Methods of Preventing Cardiovascular Events in Residual Risk Dyslipidemic Populations

Abstract

The present invention provides pharmacological interventions for the treatment of dyslipidemia, and to the reduction of residual risk of cardiovascular disease and adverse cardiovascular events in patients on intense statin use or with well-controlled LDL-C concentrations. In particular, the invention relates to the use of pemafibrate to prevent cardiovascular events in populations at-risk due to risk factors such as type 2 diabetes mellitus with dyslipidemia in spite of intense statin use or well-controlled LDL-C.

1 - 65 ) (canceled) 
     
     
         66 ) A method of treating a patient with type 2 diabetes mellitus to reduce the risk of an adverse cardiovascular event, comprising administering to the patient a therapeutically effective amounts of pemafibrate or a pharmaceutically acceptable salt thereof and a statin, wherein:
 a) prior to administering the pemafibrate or pharmaceutically acceptable salt thereof the patient has an LDL-C concentration <70 mg/dL and is on stable statin therapy selected from low to high intensity statin therapy;   b) the patient has an HDL-C concentration ≤40 mg/dL prior to commencing the pemafibrate therapy; and   c) the patient has a fasting TG concentration >200 mg/dL and <500 mg/dL prior to commencing the pemafibrate therapy.   
     
     
         67 ) The method of  claim 66 , wherein the patient does not have atherosclerosis and does not have cardiovascular disease. 
     
     
         68 ) The method of  claim 67 , wherein the patient is >50 years of age without atherosclerosis if a man, ≥55 years of age without atherosclerosis if a woman. 
     
     
         69 ) The method of  claim 67 , wherein the patient is at risk for at least one of an ischemic stroke, unstable angina, or cardiovascular death. 
     
     
         70 ) The method of  claim 67 , wherein the patient has an HDL-C level of >35 mg/dL prior to commencing the pemafibrate therapy. 
     
     
         71 ) The method of  claim 66 , wherein the statin is atorvastatin, and is administered at ≥40 mg/day (based on the weight of the free base). 
     
     
         72 ) The method of  claim 66 , wherein the statin is rosuvastatin, and is administered at ≥20 mg/day (based on the weight of the calcium salt). 
     
     
         73 ) The method of  claim 66 , wherein the statin is simvastatin, and is administered at ≥40 mg/day (based on the weight of the free base). 
     
     
         74 ) The method of  claim 66 , wherein the statin is pitavastatin, and is administered at ≥4 mg/d (based on the weight of the free base). 
     
     
         75 ) The method of  claim 66 , wherein the pemafibrate is administered at 0.4 mg per day of pemafibrate or a pharmaceutically acceptable salt thereof based on the weight of the free base. 
     
     
         76 ) The method of  claim 66 , wherein the patient has atherosclerosis or cardiovascular disease. 
     
     
         77 ) The method of  claim 66 , wherein the statin therapy is high intensity statin therapy. 
     
     
         78 ) The method of  claim 66 , wherein the statin therapy is high intensity statin therapy and the patient does not have atherosclerosis and does not have cardiovascular disease. 
     
     
         79 ) The method of  claim 66 , wherein the statin therapy is high intensity statin therapy and the patient has atherosclerosis or cardiovascular disease. 
     
     
         80 ) The method of  claim 66 , wherein the statin therapy is low or moderate intensity statin therapy. 
     
     
         81 ) The method of  claim 66 , wherein the statin therapy is low or moderate intensity statin therapy and the patient has atherosclerosis or cardiovascular disease. 
     
     
         82 ) The method of  claim 66 , wherein the statin therapy is low or moderate intensity statin therapy and the patient does not have atherosclerosis and does not have cardiovascular disease. 
     
     
         83 ) The method of  claim 66 , further comprising administering a therapeutically effective amount of a lipid lowering therapy selected from ezetimibe, probucol, niacin, cholestyramine, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). 
     
     
         84 ) The method of  claim 66 , further comprising administering a therapeutically effective amount of a cardiovascular drug selected from an angiotensin converting—enzyme inhibitor, an angiotensin-receptor blocker, aspirin, a beta-blocker, a nitrate, and a thiazide diuretic. 
     
     
         85 ) The method of  claim 66 , further comprising administering a therapeutically effective amount of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. 
     
     
         86 ) The method of  claim 66 , further comprising administering a therapeutically effective amount of a diabetes medication selected from an alpha-glucosidase inhibitor, a biguanide, a dopamine agonist, a DPP-4 inhibitor, a glucagon-like peptide, a meglitinide, a sodium glucose transporter (SGLT) 2 inhibitor, a sulfonylurea, and a thiazolidinedione. 
     
     
         87 ) The method of  claim 66 , further comprising administering a therapeutically effective amount of a diabetes medication targeting a HbA1c concentration of less than 6%. 
     
     
         88 ) The method of  claim 66 , wherein the patient is at risk for rhabdomyolysis. 
     
     
         89 ) The method of  claim 66 , wherein the patient is at risk for rhabdomyolysis as shown by elevated creatinine kinase. 
     
     
         90 ) The method of  claim 66 , wherein the patient has renal insufficiency. 
     
     
         91 ) The method of  claim 66 , wherein the patient has renal failure.