Exendins to lower cholesterol and triglycerides

Abstract

Provided herein are pharmaceutical formulations containing exendins, exendin agonists, or exendin analog agonists that are administered at therapeutic plasma concentration levels over a sustained period of time to lower total cholesterol levels; to lower LDL-cholesterol levels; to lower triglyceride levels; to treat dyslipidemia; to treat and slow the progression of atherosclerosis; and to treat, prevent, and reduce the risk of heart attacks and strokes in patients. In the pharmaceutical formulations and methods of the invention, the exendin may be exendin-4, an exendin-4 agonist, or an exendin-4 analog agonist. The pharmaceutical formulations may be polymer-based pharmaceutical formulations that may be administered once weekly. An exemplary pharmaceutical formulation comprises 5% (w/w) of exenatide, about 2% (w/w) of sucrose, and about 93% (w/w) of a poly(lactide-co-glycolide) polymer, wherein the poly(lactide-co-glycolide) polymer is in the form of microshperes encapsulating the exenatide.

1 - 32 . (canceled) 
     
     
         33 . A method for lowering total cholesterol levels, LDL-cholesterol levels, or triglyceride levels in a patient in need thereof comprising: identifying a patient in need of a reduction in total cholesterol levels, LDL-cholesterol levels, or triglyceride levels; and
 administering to the patient a pharmaceutical formulation comprising at least one exendin, exendin agonist or exendin analog agonist in an amount sufficient to maintain a steady state geometric mean plasma concentration of the exendin, exendin agonist or exendin analog agonist of 145 pg/mL to 700 pg/mL to reduce total cholesterol levels, LDL-cholesterol levels, or triglyceride levels in the patient.   
     
     
         34 . The method of  claim 33 , wherein the exendin, exendin agonist, or exendin analog agonist is (i) exendin-4 or (ii) a peptide having at least 90% sequence identity to exendin-4. 
     
     
         35 . The method of  claim 33 , wherein the steady state average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist at a level of 175 pg/mL to 650 pg/mL. 
     
     
         36 . The method of  claim 35 , wherein the steady state average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist at a level of 200 pg/mL to 600 pg/mL. 
     
     
         37 . The method of  claim 36 , wherein the steady state average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist at a level of 200 pg/mL to 400 pg/mL. 
     
     
         38 . The method of  claim 33 , wherein the pharmaceutical formulation further comprises at least one polymer. 
     
     
         39 . The method of  claim 38 , wherein the polymer is poly(lactide-co-glycolide). 
     
     
         40 . The method of  claim 33 , wherein the pharmaceutical formulation comprises about 5% (w/w) of exenatide, about 2% (w/w) of sucrose, and about 93% (w/w) of a poly(lactide-co-glycolide) polymer. 
     
     
         41 . The method of  claim 33 , wherein the average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist is at the steady state for about one week to about three months. 
     
     
         42 . The method of  claim 33 , wherein the dosage of the pharmaceutical formulation is from about 0.5 mg to about 5 mg, and wherein the dosage comprises from about 1% to about 20% of the exendin, exendin agonist, or exendin analog agonist. 
     
     
         43 . A method for treating dyslipidemia or atherosclerosis in a patient in need thereof comprising identifying a patient in need of treatment for dyslipidemia or atherosclerosis;
 and administering to the patient a pharmaceutical formulation comprising at least one exendin, exendin agonist or exendin analog agonist in an amount sufficient to maintain a steady state average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist at a level of 145 pg/mL to 700 pg/mL for at least one week to treat dyslipidemia or atherosclerosis in the patient.   
     
     
         44 . The method of  claim 43 , wherein the exendin, exendin agonist, or exendin analog agonist is (i) exendin-4 or (ii) a peptide having at least 90% sequence identity to exendin-4. 
     
     
         45 . The method of  claim 43 , wherein the average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist is at the steady state for about one week to about three months. 
     
     
         46 . The method of  claim 43 , wherein the pharmaceutical formulation further comprises at least one polymer. 
     
     
         47 . The method of  claim 46 , wherein the polymer is poly(lactide-co-glycolide). 
     
     
         48 . The method of  claim 43 , wherein the pharmaceutical formulation comprises about 5% (w/w) of exenatide, about 2% (w/w) of sucrose, and about 93% (w/w) of a poly(lactide-co-glycolide) polymer. 
     
     
         49 . The method of  claim 43 , wherein the dosage of the pharmaceutical formulation is from about 0.5 mg to about 5 mg, and wherein the dosage comprises from about 1% to about 20% of the exendin, exendin agonist, or exendin analog agonist. 
     
     
         50 . The method of  claim 43 , wherein the steady state average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist at a level of 175 pg/mL to 650 pg/mL. 
     
     
         51 . The method of  claim 50 , wherein the steady state average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist at a level of 200 pg/mL to 600 pg/mL. 
     
     
         52 . The method of  claim 51 , wherein the steady state average or minimum plasma concentration of the exendin, exendin agonist, or exendin analog agonist at a level of 200 pg/mL to 400 pg/mL.