Therapy for complications of diabetes

Abstract

A method for enhancing glycemic control and/or insulin sensitivity to a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ET A ) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ET A receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ET A receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ET A receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ET A receptor antagonist.

1 . A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome, comprising administering to the subject a selective receptor ETA antagonist in a glycemic control and/or insulin sensitivity effective amount,
 wherein the selective ETA receptor antagonist is ambrisentan, avosentan, BMS 193884, BQ-123, CI-1020, elazosentan, darusentan, edonentan, S-0139, SB-209670, sitaxsentan, TA-0201, tarasentan, TBC 3711, tezosentan, YM-598, ZD-1611, ZD-4054 or pharmaceutically acceptable salts thereof.   
     
     
         2 . The method of  claim 1 , wherein the subject is at least about 50 years of age. 
     
     
         3 . The method of  claim 1 , wherein the subject is at least about 65 years of age. 
     
     
         4 . The method of  claim 1 , wherein the subject has incipient or overt diabetic nephropathy. 
     
     
         5 . The method of  claim 4 , wherein a beneficial effect is produced in one or more morphological markers of diabetic nephropathy. 
     
     
         6 . The method of  claim 5 , wherein the one or more markers exhibiting a beneficial effect are selected from the group consisting of kidney size, kidney weight, thickening of glomerular basement membrane (GBM), mesangial expansion, deposition of collagen, fibronectin and laminin, nephron density, nodular glomerulosclerosis, atherosclerosis of renal vasculature and combinations thereof. 
     
     
         7 . The method of  claim 4 , wherein a beneficial effect is produced in renal function as indicated by glomerular filtration rate (GFR), creatinine clearance and/or albuminuria. 
     
     
         8 . The method of  claim 4 , wherein progression of diabetic nephropathy is arrested, slowed, retarded or stabilized and/or time to end-stage renal disease or chronic kidney failure is extended. 
     
     
         9 . The method of  claim 1 , wherein the subject has metabolic syndrome. 
     
     
         10 . The method of  claim 1 , wherein a subject having hypertension as a component of the diabetic nephropathy and/or metabolic syndrome exhibits resistance to a baseline antihypertensive therapy with one or more drugs other than selective ETA receptor antagonists. 
     
     
         11 . The method of  claim 10 , wherein the subject has resistant hypertension. 
     
     
         12 .- 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the selective ETA receptor antagonist is administered for a period of at least about 3 months. 
     
     
         20 . The method of  claim 19 , wherein administration of the selective ETA receptor antagonist continues for as long as a therapeutic benefit is provided thereby and any adverse side effect thereof remains commensurate with the therapeutic benefit. 
     
     
         21 .- 23 . (canceled) 
     
     
         24 . The method of  claim 1 , further comprising administering to the subject one or more antihypertensives other than the selective ETA receptor antagonist. 
     
     
         25 . The method of  claim 24 , wherein the one or more antihypertensives are selected from the group consisting of a diuretic, ACE inhibitor, angiotensin II receptor blocker, beta-adrenergic receptor blocker, calcium channel blocker, direct vasodilator, alpha-1-adrenergic receptor blocker, central alpha-2-adrenergic receptor agonist, aldosterone receptor antagonist, vasopeptidase inhibitor, NEP inhibitor, prostanoid, PDE5 inhibitor, nitrosylated compound, oral nitrate and renin inhibitor. 
     
     
         26 . (canceled) 
     
     
         27 .- 59 . (canceled) 
     
     
         60 . The method of  claim 25 , wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benzapril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, eosinopril, fosinopril, imidapril, lisinopril, moexipril, moveltipril, omapatrilat, perindopril, quinapril, ramipril, sampatrilat, spirapril, temocapril, trandolapril, and combinations thereof. 
     
     
         61 . The method of  claim 25 , wherein the angiotensin II receptor blocker is selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan and combinations thereof. 
     
     
         62 . The method of  claim 25 , wherein the diuretic is a thiazide diuretic selected from the group consisting of althiazide, bendroflumethiazide, benzthiazide, benzyl hydrochlorothiazide, buthiazide, chlorothiazide, chlorthalidone, cyclopenthiazide, ethiazide, fenquizone, hydrochlorothiazide, hydroflumethiazide, indapamide, methyclothiazide, metolazone, paraflutizide, polythiazide, quinethazone, teclothiazide, trichlormethiazide, and combinations thereof. 
     
     
         63 . The method of  claim 25 , wherein the diuretic is a loop diuretic selected from the group consisting of bumetanide, furosemide, torsemide and combinations thereof. 
     
     
         64 . The method of  claim 25 , wherein the dose of the angiotensin converting enzyme inhibitor or angiotensin II receptor blocker is the highest tolerated dose in the human subject.