Therapy for complications of diabetes

Abstract

A method for enhancing glycemic control and/or insulin sensitivity in 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 ET A  receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. 
   
   
       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 morphologic 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 ET A  receptor antagonists. 
   
   
       11 . The method of  claim 10 , wherein the subject has resistant hypertension. 
   
   
       12 . The method of  claim 1 , wherein the selective ET A  receptor antagonist comprises at least one agent selected from the group consisting of ambrisentan, atrasentan, avosentan, BMS 193884, BQ-123, CI-1020, clazosentan, darusentan, edonentan, S-0139, SB-209670, sitaxsentan, TA-0201, tarasentan, TBC 3711, tezosentan, YM-598, ZD-1611, ZD-4054, and salts, esters, prodrugs, metabolites, tautomers, racemates and enantiomers thereof. 
   
   
       13 . The method of  claim 1 , wherein the selective ET A  receptor antagonist comprises darusentan. 
   
   
       14 . The method of  claim 13 , wherein darusentan is administered in an amount of about 1 to about 600 mg/day. 
   
   
       15 . The method of  claim 13 , wherein darusentan is administered in an amount of about 10 to about 300 mg/day. 
   
   
       16 . The method of  claim 13 , wherein darusentan is administered at a frequency not greater than once a day. 
   
   
       17 . The method of  claim 1 , wherein the selective ET A  receptor antagonist is administered according to a therapeutic regimen wherein dose and frequency of administration and duration of therapy are effective to lower blood glucose level by at least about 10 mg/dl and/or to lower glycosylated hemoglobin (HbA 1c ) level by at least about 0.5 percentage points. 
   
   
       18 . The method of  claim 1 , wherein the selective ET A  receptor antagonist is administered according to a therapeutic regimen wherein dose and frequency of administration and duration of therapy are effective to achieve a goal preprandial blood glucose level of about 80 to about 120 mg/dl, a goal bedtime blood glucose level of about 100 to about 140 mg/dl and/or a goal HbA 1c  level not greater than about 7%. 
   
   
       19 . The method of  claim 1 , wherein the selective ET A  receptor antagonist is administered for a period of at least about 3 months. 
   
   
       20 . The method of  claim 19 , wherein administration of the selective ET A  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 . The method of  claim 1 , further comprising administering to the subject one or more antidiabetics other than selective ET A  receptor antagonists. 
   
   
       22 . The method of  claim 21 , wherein the one or more antidiabetics are selected from the group consisting of alpha-glucosidase inhibitors, biguanides, exendins, hormones and analogs thereof, meglitinides, sulfonylurea derivatives and thiazolidinediones. 
   
   
       23 . The method of  claim 21 , wherein the selective ET A  receptor antagonist comprises darusentan and the one or more antidiabetic agents are selected from the group consisting of acarbose, exenatide, glimepiride, insulins, metformin, nateglinide, pioglitazone, pramlintide, rosiglitazone and combinations thereof. 
   
   
       24 . The method of  claim 1 , further comprising administering to the subject one or more antihypertensives other than selective ET A  receptor antagonists. 
   
   
       25 . The method of  claim 24 , wherein the one or more antihypertensives are selected from the group consisting of diuretics, ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers, calcium channel blockers, direct vasodilators, alpha-1-adrenergic receptor blockers, central alpha-2-adrenergic receptor agonists and other centrally acting antihypertensive drugs, aldosterone receptor antagonists, vasopeptidase inhibitors, NEP inhibitors, prostanoids, PDE 5  inhibitors, nitrosylated compounds, oral nitrates and renin inhibitors. 
   
   
       26 . The method of  claim 24 , wherein a subject having hypertension as a component of the diabetic nephropathy and/or metabolic syndrome exhibits resistance to a baseline antihypertensive therapy comprising administration of said one or more antihypertensives in absence of a selective ET A  receptor antagonist. 
   
   
       27 . The method of  claim 26 , wherein the subject has resistant hypertension and said antihypertensives other than selective ET A  receptor antagonists comprise at least one diuretic and at least two antihypertensives selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. 
   
   
       28 . The method of  claim 27 , wherein the selective ET A  receptor antagonist comprises darusentan and the antihypertensives other than selective ET A  receptor antagonists comprise
 (a) a diuretic selected from the group consisting of chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, polythiazide, bumetanide, furosemide, torsemide and combinations thereof; and at least two of (b), (c) and (d);   (b) an angiotensin converting enzyme inhibitor selected from the group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril and combinations thereof, and/or an angiotensin II receptor blocker selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan and combinations thereof;   (c) a beta-adrenergic receptor blocker selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, timolol and combinations thereof; and   (d) a calcium channel blocker selected from the group consisting of amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil and combinations thereof.   
   
   
       29 . The method of  claim 9 , further comprising administering to the subject one or more anti-obesity agents. 
   
   
       30 . The method of  claim 29 , wherein the one or more anti-obesity agents are selected from the group consisting of anorexics, CB1 receptor blockers and lipase inhibitors. 
   
   
       31 . The method of  claim 29 , wherein the selective ET A  receptor antagonist comprises darusentan and the one or more anti-obesity agents are selected from the group consisting of benzphetamine, methamphetamine, orlistat, phendimetrazine, phentermine, rimonabant, sibutramine and combinations thereof. 
   
   
       32 . The method of  claim 9 , further comprising administering to the subject one or more antidyslipidemics. 
   
   
       33 . The method of  claim 32 , wherein the one or more antidyslipidemics are selected from the group consisting of bile acid sequestrants, cholesterol absorption inhibitors, fibrates, HMG CoA reductase inhibitors, nicotinic acid derivatives, and thyroid hormones and analogs thereof. 
   
   
       34 . The method of  claim 32 , wherein the selective ET A  receptor antagonist comprises darusentan and the one or more antidyslipidemics are selected from the group consisting of atorvastatin, colesevelam, ezetimibe, fenofibrate, fluvastatin, lovastatin, niacin, rosuvastatin, simvastatin and combinations thereof. 
   
   
       35 . The method of  claim 1 , wherein the selective ET A  receptor antagonist is coformulated in a fixed dose combination at least one additional agent other than a selective ET A  receptor antagonist, said at least one additional agent being selected from antidiabetics, antihypertensives, anti-obesity agents and antidyslipidemics. 
   
   
       36 . The method of  claim 1 , wherein glycemic control is enhanced. 
   
   
       37 . The method of  claim 1 , wherein insulin sensitivity is enhanced. 
   
   
       38 . A method for treating a complex of comorbidities in an elderly diabetic human subject, comprising administering to the subject a selective ET A  receptor antagonist in combination or as adjunctive therapy with (a) 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, and optionally (b) at least one antihypertensive other than a selective ET A  receptor antagonist. 
   
   
       39 . The method of  claim 38 , wherein the comorbidities comprise at least two conditions selected from the group consisting of insulin resistance, chronic kidney disease, hypertension, dyslipidemia, obesity, cardiac insufficiency and sleep apnea. 
   
   
       40 . The method of  claim 39 , wherein the comorbidities comprise at least three conditions selected from said group. 
   
   
       41 . The method of  claim 38 , wherein the subject is at least about 65 years of age. 
   
   
       42 . The method of  claim 38 , wherein the selective ET A  receptor antagonist comprises at least one agent selected from the group consisting of ambrisentan, atrasentan, avosentan, BMS 193884, BQ-123, CI-1020, clazosentan, darusentan, edonentan, S-0139, SB-209670, sitaxsentan, TA-0201, tarasentan, TBC 3711, tezosentan, YM-598, ZD-1611, ZD-4054, and salts, esters, prodrugs, metabolites, tautomers, racemates and enantiomers thereof. 
   
   
       43 . The method of  claim 38 , wherein said at least one additional agent is selected from the group consisting of antidiabetics, anti-obesity agents and antidyslipidemics. 
   
   
       44 . The method of  claim 38 , wherein the selective ET A  receptor antagonist comprises darusentan. 
   
   
       45 . The method of  claim 44 , wherein darusentan is administered in an amount of about 1 to about 600 mg/day. 
   
   
       46 . The method of  claim 44 , wherein darusentan is administered in an amount of about 10 to about 300 mg/day. 
   
   
       47 . The method of  claim 44 , wherein darusentan is administered at a frequency not greater than once a day. 
   
   
       48 . The method of  claim 44 , wherein said at least one additional agent is selected from the group consisting of acarbose, exenatide, glimepiride, insulins, metformin, nateglinide, pioglitazone, pramlintide, rosiglitazone, benzphetamine, methamphetamine, orlistat, phendimetrazine, phentermine, rimonabant, sibutramine, atorvastatin, colesevelam, ezetimibe, fenofibrate, fluvastatin, lovastatin, niacin, rosuvastatin, simvastatin and combinations thereof. 
   
   
       49 . The method of  claim 44 , wherein at least one antihypertensive other than a selective ET A  receptor antagonist is administered, said at least one antihypertensive being selected from the group consisting of chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, polythiazide, bumetanide, furosemide, torsemide, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, timolol, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil and combinations thereof. 
   
   
       50 . A therapeutic combination comprising a selective ET A  receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ET A  receptor antagonist. 
   
   
       51 . The combination of  claim 50 , comprising at least one antidiabetic selected from the group consisting of alpha-glucosidase inhibitors, biguanides, exendins, hormones and analogs thereof, meglitinides, sulfonylurea derivatives and thiazolidinediones. 
   
   
       52 . The combination of  claim 50 , comprising darusentan and at least one antidiabetic selected from the group consisting of acarbose, exenatide, glimepiride, insulins, metformin, nateglinide, pioglitazone, pramlintide, rosiglitazone and combinations thereof. 
   
   
       53 . The combination of  claim 50 , comprising at least one anti-obesity agent selected from the group consisting of anorexics, CB1 receptor blockers and lipase inhibitors. 
   
   
       54 . The combination of  claim 50 , comprising darusentan and at least one anti-obesity agent selected from the group consisting of benzphetamine, methamphetamine, orlistat, phendimetrazine, phentermine, rimonabant, sibutramine and combinations thereof. 
   
   
       55 . The combination of  claim 50 , comprising at least one antidyslipidemic selected from the group consisting of bile acid sequestrants, cholesterol absorption inhibitors, fibrates, HMG CoA reductase inhibitors, nicotinic acid derivatives, and thyroid hormones and analogs thereof. 
   
   
       56 . The combination of  claim 50 , comprising darusentan and at least one antidyslipidemic selected from the group consisting of atorvastatin, colesevelam, ezetimibe, fenofibrate, fluvastatin, lovastatin, niacin, rosuvastatin, simvastatin and combinations thereof. 
   
   
       57 . The combination of  claim 50 , further comprising at least one antihypertensive. 
   
   
       58 . The combination of  claim 57 , wherein the at least one hypertensive is selected from the group consisting of diuretics, ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers, calcium channel blockers, direct vasodilators, alpha-1-adrenergic receptor blockers, central alpha-2-adrenergic receptor agonists and other centrally acting antihypertensive drugs, aldosterone receptor antagonists, vasopeptidase inhibitors, NEP inhibitors, prostanoids, PDE5 inhibitors, nitrosylated compounds, oral nitrates and renin inhibitors. 
   
   
       59 . The combination of  claim 57 , wherein the selective ET A  receptor antagonist is darusentan and the at least one antihypertensive is selected from the group consisting of chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, polythiazide, bumetanide, furosemide, torsemide, benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, acebutolol, atenolol, betaxolol, bisoprolol, carvedilol, labetalol, metoprolol, nadolol, penbutolol, pindolol, propranolol, timolol, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamil and combinations thereof.