Treatment of Mixed Dyslipidemia

Abstract

Methods and formulations to reduce elevated levels of lipids and apolipoprotein B in subjects having type IIb hyperlipidemia. Methods for preventing, delaying or regressing complications of lipid disorders, including; type IIb hyperlipidemia, NAFLD, and NASH. Methods for preventing or delaying primary and secondary cardiovascular events. Kits useful for such methods. Methods for reducing hepatic fibrosis. Methods for reducing plasma fibrinogen levels.

1 . A method of treating a subject having type IIb hyperlipidemia comprising, administering to the subject gemcabene in combination with a low or moderate dose of a statin. 
     
     
         2 . The method of  claim 1 , wherein the daily dose of the gemcabene administered is from about 50 mg to about 900 mg and the daily dose of the statin administered is from about 1 mg to about 60 mg. 
     
     
         3 . The method of  claim 2 , wherein the daily dose of the gemcabene is from about 50 mg to about 900 mg per day wherein:
 a. the statin is atorvastatin and the daily dose of atorvastatin is from about 10 mg to about 60 mg;   b. the statin is rosuvastatin and the daily dose of rosuvastatin is from about 5 mg to about 30 mg;   c. the statin is simvastatin and the daily dose of simvastatin is from about 5 mg to about 60 mg;   d. the statin is pravastatin and the daily dose of pravastatin is from about 10 mg to about 60 mg;   e. the statin is lovastatin and the daily dose of lovastatin is from about 20 mg to about 60 mg;   f. the statin is fluvastatin and the daily dose of fluvastatin is from about 20 mg to about 40 mg; or   g. the statin is pitavastatin and the daily dose of pitavastatin is from about 1 mg to about 4 mg.   
     
     
         4 . The method of  claim 3 , wherein the daily dose gemcabene is from about 150 mg to about 600 mg. 
     
     
         5 . The method of  claim 3 , wherein the daily dose gemcabene is 150 mg, 300 mg, 450 mg, 600 mg, or 900 mg wherein:
 a) the daily dose of atorvastatin is from about 10 mg to about 40 mg;   b) the daily dose of rosuvastatin is from about 5 to about 20 mg;   c) the daily dose of simvastatin is from about 10 mg to about 20 mg;   d) the daily dose of pravastatin is from about 10 mg to about 40 mg;   e) the daily dose of lovastatin is from about 20 to about 40 mg;   f) the daily dose of fluvastatin is about 20 mg; or   g) the daily dose of pitavastatin is from about 1 mg to about 3 mg.   
     
     
         6 - 12 . (canceled) 
     
     
         13 . The method of  claim 2 , wherein the subject has one or more of familial combined hyperlipidemia, metabolic syndrome, impaired glucose tolerance, an inflammatory disorder, obesity, NASH, NAFLD, alcoholic liver disease, or primary biliary cirrhosis. 
     
     
         14 . The method of  claim 2 , wherein the statin and gemcabene are administered as a fixed dose combination. 
     
     
         15 . The method of  claim 2 , wherein the subject's plasma triglyceride level is reduced to below 150 mg/dl within 8 weeks of administration of gemcabene and the statin. 
     
     
         16 . The method of  claim 2 , wherein the subject's plasma LDL cholesterol level is reduced to below 130 mg/dl within 8 weeks of administration of gemcabene and the statin. 
     
     
         17 . The method of  claim 2 , wherein the subject's ApoB level is reduced to below 120 mg/dl within 8 weeks of administration of gemcabene and the statin. 
     
     
         18 . The method of  claim 2 , wherein the subject's risk of myopathy is not increased from the risk of administration of the statin alone. 
     
     
         19 . The method of  claim 2 , wherein the subject's risk of myositis is not increased from the risk of administration of the statin alone. 
     
     
         20 . The method of  claim 2 , wherein the subject's risk of rhabdomyolysis is not increased from the risk of administration of the statin alone. 
     
     
         21 . The method of  claim 2 , wherein the subject is administered an additional lipid lowering agent, a PCSK9 inhibitor, cholesterol absorption inhibitor, an ACC inhibitor, an ApoC-III inhibitor, an ACL inhibitor, prescription fish oil, or a CETP inhibitor. 
     
     
         22 . The method of  claim 21 , wherein the additional lipid lowering agent is ezetimibe. 
     
     
         23 . The method of  claim 2 , wherein the subject's risk of having a primary cardiovascular event is reduced. 
     
     
         24 . The method of  claim 2 , wherein the subject's risk of having a secondary cardiovascular event is reduced. 
     
     
         25 . A fixed dose combination comprising an amount of gemcabene from about 50 mg to about 900 mg and an amount of a statin from about 1 mg to about 60 mg. 
     
     
         26 . The fixed dose combination of  claim 25 , wherein the statin is atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin wherein:
 a. the amount of atorvastatin is from about 10 mg to about 60 mg;   b. the amount of rosuvastatin is from about 5 mg to about 30 mg;   c. the amount of simvastatin is from about 5 mg to about 60 mg;   d. the amount of pravastatin is from about 10 mg to about 60 mg;   e. the amount of lovastatin is from about 20 mg to about 60 mg;   f. the amount of fluvastatin is from about 20 mg to about 40 mg; or   g. the amount of pitavastatin is from about 1 mg to about 4 mg.   
     
     
         27 . The fixed dose combination of  claim 26 , wherein the amount of gemcabene is from about 150 mg to about 600 mg. 
     
     
         28 - 29 . (canceled) 
     
     
         30 . The fixed dose combination of  claim 26 , wherein the amount of gemcabene is 150 mg, 300 mg, 450 mg, 600 mg. 
     
     
         31 . The fixed dose combination of  claim 30 , wherein
 a. the amount of atorvastatin is 10 mg, 20 mg,. or 40 mg;   b. the amount of rosuvastatin is 5 mg, 10 mg, or 20 mg;   c. the amount of simvastatin is 10 mg or 20 mg;   d. the amount of pravastatin is 10 mg or 20 mg;   e. the amount of lovastatin is 20 mg or 40 mg;   f. the amount of fluvastatin is 20 mg; or   g. the amount of pitavastatin is 1 mg, 2 mg, or 3 mg.   
     
     
         32 . The fixed dose combination of  claim 30 , wherein the fixed dose combination comprises
 a. 150 mg gemcabene and 10 mg of atorvastatin;   b. 150 mg gemcabene and 20 mg of atorvastatin;   c. 150 mg gemcabene and 40 mg of atorvastatin;   d. 300 mg gemcabene and 10 mg of atorvastatin;   e. 300 mg gemcabene and 20 mg of atorvastatin;   f. 300 mg gemcabene and 40 mg of atorvastatin;   g. 600 mg gemcabene and 10 mg of atorvastatin;   h. 600 mg gemcabene and 20 mg of atorvastatin;   i. 600 mg gemcabene and 40 mg of atorvastatin;   j. 900 mg gemcabene and 10 mg of atorvastatin;   k. 900 mg gemcabene and 20 mg of atorvastatin; or   l. 900 mg gemcabene and 40 mg of atorvastatin.   
     
     
         33 - 79 . (canceled) 
     
     
         80 . A method for reducing plasma fibrinogen levels in a subject in need thereof, comprising administering to the subject gemcabene. 
     
     
         81 . The method of  claim 80 , wherein the subject's fibrinogen level is greater than 300 mg/dL comprising administering gemcabene to the subject. 
     
     
         82 . (canceled) 
     
     
         83 . The method of  claim 81 , wherein the daily dose of gemcabene is from 50 mg to 900 mg wherein the gemcabene is optionally administered in combination with a statin. 
     
     
         84 . (canceled) 
     
     
         85 . The method of  claim 83 , wherein the gemcabene is administered with a statin and the statin is atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin and the daily dose of statin if from 1 mg to 80 mg. 
     
     
         86 . (canceled) 
     
     
         87 . The method of  claim 85 , wherein the daily dose of gemcabene is 300 mg, 600 mg or 900 mg and the statin is atorvastatin administered at a daily dose of 10 mg, 20, or 40 mg. 
     
     
         88 . (canceled) 
     
     
         89 . The fixed dose combination of  claim 25 , further comprising ezetimibe. 
     
     
         90 . A fixed dose combination comprising 150 mg, 300 mg, 450 mg, or 600 mg gemcabene and 10 mg ezetimibe.