Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Associations between lipid abnormalities and diabetic retinopathy across a large United States national database

Eye volume 38, pages 1870–1875 (2024)Cite this article

Subjects

Abstract

Background/Objectives

While dyslipidaemia has been suggested as a potential risk factor for diabetic retinopathy (DR), previous studies have reported conflicting findings. This study aimed to better characterize the relationship between abnormal serum levels of various lipid markers and the risk of the development and progression of DR.

Subjects/Methods

This retrospective cohort study utilized a United States national database of electronic medical records. Adults with a history of type 2 diabetes mellitus without type 1 diabetes mellitus were divided into cohorts based on the presence of abnormal serum levels of various lipid markers. Propensity score matching was performed to match cohorts with abnormal lipid levels to those with normal lipid levels on covariates. The cohorts were then compared to evaluate the hazard ratios (HR) of receiving a new DR diagnosis, pars plana vitrectomy, panretinal photocoagulation, vitreous haemorrhage, proliferative diabetic retinopathy, diabetic macular oedema (DMO), and traction retinal detachment.

Results

The database contained 1,126,231 eligible patients (mean age: 60.8 [14.2] years; 46.0% female). Among patients without prior DR, low HDL (HR = 0.94, CI = 0.90–0.98), total cholesterol (HR = 0.88, CI = 0.85–0.91), and high triglyceride (HR = 0.91, CI = 0.86–0.97) levels were associated with a decreased risk of receiving a DR diagnosis. Among patients with preexisting DR, high LDL levels was associated with an increased risk of DMO (HR = 1.42, CI = 1.15–1.75), whereas low HDL levels was associated with a marginally decreased risk (HR = 0.92, CI = 0.85–0.99).

Conclusions

Elevated levels of markers of dyslipidaemia are inversely associated with the risk of receiving a DR diagnosis, but this relationship is blunted after the onset of DR.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Data availability

The de-identified data used in this research is available in the TriNetX research platform at https://live.trinetx.com, but a request may be necessary and costs may be incurred.

References

  1. Kollias AN, Ulbig MW. Diabetic Retinopathy. Dtsch Arztebl Int. 2010;107:75–84.

    PubMed  PubMed Central  Google Scholar 

  2. Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, et al. Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis. Ophthalmology 2021;128:1580–91.

    PubMed  Google Scholar 

  3. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17.

    PubMed  Google Scholar 

  4. Wong TY, Cheung CMG, Larsen M, Sharma S, Simó R. Diabetic retinopathy. Nat Rev Dis Prim. 2016;2:1–17.

    Google Scholar 

  5. Ulbig MRW, Hamilton AMP. Factors influencing the natural history of diabetic retinopathy. Eye. 1993;7:242–9.

    PubMed  Google Scholar 

  6. Porta M, Sjoelie AK, Chaturvedi N, Stevens L, Rottiers R, Veglio M, et al. Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study. Diabetologia. 2001;44:2203–9.

    CAS  PubMed  Google Scholar 

  7. Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM, UK Prospective Diabetes Study Group. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol. 2004;122:1631–40.

    PubMed  Google Scholar 

  8. Chang YC, Wu WC. Dyslipidemia and Diabetic Retinopathy. Rev Diabet Stud. 2013;10:121–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhou Y, Wang C, Shi K, Yin X. Relationship between dyslipidemia and diabetic retinopathy: A systematic review and meta-analysis. Medicine. 2018;97:e12283.

    PubMed  PubMed Central  Google Scholar 

  10. Modjtahedi BS, Bose N, Papakostas TD, Morse L, Vavvas DG, Kishan AU. Lipids and Diabetic Retinopathy. Semin Ophthalmol. 2016;31:10–8.

    PubMed  Google Scholar 

  11. Chou Y, Ma J, Su X, Zhong Y. Emerging insights into the relationship between hyperlipidemia and the risk of diabetic retinopathy. Lipids Health Dis. 2020;19:241.

    PubMed  PubMed Central  Google Scholar 

  12. van Leiden HA, Dekker JM, Moll AC, Nijpels G, Heine RJ, Bouter LM, et al. Risk Factors for Incident Retinopathy in a Diabetic and Nondiabetic Population: The Hoorn Study. Arch Ophthalmol. 2003;121:245–51.

    PubMed  Google Scholar 

  13. Wang NK, Lai CC, Wang JP, Wu WC, Liu L, Yeh LK, et al. Risk factors associated with the development of retinopathy 10 yr after the diagnosis of juvenile-onset type 1 diabetes in Taiwan: a cohort study from the CGJDES. Pediatr Diabetes. 2016;17:407–16.

    CAS  PubMed  Google Scholar 

  14. Davis MD, Fisher MR, Gangnon RE, Barton F, Aiello LM, Chew EY, et al. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18. Invest Ophthalmol Vis Sci. 1998;39:233–52.

    CAS  PubMed  Google Scholar 

  15. Klein R, Marino EK, Kuller LH, Polak JF, Tracy RP, Gottdiener JS, et al. The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. Br J Ophthalmol. 2002;86:84–90.

    PubMed  PubMed Central  Google Scholar 

  16. Chung YR, Park SW, Choi SY, Kim SW, Moon KY, Kim JH, et al. Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovasc Diabetol. 2017;16:4.

    PubMed  PubMed Central  Google Scholar 

  17. Wong TY, Cheung N, Tay WT, Wang JJ, Aung T, Saw SM, et al. Prevalence and risk factors for diabetic retinopathy: the Singapore Malay Eye Study. Ophthalmology 2008;115:1869–75.

    PubMed  Google Scholar 

  18. Miljanovic B, Glynn RJ, Nathan DM, Manson JE, Schaumberg DA. A Prospective Study of Serum Lipids and Risk of Diabetic Macular Edema in Type 1 Diabetes. Diabetes 2004;53:2883–92.

    CAS  PubMed  Google Scholar 

  19. Tan GS, Gan A, Sabanayagam C, Tham YC, Neelam K, Mitchell P, et al. Ethnic Differences in the Prevalence and Risk Factors of Diabetic Retinopathy: The Singapore Epidemiology of Eye Diseases Study. Ophthalmology 2018;125:529–36.

    PubMed  Google Scholar 

  20. Keech AC, Mitchell P, Summanen PA, O’Day J, Davis TME, Moffitt MS, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet. 2007;370:1687–97.

    CAS  PubMed  Google Scholar 

  21. Klein BE, Moss SE, Klein R, Surawicz TS. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XIII. Relationship of serum cholesterol to retinopathy and hard exudate. Ophthalmology. 1991;98:1261–5.

    CAS  PubMed  Google Scholar 

  22. Ioannidou E, Tseriotis VS, Tziomalos K. Role of lipid-lowering agents in the management of diabetic retinopathy. World J Diabetes. 2017;8:1–6.

    PubMed  PubMed Central  Google Scholar 

  23. Kronenberg F. Lipoprotein(a). Handb Exp Pharm. 2022;270:201–32.

    CAS  Google Scholar 

  24. Kang EYC, Chen TH, Garg SJ, Sun CC, Kang JH, Wu WC, et al. Association of Statin Therapy With Prevention of Vision-Threatening Diabetic Retinopathy. JAMA Ophthalmol. 2019;137:363–71.

    PubMed  PubMed Central  Google Scholar 

  25. Vail D, Callaway NF, Ludwig CA, Saroj N, Moshfeghi DM. Lipid-Lowering Medications Are Associated with Lower Risk of Retinopathy and Ophthalmic Interventions among United States Patients with Diabetes. Am J Ophthalmol. 2019;207:378–84.

    CAS  PubMed  Google Scholar 

  26. Kawasaki R, Konta T, Nishida K. Lipid-lowering medication is associated with decreased risk of diabetic retinopathy and the need for treatment in patients with type 2 diabetes: A real-world observational analysis of a health claims database. Diabetes, Obes Metab. 2018;20:2351–60.

    CAS  PubMed  Google Scholar 

  27. Pranata R, Vania R, Victor AA. Statin reduces the incidence of diabetic retinopathy and its need for intervention: A systematic review and meta-analysis. Eur J Ophthalmol. 2021;31:1216–24.

    PubMed  Google Scholar 

  28. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–61.

    CAS  PubMed  Google Scholar 

  29. ACCORD Study Group, ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, Danis RP, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363:233–44.

    Google Scholar 

  30. Schoenfeld D. Partial residuals for the proportional hazards regression model. Biometrika. 1982;69:239–41.

    Google Scholar 

  31. In J, Lee DK. Survival analysis: part II – applied clinical data analysis. Korean J Anesthesiol. 2019;72:441–57.

    PubMed  PubMed Central  Google Scholar 

  32. Kuitunen I, Ponkilainen VT, Uimonen MM, Eskelinen A, Reito A. Testing the proportional hazards assumption in cox regression and dealing with possible non-proportionality in total joint arthroplasty research: methodological perspectives and review. BMC Musculoskelet Disord. 2021;22:489.

    PubMed  PubMed Central  Google Scholar 

  33. Hancock MJ, Maher CG, Costa LdaCM, Williams CM. A guide to survival analysis for manual therapy clinicians and researchers. Man Ther. 2014;19:511–6.

    PubMed  Google Scholar 

  34. Scott IU, Campochiaro PA, Newman NJ, Biousse V. Retinal Vascular Occlusions. Lancet. 2020;396:1927–40.

    PubMed  PubMed Central  Google Scholar 

  35. Stroke - Causes and Risk Factors | NHLBI, NIH [Internet]. [cited 2023 Jun 19]. Available from: https://www.nhlbi.nih.gov/health/stroke/causes (2022).

  36. Wilson PW. Established risk factors and coronary artery disease: the Framingham Study. Am J Hypertens. 1994;7:7S–12S.

    CAS  PubMed  Google Scholar 

  37. Cheung N, Wang JJ, Klein R, Couper DJ, Sharrett AR, Wong TY. Diabetic Retinopathy and the Risk of Coronary Heart Disease: The Atherosclerosis Risk in Communities Study. Diabetes Care. 2007;30:1742–6.

    PubMed  Google Scholar 

  38. Miksenas H, Januzzi JL Jr, Natarajan P. Lipoprotein(a) and Cardiovascular Diseases. JAMA 2021;326:352–3.

    PubMed  Google Scholar 

  39. Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP, Kamstrup PR, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arteriosclerosis, Thrombosis, Vasc Biol. 2022;42:e48–60.

    CAS  Google Scholar 

  40. Lu M, Lu Q, Zhang Y, Tian G. ApoB/apoA1 is an effective predictor of coronary heart disease risk in overweight and obesity. J Biomed Res. 2011;25:266–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082–143.

    PubMed  Google Scholar 

  42. Davidson MH, Ballantyne CM, Jacobson TA, Bittner VA, Braun LT, Brown AS, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: Advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5:338–67.

    PubMed  Google Scholar 

  43. Mozetic V, Pacheco RL, Latorraca C, de Oliveira Cruz Latorraca C, Riera R. Statins and/or fibrates for diabetic retinopathy: a systematic review and meta-analysis. Diabetol Metab Syndr. 2019;11:92.

    PubMed  PubMed Central  Google Scholar 

  44. Narang S, Sood S, Kaur B, Singh R, Mallik A, Kaur J. Atorvastatin in clinically-significant macular edema in diabetics with a normal lipid profile. Nepal J Ophthalmol. 2012;4:23–8.

    CAS  PubMed  Google Scholar 

  45. Zhang J, McGwin G. Association of statin use with the risk of developing diabetic retinopathy. Arch Ophthalmol. 2007;125:1096–9.

    PubMed  Google Scholar 

  46. Dodson PM. Management of diabetic retinopathy: could lipid-lowering be a worthwhile treatment modality? Eye. 2009;23:997–1003.

    CAS  PubMed  Google Scholar 

  47. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of Action of Fibrates on Lipid and Lipoprotein Metabolism. Circulation. 1998;98:2088–93.

    CAS  PubMed  Google Scholar 

  48. Bradford RH, Goldberg AC, Schonfeld G, Knopp RH. Double-blind comparison of bezafibrate versus placebo in male volunteers with hyperlipoproteinemia. Atherosclerosis 1992;92:31–40.

    CAS  PubMed  Google Scholar 

  49. Trudeau K, Roy S, Guo W, Hernández C, Villarroel M, Simó R, et al. Fenofibric Acid Reduces Fibronectin and Collagen Type IV Overexpression in Human Retinal Pigment Epithelial Cells Grown in Conditions Mimicking the Diabetic Milieu: Functional Implications in Retinal Permeability. Invest Ophthalmol Vis Sci. 2011;52:6348–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Hsu YJ, Lin CW, Cho SL, Yang WS, Yang CM, Yang CH. Protective Effect of Fenofibrate on Oxidative Stress-Induced Apoptosis in Retinal–Choroidal Vascular Endothelial Cells: Implication for Diabetic Retinopathy Treatment. Antioxid (Basel). 2020;9:712.

    CAS  Google Scholar 

  51. Ding L, Cheng R, Hu Y, Takahashi Y, Jenkins AJ, Keech AC, et al. Peroxisome Proliferator–Activated Receptor α Protects Capillary Pericytes in the Retina. Am J Pathol. 2014;184:2709–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Huang L, Liang W, Zhou K, Wassel RA, Ridge ZD, Ma JX, et al. Therapeutic Effects of Fenofibrate Nano-Emulsion Eye Drops on Retinal Vascular Leakage and Neovascularization. Biol (Basel). 2021;10:1328.

    CAS  Google Scholar 

  53. Noonan JE, Jenkins AJ, Ma JX, Keech AC, Wang JJ, Lamoureux EL. An Update on the Molecular Actions of Fenofibrate and Its Clinical Effects on Diabetic Retinopathy and Other Microvascular End Points in Patients With Diabetes. Diabetes. 2013;62:3968–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang F, Wang X, Ye P, Cao R, Zhang Y, Qi Y, et al. High-density lipoprotein 3 cholesterol is a predictive factor for arterial stiffness: a community-based 4.8-year prospective study. Lipids Health Dis. 2018;17:5.

    PubMed  PubMed Central  Google Scholar 

  55. Salonen JT, Salonen R, Seppänen K, Rauramaa R, Tuomilehto J. HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. Circulation. 1991;84:129–39.

    CAS  PubMed  Google Scholar 

  56. Williams PT, Feldman DE. Prospective study of coronary heart disease vs HDL2, HDL3, and other lipoproteins in Gofman’s Livermore Cohort. Atherosclerosis 2011;214:196–202.

    CAS  PubMed  Google Scholar 

  57. Hoogeveen RC, Gaubatz JW, Sun W, Dodge RC, Crosby JR, Jiang J, et al. Small Dense LDL Cholesterol Concentrations Predict Risk for Coronary Heart Disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol. 2014;34:1069–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Johansson J, Carlson LA, Landou C, Hamsten A. High density lipoproteins and coronary atherosclerosis. A strong inverse relation with the largest particles is confined to normotriglyceridemic patients. Arterioscler Thromb. 1991;11:174–82.

    CAS  PubMed  Google Scholar 

  59. Pirillo A, Norata GD, Catapano AL. High-Density Lipoprotein Subfractions - What the Clinicians Need to Know. Cardiology. 2013;124:116–25.

    CAS  PubMed  Google Scholar 

  60. Fu D, Yu JY, Wu M, Du M, Chen Y, Abdelsamie SA, et al. Immune complex formation in human diabetic retina enhances toxicity of oxidized LDL towards retinal capillary pericytes1. J Lipid Res. 2014;55:860–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Lyons TJ, Jenkins AJ. Glycation, oxidation, and lipoxidation in the development of the complications of diabetes: a carbonyl stress hypothesis. Diabetes Rev (Alex). 1997;5:365–91.

    PubMed  Google Scholar 

  62. Du M, Wu M, Fu D, Yang S, Chen J, Wilson K, et al. Effects of modified LDL and HDL on retinal pigment epithelial cells: a role in diabetic retinopathy? Diabetologia 2013;56:2318–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yu JY, Du M, Elliott MH, Wu M, Fu D, Yang S, et al. Extravascular modified lipoproteins: a role in the propagation of diabetic retinopathy in a mouse model of type 1 diabetes. Diabetologia. 2016;59:2026–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Norata GD, Pirillo A, Catapano AL. Modified HDL: Biological and physiopathological consequences. Nutr, Metab Cardiovasc Dis. 2006;16:371–86.

    CAS  PubMed  Google Scholar 

  65. Bonizzi A, Piuri G, Corsi F, Cazzola R, Mazzucchelli S. HDL Dysfunctionality: Clinical Relevance of Quality Rather Than Quantity. Biomedicines. 2021;9:729.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017;38:2478–86.

    CAS  PubMed  Google Scholar 

  67. Márquez AB, Nazir S, van der Vorst EPC. High-Density Lipoprotein Modifications: A Pathological Consequence or Cause of Disease Progression? Biomedicines 2020;8:549.

    PubMed  PubMed Central  Google Scholar 

  68. Farbstein D, Levy AP. HDL dysfunction in diabetes: causes and possible treatments. Expert Rev Cardiovasc Ther. 2012;10:353–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Kohner EM. The evolution and natural history of diabetic retinopathy. Int Ophthalmol Clin. 1978;18:1–16.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Dr. David Kaelber and the MetroHealth Medical Center in Cleveland for providing access to the TriNetX database.

Funding

This study was supported by the Clinical and Translational Science Collaborative (CTSC) of Cleveland which is funded by the National Institutes of Health (NIH), National Center for Advancing Translational Science (NCATS), Clinical and Translational Science Award (CTSA) grant, UL1TR002548. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support was provided by P30EY025585(BA-A), the Research to Prevent Blindness (RPB) Challenge Grant, Cleveland Eye Bank Foundation Grant.

Author information

Authors and Affiliations

  1. Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Hejin Jeong & Christopher M. Maatouk

  2. Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

    Christopher M. Maatouk, Matthew W. Russell & Rishi P. Singh

  3. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    Matthew W. Russell

  4. Cleveland Clinic Martin Health, Cleveland Clinic Florida, Stuart, FL, USA

    Rishi P. Singh

Authors
  1. Hejin Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher M. Maatouk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew W. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rishi P. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the conception and design of the study, revised the manuscript, and reviewed the final manuscript. Data collection and statistical analysis were performed by HJ and CMM. Interpretation of the data, writing of the manuscript, and revision of the study design were performed by HJ.

Corresponding author

Correspondence to Rishi P. Singh.

Ethics declarations

Competing interests

RPS reports personal fees from Genentech/Roche, personal fees from Alcon/Novartis, grants from Apellis and Graybug, personal fees from Zeiss, personal fees from Bausch + Lomb, personal fees from Regeneron Pharmaceuticals, Inc. Inc. All other authors report no disclosures.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jeong, H., Maatouk, C.M., Russell, M.W. et al. Associations between lipid abnormalities and diabetic retinopathy across a large United States national database. Eye 38, 1870–1875 (2024). https://doi.org/10.1038/s41433-024-03022-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41433-024-03022-3

Search

Advanced search

Quick links