Ketone bodies and ketone body esters as blood lipid lowering agents
Inventors
Clarke, Kieran • Veech, Richard Lewis
Assignees
Oxford University Innovation Ltd • US Department of Health and Human Services
Publication Number
US-11311509-B2
Publication Date
2022-04-26
Expiration Date
2029-01-05
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Abstract
The subject disclosure provides compositions for reducing serum cholesterol and/or triglyceride levels in subjects. These compositions can comprise racemic β-hydroxybutyrate or D-β-hydroxybutyrate, optionally in the acid form, physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate, esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 or more monomeric units in either linear or cyclic form, racemic 1,3 butandiol or R-1,3 butandiol alone and can be, optionally, administered in conjunction with a low fat diet to a subject. Alternatively, compositions comprising racemic β-hydroxybutyrate or D-β-hydroxybutyrate, optionally in the acid form, physiologically compatible salts of racemic β-hydroxybutyrate or D-β-hydroxybutyrate, esters of D-β-hydroxybutyrate, oligomers of D-β-hydroxybutyrate containing from 2 to 20 or more monomeric units in either linear or cyclic form, racemic 1,3 butandiol, R-1,3 butandiol or combinations thereof can be formulated as nutritional supplements (also referred to as nutritional compositions) or incorporated into therapeutic compositions containing a) anti-hypertensive agents; b) anti-inflammatory agents; c) glucose lowering agents; or d) anti-lipemic agents) which are administered to a subject, optionally in combination with a low fat diet, in order to cause a reduction or lowering of: serum cholesterol levels; triglyceride levels; serum glucose levels, serum homocysteine levels, inflammatory proteins (e.g., C reactive protein) and/or hypertension in treated subjects. Alternatively, compositions disclosed herein can be administered alone, or in combination with other therapeutic agents to prevent or reverse vascular disease.
Core Innovation
The invention provides compositions for reducing serum cholesterol and/or triglyceride levels in subjects. These compositions comprise racemic β-hydroxybutyrate or D-β-hydroxybutyrate, optionally in the acid form, physiologically compatible salts thereof, esters and oligomers of D-β-hydroxybutyrate, racemic 1,3 butandiol, R-1,3 butandiol, or combinations thereof. The compositions can be administered alone or in combination with a low fat diet to lower serum cholesterol, triglycerides, glucose, homocysteine, inflammatory proteins, and hypertension.
The invention addresses the problem of vascular insufficiency caused by occlusive processes in the vasculature, which are linked to elevated serum cholesterol, triglycerides, glucose, homocysteine, inflammation, and hypertension. Current sources of blood cholesterol and triglycerides come from liver synthesis. Ketone bodies cannot be used by the liver to synthesize triglycerides or cholesterol, indicating a novel approach to lowering these factors.
Feeding subjects a diet comprising esters or oligomers of the ketone body D-β-hydroxybutyrate combined with lower dietary fat can reverse several predisposing factors leading to vascular diseases. The compositions may be formulated as nutritional supplements or therapeutic compositions combined with anti-hypertensive, anti-inflammatory, glucose lowering, or anti-lipemic agents to produce reductions in multiple serum markers and hypertension, thereby preventing or reversing vascular disease.
Claims Coverage
The patent includes one independent claim focused on a method for lowering serum glucose levels in diabetic subjects using a specific ketone body ester, alone or with therapeutic agents. The main inventive features relate to the composition, administration parameters, and combined use with other agents.
Use of R-1,3-butanediol ester of monomeric D-β-hydroxybutyrate for lowering serum glucose
The method involves orally administering a composition comprising an R-1,3-butanediol ester of monomeric D-β-hydroxybutyrate alone or with an additional therapeutic agent to raise blood D-β-hydroxybutyrate plus acetoacetate within specified mM ranges, resulting in lowered serum glucose levels in diabetic subjects.
Administration methods and dosage form
The composition can be administered as part of the subject's diet or in unit dosage forms. The method supports separate, sequential, or combined administration of the ketone ester composition and therapeutic agents in unit dosage form.
Combination therapy with therapeutic agents
The method includes combining the ketone ester with glucose/blood sugar lowering agents, lipid lowering agents, blood pressure lowering agents, or anti-inflammatory agents to enhance treatment efficacy.
Therapeutic effects beyond glucose lowering
The method also lowers or reduces elevated blood homocysteine, serum C-reactive protein levels, and blood pressure without inducing insulin shock.
Dosage and blood level ranges
The administration achieves blood levels of D-β-hydroxybutyrate plus acetoacetate between specific ranges (e.g., 0.1 to 25 mM) or percentage of total caloric intake (2-100%, preferably 5-70% or 5-30%).
The independent claim discloses a method utilizing the ketone ester R-1,3-butanediol ester of monomeric D-β-hydroxybutyrate to lower serum glucose and related markers in diabetic subjects, through controlled administration alone or in combination with other therapeutic agents, in specific caloric or blood concentration ranges.
Stated Advantages
Lowering serum cholesterol, triglyceride, and glucose levels in subjects.
Ability to reduce serum homocysteine levels, inflammatory proteins such as C reactive protein, and hypertension in treated subjects.
Potential to prevent or reverse vascular disease through administration alone or in combination with other therapeutic agents.
Oral administration improving feasibility as a nutritional supplement or therapeutic composition.
Documented Applications
Treatment of elevated serum cholesterol and triglycerides to reduce vascular insufficiency and related diseases including coronary, cerebrovascular, and peripheral vascular insufficiency.
Use in diabetic subjects to lower serum glucose levels without inducing insulin shock.
Formulation in combination with anti-lipemic, anti-hypertensive, glucose lowering, or anti-inflammatory agents to treat vascular disease and related metabolic disorders.
Nutritional supplementation or therapeutic use in lowering blood markers including cholesterol, triglycerides, glucose, homocysteine, inflammatory proteins, and hypertension.
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