Abstract
Background
Although controlling hyperglycemia and proteinuria is currently the main focus of
diabetic kidney disease management, some existing drugs and other new compounds are
being evaluated for their ability to interrupt the disease process. Specifically,
drugs that interfere with the formation and action of advanced glycation end products
and reduce or inhibit fibrosis of the glomerular structures in the presence of hyperglycemia
are just 2 examples.
Objective
The aim is to provide an in-depth review of drugs currently being investigated to
treat diabetic kidney disease (DKD) through novel mechanisms of action that interrupt
the pathologic process.
Methods
A literature search was performed of the search engines PubMed (www.pubmed.gov) and ClinicalTrials.gov (www.clinicaltrials.gov), initially using the broad search terms diabetic nephropathy, diabetic kidney disease, and advanced glycation end products. Limits were set to include only English-language articles and studies performed
in human subjects from January 2000. Previous review articles on this subject captured
through the initial search also served as a basis for identifying drugs that had been
under evaluation. Once a list of drugs and compounds was established, each agent was
used as an independent search term through the same search engines listed to capture
any new and/or ongoing studies for inclusion in this review. Any trials in DKD patients
collected through this process were evaluated in this review including Phase I, II,
and III studies.
Results
Fifteen drugs were identified, and 24 studies were reviewed. Ten drugs have evidence
of beneficial effects in treating DKD patients as reported by improvements in glomerular
filtration rate, albumin-to-creatinine ratio, proteinuria, or serum creatinine concentrations.
Five drugs demonstrated no significant benefit or side-effect profiles that would
prohibit their routine use.
Conclusions
Pirfenidone, doxycycline, bardoxolone, pentoxifylline, ruboxistaurin, pyridoxamine,
paricalcitol, FG-3019, AST-120, and allopurinol have shown beneficial effects in treating
patients with DKD through modification of the pathologic mechanisms by which hyperglycemia
alters the structure and function of the glomerulus. Further evaluation using well-controlled
trials in larger patient populations are needed to confirm these benefits.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, Ga2011
- National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, 2003. Rev ed. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, Ga2004
- USRDS 2011 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md2011
- Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease.Am J Kidney Dis. 2007; 49 (S113–S119): S25-S77
- Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials.Nat Rev Drug Discov. 2009; 8: 417-429
- RAGE and the pathogenesis of chronic kidney disease.Nat Rev Nephrol. 2010; 6: 352-360
- New pharmacological treatments for improving renal outcomes in diabetes.Nat Rev Nephrol. 2010; 6: 371-380
- The RAAS in the pathogenesis and treatment of diabetic nephropathy.Nat Rev Nephrol. 2010; 6: 319-330
- The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993; 329: 977-986
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet. 1998; 352: 837-853
- Continuously evolving management concepts for diabetic CKD and ESRD.Semin Dial. 2010; 23: 134-139
- Renal and Urology News.(Accessed November 15, 2011)
- Pathology of human diabetic nephropathy.Contrib Nephrol. 2011; 170: 36-47
- Advanced glycation end-products: a review.Diabetologia. 2001; 44: 129-146
- Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies.Diabetes Metab. 2010; 36: 1-10
- Diabetes and advanced glycation endproducts.J Intern Med. 2002; 251: 87-101
- Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy.Nat Rev Nephrol. 2011; 7: 327-340
- New potential agents in treating diabetic kidney disease: the fourth act.Drugs. 2006; 66: 2287-2298
- Agents in development for the treatment of diabetic nephropathy.Expert Opin Investig Drugs. 2005; 14: 279-294
- Potential new therapeutic agents for diabetic kidney disease.Am J Kidney Dis. 2010; 55: 928-940
- Pirfenidone is renoprotective in diabetic kidney disease.J Am Soc Nephrol. 2009; 20: 1765-1775
- Pirfenidone for DKD.J Am Soc Nephrol. 2011; 22: 1144-1151
- Evolution of role of doxycycline (a matrix metalloproteinase inhibitor) on renal function in patients of diabetic nephropathy.Ren Fail. 2010; 32: 941-946
- Novel therapies of diabetic nephropathy.Curr Opin Nephrol Hypertens. 2009; 18: 107-111
- Time course of the antiproteinuric and antihypertensive effects of direct renin inhibition in type 2 diabetes.Kidney Int. 2008; 73: 1419-1425
- Aliskiren combined with losartan in type 2 diabetes and nephropathy [in Danish].N Engl J Med. 2008; 358: 2433-2446
- Aliskiren improves insulin resistance and ameliorates diabetic vascular complications in db/db mice.Nephrol Dial Transplant. 2011; 26: 1194-1204
- Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design.Nephrol Dial Transplant. 2009; 24: 1663-1671
- Novartis Press Release.(Accessed March 2, 2012)
- Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy.Am J Nephrol. 2007; 27: 605-614
- A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with DKD.Diabetes Care. 2010; 33: 1598-1601
- Effect of B-vitamin therapy on progression of DKD: a randomized controlled trial.JAMA. 2010; 303: 1603-1609
- Bardoxolone methyl and kidney function in CKD with type 2 diabetes.N Engl J Med. 2011; 365: 327-336
- Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON).(Clinical Trial NCT01351675) (Accessed March 2, 2012)
- Pentoxifylline, total urinary protein excretion rate and arterial blood pressure in long term insulin dependent diabetic patients with overt nephropathy.Acta Diabetol Lat. 1987; 24: 229-239
- Pentoxifylline reduces proteinuria in insulin-dependent and non insulin-dependent diabetic patients.Clin Nephrol. 1995; 43: 116-121
- Pentoxifylline attenuated the renal disease progression in rats with remnant kidney.J Am Soc Nephrol. 2002; 13: 2916-2929
- Pentoxifylline suppresses renal tumor necrosis factor-alpha and ameliorates experimental crescentic glomerulonephritis in rats.Nephrol Dial Transplant. 2004; 19: 1106-1115
- Vasodilator agents modulate rat glomerular mesangial cell growth and collagen synthesis.Nephron. 1995; 70: 91-99
- Captopril and combination therapy of captopril and pentoxifylline in reducing proteinuria in diabetic nephropathy.Ren Fail. 2010; 32: 172-178
- Pentoxifylline for renoprotection in diabetic nephropathy.J Diabetes Complications. 2011; 25: 314-319
- Effect of Pentoxifylline on Proteinuria in Korean Type 2 Diabetic Patients study.(Clinical Trial NCT01382303) (Accessed December 7, 2011)
- Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial.J Am Soc Nephrol. 2002; 13: 1615-1625
- Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria.Nephrol Dial Transplant. 2008; 23: 1946-1954
- Effect of Sulodexide in Early Diabetic Nephropathy study.(Clinical Trial NCT00130208) (Accessed May 23, 2011)
- Effect of Sulodexide in Overt Diabetic Nephropathy study.(Clinical Trial NCT00130312) (Accessed May 23, 2011)
- Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial.Am J Kidney Dis. 2011; 58: 729-736
- Kidney outcomes in long-term studies of ruboxistaurin for diabetic eye disease.Clin J Am Soc Nephrol. 2007; 2: 631-636
- Selective PKC beta inhibition with ruboxistaurin and endothelial function in type 2 diabetes mellitus.Cardiovasc Drugs Ther. 2009; 23: 17-24
- Inhibition of protein kinase CB does not improve endothelial function in type 2 diabetes.J Clin Endocrinol Metab. 2010; 95: 3783-3787
- Effect of ruboxistaurin on urinary transforming growth factor-B in patients with DKD and type 2 diabetes.Diabetes Care. 2007; 30: 995-996
- The effect of ruboxistaurin on nephropathy in type 2 diabetes.Diabetes Care. 2005; 28: 2686-2690
- Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomized trial.Lancet. 2010; 376: 1543-1551
- Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria.Clin J Am Soc Nephrol. 2010; 5: 1420-1428
- AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects.Diabetes Res Clin Pract. 2008; 81: 310-315
- Cost-effectiveness of administering oral adsorbent AST-120 to patients with diabetes and advance-stage chronic kidney disease.Diabetes Res Clin Pract. 2010; 90: 154-159
- Protective effect of an oral adsorbent on renal function in chronic renal failure: determinants of its efficacy in diabetic nephropathy.Ther Apher Dial. 2004; 8: 232-240
- An oral adsorbent reduces overload in indoxyl sulphate and gene expression of TGF-beta1 in uremic rat kidneys.Nephrol Dial Transplant. 2000; 15: 1773-1781
- Pharmacodynamic and pharmacokinetics of urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients.Clin Pharmacol Ther. 2006; 80: 246-256
- Effect of the urotensin receptor antagonist palosuran in hypertensive patients with type 2 diabetic nephropathy.Hypertension. 2010; 55: 1206-1209
- Effect of allopurinol in decreasing proteinuria in type 2 diabetic patients.Iran J Kidney Dis. 2010; 4: 128-132
- Beneficial effect of camel milk in DKD.Acta Biomed. 2009; 80: 131-134
- Bardoxolone methyl, chronic kidney disease, and type 2 diabetes.N Engl J Med. 2011; 365 (author reply 1746–1747): 1746
- Bardoxolone methyl, chronic kidney disease, and type 2 diabetes.N Engl J Med. 2011; 365 (author reply 1746–1747): 1745-1746
Article info
Publication history
Published online: May 14, 2012
Accepted:
April 25,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
