Can Lipoprotein(a) Predict the Risk of Diabetic Nephropathy in Type 2 Diabetes Mellitus?: A Systematic Review and Meta-Analysis

Abstract

We aimed to examine if serum lipoprotein(a) [Lp(a)] values could be used to predict the risk of diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM). English-language observational studies available as full-texts on PubMed, Embase, Scopus, and Web of Science databases up to 28th November 2024 were included in the review. Studies were to assess the association between Lp(a) and DN and report adjusted effect size. Random-effects meta-analysis was conducted. Five cross-sectional, two case-control, and eight studies prospective cohort were included. Six studies used Lp(a) as a continuous variable while eight used it as a categorical variable. Two studies used Lp(a) as both. Meta-analysis showed that an incremental increase in Lp(a) was associated with a small increase in the risk of DN (OR: 1.03 95% CI: 1.01, 1.04 I²=86%). Meta-analysis also showed that high levels of Lp(a) were associated with a significant increase in the risk of DN (OR: 1.64 95% CI: 1.24, 2.17 I²=67%). Subgroup analysis based on study design, location, sample size, T2DM duration, baseline HbA1c, and definition of DN yielded mixed results. Lp(a) could be a potential marker for DN in T2DM. Further investigations may provide better evidence.

Keywords

lipids - diabetic kidney disease - renal dysfunction - microvascular complications

Publication History

Received: 08 December 2024

Accepted after revision: 05 March 2025

Article published online:
10 April 2025

• References

• 1 Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol 2018; 14: 88-98
• 2 Sun H, Saeedi P, Karuranga S. et al. IDF diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract 2022; 183: 109119
• 3 Dal Canto E, Ceriello A, Rydén L. et al. Diabetes as a cardiovascular risk factor: an overview of global trends of macro and micro vascular complications. Eur J Prev Cardiol 2019; 26: 25-32
• 4 Zhang X-X, Kong J, Yun K. Prevalence of diabetic nephropathy among patients with type 2 diabetes mellitus in China: a meta-analysis of observational studies. J Diabetes Res. 2020 2315607.
• 5 Pálsson R, Patel UD. Cardiovascular complications of diabetic kidney disease. Adv Chronic Kidney Dis 2014; 21: 273-280
• 6 Eid S, Sas KM, Abcouwer SF. et al. New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia 2019; 62: 1539-1549
• 7 Wu L, Parhofer KG. Diabetic dyslipidemia. Metabolism 2014; 63: 1469-1479
• 8 Chang H-J, Lin K-R, Chang J-L. et al. Risk factors for chronic kidney disease in older adults with hyperlipidemia and/or cardiovascular diseases in Taipei city, Taiwan: a community-based cross-sectional analysis. Int J Environ Res Public Health 2020; 17: 8763
• 9 Duarte Lau F, Giugliano RP. Lipoprotein(a) and its significance in cardiovascular disease: a review. JAMA Cardiol 2022; 7: 760-769
• 10 Alhomoud IS, Talasaz A, Mehta A. et al. Role of lipoprotein(a) in atherosclerotic cardiovascular disease: a review of current and emerging therapies. Pharmacotherapy 2023; 43: 1051-1063
• 11 Ren X, Zhang Z, Yan Z. Association between lipoprotein (A) and diabetic nephropathy in patients with Type 2 diabetes mellitus: a meta-analysis. Front Endocrinol (Lausanne) 2021; 12: 633529
• 12 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg 2021; 88: 105906
• 13 Song KH, Ko SH, Kim HW. et al. Prospective study of lipoprotein(a) as a risk factor for deteriorating renal function in type 2 diabetic patients with overt proteinuria. Diabetes Care 2005; 28: 1718-1723
• 14 Tseng CH. Differential dyslipidemia associated with albuminuria in type 2 diabetic patients in Taiwan. Clin Biochem 2009; 42: 1019-1024
• 15 Lin J, Hu FB, Mantzoros C. et al. Lipid and inflammatory biomarkers and kidney function decline in type 2 diabetes. Diabetologia 2010; 53: 263-267
• 16 Xuan L, Wang T, Dai H. et al. Serum lipoprotein (a) associates with a higher risk of reduced renal function: prospective investigation. J Lipid Res 2020; 61: 1320-1327
• 17 Senba H, Furukawa S, Sakai T. et al. Serum lipoprotein(a) levels and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. J Diabetes Complications 2016; 30: 923-927
• 18 Yun JS, Ahn YB, Song KH. et al. Lipoprotein(a) predicts a new onset of chronic kidney disease in people with Type 2 diabetes mellitus. Diabet Med 2016; 33: 639-643
• 19 Aryan Z, Afarideh M, Ghajar A. et al. Conflicting interactions of apolipoprotein A and high density lipoprotein cholesterol with microvascular complications of type 2 diabetes. Diabetes Res Clin Pract 2017; 133: 131-141
• 20 Heinrich NS, von Scholten BJ, Reinhard H. et al. Lipoprotein(a)and renal function decline, cardiovascular disease and mortality in type 2 diabetes and microalbuminuria. J Diabetes Complications 2020; 34: 107593
• 21 Moosaie F, Firouzabadi FD, Abouhamzeh K. et al. Lp(a) and apo-lipoproteins as predictors for micro- and macrovascular complications of diabetes: a case-cohort study. Nutr Metab Cardiovasc Dis 2020; 30: 1723-1731
• 22 Singh SS, Rashid M, Lieverse AG. et al. Lipoprotein(a) plasma levels are not associated with incident microvascular complications in type 2 diabetes mellitus. Diabetologia 2020; 63: 1248-1257
• 23 Xie Y, Qi H, Li B. et al. Serum lipoprotein (a) associates with the risk of renal function damage in the CHCN-BTH study: cross-sectional and mendelian randomization analyses. Front Endocrinol (Lausanne) 2022; 13: 1-15
• 24 Gao RH, Liu B, Yang Y. et al. Serum lipoprotein(a) and high-density lipoprotein cholesterol associate with diabetic nephropathy: evidence from machine learning perspectives. Diabetes Metab Syndr Obes 2023; 16: 1847-1858
• 25 Li M, Wang Y, Yao Q. et al. Association between lipoprotein(a) and diabetic nephropathy in patients with type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14: 1-7
• 26 Liu Y, Wang R, Li S. et al. Relationship between lipoprotein(a), renal function indicators, and chronic kidney disease: evidence from a large prospective cohort study. JMIR Public Heal Surveill 2024; 10: 1-25
• 27 Wang T. Association between lipoprotein(a) plasma levels and diabetic nephropathy in Han Chinese patients with type 2 diabetes mellitus. PLoS One 2024; 19: 1-14
• 28 Lin J, Reilly MP, Terembula K. et al. Plasma lipoprotein(a) levels are associated with mild renal impairment in type 2 diabetics independent of albuminuria. PLoS One 2014; 9: e114397
• 29 Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg 2011; 128: 305-310
• 30 Guan W, Cao J, Steffen BT. et al. Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 2015; 35: 996-1001
• 31 Forbang NI, Criqui MH, Allison MA. et al. Sex and ethnic differences in the associations between lipoprotein(a) and peripheral arterial disease in the multi-ethnic study of atherosclerosis. J Vasc Surg 2016; 63: 453-458
• 32 Kovesdy CP, Astor BC, Longenecker JC. et al. Association of kidney function with serum lipoprotein(a) level: the third national health and nutrition examination survey (1991-1994). Am J Kidney Dis 2002; 40: 899-908
• 33 Gross JL, de Azevedo MJ, Silveiro SP. et al. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 2005; 28: 164-176
• 34 Tada H, Yamagami K, Nishikawa T. et al. Lipoprotein (a) and the risk of chronic kidney disease in hospitalized Japanese patients. Intern Med 2020; 59: 1705-1710
• 35 Bay Simony S, Rørbæk Kamstrup P, Bødtker Mortensen M. et al. High lipoprotein(a) as a cause of kidney disease: a population-based Mendelian randomization study. J Am Coll Cardiol 2024; 84: 2407-2410
• 36 Xie Y, Qi H, Li B. et al. Serum lipoprotein (a) associates with the risk of renal function damage in the CHCN-BTH study: cross-sectional and Mendelian randomization analyses. Front Endocrinol (Lausanne) 2022; 13: 1023919
• 37 Rosas S, Joffe M, Wolfe M. et al. Effects of renal replacement therapy on plasma lipoprotein(a) levels. Am J Nephrol 2008; 28: 361-365
• 38 Hopewell JC, Haynes R, Baigent C. The role of lipoprotein (a) in chronic kidney disease. J Lipid Res 2018; 59: 577-585
• 39 Greiber S, Krämer-Guth A, Pavenstädt H. et al. Effects of lipoprotein(a) on mesangial cell proliferation and viability. Nephrol Dial Transplant 1996; 11: 778-785
• 40 Takahashi A, Taniguchi T, Fujioka Y. et al. Effects of lipoprotein(a) and low density lipoprotein on growth of mitogen-stimulated human umbilical vein endothelial cells. Atherosclerosis 1996; 120: 93-99
• 41 Riis Hansen P, Kharazmi A, Jauhiainen M. et al. Induction of oxygen free radical generation in human monocytes by lipoprotein(a). Eur J Clin Invest 1994; 24: 497-499
• 42 Jha JC, Ho F, Dan C. et al. A causal link between oxidative stress and inflammation in cardiovascular and renal complications of diabetes. Clin Sci (Lond) 2018; 132: 1811-1836