MTP Inhibitor and PPAR Agonist Combination for Hyperlipidemia
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Solution Overview
Problem
Current treatments for high plasma lipids and lipoproteins often cause liver injury and increase plasma aminotransferases, such as ALT and AST, due to the induction of Endoplasmic Reticulum stress and cell death, which limits their effectiveness in managing hyperlipidemias without adverse effects.
Innovation Solution
A combination of Microsomal Triglyceride Transfer Protein (MTP) inhibitors with lipid-lowering agents, such as PPARα/PPARγ agonists or statins, is administered to reduce plasma lipids and hepatic triglycerides and free cholesterol, thereby avoiding increases in plasma AST/ALT and ER stress.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If MTP inhibitors are used to lower plasma lipids and lipoproteins, then plasma cholesterol levels are reduced, but plasma aminotransferases (ALT and AST) increase indicating liver injury
Solution Approach 1:
The patent combines MTP inhibitors with PPARα agonists or PPARγ agonists into a single therapeutic regimen. This combination therapy allows the MTP inhibitor to effectively lower plasma cholesterol while the PPAR agonist simultaneously protects the liver by reducing hepatic triglyceride accumulation and preventing ER stress, thus resolving the contradiction between lipid-lowering efficacy and liver safety
Solution Approach 2:
The PPAR agonist acts as a mediator that bridges the gap between MTP inhibition and liver protection. It mediates the protective effect by activating PPARα or PPARγ pathways that reduce hepatic lipid accumulation and prevent ER stress, thereby allowing MTP inhibitors to lower plasma cholesterol without causing liver injury
2Quantity of substance
If MTP inhibitors are used to decrease apoB-lipoprotein secretion, then plasma cholesterol is lowered, but Endoplasmic Reticulum stress and cell death are induced
Solution Approach 1:
The patent merges MTP inhibition with PPAR agonist therapy to create a balanced treatment approach. The PPAR agonist component actively counteracts the ER stress and cell death induced by MTP inhibition, thereby maintaining cell viability while preserving the cholesterol-lowering benefit
Solution Approach 2:
The PPAR agonist provides preliminary anti-action by preemptively protecting hepatocytes from ER stress and cell death before they can be fully induced by MTP inhibition. This preventive mechanism ensures cell survival while allowing effective cholesterol reduction
3Quantity of substance
If statin dosage is increased to reach target cholesterol levels, then plasma cholesterol is lowered, but statin-related side effects such as rhabdomyolysis increase
Solution Approach 1:
The patent combines MTP inhibitors with PPAR agonists to achieve synergistic cholesterol lowering at lower effective doses. This combination allows reaching target cholesterol levels without the high doses of single agents that cause side effects like rhabdomyolysis, as the two mechanisms work together to reduce plasma cholesterol more efficiently
Solution Approach 2:
The patent changes the therapeutic parameter from high-dose single-agent therapy to low-dose combination therapy. By using lower doses of MTP inhibitors combined with PPAR agonists, the treatment achieves the same cholesterol-lowering effect with reduced incidence of muscle-related side effects
Data Source
AI summary
The present invention is directed to a composition and method for the treatment of hyperlipidemias by targeting Microsomal triglyceride transfer protein (MTP). In particular, the present invention is directed to a combination of at least one MTP inhibitor and at least one lipid-lowering agent, both in an amount effective to treat hyperlipidemias.