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Current Diabetes Reviews

Author(s): Elena Vakali, Dimitrios Rigopoulos, Andres E. Carrillo, Andreas D. Flouris and Petros C. Dinas*

DOI: 10.2174/1573399817666210914103329

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Effects of Alpha-lipoic Acid Supplementation on Human Diabetic Nephropathy: A Systematic Review and Meta-analysis

Article ID: e140921196457 Pages: 8

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Abstract

Background: Diabetic nephropathy (DN) is kidney dysfunction, which occurs due to elevated urine albumin excretion rate and reduced glomerular filtration rate. Studies on animals have shown that alpha-lipoic acid (ALA) supplementation can reduce the development of DN.

Objectives: We performed a systematic review and meta-analysis to examine the effects of ALA supplementation on biological indices (albumin, creatinine, etc.) indicative of human DN.

Methods: The search procedure included PubMed Central, Embase, Cochrane Library (trials), and Web of Science (protocol registration: INPLASY202060095).

Results: We found that ALA supplementation decreased 24h urine albumin excretion rate in patients with diabetes (standardized mean difference=-2.27; confidence interval (CI)=(-4.09)-(-0.45); I2=98%; Z=2.44; p=0.01). A subgroup analysis revealed that the results of studies examining only ALA did not differ from those examined ALA in combination with additional medicines (Chisquared= 0.19; p=0.66; I2=0%), while neither ALA nor ALA plus medication had an effect on 24h urine albumin excretion rate (p>0.05). Also, ALA supplementation decreased urine albumin mg/l (mean difference (MD)=-12.95; CI=(-23.88)-(-2.02); I2=44%; Z=2.32; p=0.02) and urine albumin to creatinine ratio (MD=-26.96; CI=(-35.25)-(-18.67); I2=0%; Z=6.37; p<0.01) in patients with diabetes. When the studies examining ALA plus medication were excluded, it was found that ALA supplementation had no effect on urine albumin mg/l (p>0.05) but did significantly decrease urine albumin to creatinine ratio (MD=-25.88, CI=(34.40-(-17.36), I2=0%, Z=5.95, p<0.00001).

Conclusion: The available evidence suggests that ALA supplementation does not improve biological indices that reflect DN in humans. Overall, we identified limited evidence, and therefore, the outcomes should be considered with caution.

Keywords: Albumin, α-lipoic acid, supplement, diabetes, nephropathy, creatinine.

[1]
WHO.Diabetes. Geneva: World health organization (fact sheets) 2020.
[2]
Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract 2019; 157: 107843.
[http://dx.doi.org/10.1016/j.diabres.2019.107843] [PMID: 31518657]
[3]
Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metabo Syndrome 2014; 6(1): 80.
[http://dx.doi.org/10.1186/1758-5996-6-80]
[4]
Rabkin R. Diabetic nephropathy. Clin Cornerstone 2003; 5(2): 1-11.
[http://dx.doi.org/10.1016/S1098-3597(03)90014-7] [PMID: 12800476]
[5]
Nazar CM. Diabetic nephropathy; principles of diagnosis and treatment of diabetic kidney disease. J Nephropharmacol 2014; 3(1): 15-20. PMID: 28197454
[6]
Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380(9854): 1662-73.
[http://dx.doi.org/10.1016/S0140-6736(12)61350-6] [PMID: 23013602]
[7]
Kim K, Lee E-Y. Excessively enlarged mitochondria in the kidneys of diabetic nephropathy. Antioxidants 2021; 10(5): 741.
[http://dx.doi.org/10.3390/antiox10050741] [PMID: 34067150]
[8]
Zhang P, Li T, Wu X, Nice EC, Huang C, Zhang Y. Oxidative stress and diabetes: antioxidative strategies. Front Med 2020; 14(5): 583-600.
[http://dx.doi.org/10.1007/s11684-019-0729-1] [PMID: 32248333]
[9]
Gheith O, Farouk N, Nampoory N, Halim MA, Al-Otaibi T. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol 2015; 5(1): 49-56. PMID: 28197499
[10]
Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: a report from an ADA Consensus Conference. Am J Kidney Dis 2014; 64(4): 510-33.
[http://dx.doi.org/10.1053/j.ajkd.2014.08.001] [PMID: 25257325]
[11]
Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among us adults with diabetes, 1988-2014. JAMA 2016; 316(6): 602-10.
[http://dx.doi.org/10.1001/jama.2016.10924] [PMID: 27532915]
[12]
de Boer IH, Group DER. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 2014; 37(1): 24-30.
[http://dx.doi.org/10.2337/dc13-2113] [PMID: 24356594]
[13]
Saran R, Li Y, Robinson B, et al. US renal data system 2015 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis 2016; 67(3 Suppl 1): Svii, S1-305.
[http://dx.doi.org/10.1053/j.ajkd.2015.12.014]
[14]
Bjornstad P, Cherney D, Maahs DM. Early diabetic nephropathy in type 1 diabetes: new insights. Curr Opin Endocrinol Diabetes Obes 2014; 21(4): 279-86.
[http://dx.doi.org/10.1097/MED.0000000000000074] [PMID: 24983394]
[15]
Moini H, Packer L, Saris NE. Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Toxicol Appl Pharmacol 2002; 182(1): 84-90.
[http://dx.doi.org/10.1006/taap.2002.9437] [PMID: 12127266]
[16]
Bast A, Haenen GR. Lipoic acid: a multifunctional antioxidant. Biofactors 2003; 17(1-4): 207-13.
[http://dx.doi.org/10.1002/biof.5520170120] [PMID: 12897442]
[17]
Dinçer Y, Telci A, Kayali R, Yilmaz IA, Cakatay U, Akçay T. Effect of alpha-lipoic acid on lipid peroxidation and anti-oxidant enzyme activities in diabetic rats. Clin Exp Pharmacol Physiol 2002; 29(4): 281-4.
[http://dx.doi.org/10.1046/j.1440-1681.2002.03642.x] [PMID: 11985536]
[18]
Melhem MF, Craven PA, Liachenko J, DeRubertis FR. Alpha-lipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes. J Am Soc Nephrol 2002; 13(1): 108-16.
[http://dx.doi.org/10.1681/ASN.V131108] [PMID: 11752027]
[19]
Nagamatsu M, Nickander KK, Schmelzer JD, et al. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 1995; 18(8): 1160-7.
[http://dx.doi.org/10.2337/diacare.18.8.1160] [PMID: 7587852]
[20]
Obrosova IG, Fathallah L, Greene DA. Early changes in lipid peroxidation and antioxidative defense in diabetic rat retina: effect of DL-alpha-lipoic acid. Eur J Pharmacol 2000; 398(1): 139-46.
[http://dx.doi.org/10.1016/S0014-2999(00)00286-7] [PMID: 10856458]
[21]
Bhatti F, Mankhey RW, Asico L, Quinn MT, Welch WJ, Maric C. Mechanisms of antioxidant and pro-oxidant effects of alpha-lipoic acid in the diabetic and nondiabetic kidney. Kidney Int 2005; 67(4): 1371-80.
[http://dx.doi.org/10.1111/j.1523-1755.2005.00214.x] [PMID: 15780089]
[22]
Yi X, Xu L, Hiller S, et al. Reduced expression of lipoic acid synthase accelerates diabetic nephropathy. J Am Soc Nephrol 2012; 23(1): 103-11.
[http://dx.doi.org/10.1681/ASN.2011010003] [PMID: 22021711]
[23]
Cicek M, Yıldırır A, Okyay K, et al. Use of alpha-lipoic acid in prevention of contrast-induced nephropathy in diabetic patients. Ren Fail 2013; 35(5): 748-53.
[http://dx.doi.org/10.3109/0886022X.2013.790298] [PMID: 23650950]
[24]
Borcea V, Nourooz-Zadeh J, Wolff SP, et al. alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Free Radic Biol Med 1999; 26(11-12): 1495-500.
[http://dx.doi.org/10.1016/S0891-5849(99)00011-8] [PMID: 10401614]
[25]
Morcos M, Borcea V, Isermann B, et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res Clin Pract 2001; 52(3): 175-83.
[http://dx.doi.org/10.1016/S0168-8227(01)00223-6] [PMID: 11323087]
[26]
Hong S, Uhm W, Joo W, Nam M, Lee S, Song J. Plasma markers of oxidative stress, inflammation and endothelial cell injury in diabetic patients with overt nephropathy administered alpha-lipoic acid and angiotensin II receptor blocker. Mol Cell Toxicol 2010; 6: 179-85.
[http://dx.doi.org/10.1007/s13273-010-0025-2]
[27]
Jiang Z, Tan Z, Meng F, Li X. Curative effects of valsartan alone or combined with alpha-lipoic acid on inflammatory cytokines and renal function in early-stage diabetic kidney disease. J Coll Physicians Surg Pak 2019; 29(10): 1009-11.
[http://dx.doi.org/10.29271/jcpsp.2019.10.1009] [PMID: 31564281]
[28]
Rahman ST, Merchant N, Haque T, et al. The impact of lipoic acid on endothelial function and proteinuria in quinapril-treated diabetic patients with stage I hypertension: results from the QUALITY study. J Cardiovasc Pharmacol Ther 2012; 17(2): 139-45.
[http://dx.doi.org/10.1177/1074248411413282] [PMID: 21750253]
[29]
Sun H, Yao W, Tang Y, et al. Urinary exosomes as a novel biomarker for evaluation of α-lipoic acid’s protective effect in early diabetic nephropathy. J Clin Lab Anal 2017; 31(6)
[http://dx.doi.org/10.1002/jcla.22129] [PMID: 28116765]
[30]
Bao XH, Xu J, Chen Y, Yang CL, Ye SD. Alleviation of podocyte injury: the possible pathway implicated in anti-inflammation of alpha-lipoic acid in type 2 diabetics. Aging Clin Exp Res 2014; 26(5): 483-9.
[http://dx.doi.org/10.1007/s40520-014-0207-1] [PMID: 24659493]
[31]
Lin H, Ye S, Xu J, Wang W. The alpha-lipoic acid decreases urinary podocalyxin excretion in type 2 diabetics by inhibiting oxidative stress in vivo. J Diabetes Complications 2015; 29(1): 64-7.
[http://dx.doi.org/10.1016/j.jdiacomp.2014.09.011] [PMID: 25312599]
[32]
Moher D, Liberati A, Tetzlaff J, Altman DG. Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535.
[http://dx.doi.org/10.1136/bmj.b2535] [PMID: 19622551]
[33]
Higgins J, James Thomas J. Cochrane handbook for systematic reviews of interventions version 61, 2020. The Cochrane Collaboration 2020.
[34]
Viswanathan M, Berkman ND, Dryden DM, Hartling L. Assessing risk of bias and confounding in observational studies of interventions or exposures: further development of the RTI item bank.AHRQ Methods for Effective Health Care. Rockville (MD) 2013.
[35]
Margulis AV, Pladevall M, Riera-Guardia N, et al. Quality assessment of observational studies in a drug-safety systematic review, comparison of two tools: the Newcastle-Ottawa Scale and the RTI item bank. Clin Epidemiol 2014; 6: 359-68.
[http://dx.doi.org/10.2147/CLEP.S66677] [PMID: 25336990]
[36]
Al-Saleh MA, Armijo-Olivo S, Thie N, et al. Morphologic and functional changes in the temporomandibular joint and stomatognathic system after transmandibular surgery in oral and oropharyngeal cancers: systematic review. J Otolaryngol Head Neck Surg 2012; 41(5): 345-60. PMID: 23092837
[37]
Centre TNC. Review Manager (RevMan) (Computer program). Version 53 Copenhagen The Cochrane Collaboration 2014.
[38]
Schünemann H, Brożek J, Guyatt G, Oxman A. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. 2013.
[39]
Noori N, Tabibi H, Hosseinpanah F, Hedayati M, Nafar M. Effects of combined lipoic acid and pyridoxine on albuminuria, advanced glycation end-products, and blood pressure in diabetic nephropathy. Int J Vitam Nutr Res 2013; 83(2): 77-85.
[http://dx.doi.org/10.1024/0300-9831/a000147] [PMID: 24491880]
[40]
Porasuphatana S, Suddee S, Nartnampong A, Konsil J, Harnwong B, Santaweesuk A. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study. Asia Pac J Clin Nutr 2012; 21(1): 12-21. PMID: 22374556
[41]
Stalin D, Benny M, Nandhini S, Dominic N. M. N. A Clinical Study on the Effect of Telmisartan with Alpha Lipoic Acid on Microalbuminuria in Type 2 Diabetes and Hypertensive Patients. Int J Pharm Sci Rev Res 2019; 57(1): 139-42.
[42]
Hofmann MA, Schiekofer S, Isermann B, et al. Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kappaB. Diabetologia 1999; 42(2): 222-32.
[http://dx.doi.org/10.1007/s001250051142] [PMID: 10064103]
[43]
Ioannidis J. Next-generation systematic reviews: prospective meta-analysis, individual-level data, networks and umbrella reviews. Br J Sports Med 2017; 51(20): 1456-8.
[http://dx.doi.org/10.1136/bjsports-2017-097621] [PMID: 28223307]
[44]
Kanter M, Sen S, Donmez S, Aktas C, Ustundag S, Erboga M. Protective effects of irbesartan and alpha lipoic acid in STZ-induced diabetic nephropathy in rats. Ren Fail 2010; 32(4): 498-505.
[http://dx.doi.org/10.3109/08860221003646360] [PMID: 20446791]
[45]
Ayhan M, Guney E, Atile NS, Serter M, Meteoglu I. Preventive effects of alpha-lipoic acid on diabetic nephropathy in a rat model. Acta Med Mediter 2014; 30(6): 1221-5.
[46]
Thirunavukkarasu V, Anitha Nandhini AT, Anuradha CV. Lipoic acid attenuates hypertension and improves insulin sensitivity, kallikrein activity and nitrite levels in high fructose-fed rats. J Comp Physiol B 2004; 174(8): 587-92.
[http://dx.doi.org/10.1007/s00360-004-0447-z] [PMID: 15565449]
[47]
Prabhakar S, Starnes J, Shi S, Lonis B, Tran R. Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. J Am Soc Nephrol 2007; 18(11): 2945-52.
[http://dx.doi.org/10.1681/ASN.2006080895] [PMID: 17928507]
[48]
Winiarska K, Malinska D, Szymanski K, Dudziak M, Bryla J. Lipoic acid ameliorates oxidative stress and renal injury in alloxan diabetic rabbits. Biochimie 2008; 90(3): 450-9.
[http://dx.doi.org/10.1016/j.biochi.2007.11.010] [PMID: 18157951]
[49]
Yi X, Nickeleit V, James LR, Maeda N. α-Lipoic acid protects diabetic apolipoprotein E-deficient mice from nephropathy. J Diabetes Complications 2011; 25(3): 193-201.
[http://dx.doi.org/10.1016/j.jdiacomp.2010.07.004] [PMID: 20801062]
[50]
Liberati A, Altman D, Tetzlaff J, Mulrow C, Gøtzsche P, Ioannidis J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ, Research methods & reporting 2009; 339: b2700.
[http://dx.doi.org/10.1136/bmj.b2700]
[51]
Harris JD, Quatman CE, Manring MM, Siston RA, Flanigan DC. How to write a systematic review. Am J Sports Med 2014; 42(11): 2761-8.
[http://dx.doi.org/10.1177/0363546513497567] [PMID: 23925575]