WO 2006/121853 PCT/US2006/017403 COMBINATION THERAPY WITH SULODEXIDE AND A BLOOD PRESSURE REDUCING AGENT IN THE TREATMENT OF DIABETIC NEPHROPATHY The present application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60/679,096 filed May 5, 2005 and U.S. Provisional Application No. 60/736,973 filed November 14, 2005, the disclosure of each of which is incorporated by 5 reference herein in its entirety. This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights. 10 1. FIELD OF THE INVENTION The present invention is directed to a method of treating patients suffering from nephropathy of diabetic origin by administration of sulodexide in combination with an inhibitor of an angiotensin converting enzyme (ACE) and/or with an angiotensin II receptor blocker (ARB). 15 2. BACKGROUND OF THE INVENTION Diabetes is now the most common cause of end-stage renal disease (ESRD) in the U.S. and in many other developed nations. Diabetic nephropathy now represents 44% of all new cases of ESRD in the U.S. Despite advances in clinical care, including improvements in glycemic and blood pressure control, the number of new cases of diabetes mellitus related 20 ESRD continues to rise. In particular, the incidence of type 2 diabetes mellitus (DM2) related cases of ESRD is rapidly increasing. From 1993 to 1997, 71% of all diabetes-related ESRD was attributable to DM2. -1- WO 2006/121853 PCT/US2006/017403 The current standard of care for the prevention and treatment of diabetic renal disease is treating patients who test positive for microalbuminuria with a blood pressure reducing agent such as an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (A2) receptor blocker (ARB). ACE inihibitors and ARBs are known to reduce blood 5 pressure, but exhibit differential clinical effects. The final active messenger of the rennin angiotensin pathway is angiotensin II which binds to AT1 receptors to cause vasoconstriction and fluid retention, both of which lead to an increase in blood pressure. ACE inhibitors are known to reduce blood pressure and act as vasodilators in hypertension and congestive heart failure by inhibiting in the renin-angiotensin pathway angiotensin II 10 which binds to the AT1 receptors to cause vasoconstriction and fluid retention. ARB also reduces blood pressure by blocking the AT1 receptors. Several ACE inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, and ramipril) are currently available on the market. Several ARB's are also currently available of the market (e.g., losartan, valsartan, irbesartan and candesartan). 15 Therapies involving ACE inhibitors and ARBs have been shown to reduce levels of albuminuria in select patient populations. This improvement in proteinuria has been accompanied by a concomitant improvement in or delay of progression to a number of additional renal function parameters, as well as a minimal delay in certain clinical events including ESRD. However, reductions in albuminuria are not always clinically meaningful 20 or consistently produced. Some patients achieve the majority of their therapeutic effect of ACE inhibitors or ARBs within the first six months of therapy, yet many of these patients continue to exhibit persistent microalbuminuria, and some of these patients do not have the desired therapeutic response. Therefore, these patients are at an increased risk of progressing to ESRD due to the lack of adequate benefit from their current standard of 25 therapy. -2- WO 2006/121853 PCT/US2006/017403 Sulodexide which belongs to a class of drugs known as glycosaminoglycans (GAGs) has been approved for "vascular indications" and has been marketed in multiple countries for such indications. US Patent No. 5,496,807 reports on the evaluation of sulodexide in the treatment of diabetic nephropathy, and when administered intramuscularly or orally in doses 5 of approximately 50 to 100 mg/day, produces reductions in albumin excretion rate (AER) of 35 to 62% in macroalbuminuric patients and 20 to 50% in microalbuminuric patients. Sulodexide has also been evaluated at a dose of at least 200 mg/day (US Patent Publication No. 2002/0065233) and normoalbuminuria was achieved in 42% of patients. Not intending to be limited to a particular mechanism of action, the mechanism by 10 which sulodexide decreases albumin excretion in patients with diabetic nephropathy is believed to include the following: (1) the restoration of the physiologic glomerular membrane anionic charge barrier via enhanced synthesis and sulfation of heparan sulfate in renal vascular membranes, and direct replenishment of renal heparan sulfate, (2) the inhibition of TGF beta-1 mediated mesangial matrix overproduction, (3) the inhibition of 15 endothelin mediated tubulo-interstitial fibrosis, and (4) the inhibition of mesangial cell hyperplasia. (See Harenberg J., Med. Res. Rev. vol. 18, 1-20 (1998), Gambaro G. and Van Der Woude, J. Am. Soc. Nephrol. 11:359-368 (2000)). Kanwar Y. S. et al., Sem. Nephrol., 5, 307, (1985) and Groggel G. C. et al., Kidney Int., 33, 517, (1988) have produced evidence of the probable role of glycosaminoglycans in helping the integrity and the 20 functioning of renal cells. Moreover, Canfield J. P. et al., Lab. Invest., 39, 505, (1978), previously showed a decrease of glycosaminoglycans in the glomerular basement membrane in many conditions of nephropathy, while Baggio B. et al., Nephron., 43, 187, (1986) showed an increased urinary elimination of glycosaminoglycans in diabetic, non albuminuric, patients. This increased excretion of glycosaminoglycans in diabetic 25 nephropathies was shown also by Partasarathy N. et al., Diabetes, 31, 738, (1982). In addition, Diamond J. R. et al., Renal Physiol., 9, 366, (1986) and Parkerson M. B. et al., J. -3- WO 2006/121853 PCT/US2006/017403 Clin. Invest., 81, 69, (1988), showed in animals the potential protective effect of heparin and its derivatives in models of experimental nephropathy not related to diabetic nephropathy, like chronic nephrosis from aminoglycosides and renal pathologies resulting from the subtotal renal ablation in the rat. Sulodexide therapy was administered to patients 5 receiving ongoing ACE inhibitor therapy. Results demonstrate that reductions in AER were equivalent in patients treated concomitantly with ACE inhibitors and those not treated with ACE inhibitors. Therefore, there is a need in the art to optimize the oral administration of sulodexide with the concurrent administration of a blood pressure reducing agent such as an ACE 10 inhibitor or an ARB to achieve a maximum reduction in urinary albumin. Citation or identification of any reference in Section 2 or in any other section of this application shall not be construed as an admission that such reference is available as prior art to the present invention. 3. SUMMARY OF THE INVENTION 15 The present invention is directed to a pharmaceutical composition comprising (a) sulodexide in an amount sufficient to significantly decrease the amount of urinary albumin; (b) a blood pressure reducing agent; and (c) a pharmaceutically acceptable carrier. In one embodiment, the blood pressure reducing agent is an angiotensin converting enzyme (ACE) inhibitor. In another embodiment, the blood pressure reducing agent is an angiotensin II 20 (A2) receptor blocker (ARB). In specific embodiments, the amount of the blood pressure reducing agent in the composition is the maximal approved dosage for that particular agent. In yet another embodiment, the present invention is directed to a method for treating a patient suffering from type I or type II diabetic nephropathy comprising administering a pharmaceutical composition comprising sulodexide to a patient concurrently with a blood 25 pressure reducing agent. In certain embodiments, concurrently administering includes administering the ACE inhibitor and/or ARB simultaneously with sulodexide, or within 30 -4- WO 2006/121853 PCT/US2006/017403 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours or within 24 hours of each other. In a specific embodiment, the blood pressure reducing agent is an ACE inhibitor and/or an ARB. In yet another embodiment, the dosage of the blood pressure reducing agent administered to the patient is the maximum approved dose of such agent. In 5 certain embodiments, the sulodexide and the blood pressure reducing agent can be administered together in a single dose or can be administered separately. In yet other embodiments, patients were already being treated with a blood pressure reducing agent prior to the start of sulodexide administration. In an embodiment of the invention, the patient is a mammal, preferably a human. In 10 other embodiments, sulodexide is administered in an amount of 10-1000 mg/day, preferably 50-500 mg/day, more preferably 100-400 mg/day. In a specific embodiment, the patient is administered 200 mg/day. In another specific embodiment, the patient is administered 400 mg/day. In other preferred embodiments, the sulodexide is administered orally. 4. DETAILED DESCRIPTION OF THE INVENTION 15 The present invention is directed to pharmaceutical compositions and methods for the treatment of a patient suffering from diabetic nephropathy with persistent microalbuminuria in type 1 and type 2 diabetes which encompasses co-administering an effective amount of sulodexide, preferably in orally administrable form, which effective amount is sufficient to significantly decrease the amount of albumin excreted in the urine of 20 the patient, and a blood pressure reducing agent. In one embodiment, such blood pressure reducing agent is an angiotensin converting enzyme (ACE) inhibitor. In another embodiment, such blood pressure reducing agent is an angiotensin II (A2) receptor blockers (ARB). In yet another embodiment, the blood pressure reducing agent is a combination of one or more ACE inhibitors and/or one or more ARBs. In another embodiment, the amount 25 of the blood pressure reducing agent is a maximum approved dose for such agent. -5- WO 2006/121853 PCT/US2006/017403 The amount of sulodexide can be administered one or more times per day, and said amount being sufficient to reduce albumin excretion but insufficient to cause adverse side effects. The present invention encompasses unit dosage forms of sulodexide in a range from about 100 mg to about 1000 mg, and includes any value encompassed within the 5 range. In a specific embodiment, a 200 mg dose of sulodexide is administered. In another embodiment, a 400 mg dose of sulodexide is administered. The method of administration, according to the present invention, may be oral, mucosal, parenteral, intramuscular or transdermal, and is preferably oral. ACE inhibitors are well known in the art. Exemplary ACE inhibitors and their 10 approved maximum dose include, but are not limited to, Lotensin® (benazepril) 40 mg/day, Capoten® (captopril) 450 mg/day, Vasotec® (enalapril) 40 mg/day, Monopril® (fosinopril) 40 mg/day, Univasc® (moexipril) 30 mg/day, Aceon® (perindopril) 16 mg/day, Accupril® (quinapril) 80 mg/day, Altace® (ramipril) 20 mg/day, Mavik® (trandolapril) 8 mg/day, and Zestril® or Prinivil® (lisinopril) 80 mg/day. ARBs are also well known in the art. 15 Exemplary ARBs and their approved maximum dose incldue, but are not limited to, Atacand® (candesartan) 32 mg/day, Teveten® (eprosartan) 800 mg/day, Avapro® (irbesartan) 300 mg/day, Cozaar® (losartan) 100 mg/day, Diovan® (valsartan) 320 mg/day, Micardis® (telmisartan) 80 mg/day, and Benicar® (olmesartan) 40 mg/day. In evaluating the efficacy of the dosage of sulodexide, the following parameters can 20 be measured: (A) observed urinary albumin creatinine ratio (ACR) level, (B) percentage of patients achieving therapeutic "success," a binary composite endpoint defined as conversion to normoalbuminuria (ACR < 20 mg/g) and a 25% reduction in ACR level relative to baseline or a 50% reduction in ACR level relative to baseline, (C) percentage of patients achieving normoalbuminuria, (D) percent change from baseline on various additional 25 endpoints, including plasma fibrinogen, serum creatinine, reciprocal of the serum creatinine, and serum albumin. The safety assessments included adverse events monitoring, -6- WO 2006/121853 PCT/US2006/017403 concomitant medication use, physical examinations, sequential blood chemistries, hematology, coagulation profiles, urinalysis, and serum creatinine. The invention having been described, the following examples are offered by way of illustration and not limitation. 5 5. EXAMPLE 1 The therapeutic efficacy and safety of sulodexide administered in the treatment of persistent microalbuminuria in type I or type II diabetic nephropathic patients who are concurrently receiving maximal dosage of a blood pressure reducing agent, e.g., an inhibitor of an angiotensin converting enzyme (ACE) and/or an angiotensin II (A2) receptor blocker 10 as background therapy has been evaluated in the following study. The patients were microalbuminuric diabetes mellitus (DM)-1 and DM-2 patients who were currently receiving a maximum approved dose of either an ACE inhibitor or A2 receptor blocker (stable for 2 months). All patients gave informed consent and the study was conducted in compliance with U.S. Food and Drug Administration regulations. 15 Exemplary ACE inhibitors and their approved maximum dose that were being taken by the patients in this study include Lotensin® (benazepril) 40 mg/day, Capoten® (captopril) 450 mg/day, Vasotec® (enalapril) 40 mg/day, Monopril® (fosinopril) 40 mg/day, Univasc® (moexipril) 30 mg/day, Aceon® (perindopril) 16 mg/day, Accupril® (quinapril) 80 mg/day, Altace® (ramipril) 20 mg/day, Mavik® (trandolapril) 8 mg/day, and 20 Zestril® or Prinivil® (lisinopril) 80 mg/day. Exemplary A2 receptor blockers and their approved maximum dose that were being taken by the patients in this study include Atacand® (candesartan) 32 mg/day, Teveten® (eprosartan) 800 mg/day, Avapro® (irbesartan) 300 mg/day, Cozaar® (losartan) 100 mg/day, Diovan® (valsartan) 320 mg/day, Micardis® (telmisartan) 80 mg/day, and Benicar® (olmesartan) 40 mg/day. 25 The patients were placed into one of three groups; Group I was administered 200 mg of sulodexide orally for 6 months, Group II was administered 400 mg of sulodexide orally -7- WO 2006/121853 PCT/US2006/017403 for 6 months, and Group III was not administered any dosage of sulodexide but instead was administered a placebo. Patients on a maximum approved dose of a blood pressure reducing agent are treated with sulodexide or placebo for six (6) months and are post-treated for an additional two (2) months. 5 The following efficacy endpoints were analyzed after 2, 4, and 6 months of therapy and at the 2-month post-treatment follow-up: (A) observed urinary albumin creatinine ratio (ACR) level, (B) percentage of patients achieving "therapeutic success", which is a binary composite end point defined as conversion from microalbuminuria to normalbunimuria (with a least a 25% reduction in microalbumnuria) as measured by albumin/creatinine ratio 10 (ACR), or at least a 50% reduction in ACR level relative to baseline, (C) percentage of patients achieving normoalbuminuria, (D) percent change from baseline on various additional endpoints, including plasma fibrinogen, serum creatinine, reciprocal of the serum creatinine, and serum albumin. The safety assessments in this study included adverse events monitoring, 15 concomitant medication use, physical examinations, sequential blood chemistries, hematology, coagulation profiles, urinalysis, and serum creatinine. Patients were randomized 1:1:1, placebo, 200 mg sulodexide and 400 mg sulodexide, respectively. Table 1 summarizes therapeutic success for Group I and Group II patients combined as compared to Group III patients. Table 2 summarizes therapeutic 20 success for Group I patients as compared to Group III patients. Table 1 Sulodexide Placebo (200 mg and 400 mg) (No. of patients = 38) (No. of patients = 82) Therapeutic Success 24% 13% > 50% reduction 21% 11% Normalization 13% 8% -8- WO 2006/121853 PCT/US2006/017403 Table 2 Sulodexide Placebo (200 mg) (No. of Patients = 38) No. of Patients = 38) Therapeutic Success 29% 13% > 50% reduction 24% 11% Normalization 16% 8% The results of the study showed that administration of sulodexide as compared to 5 placebo improved patients with persistent microalbuminuria. Further, the safety assessments showed that administration of sulodexide at either dosage amounts was not believed to be related to any serious adverse events. 6. EXAMPLE 2 In this study, two doses of sulodexide ("KRX-101") (200 mg and 400 mg) were 10 compared to placebo in patients with diabetic microalbuminuria on maximal therapy with an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were treated with sulodexide or placebo for six months and followed for an additional two months post-treatment. Patients were randomized 1:1:1, placebo, 200 mg and 400 mg of sulodexide, respectively. 15 In this study, the primary endpoint for the study was the percentage of patients achieving "Therapeutic Success" at six months. A patient is considered a "Therapeutic Success" if they achieve one of the following outcomes following 6 months on study: (1) 50% reduction in albumin to creatinine ratio or "ACR" -- ACR is a standard measurement used to assess the level of kidney disease in these patients. ACR measures the 20 level of albumin protein in urine, also referred to as "albuminuria," or (2) Normalization of ACR with at least a 25% reduction in ACR-in this study the normal laboratory range for albuminuria was defined as less than 20 mg of albumin to 1g of creatinine. -9- WO 2006/121853 PCT/US2006/017403 Data Analysis: A total of 149 patients were randomized into the study. All patients evaluable for Therapeutic Success at 6 months (i.e., all patients with a baseline ACR and a 6-month ACR) were included in the Intent to Treat analysis, for a total of 136 patients in the Intent to Treat 5 population. All patients in the Intent to Treat population that at baseline were within the target eligibility range of microalbuminuria as defined in the protocol (ACR 20 mg/G to 200 mg/G) were included in the Per Protocol analysis, for a total population of 117 patients in the Per Protocol population. All of the primary and secondary analyses shown were pre-specified. For the 10 primary endpoint analysis, statistical nominal p values have been provided for informational purposes only since this study, as a pilot study, had less than a 20% power to show statistically significant results for these endpoints. The data is being presented in two ways. First, the 200 mg arm is compared to placebo. Next, the data is presented as Active (200 mg and 400 mg) vs. Placebo; this was 15 the primary endpoint defined by the protocol. Information on the effects of the 400 mg arm alone can be found in the footnotes to the tables. The dose response relationship of sulodexide previously demonstrated up to 200 mg was not observed from 200 mg to 400 mg in this study. Table 3 - Primary Endpoint Analysis (Therapeutic Success at 6 months) (200 ming vs. 20 Placebo) Number of p value Patients Fisher's Exact Test (Placebo/200mg) Placebo 200mg (2-sided) Per Protocol 36/36 11.0% 33.0% P=.045 Intent to Treat 42/44 14.0% 32.0% P=.074 Table 4 - Primary Endpoint Analysis (Therapeutic Success at 6 months) (200 mg and 400 25 mgI vs. Placebo) Number of Active p value Patients (200 mg and Fisher's Exact Test (Placebo/Active) Placebo 400 mg) (2-sided) -10- WO 2006/121853 PCT/US2006/017403 Per Protocol 36/81 1 11.0 % 25 % P=.136 Intent to Treat 42/94 14.0 % 26 % P=.180 1 For the 400mg group alone, the Therapeutic Success was 20% on intent to treat basis and 18% on a per protocol basis. 5 Table 5 - Secondary Endpoint Analysis at 6 months (Intent to Treat) Active (200 mg and 400 Placebo 200 mg mg) n=42 n=44 n=94 >50 % reduction in ACR 12.0 % 27.0 % 22.0 % Normalization of ACR 9.0 % 23.0 % 17.0 % 1 For the 400ing group alone, the 50% reduction and normalization were 18% and 10%, respectively. 10 Table 6 - Average Changes of ACR Over Time (Intent to Treat)' 200 mg vs. Placebo vs. 200 mg vs. Placebo Baseline Baseline Two months -17.00 % -4.00 % -21.00 % Four months -25.78% 7.50% -18.28% Six months -28.03 % 12.57 % -15.46 % Eight months (2 months off therapy) -28.98% 18.50% -10.48 % 1 The average changes from baseline over time for the 400ng dose group were 3.4%, 3.24%, 5.59% and 12.59%, respectively. 15 There were no serious adverse events (SAEs) that were deemed by the investigators to be related, probably related or possibly related to the study drug. A statistically significant benefit was achieved in the 200 mg group over placebo in patients with microalbuminuria, and a very strong trend nearing statistical significance was demonstrated in the intent to treat population. 20 Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is to be limited only by the terms of the appended claims, along with the full scope of equivalents -11- WO 2006/121853 PCT/US2006/017403 to which such claims are entitled. Such modifications are intended to fall within the scope of the appended claims. All references, patent and non-patent, cited herein are incorporated herein by reference in their entireties and for all purposes, to the same extent as if each individual 5 publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. -12-