American Journal of Cardiovascular Drugs

, Volume 13, Issue 6, pp 443–450 | Cite as

Association Between Urinary Albumin Excretion and Low-density Lipoprotein Heterogeneity Following Treatment of Type 2 Diabetes Patients with the Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin: A Pilot Study

  • Shigemasa TaniEmail author
  • Ken Nagao
  • Atsushi Hirayama
Short Communication



Few data exist as to whether dipeptidyl peptidase (DPP)-4 inhibitors affect cardio-renal interaction, which is a strong independent prognostic factor for cardiovascular disease (CVD), in diabetic patients. We evaluated the effects of a DPP-4 inhibitor on atherogenic low-density lipoprotein (LDL) heterogeneity and albuminuria in diabetics as an indicator of the severity of diabetic nephropathy.


Type 2 diabetes patients (n = 47) inadequately controlled with diabetes therapy were treated with vildagliptin 50 mg bid for 8 weeks. LDL heterogeneity was evaluated on the basis of the patients’ small dense (sd) LDL levels and sd-LDL proportion (sd-LDL/LDL cholesterol [LDL-C]). The level of albuminuria was evaluated on the basis of the urinary albumin-to-creatinine ratio (UACR).


After 8 weeks of treatment, there was no significant change in serum LDL-C level, but the serum sd-LDL level had decreased significantly by 8.8 %, and the UACR had also decreased significantly by 44.6 %. Triglyceride (TG)-metabolism-related markers (TG, remnant-like particle cholesterol, apolipoprotein [apo] B, apoC-2, and apoC-3) had decreased significantly. The Δ (absolute change from baseline) sd-LDL values correlated positively with ΔTG-metabolism-related markers, but not with the Δ hemoglobin (Hb) A1c or Δ fasting blood sugar (ΔFBS). Furthermore, multivariate regression analysis revealed that Δsd-LDL proportion, but not ΔHbA1c or ΔFBS, was an independent predictor of ΔUACR (β = 0.292, p = 0.0016).


Although this was a single-arm study, treatment of type 2 diabetes with vildagliptin might prevent the progression of CVD complicating diabetes by improving LDL heterogeneity, and it might improve renal function by decreasing albuminuria. A randomized controlled trial is warranted.


Diabetic Nephropathy Sitagliptin Urinary Albumin Excretion Vildagliptin Vildagliptin Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Conflict of interest

All the authors declare that they have no competing interests.


  1. 1.
    Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187–215.PubMedCrossRefGoogle Scholar
  2. 2.
    Patil HR, Al Badarin FJ, Al Shami HA, Bhatti SK, Lavie CJ, Bell DS, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol. 2012;110:826–33.Google Scholar
  3. 3.
    Hendarto H, Inoguchi T, Maeda Y, Ikeda N, Zheng J, Takei R, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism. 2012;61:1422–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J ClinEndocrinol Metab. 2004;89:3055–61.CrossRefGoogle Scholar
  5. 5.
    Kwiterovich PO Jr. Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. Am J Cardiol. 2002;90:30i–47i.PubMedCrossRefGoogle Scholar
  6. 6.
    St-Pierre AC, Cantin B, Dagenais GR, Mauriège P, Bernard PM, Després JP, et al. Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Québec Cardiovascular Study. Arterioscler Thromb Vasc Biol. 2005;25:553–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154–69.PubMedCrossRefGoogle Scholar
  8. 8.
    Sciffrin EL, Lipman ML, Mann JFE. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116:85–97.CrossRefGoogle Scholar
  9. 9.
    Mattock MB, Barnes DJ, Viberti G, Keen H, Burt D, Hughes JM, et al. Microalbuminuria and coronary heart disease in NIDDM: an incidence study. Diabetes. 1998;47:1786–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage: the steno hypothesis. Diabetologia. 1989;32:219–26.PubMedCrossRefGoogle Scholar
  11. 11.
    Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation. 2010;121:2592–600.PubMedCrossRefGoogle Scholar
  12. 12.
    Imai E, Horio M, Nitta K, Yamagata K, Iseki K, Hara S, et al. Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease. Clin Exp Nephrol. 2007;11:41–50.PubMedCrossRefGoogle Scholar
  13. 13.
    Sniderman AD, Blank D, Zakarian R, Bergeron J, Frohlich J. Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula. Clin Biochem. 2003;36:499–504.PubMedCrossRefGoogle Scholar
  14. 14.
    Hoefner DM, Hodel SD, O’Brien JF, Branum EL, Sun D, Meissner I, et al. Development of a rapid, quantitative method for LDL subfractionation with use of the Quantimetrix Lipoprint LDL System. Clin Chem. 2001;47:266–74.PubMedGoogle Scholar
  15. 15.
    Hirano T, Ito Y, Yoshino G. Measurement of small dense low-density lipoprotein particles. J Atheroscler Thromb. 2005;12:67–72.PubMedCrossRefGoogle Scholar
  16. 16.
    Tani S, Saito Y, Anazawa T, Kawamata H, Furuya S, Takahashi H, et al. Low-density lipoprotein cholesterol/apolipoprotein B ratio may be a useful index differing in statin-treated patients with and without coronary artery disease: a case control study. Int Heart J. 2011;52:343–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Hayashi T, Hirano T, Yamamoto T, Ito Y, Adachi M. Intensive insulin therapy reduces small dense low-density lipoprotein particles in patients with type 2 diabetes mellitus: relationship to triglyceride-rich lipoprotein subspecies. Metabolism. 2006;55:879–84.PubMedCrossRefGoogle Scholar
  18. 18.
    Inoue I, Shinoda Y, Nakano T, Sassa M, Goto S, Awata T, et al. Acarbose ameliorates atherogenecity of low-density lipoprotein in patients with impaired glucose tolerance. Metabolism. 2006;55:946–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, et al. American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292–333.PubMedCrossRefGoogle Scholar
  20. 20.
    Qin X, Shen H, Liu M, Yang Q, Zheng S, Sabo M, et al. GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats. Am J Physiol Gastrointest Liver Physiol. 2005;288:G943–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Ansar S, Koska J, Reaven PD. Postprandial hyperlipidemia, endothelial dysfunction and cardiovascular risk: focus on incretins. Cardiovasc Diabetol. 2011;10:61. doi: 10.1186/1475-2840-10-61.PubMedCrossRefGoogle Scholar
  22. 22.
    Matikainen N, Mänttäri S, Schweizer A, Ulvestad A, Mills D, Dunning BE, et al. Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes. Diabetologia. 2006;49:2049–57.PubMedCrossRefGoogle Scholar
  23. 23.
    Matikainen N, Taskinen MR. The effect of vildagliptin therapy on atherogenic postprandial remnant particles and LDL particle size in subjects with type 2 diabetes. Diabet Med. 2013;30:756–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Stehouwer CDA, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106–11.PubMedCrossRefGoogle Scholar
  25. 25.
    Tojo A, Kinugasa S. Mechanisms of glomerular albumin filtration and tubular reabsorption. Int J Nephrol. 2012;2012:481520. doi: 10.1155/2012/481520.Epub2012May20.PubMedGoogle Scholar
  26. 26.
    Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P, Scharling H, 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;110:32–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation endproduct (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression. Biochem Biophys Res Commun. 2010;391:1405–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Dozier KC, Cureton EL, Kwan RO, Curran B, Sadjadi J, Victorino GP. Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation. Peptides. 2009;30:1735–41.PubMedCrossRefGoogle Scholar
  29. 29.
    Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J. 2011;58:69–73.PubMedCrossRefGoogle Scholar
  30. 30.
    Sarafidis PA, Stafylas PC, Georgianos PI, Saratzis AN, Lasaridis AN. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis. Am J Kidney Dis. 2010;55:835–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Mattock MB, Cronin N, Cavallo-Perin P, Idzior-Walus B, Penno G, Bandinelli S, et al. EURODIAB IDDM Complications Study. Plasma lipids and urinary albumin excretion rate in type 1 diabetes mellitus: the EURODIAB IDDM Complications Study. Diabet Med. 2001;18:59–67.PubMedCrossRefGoogle Scholar
  32. 32.
    Hirano T, Naito H, Kurokawa M, Ebara T, Nagano S, Adachi M, et al. High prevalence of small LDL particles in non-insulin-dependent diabetic patients with nephropathy. Atherosclerosis. 1996;123:57–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N. Fluvastatin improves endothelial dysfunction in overweight postmenopausal women through small dense low-density lipoprotein reduction. Metabolism. 2004;53:733–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Department of CardiologySurugadai Nihon University HospitalTokyoJapan
  2. 2.Division of Cardiology, Department of MedicineNihon University School of MedicineTokyoJapan

Personalised recommendations