Clinical Investigation| Volume 355, ISSUE 5, P442-448, May 2018

Beneficial Effects of Pentoxifylline Plus Losartan Dual Therapy in Type 2 Diabetes with Nephropathy



      This study was designed to comparatively assess the effects of add-on pentoxifylline to losartan versus increasing the dose of losartan on serum N-terminal pro-brain natriuretic peptide (NT-proBNP), serum highly sensitive C-reactive protein (hsCRP) and the urinary albumin excretion (UAE) rate in patients with type 2 diabetes and nephropathy.


      In an open-label, single-center, parallel-group, randomized clinical trial (NCT03006952), 30 patients received b.i.d. dose of pentoxifylline 400 mg plus daily dose of losartan 50 mg (pentoxifylline arm) and 29 patients received b.i.d. dose of losartan 50 mg (losartan arm) during a 12-week follow-up period.


      Serum NT-proBNP, serum hsCRP and UAE levels all significantly decreased from baseline in both trial arms. The pentoxifylline and losartan trial arms were equally effective in reducing serum NT-proBNP levels during the course of trial (multivariable adjusted model P value = 0.864, effect size = 0.2%). There was a greater decrease in UAE and serum hsCRP levels in the pentoxifylline arm (P = 0.034, effect size = 7.8%; P = 0.009, effect size = 11.7%, respectively). Conversely, patients in the losartan arm achieved better systolic and diastolic blood pressure control (P < 0.001, effect size = 25.4%; P = 0.010, effect size = 11.3%, respectively).


      Circulating NT-proBNP levels equally and significantly reduced from baseline in the pentoxifylline and losartan treatment arms, in parallel with comparatively superior decreases of UAE and serum hsCRP in the pentoxifylline arm, and larger decreases of systolic and diastolic blood pressures in the losartan arm.

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        • Esteghamati A.
        • Larijani B.
        • Aghajani M.H.
        • et al.
        Diabetes in Iran: prospective analysis from first nationwide diabetes report of National Program for Prevention and Control of Diabetes (NPPCD-2016).
        Sci Rep. 2017; 7: 13461
        • Noshad S.
        • Afarideh M.
        • Heidari B.
        • et al.
        Diabetes care in Iran: where we stand and where we are headed.
        Ann Glob Health. 2015; 81: 839-850
        • Gross J.L.
        • de Azevedo M.J.
        • Silveiro S.P.
        • et al.
        Diabetic nephropathy: diagnosis, prevention, and treatment.
        Diabetes Care. 2005; 28: 164-176
        • Lambers Heerspink H.J.
        • Gansevoort R.T.
        Albuminuria is an appropriate therapeutic target in patients with CKD: the pro view.
        Clin J Am Soc Nephrol. 2015; 10: 1079-1088
        • Krolewski A.S.
        • Niewczas M.A.
        • Skupien J.
        • et al.
        Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria.
        Diabetes Care. 2014; 37: 226-234
        • Garg J.P.
        • Bakris G.L.
        Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease.
        Vasc Med. 2002; 7: 35-43
        • Klausen K.
        • Borch-Johnsen K.
        • Feldt-Rasmussen B.
        • et al.
        Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes.
        Circulation. 2004; 110: 32-35
        • Esteghamati A.
        • Khandan A.
        • Momeni A.
        • et al.
        Circulating levels of fibroblast growth factor 21 in early-stage diabetic kidney disease.
        Ir J Med Sci. 2017; 186: 785-794
        • Irannejad A.
        • Ghajar A.
        • Afarideh M.
        • et al.
        Association of peripheral nesfatin-1 with early stage diabetic nephropathy.
        Pathophysiology. 2017; 24: 17-22
        • Gaede P.
        • Hildebrandt P.
        • Hess G.
        • et al.
        Plasma N-terminal pro-brain natriuretic peptide as a major risk marker for cardiovascular disease in patients with type 2 diabetes and microalbuminuria.
        Diabetologia. 2005; 48: 156-163
        • Tarnow L.
        • Gall M.-A.
        • Hansen B.V.
        • et al.
        Plasma N-terminal pro-B-type natriuretic peptide and mortality in type 2 diabetes.
        Diabetologia. 2006; 49: 2256-2262
        • Price A.H.
        • Welsh P.
        • Weir C.J.
        • et al.
        N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in older patients with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.
        Diabetologia. 2014; 57: 2505-2512
        • Jurado J.Y.J.
        • Ferrandiz M.
        • Comerma L.
        • et al.
        Amino-terminal brain natriuretic peptide is related to the presence of diabetic polyneuropathy independently of cardiovascular disease.
        Diabetes Care. 2007; 30: e86
        • Doi Y.
        • Ninomiya T.
        • Hata J.
        • et al.
        N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in a Japanese community: the Hisayama study.
        Arterioscler Thromb Vasc Biol. 2011; 31: 2997-3003
        • Danis R.
        • Ozmen S.
        • Arikan S.
        • et al.
        Predictive value of serum NT-proBNP levels in type 2 diabetic people with diabetic nephropathy.
        Diabetes Res Clin Pract. 2012; 95: 312-316
        • Zhou L.
        • Cai X.
        • Li M.
        • et al.
        Plasma NT-proBNP is independently associated with albuminuria in type 2 diabetes.
        J Diabetes Complications. 2016; 30: 669-674
        • Oliaei F.
        • Hushmand S.
        • Khafri S.
        • et al.
        Efficacy of pentoxifylline for reduction of proteinuria in type II diabetic patients.
        Caspian J Intern Med. 2011; 2: 309-313
        • Carson C.
        • Al-Makki A.
        • Shepler B.
        Can pentoxifylline be used as adjunct therapy to ACE inhibitors and ARBs in preserving kidney function?.
        J Pharm Pharm Sci. 2016; 19: 1-7
        • Kang S.W.
        Effect of phosphodiesterase inhibitor on diabetic nephropathy.
        Korean J Intern Med. 2012; 27: 151-153
        • Kapoor S.
        The renoprotective effects of pentoxifylline: beyond its role in diabetic nephropathy.
        Korean J Intern Med. 2013; 28: 374-375
        • McCarty M.F.
        • O’Keefe J.H.
        • DiNicolantonio J.J.
        Pentoxifylline for vascular health: a brief review of the literature.
        Open Heart. 2016; 3: e000365
        • Sliwa K.
        • Woodiwiss A.
        • Kone V.N.
        • et al.
        Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study.
        Circulation. 2004; 109: 750-755
      1. Esteghamati A, Momeni A, Abdollahi A, et al. Serum fibroblast growth factor 21 concentrations in type 2 diabetic retinopathy patients. Annales d'Endocrinologie 77(5):586–92.

        • Esteghamati A.
        • Afarideh M.
        • Feyzi S.
        • et al.
        Comparative effects of metformin and pioglitazone on fetuin-A and osteoprotegerin concentrations in patients with newly diagnosed diabetes: a randomized clinical trial.
        Diabetes Metab Syndr. 2015; 9: 258-265
        • Esteghamati A.
        • Azizi R.
        • Ebadi M.
        • et al.
        The comparative effect of pioglitazone and metformin on serum osteoprotegerin, adiponectin and intercellular adhesion molecule concentrations in patients with newly diagnosed type 2 diabetes: a randomized clinical trial.
        Exp Clin Endocrinol Diabetes. 2015; 123: 289-295
        • Afarideh M.
        • Behdadnia A.
        • Noshad S.
        • et al.
        Association of peripheral 5-hydroxyindole-3-acetic acid, a serotonin derivative, with metabolic syndrome and low-grade inflammation.
        Endocr Pract. 2015; 21: 711-718
        • Gruden G.
        • Landi A.
        • Bruno G.
        Natriuretic peptides, heart, and adipose tissue: new findings and future developments for diabetes research.
        Diabetes Care. 2014; 37: 2899-2908
        • Sundqvist S.
        • Larson T.
        • Cauliez B.
        • et al.
        Clinical value of natriuretic peptides in predicting time to dialysis in stage 4 and 5 chronic kidney disease patients.
        PLoS One. 2016; 11: e0159914
        • Birn H.
        • Christensen E.I.
        Renal albumin absorption in physiology and pathology.
        Kidney Int. 2006; 69: 440-449
        • Navarro J.F.
        • Mora C.
        • Macıéa M.
        • et al.
        Inflammatory parameters are independently associated with urinary albumin in type 2 diabetes mellitus.
        Am J Kidney Dis. 2003; 42: 53-61
        • Kuo K.L.
        • Hung S.C.
        • Liu J.S.
        • et al.
        Add-on protective effect of pentoxifylline in advanced chronic kidney disease treated with renin-angiotensin-aldosterone system blockade—a nationwide database analysis.
        Sci Rep. 2015; 5: 17150
        • Ghorbani A.
        • Omidvar B.
        • Beladi-Mousavi S.S.
        • et al.
        The effect of pentoxifylline on reduction of proteinuria among patients with type 2 diabetes under blockade of angiotensin system: a double blind and randomized clinical trial.
        Nefrologia. 2012; 32: 790-796
        • Navarro-Gonzalez J.F.
        • Mora-Fernandez C.
        • Muros de Fuentes M.
        • et al.
        Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial.
        J Am Soc Nephrol. 2015; 26: 220-229
        • You Y.K.
        • Huang X.R.
        • Chen H.Y.
        • et al.
        C-Reactive protein promotes diabetic kidney disease in db/db mice via the CD32b-Smad3-mTOR signaling pathway.
        Sci Rep. 2016; 6: 26740
        • Ward Alan
        • Clissold S.P.
        Pentoxifylline, a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy.
        Drugs. 1987; 34: 50-97
        • Navarro J.F.
        • Milena F.J.
        • Mora C.
        • et al.
        Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: effect of angiotensin-converting enzyme inhibition and pentoxifylline administration.
        Am J Nephrol. 2006; 26: 562-570
        • Nielsen S.E.
        • Schjoedt K.J.
        • Rossing K.
        • et al.
        Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease.
        J Renin Angiotensin Aldosterone Syst. 2013; 14: 161-166