Abstract
Background
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.
Methods
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).
Results
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).
Conclusions
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.
References
Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187–215.
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.
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.
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.
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.
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.
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.
Sciffrin EL, Lipman ML, Mann JFE. Chronic kidney disease: effects on the cardiovascular system. Circulation. 2007;116:85–97.
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.
Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage: the steno hypothesis. Diabetologia. 1989;32:219–26.
Bock JS, Gottlieb SS. Cardiorenal syndrome: new perspectives. Circulation. 2010;121:2592–600.
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.
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.
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.
Hirano T, Ito Y, Yoshino G. Measurement of small dense low-density lipoprotein particles. J Atheroscler Thromb. 2005;12:67–72.
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.
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.
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.
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.
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.
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.
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.
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.
Stehouwer CDA, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106–11.
Tojo A, Kinugasa S. Mechanisms of glomerular albumin filtration and tubular reabsorption. Int J Nephrol. 2012;2012:481520. doi:10.1155/2012/481520.Epub2012May20.
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.
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.
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.
Hattori S. Sitagliptin reduces albuminuria in patients with type 2 diabetes. Endocr J. 2011;58:69–73.
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.
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.
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.
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.
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All the authors declare that they have no competing interests.
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Clinical Trial Registration Information: UMIN (http://www.umin.ac.jp/), Study ID: UMIN000010451.
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Tani, S., Nagao, K. & Hirayama, A. 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. Am J Cardiovasc Drugs 13, 443–450 (2013). https://doi.org/10.1007/s40256-013-0043-2
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DOI: https://doi.org/10.1007/s40256-013-0043-2