Treatment for obstructive sleep apnea-associated atherosclerosis

Abstract

Compositions and methods for treating Obstructive Sleep Apnea (OSA)-associated atherosclerosis comprising administering to a subject in need thereof an effective amount of a bile salt hydrolase (BSH) inhibitor such as caffeic acid phenethyl ester

Description

TREATMENT FOR OBSTRUCTIVE SLEEP APNEA-ASSOCIATED ATHEROSCLEROSISCROSS REFERENCED TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 644,935, filed May 9, 2024, which is incorporated by reference herein.GOVERNMENT SPONSORSHIP

[0002] This invention was made with government support under grant HL148801 awarded by the National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD

[0003] The present invention relates to the treatment of atherosclerosis.BACKGROUND

[0004] Obstructive Sleep Apnea (OSA) is a condition characterized by repeated cessation of breathing while sleeping, resulting in an increased risk of co-morbidities including cardiovascular diseases like atherosclerosis. The mechanisms for the increased risk for atherosclerosis in OSA is poorly understood. The current treatments for OSA are scarce, with the prominent approach being using a Continuous Positive Airway Pressure (CPAP) treatment, which can be ineffective due to poor adherence rates.

[0005] Novel therapies are needed for preventing and treating OSA-associated atherosclerosis.SUMMARY OF THE INVENTION

[0006] In embodiments, the invention provides compositions and methods for treatment of Obstructive Sleep Apnea (OSA)-associated atherosclerosis. In embodiments, the methods comprise administering to a subject in need thereof a treatment effectiveamount of a bile salt hydrolase (BSH) inhibitor. In embodiments, the BSH inhibitor is caffeic acid phenethyl ester, or a salt or derivative thereof. In embodiments, the administration inhibits atherosclerosis.

[0007] The invention provides that atherosclerosis associated with OSA can be treated by inhibiting gut microbial function, such as BSH activity.

[0008] In embodiments, the invention provides for the inhibition of gut microbial function by oral administration of a BSH inhibitor to inhibit atherosclerosis associated with OSA.

[0009] In embodiments, the invention provides that the BSH inhibitor is caffeic acid phenethyl ester, or a salt or derivative thereof. In embodiments, the invention provides that the BSH inhibitor is administered orally. In embodiments, the BSH inhibitor is administered in combination with OSA therapy.

[0010] In embodiments, the invention provides a pharmaceutical composition comprising a BSH inhibitor, or derivative thereof, and a pharmaceutically acceptable carrier, formulated for use in treating OSA-associated atherosclerosis. In embodiments, the BSH inhibitor is caffeic acid phenethyl ester, or a salt or derivative thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Fig. 1. shows the methodology for testing BSH overexpression impact on atherosclerosis under intermittent hypoxia and hypercapnia (IHC) conditions.

[0012] Fig. 2 shows that BSH overexpression may mimic IHC to produce the atherosclerotic phenotype.

[0013] Fig. 3 shows no significant changes in total lipid levels in serum with BSH overexpression and IHC conditions.

[0014] Fig. 4 shows the methodology for testing whether IHC conditions exacerbate atherosclerosis through increased luminal BSH.

[0015] Fig. 5 shows inhibition of BSH results in decreased atherosclerosis under IHC conditions.

[0016] Fig. 6 shows BSH inhibitor does not impact AGD-induced changes in serum cholesterol and triglyceride levels.DETAILED DESCRIPTION

[0017] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0018] Unless defined otherwise, all technical and scientific terms and any acronyms used herein have the same meanings as commonly understood by one of ordinary7skill in the art in the field of the invention. Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the exemplary7methods, devices, and materials are described herein.

[0019] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology7, which are within the skill of the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, 2nded. (Sambrook et al., 1989); Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Animal Cell Culture (R. I. Freshney, ed.. 1987); Methods in Enzymology (Academic Press, Inc.); Current Protocols in Molecular Biology (F. M. Ausubel et al., eds., 1987, and periodic updates); PCR: The Polymerase Chain Reaction (Mullis et al., eds., 1994); Remington, The Science and Practice of Pharmacy, 20thed., (Lippincott, Williams & Wilkins 2003), and Remington, The Science and Practice of Pharmacy, 22thed., (Pharmaceutical Press and Philadelphia College of Pharmacy at University7of the Sciences 2012).

[0020] In embodiments, the invention provides compositions and methods for treatment, prevention and / or inhibition of Obstructive Sleep Apnea (OSA)-associated atherosclerosis. In embodiments, the methods comprise administering to a subject in need thereof a treatment effective amount of a bile salt hydrolase (BSH) inhibitor, or a salt or derivative thereof. In embodiments, the BSH inhibitor is caffeic acid phenethyl ester. In embodiments, the administration inhibits atherosclerosis.

[0021] The invention provides that atherosclerosis associated with OSA can be reduced by inhibiting gut microbial function, such as BSH activity.

[0022] In embodiments, the invention provides for the inhibition of gut microbial function, such as BSH activity, by oral administration of a BSH inhibitor to inhibit atherosclerosis associated with OSA.

[0023] In embodiments, the invention provides that the BSH inhibitor is caffeic acid phenethyl ester, or a salt or derivative thereof. In embodiments, the invention provides that the BSH inhibitor is administered orally. In embodiments, the BSH inhibitor is administered in combination with OSA therapy.

[0024] In embodiments, the OSA therapy used in combination with a BSH inhibitor includes, for example, a Continuous Positive Airway Pressure (CPAP), positional therapy, use of oral appliances, nasal resistors, oropharyngeal exercises, and behavioral measures, including weight loss when indicated, frequent physical exercise, avoidance of alcohol and sedative medication before bedtime.

[0025] In embodiments, the invention provides a pharmaceutical composition comprising a BSH inhibitor, or salt or derivative thereof, and a pharmaceutically acceptable carrier, formulated for use in treating OSA-associated atherosclerosis.

[0026] Bile salt hydrolases are members of the N-terminal nucleophilic hydrolase family, characterized by autocatalytic activation by an N-terminal nucleophile and subsequent amide bond cleavage. The majority’ of BSH enzymes are composed of homotetramers, although they have been known to assume other forms including homodimers and heterotrimers. BSHs contain a catalytic Cys2 nucleophile residue, which is located at the N-terminus of the enzyme. Many BSH inhibitors are well-known in the art, such as caffeic acid phenethyl ester (CAPE), riboflavin, camosic acid, epicatechin monogallate, gossypetin, menadione, purpurogallin, theaflavanin, and antibiotics such as oxy tetracycline, roxarsone, tetracycline, beta-lactam, arsenicals, lincosamide, sulfonamide and macrolide. The invention encompasses the use of know n BSH inhibitors, both synthetic and naturally occurring, and those discovered in the future.

[0027] In embodiments, the BSH inhibitor is caffeic acid phenethyl ester (CAPE). CAPE has an empirical formula of C17H16O4 , and is available from Sigma-Aldrich as product number C8221. CAPE has a structure as follows:

[0028] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains”, “containing,” “characterized by,” or any other variation thereof, are intended to encompass a non-exclusive inclusion, subject to any limitation explicitly indicated otherwise, of the recited components. For example, a fusion protein, a pharmaceutical composition, and / or a method that “comprises” a list of elements (e.g., components, features, or steps) is not necessarily limited to only those elements (or components or steps), but may include other elements (or components or steps) not expressly listed or inherent to the fusion protein, pharmaceutical composition and / or method.

[0029] As used herein, the transitional phrases “consists of and “consisting of’ exclude any element, step, or component not specified. For example, “consists of or “consisting of’ used in a claim would limit the claim to the components, materials or steps specifically recited in the claim except for impurities ordinarily associated therewith (i.e., impurities within a given component). When the phrase “consists of or “consisting of’ appears in a clause of the body of a claim, rather than immediately following the preamble, the phrase “consists of’ or “consisting of’ limits only the elements (or components or steps) set forth in that clause; other elements (or components) are not excluded from the claim as a whole.

[0030] As used herein, the transitional phrases “consists essentially of’ and “consisting essentially of’ are used to define a fusion protein, pharmaceutical composition, and / or method that includes materials, steps, features, components, or elements, in addition to those literally disclosed, provided that these additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristic(s) of theclaimed invention. The term '‘consisting essentially of’ occupies a middle ground between “comprising” and “consisting of’.

[0031] When introducing elements of the present invention or the preferred embodiment(s) thereof, the articles “a”, '‘an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0032] The term “and / or” when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items. For example, the expression “A and / or B” is intended to mean either or both of A and B, i.e. A alone, B alone or A and B in combination. The expression “A, B and / or C” is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination or A, B, and C in combination.

[0033] It is understood that aspects and embodiments of the invention described herein include “consisting” and / or “consisting essentially of’ aspects and embodiments.

[0034] It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4. from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Values or ranges may also be expressed herein as “about,” from “about” one particular value, and / or to “about” another particular value. When such values or ranges are expressed, other embodiments disclosed include the specific value recited, from the one particular value, and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that there are a number of values disclosed therein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. In embodiments, “about” can be used tomean, for example, within 10% of the recited value, within 5% of the recited value, or within 2% of the recited value.

[0035] As used herein, “patient” or “subject” means a human or animal subject to be treated.

[0036] As used herein the term “pharmaceutical composition” refers to pharmaceutically acceptable compositions, wherein the composition comprises a pharmaceutically active agent, and in some embodiments further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may be a combination of pharmaceutically active agents and carriers.

[0037] The term “combination” refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where one or more active compounds and a combination partner (e.g., another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals. In some circumstances, the combination partners show a cooperative, e.g., synergistic effect. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0038] As used herein the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia,other generally recognized pharmacopoeia in addition to other formulations that are safe for use in animals, and more particularly in humans and / or non-human mammals.

[0039] As used herein the term '’pharmaceutically acceptable carrier’" refers to an excipient, diluent, preservative, solubilizer, emulsifier, adjuvant, and / or vehicle with which compound(s), is administered. Such carriers may be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil. mineral oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be a carrier. Methods for producing compositions in combination with earners are known to those of skill in the art. In some embodiments, the language ‘’pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. See, e.g.. Remington, The Science and Practice of Pharmacy, 20th ed., (Lippincott, Williams & Wilkins 2003). Except insofar as any conventional media or agent is incompatible with the active compound, such use in the compositions is contemplated.

[0040] Sterile compositions are within the present disclosure, including compositions that are in accord with national and local regulations governing such compositions. Pharmaceutical compositions, alone or in combination with other active ingredient(s), described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. A glycosidase, alone or in combination with other active ingredient(s), described herein, and preferably in the form of a pharmaceutical composition, may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. In some embodiments, the compositions are formulated for intravenous or oral administration.

[0041] For oral administration, BSH inhibitor may be provided in a solid form. In embodiments, BSH inhibitor or derivatives thereof, alone or in combination with another active ingredient, may be provided in a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions. BSH inhibitor or derivatives thereof, alone or in combination with another active ingredient, may be formulated to yield an effective dosage. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, poly vinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0042] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil. such as peanut oil or olive oil, liquid paraffin, a mixture of mono and diglycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0043] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0044] For parenteral use, including, intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, BSH inhibitor, alone or in combination with other active ingredient(s), may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles can include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or preconcentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0045] For nasal, inhaled, or oral administration, BSH inhibitor, alone or in combination with other active ingredient(s), may be administered using, for example, a spray formulation also containing a suitable carrier.

[0046] For topical applications, BSH inhibitor, alone or in combination with other active ingredient(s), are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, BSH inhibitor, alone or in combination with other active ingredient(s), may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering a BSH inhibitor, alone or in combination with other active ingredient(s), may utilize a patch formulation to effect transdermal delivery.

[0047] One of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration. In particular, BSH inhibitor, alone or in combination with other active ingredient(s), may be modified to render them more soluble in water or other vehicle. It is also well within the ordinary7skill of the art to modify the route of administration and dosage regimen of the compositions, alone or in combination with other active ingredient(s), in order to manage the pharmacokinetics of the present compositions for maximum beneficial effect in a patient.

[0048] As used herein, “therapeutically effective amount’' refers to an amount of a pharmaceutically active compound(s) that is sufficient to treat, or ameliorate, or in some manner reduce the symptoms associated with diseases and medical conditions. When usedwith reference to a method, the method is sufficiently effective to treat or ameliorate, or in some manner reduce the symptoms associated with diseases or conditions. For example, an effective amount in reference to diseases is that amount which is sufficient to block or prevent onset; or if disease pathology has begun, to palliate, ameliorate, stabilize, reverse or slow progression of the disease, or otherwise reduce pathological consequences of the disease. In any case, an effective amount may be given in single or divided doses.

[0049] As used herein, the terms "‘treat,” “treatment,” or “treating” embraces at least an amelioration of the symptoms associated with diseases in the patient, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. a symptom associated with the disease or condition being treated. As such, “treatment” also includes situations where the disease, disorder, or pathological condition, or at least symptoms associated therewith, are completely inhibited (e.g. prevented from happening) or stopped (e.g. terminated) such that the patient no longer suffers from the condition, or at least the symptoms that characterize the condition.

[0050] As used herein, and unless otherwise specified, the terms "prevent," "preventing" and "prevention" refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. In certain embodiments, the terms refer to the treatment with or administration of a compound or dosage form provided herein, with or without one or more other additional active agent(s), prior to the onset of symptoms, particularly to subjects at risk of disease or disorders provided herein. The terms encompass the inhibition or reduction of a symptom of the particular disease. In certain embodiments, subjects with familial history of a disease are potential candidates for preventive regimens. In certain embodiments, subjects who have a history of recurring symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be interchangeably used with the term "prophylactic treatment."

[0051] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effectiveamount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0052] A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only, and are not intended to limit the scope of the invention.EXAMPLES

[0053] Mice exposed to OSA conditions were treated with daily gavages of either vehicle or BSH inhibitor caffeic acid phenethyl ester (including respective controls), following which they were euthanized and assessed for extent of aortic atherosclerosis. The results show that administration of BSH inhibitor results in decreased aortic atherosclerosis compared to vehicle-treated mice exposed to OSA.

[0054] The gut microbiome function of Ldlr- / - mice was manipulated under intermittent hypoxia and hypercapnia (IHC) conditions by overexpressing BSH using engineered native bacteria. Atherogenic diet-fed Ldlr- / - mice, gavaged with engineered bacteria with BSH (BSH+) or without (control, BSH-), were subjected to either room-air (Air, control) or IHC conditions. Host transcriptome changes were assessed during the light (ZT3) and dark (ZT13) phases after 6 weeks and atherosclerotic lesion formation, fecal microbiome and metabolome after 12 weeks post-exposure.

[0055] Mice under Air / BSH+ conditions had increased atherosclerotic lesions and were similar to those in the IHC / BSH- group, compared to controls. Furthermore, lesion extent when both BSH and IHC were present (i.e. IHC / BSH+) was comparable to levels found in either IHC or BSH alone, implying that luminal BSH overexpression may mimic IHC to promote atherosclerosis. Differential abundance analysis of fecal microbiome and metabolome showed a significant overlap between IHC / BSH- and Air / BSH+ groups, suggesting that IHC and BSH overexpression similarly impact the gut microbiome and metabolome of Ldlr- / - mice. There were similar changes to some novel bile acids under IHC / BSH- and Air / BSH+ conditions that positively correlated with atherosclerotic lesion extent under both BSH-overexpression and IHC conditions. Further, both IHC / BSH- and Air / BSH+ similarly trigger inflammatory and circadian hepatic pathways in the light anddark phases respectively, suggesting that these conditions have an overlapping effect on the host transcriptome in a phase-dependent manner.

[0056] Fig. 1. shows the methodology for testing BSH overexpression impact on atherosclerosis under IHC conditions.

[0057] Fig. 2 shows that BSH overexpression may mimic IHC to produce the atherosclerotic phenotype.

[0058] Fig. 3 shows no significant changes in total lipid levels in serum with BSH overexpression and IHC conditions.

[0059] Fig. 4 shows the methodology for testing whether IHC exacerbate atherosclerosis through increased luminal BSH.

[0060] Fig. 5 shows inhibition of BSH results in decreased atherosclerosis under IHC conditions.

[0061] Fig. 6 shows BSH inhibitor does not impact AGD-induced changes in serum cholesterol and triglyceride levels.

[0062] The data demonstrates a link between the gut microbiome and OSA- associated atherosclerosis. The invention is the first to establish a relationship between a specific gut microbial function (BSH) and OSA-associated atherosclerosis, and that by inhibiting BSH activity, one can decrease the extent of atherosclerosis in OSA.

Claims

What is claimed is:

1. A method of treating Obstructive Sleep Apnea (OSA)-associated atherosclerosis comprising administering to a subject in need thereof an effective amount of a bile salt hydrolase (BSH) inhibitor to treat OSA-associated atherosclerosis of the subj ect.

2. The method of claim 1, wherein the BSH inhibitor is caffeic acid phenethyl ester.

3. The method of claim 1, wherein the BSH inhibitor is administered in combination with OSA therapy.

4. The method of claim 1, wherein the BSH inhibitor is administered orally.

5. A method of treating atherosclerosis comprising administering to a subject in need thereof an effective amount of a bile salt hydrolase (BSH) inhibitor to treat atherosclerosis of the subject.

6. The method of claim 5, wherein the BSH inhibitor is caffeic acid phenethyl ester.

7. The method of claim 5, wherein the atherosclerosis is OSA-associated atherosclerosis.

8. The method of claim 7, wherein the BSH inhibitor is administered in combination with OSA therapy.

9. The method of claim 5, wherein the BSH inhibitor is administered orally.

10. A pharmaceutical composition comprising an amount of a BSH inhibitor effective to treat OSA-associated atherosclerosis of a subject, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, wherein the BSH inhibitor is caffeic acid phenethyl ester.

12. The pharmaceutical composition of claim 10, wherein the BSH inhibitor is formulated for oral administration.

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