Current Diabetes Reports

, 19:6 | Cite as

New Areas of Interest: Is There a Role for Omega-3 Fatty Acid Supplementation in Patients With Diabetes and Cardiovascular Disease?

  • Francine K. WeltyEmail author
Macrovascular Complications in Diabetes (VR Aroda and A Getaneh, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Macrovascular Complications in Diabetes


Purpose of Review

Summarize studies on omega-3 fatty acids in prevention of albuminuria in subjects with diabetes.

Recent Findings

Several small, short-term trials suggested benefit on albuminuria in subjects with diabetes; however, results were not definitive. Welty et al. showed that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for 1 year slowed progression of early-stage albuminuria in subjects with diabetes with clinical coronary artery disease on an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, the majority of whom had an albumin/creatinine ratio (ACR) < 30 μg/mg. Moreover, significantly more (3-fold) subjects on EPA and DHA had a decrease in ACR compared to control, and three on EPA and DHA had a change in category from > 30 μg/mg to < 30 μg/mg, whereas no controls did. Potential mechanisms for benefit are discussed.


These results suggest that there is benefit and perhaps even reversal of albuminuria with EPA and DHA at an early stage of disease in those with ACR < 30 μg/mg and those with microalbuminuria (ACR > 30).


Omega-3 fatty acids Diabetes Albuminuria Coronary artery disease Eicosapentaenoic acid Docosahexaenoic acid 


Compliance with Ethical Standards

Conflict of Interest

The author declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Montero RM, Covic A, Gnudi L, Goldsmith D. Diabetic nephropathy: what does the future hold? Int Urol Nephrol. 2016;48:99–113.CrossRefGoogle Scholar
  2. 2.
    National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60:850–86.CrossRefGoogle Scholar
  3. 3.
    Keen H, Chlouverakis C, Fuller J, Jarrett RJ. The concomitants of raised blood sugar: studies in newly-detected hyperglycemics II. Urinary albumin excretion, blood pressure and their relation to blood sugar levels. Guys Hospital Reports. 1969;118:247–54.Google Scholar
  4. 4.
    Parving HH, Mogensen CE, Jensen HA, Evrin PE. Increase urinary albumin-excretion rate in benign essential hypertension. Lancet. 1974;1:1190–2.CrossRefGoogle Scholar
  5. 5.
    Hillege HL, Janssen WM, Bak AA, Diercks GF, Grobbee DE, Crijns HJ, et al. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249:519–26.CrossRefGoogle Scholar
  6. 6.
    Jones CA, Francis ME, Eberbardt MS, Chavers B, Coresh J, Engelgau M, et al. Microalbuminuria in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2002;39:445–59.CrossRefGoogle Scholar
  7. 7.
    Jager A, Kostense PJ, Ruhé HG, Heine RJ, Nijpels G, Dekker JM, et al. Microalbuminuria and peripheral arterial disease are independent predictors of cardiovascular and all-cause mortality, especially among hypertensive subjects: five-year follow-up of the Hoorn Study. Arterioscler Thromb Vasc Biol. 1999;19:617–24.CrossRefGoogle Scholar
  8. 8.
    Bigazzi R, Bianchi S, Baldari D, Campese VM. Microalbuminuria predicts cardiovascular events and renal insufficiency in patients with essential hypertension. J Hypertens. 1998;16:1325–33.CrossRefGoogle Scholar
  9. 9.
    Messent JW, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty three year follow-up study. Kidney Int. 1992;41:836–9.CrossRefGoogle Scholar
  10. 10.
    Rossing P, Hougaard P, Borch-Johnsen K, Parving HH. Predictors of mortality in insulin dependent diabetes: 10-year observational follow-up study. BMJ. 1996;313:779–84.CrossRefGoogle Scholar
  11. 11.
    Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and non-diabetic individuals. JAMA. 2001;286:421–6.CrossRefGoogle Scholar
  12. 12.
    Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med. 1997;157:1413–8.CrossRefGoogle Scholar
  13. 13.
    Yudkin JS, Forrest RD, Jackson CA. Microalbuminuria as predictor of vascular disease in non-diabetic subjects. Islington Diabetes Survey Lancet. 1998;2:530–3.Google Scholar
  14. 14.
    Borch-Johnsen K, Feldt-Rasmussen B, Strandgaard S, Schroll M, Jensen JS. Urinary albumin excretion: an independent predictor of ischemic heart disease. Arterioscler Thromb Vasc Biol. 1999;19:1992–7.CrossRefGoogle Scholar
  15. 15.
    Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002;106:1777–82.CrossRefGoogle Scholar
  16. 16.
    Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, Day NE, et al. Microalbuminuria independently predicts all-cause and cardiovascular mortality in a British population: the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study. Int J Epidemiol. 2004;33:189–98.CrossRefGoogle Scholar
  17. 17.
    Arnlov J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, et al. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham heart Study. Circulation. 2005;112:969–75.CrossRefGoogle Scholar
  18. 18.
    Wang Y, Yuan A, Yu C. Correlation between microalbuminuria and cardiovascular events. Int J Clin Exp Med. 2013;6:973–8.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Romundstad S, Holmen J, Kvenild K, Hallan H, Ellekjaer H. Microalbuminuria and all-cause mortality in 2,089 apparently healthy individuals: a 4.4-year follow-up study. The Nord-Trondelag health Study (HUNT), Norway. Am J Kidney Dis. 2003;42:466–73.CrossRefGoogle Scholar
  20. 20.
    •• Sung KC, Ryu S, Lee JY, Lee SH, Cheong E, Hyun YY, et al. Urine albumin/creatinine ratio below 30 mg/g is a predictor of incident hypertension and cardiovascular mortality. J Am Heart Assoc. 2016;5(9):e003245. Urine albumin to creatinine ratio (ACR) < 30 μg/mg, which has generally been considered in the normal range, predicted incident hypertension and cardiovascular disease mortality at 11-year follow-up in subjects who were healthy and nondiabetic at baseline. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Berton G, Cordiano R, Palmieri R, Cavuto F, Buttazzi P, Palatini P. Comparison of C-reactive protein and albumin excretion as prognostic markers for 10-year mortality after myocardial infarction. Clin Cardiol. 2010;33:508–15.CrossRefGoogle Scholar
  22. 22.
    Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106–11.CrossRefGoogle Scholar
  23. 23.
    Kshirsagar AV, Bomback AS, Bang H, Gerber LM, Vupputuri S, Shoham DA, et al. Association of C-reactive protein and microalbuminuria (from the National Health and Nutrition Examination Surveys, 1999 to 2004). Am J Cardiol. 2008;101:401–6.CrossRefGoogle Scholar
  24. 24.
    Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–9.CrossRefGoogle Scholar
  25. 25.
    Choi BJ, Prasad A, Gulati R, Best PJ, Lennon RJ, Barsness GW, et al. Coronary endothelial dysfunction in patients with early coronary artery disease is associated with the increase in intravascular lipid core plaque. Eur Heart J. 2013;34:2047–54.CrossRefGoogle Scholar
  26. 26.
    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The seno hypothesis. Diabetologia. 1989;32:219–26.CrossRefGoogle Scholar
  27. 27.
    Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al. Association of estimated glomerular filtration rate and albuminuria with all cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073–81.CrossRefGoogle Scholar
  28. 28.
    •• Matsushita K, Coresh J, Sang Y, Chalmers J, Fox C, Guallar E, et al. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diab Endocrinol. 2015;3:514–25. The Chronic Kidney Disease Prognosis Consortium reported that an increase in urine albumin excretion as low as 10 μg/ml is associated with an increased risk of cardiovascular disease, end-stage renal disease and mortality in the general population and among those with kidney disease, a finding highlighting the need for studies targeting albuminuria as a risk factor. CrossRefGoogle Scholar
  29. 29.
    Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspsectives. Lancet. 2013;382(9888):260–72.CrossRefGoogle Scholar
  30. 30.
    de Zeeuw D, Hillege HL, de Jong PE. The kidney, a cardiovascular risk marker and a new target for therapy. Kidney Int. 2005;68:S25–9.CrossRefGoogle Scholar
  31. 31.
    Ferenbach D, Kluth DC, Hughes J. Inflammatory cells in renal injury and repair. Semin Nephrol. 2007;27(3):250.e259.CrossRefGoogle Scholar
  32. 32.
    Duffield JS. Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest. 2014;124(6):2299.e2306.CrossRefGoogle Scholar
  33. 33.
    Checheriţă IA, Manda G, Hinescu ME, Peride I, Niculae A, Bîlha Ş, et al. New molecular insights in diabetic nephropathy. Int Urol Nephrol. 2016;48(3):373–87.CrossRefGoogle Scholar
  34. 34.
    Ricardo SD, van Goor H, Eddy AA. Macrophage diversity in renal injury and repair. J Clin Invest. 2008;118:3522–30.CrossRefGoogle Scholar
  35. 35.
    HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355:253–9.CrossRefGoogle Scholar
  36. 36.
    Ibsen H, Olsen MH, Wachtell K, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study. Hypertension. 2005;45(2):198–202.CrossRefGoogle Scholar
  37. 37.
    Ibsen H, Wachtell K, Olsen MH, Borch-Johnsen K, Lindholm LH, Mogensen CE, et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy. J Hypertens. 2004;22(9):1805–11.CrossRefGoogle Scholar
  38. 38.
    American Diabetes Association. Microvascular complications and foot care. Diabetes Care. 2016;39(Supplement 1):S72–80.CrossRefGoogle Scholar
  39. 39.
    Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol. 2010;6(6):319e330.CrossRefGoogle Scholar
  40. 40.
    Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93(1):137e188.CrossRefGoogle Scholar
  41. 41.
    Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370(16):1514–23.CrossRefGoogle Scholar
  42. 42.
    •• Fukami A, Adachi H, Hirai Y, Enomoto M, Otsuka M, Kumagai E, et al. Association of serum eicosapentaenoic acid to arachidonic acid ratio with microalbuminuria in a population of community-dwelling Japanese. Atherosclerosis. 2015;239(2):577–82. In a prospective study of 444 Japanese subjects, those with a low EPA/arachidonic acid (AA) ratio had a 3.45-fold higher odds ratio of microalbuminuria (ACR ≥ 30 mg/g Cr) after adjustment for confounding factors. This finding suggests that the ratio of pro-resolving to pro-inflammatory fatty acids is important in determining progression of albuminuria. CrossRefPubMedGoogle Scholar
  43. 43.
    • Han E, Yun Y, Kim G, Lee YH, Wang HJ, Lee BW, et al. Effects of omega-3 fatty acid supplementation on diabetic nephropathy progression in patients with diabetes and hypertriglyceridemia. PLoS One. 2016;11(5):e0154683. eCollection 2016. In this retrospective study of subjects with type 2 DM who received omega-3 FAs to manage hypertriglyceridemia, those receiving 4 g/day of omega-3 FAs had a reduction in albuminuria after adjustment for multiple variables ( p< 0.001). CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lee CC, Sharp SJ, Wexler DJ, Adler AI. Dietary intake of eicosapentaenoic and docosahexaenoic acid and diabetic nephropathy: cohort analysis of the Diabetes Control and Complications Trial. Diabetes Care. 2010;33:1454–6.CrossRefGoogle Scholar
  45. 45.
    Hamazaki T, Takazakura E, Osawa K, Urakaze M, Yano S. Reduction in microalbuminuria in diabetics by eicosapentaenoic acid ethyl ester. Lipids. 1990;9:541–5.CrossRefGoogle Scholar
  46. 46.
    Lee CC, Adler AI. Recent findings on the effects of marine-derived n-3 polyunsaturated fatty acids on urinary albumin excretion and renal function. Curr Atheroscler Rep. 2012;14:535–54.CrossRefGoogle Scholar
  47. 47.
    Miller ER III, Juraschek ST, Appel LJ, Mandala M, Anderson CA, Bleys J, et al. The effect of n-3 long chain polyunsaturated fatty acid supplementation on urine protein excretion and kidney function: meta-analysis of clinical trials. Am J Clin Nutr. 2009;89:1937–45.CrossRefGoogle Scholar
  48. 48.
    Okuda Y, Mizutani M, Ogawa M, Sone H, Asano M, Asakura Y, et al. Long-term effects of eicosapentaenoic acid on diabetic peripheral neuropathy and serum lipids in patients with type II diabetes mellitus. J Diabetes Complicat. 1996;10:280–7.CrossRefGoogle Scholar
  49. 49.
    Zeman M, Zak A, Vecka M, Tvrzická E, Písaríková A, Stanková B. N-3 fatty acid supplementation decreases plasma homocysteine in diabetic dyslipidemia treated with statin-fibrate combination. J Nutr Biochem. 2006;17:379–84.CrossRefGoogle Scholar
  50. 50.
    Miller ER III, Juraschek SP, Anderson CA, Guallar E, Henoch-Ryugo K, Charleston J, et al. The effects of n-3 long-chain polyunsaturated fatty acid supplementation on biomarkers of kidney injury in adults with diabetes: results of the GO-FISH trial. Diabetes Care. 2013;36:1462–9.CrossRefGoogle Scholar
  51. 51.
    •• Elajami TK, Alfaddagh A, Lakshminarayan D, Soliman M, Chandnani M, Welty FK. Eicosapentaenoic and docosahexaenoic acids attenuate progression of albuminuria in patients with type 2 diabetes and coronary artery disease. J Am Heart Assoc. 2017;6:e004740. A randomized, parallel, controlled 1-year trial which showed that high-dose EPA and DHA prevented progression of albuminuria in subjects with diabetes and coronary artery disease. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Shimizu H, Ohtani K, Tanaka Y, Sato N, Mori M, Shimomura Y. Long-term effect of eicosapentaenoic acid ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic patients. Diabetes Res Clin Pract. 1995;28:35–40.CrossRefGoogle Scholar
  53. 53.
    • Al Faddagh A, Elajami TK, Ashfaque H, Saleh M, Bistrian B, Welty FK. Effect of eicosapentaenoic and docosahexaenoic acids on coronary artery plaque: a randomized controlled trial. J Am Heart Assoc. 2017;6:e006981. A randomized, parallel, controlled 1-year trial which showed that high-dose EPA and DHA prevented progression of coronary artery plaque in subjects with coronary artery disease. CrossRefGoogle Scholar
  54. 54.
    Garman JH, Mulroney S, Manigrasso M, Flynn E, Maric C. Omega-3 fatty acid rich diet prevents diabetic renal disease. Am J Physiol Ren Physiol. 2009;296:F306–16.CrossRefGoogle Scholar
  55. 55.
    Thomas G, Sehgal AR, Kashyap SR, Srinivas TR, Kirwan JP, Navaneethan SD. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2011;6:2364–73.CrossRefGoogle Scholar
  56. 56.
    Keane WF. The role of lipids in renal disease: future challenges. Kidney Int Suppl. 2000;75:S27–31.CrossRefGoogle Scholar
  57. 57.
    Oda H, Keane WF. Lipids in progression of renal disease. Kidney Int Suppl. 1997;62:S36–8.PubMedGoogle Scholar
  58. 58.
    Mozaffarian D, Wu JHY. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58:2047–67.CrossRefGoogle Scholar
  59. 59.
    An WS, Kim HJ, Cho KH, Vaziri ND. Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation and tubulointerstitial fibrosis in the remnant kidney. Am J Phys. 2009;297(4):F895–eF903.Google Scholar
  60. 60.
    Kumar V, Abbas AK, Aster JC. Inflammation and repair. In: Kumar V, Abbas AK, Aster JC, editors. Robbins and Cotran pathologic basis of disease. 9th ed. Philadelphia: Elsevier/Saunders; 2015. p. 69–111.Google Scholar
  61. 61.
    Samuelsson B. Role of basic science in the development of new medicines: examples from the eicosanoid field. J Biol Chem. 2012;287:10070–80.CrossRefGoogle Scholar
  62. 62.
    Haeggström JZ, Funk CD. Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chem Rev. 2011;111:5866–98.CrossRefGoogle Scholar
  63. 63.
    Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001;2:612–9.CrossRefGoogle Scholar
  64. 64.
    Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92–101.CrossRefGoogle Scholar
  65. 65.
    Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science. 2013;339:166–72.CrossRefGoogle Scholar
  66. 66.
    Duffield JS, Hong S, Vaidya VS, Lu Y, Fredman G, Serhan CN, et al. Resolvin D series and protectin D1 mitigate acute kidney injury. J Immunol. 2006;177:5902–11.CrossRefGoogle Scholar
  67. 67.
    Hassan IR, Gronert K. Acute changes in dietary omega-3 and omega-6 polyunsaturated fatty acids have a pronounced impact on survival following ischemic renal injury and formation of renoprotective docosahexaenoic acid-derived protectin D1. J Immunol. 2009;182:3223–32.CrossRefGoogle Scholar
  68. 68.
    Kieran NE, Doran PP, Connolly SB, Greenan MC, Higgins DF, Leonard M, et al. Modification of the transcriptomic response to renal ischemia/reperfusion injury by lipoxin analog. Kidney Int. 2003;64:480–92.CrossRefGoogle Scholar
  69. 69.
    Wu SH, Wu XH, Lu C, Dong L, Zhou GP, Chen ZQ. Lipoxin A4 inhibits connective tissue growth factor-induced production of chemokines in rat mesangial cells. Kidney Int. 2006;69:248–56.CrossRefGoogle Scholar
  70. 70.
    McMahon B, Stenson C, McPhillips F, Fanning A, Brady HR, Godson C. Lipoxin A4 antagonizes the mitogenic effects of leukotriene D4 in human renal mesangial cells. Differential activation of MAP kinases through distinct receptors. J Biol Chem. 2000;275:27566–75.PubMedGoogle Scholar
  71. 71.
    Börgeson E, Docherty NG, Murphy M, Rodgers K, Ryan A, O'Sullivan TP, et al. Lipoxin A4 and benzo-lipoxin A4 attenuate experimental renal fibrosis. FASEB J. 2011;25:2967–79.CrossRefGoogle Scholar
  72. 72.
    Qu X, Zhang X, Yao J, Song J, Nikolic-Paterson DJ, Li J. Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation. J Pathol. 2012;228:506–19.CrossRefGoogle Scholar
  73. 73.
    •• Mas E, Barden A, Burke V, Beilin LJ, Watts GF, Huang RC, et al. A randomized control trial of the effects of n-3 fatty acids on resolvins in chronic kidney disease. Clin Nutr. 2015;35(2):331–6. A randomized trial which reported that omega-3 fatty acids increase plasma levels of their downstream products, resolvins, which actively terminate chronic inflammation, in subjects with chronic kidney disease.CrossRefGoogle Scholar
  74. 74.
    de Zeeuw D, Hillege HL, de Jong PE. The kidney, a cardiovascular risk marker and a new target for therapy. Kidney Int. 2005;98:S25–9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Cardiology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

Personalised recommendations