT2 Inhibitor Combination for Over-Additive Natriuresis

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Solution Overview

Problem

Current treatments for cardiovascular and renal diseases characterized by chronic sodium retention, such as congestive heart failure and chronic kidney disease, have limited natriuretic potency due to the limited effectiveness of mineralocorticoid receptor antagonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors in promoting sodium excretion.

Innovation Solution

Combining finerenone, a mineralocorticoid receptor antagonist, with an SGLT2 inhibitor to enhance sodium excretion beyond the effects of monotherapy, targeting different pathways to achieve over-additive natriuretic effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If MR antagonists are used to promote sodium excretion, then natriuretic effect is achieved, but natriuretic potency is limited due to aldosterone only influencing about 2% of total sodium reabsorption

Engineering Contradiction:

Improvesodium excretionVSAvoidnatriuretic potency

Core Design Contradiction:

Quantity of substanceVSProductivity

Solution Approach 1:

The invention segments the sodium reabsorption process into two distinct targets: proximal tubule SGLT2 transporters (handling ~90% of sodium reabsorption) and distal tubule/collecting duct MR receptors (handling ~2% of sodium reabsorption). By combining SGLT2 inhibitors and MR antagonists, the treatment addresses both segments simultaneously, achieving synergistic natriuretic effects that overcome the limited potency of MR antagonists alone.

Inventive Principle:

Principle #1Segmentation

2Quantity of substance

If SGLT2 inhibitors are used to block glucose and sodium reabsorption, then glycosuric and natriuretic effects are achieved, but natriuretic effect is only transient

Engineering Contradiction:

Improvesodium excretionVSAvoidduration of natriuretic effect

Core Design Contradiction:

Quantity of substanceVSDuration of action of moving object

Solution Approach 1:

The combination therapy ensures continuous natriuretic action by addressing both the proximal tubule (SGLT2 inhibition) and distal tubule/collecting duct (MR antagonism). While SGLT2 inhibitor natriuretic effect may be transient, the concurrent MR antagonist provides sustained natriuretic support, and the combination creates a continuous natriuretic effect throughout the renal tubule system.

Inventive Principle:

Principle #20Continuity of useful action

3Quantity of substance

If combination of finerenone and SGLT2 inhibitor is used, then over-additive sodium excretion is achieved, but device complexity increases

Engineering Contradiction:

Improvesodium excretionVSAvoidtreatment complexity

Core Design Contradiction:

Quantity of substanceVSDevice complexity

Solution Approach 1:

The invention merges two distinct pharmacological mechanisms (SGLT2 inhibition and MR antagonism) into a single combination treatment regimen. This merging approach achieves over-additive natriuretic effects while simplifying the overall treatment strategy compared to using multiple separate therapies, as the two agents work synergistically through complementary mechanisms in different renal segments.

Inventive Principle:

Principle #5Merging (Combining)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The combination of finerenone and an SGLT2 inhibitor leads to significant over-additive sodium excretion, relieving congestion, reducing preload on the heart, and improving overall circulation, potentially reducing mortality and morbidity in patients with cardiovascular and renal diseases.

Implementation Method 1

Finerenone... is a mineralocorticoid receptor antagonist (MR antagonist)... MR antagonists counteract aldosterone-mediated sodium retention in the kidneys (natriuretic effect)

Methodology Applied

Scientific EffectMineralocorticoid receptor antagonism:

Implementation Method 2

The sodium-glucose co-transporter-2 (SGLT2) is expressed in the proximal renal tubule and reabsorbs ca. 97% of filtered glucose. Since SGLT2 inhibitors block the reabsorption of both glucose and sodium, they act glycosuric and natriuretic

Methodology Applied

Scientific EffectSGLT2 inhibition:

Implementation Method 3

Methodology Applied

Scientific EffectOver-additive natriuretic effect:

Data Source

PatentUS20230201174A1Combination of finerenone and a SGLT2 inhibitor for the treatment and/or prevention of cardiovascular and/or renal diseases

Publication Date: 2023.06.29 BAYER AG

AI summary

The present invention relates to pharmaceutical compositions and combinations comprising finerenone or a hydrate, solvate or pharmaceutically acceptable salt thereof or a polymorph thereof and a SGLT2 inhibitor, or a hydrate, solvate or pharmaceutically acceptable salt thereof or a polymorph thereof. The combination can be used for the treatment and/or prevention of cardiovascular and/or renal diseases in humans and other mammals.