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Residual microvascular risk in diabetes: unmet needs and future directions

Nature Reviews Endocrinology volume 6, pages 19–25 (2010)Cite this article

Abstract

The burden of microvascular disease in patients with type 2 diabetes mellitus continues to escalate worldwide. Current standards of care reduce but do not eliminate the risk of diabetic retinopathy, nephropathy or neuropathy in these patients. Correction of atherogenic dyslipidemia, which is characterized by elevated triglyceride levels and low levels of HDL cholesterol, might provide additional benefit. Whereas promising data have been published with respect to fibrate therapy for maculopathy, fenofibrate for diabetic retinopathy, and statin or fibrate therapy for diabetic nephropathy, further studies are warranted to define optimal management strategies for reducing the residual microvascular risk. Such strategies are especially relevant in cases of diabetic peripheral neuropathy, where even optimal care fails to affect disease progression. Identification of those factors that are most relevant to residual diabetes-related microvascular risk is a priority of an ongoing multinational epidemiological study. In this Review, we highlight an urgent need to address the issue of microvascular residual risk in patients with or at risk of type 2 diabetes mellitus.

Key Points

  • Patients with type 2 diabetes mellitus remain exposed to a high residual risk of microvascular complications even if they are treated with optimal standards of care

  • Atherogenic dyslipidemia, which is a combination of elevated triglyceride levels and low plasma levels of HDL cholesterol, might contribute to microvascular complications

  • Fibrates, in particular fenofibrate, might have a preventive role in diabetic eye disease, possibly mediated via pleiotropic mechanisms

  • Statins or fibrates might be useful to prevent progression of diabetic nephropathy, particularly in the early stages of renal disease

  • Further studies are needed to define optimal management strategies for reduction of residual microvascular risk in patients with type 2 diabetes mellitus, especially in the case of peripheral diabetic neuropathy

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Figure 1: Risk of diabetic retinopathy.
Figure 2: Risk of diabetic nephropathy.
Figure 3: Risk of diabetic neuropathy.

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References

  1. International Diabetes Federation (IDF) Diabetes atlas (e-Atlas) [online] (2008).

  2. Centers for Disease Control and Prevention (CDC) Diabetes data and trends [online] (2008).

  3. Jörneskog, G. et al. Early microvascular dysfunction in healthy normal-weight males with heredity for type 2 diabetes. Diabetes Care 28, 1495–1497 (2005).

    Article  Google Scholar 

  4. Centers for Disease Control and Prevention (CDC) National Diabetes Fact Sheet [online] (2007).

  5. Ziegler, D. et al. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care 31, 464–469 (2008).

    Article  CAS  Google Scholar 

  6. Fang, Z. Y., Prins, J. B. & Marwick, T. H. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr. Rev. 25, 543–567 (2004).

    Article  CAS  Google Scholar 

  7. ADVANCE Collaborative Group et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

  8. Patel, A. et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370, 829–840 (2007).

    Article  CAS  Google Scholar 

  9. The Action to Control Cardiovascular Risk in Diabetes Study Group et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545–2559 (2008).

  10. Gaede, P., Vedel, P., Parving, H. H. & Pedersen, O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 353, 617–622 (1999).

    Article  CAS  Google Scholar 

  11. Gaede, P. et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med. 348, 383–393 (2003).

    Article  Google Scholar 

  12. Gaede, P., Lund-Andersen, H., Parving, H. H. & Pedersen, O. Effect of a multifactorial intervention in mortality in type 2 diabetes. N. Engl. J. Med. 358, 580–591 (2008).

    Article  CAS  Google Scholar 

  13. Shilo, S., Roy., S., Khanna, S. & Sen, C. K. Evidence for the involvement of miRNA in redox regulated angiogenic response of human microvascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 28, 471–477 (2008).

    Article  CAS  Google Scholar 

  14. Orchard, T. J. et al. Factors associated with avoidance of severe complications after 25 yr of IDDM. Pittsburgh Epidemiology of Diabetes Complications Study I. Diabetes Care 13, 741–747 (1990).

    Article  CAS  Google Scholar 

  15. Miljanovic, B., Glynn, R. J., Nathan, D. M., Manson, J. E. & Schaumberg, D. A. A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes. Diabetes 53, 2883–2892 (2004).

    Article  CAS  Google Scholar 

  16. Davis, M. D. 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. 39, 233–252 (1998).

    CAS  PubMed  Google Scholar 

  17. Hadjadj, S. et al. Serum triglycerides are a predictive factor for the development and the progression of renal and retinal complications in patients with type 1 diabetes. Diabetes Metab. 30, 43–51 (2004).

    Article  CAS  Google Scholar 

  18. Lyons, T. J. et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest. Ophthalmol. Vis. Sci. 45, 910–918 (2004).

    Article  Google Scholar 

  19. Chew, E. Y. et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch. Ophthalmol. 114, 1079–1084 (1996).

    Article  CAS  Google Scholar 

  20. Dodson, P. M. Medical treatment for diabetic retinopathy: do the FIELD microvascular study results support a role for lipid lowering? Practical Diabetes International 25, 76–79 (2008).

    Google Scholar 

  21. Harrold, B. P., Marmion, V. J. & Gough, K. R. A double-blind controlled trial of clofibrate in the treatment of diabetic retinopathy. Diabetes 18, 285–291 (1969).

    Article  CAS  Google Scholar 

  22. Freybarger, H., Schifferdecker, E. & Schatz, H. Regression of hard exudates in diabetic background retinopathy in therapy with etofibrate antilipaemic agent [German]. Med. Klin. (Munich) 89, 594–597 (1994).

    Google Scholar 

  23. Keech, A. C. et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370, 1687–1697 (2007).

    Article  CAS  Google Scholar 

  24. Keech, A. et al. Effect of long-term fenofibrate therapy on cardiovascular events in 9,795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005).

    Article  CAS  Google Scholar 

  25. Kim, J. et al. Fenofibrate regulates retinal endothelial cell survival through the AMPK signal transduction pathway. Exp. Eye Res. 84, 886–893 (2007).

    Article  CAS  Google Scholar 

  26. Goetze, S. et al. PPAR activators inhibit endothelial cell migration by targeting Akt. Biochem. Biophys. Res. Comm. 293, 1431–1437 (2002).

    Article  CAS  Google Scholar 

  27. Rosenson, R. S., Wolff, D. A., Huskin, A. L., Helenowski, I. B. & Rademaker, A. W. Fenofibrate therapy ameliorates fasting and postprandial lipoproteinemia, oxidative stress, and the inflammatory response in subjects with hypertriglyceridemia and the metabolic syndrome. Diabetes Care 30, 1945–1951 (2007).

    Article  CAS  Google Scholar 

  28. Tsimihodimos, V., Liberopoulos, E. & Elisaf, M. Pleiotropic effects of fenofibrate. Curr. Pharm. Des. 15, 517–528 (2009).

    Article  CAS  Google Scholar 

  29. Ansquer, J. C., Foucher, C., Aubonnet, P. & Le Malicot, K. Fibrates and microvascular complications in diabetes–insight from the FIELD study. Curr. Pharm. Des. 15, 537–552 (2009).

    Article  CAS  Google Scholar 

  30. Retnakaran, R. et al. Risk factors for renal dysfunction in type 2 diabetes. UK Prospective Diabetes Study 74. Diabetes 55, 1832–1839 (2006).

    Article  CAS  Google Scholar 

  31. Molitch, M. E., Rupp, D. & Carnethon, M. Higher levels of HDL cholesterol are associated with a decreased likelihood of albuminuria in patients with long-standing type 1 diabetes. Diabetes Care 29, 78–82 (2006).

    Article  CAS  Google Scholar 

  32. Sandhu, S., Wiebe, N., Fried, L. F. & Tonelli, M. Statins for improving renal outcomes: a meta-analysis. J. Am. Soc. Nephrol. 17, 2006–2016 (2006).

    Article  CAS  Google Scholar 

  33. Douglas, K., O'Malley, P. G. & Jackson, J. L. Meta-analysis: the effect of statins on albuminuria. Ann. Intern. Med. 145, 117–124 (2006).

    Article  CAS  Google Scholar 

  34. Atthobari, J. et al. The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study. Nephrol. Dial. Transplant. 21, 3106–3114 (2006).

    Article  CAS  Google Scholar 

  35. Rahman, M. et al. Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am. J. Kidney Dis. 52, 412–424 (2008).

    Article  Google Scholar 

  36. Vidt, D. G. Statins and proteinuria. Curr. Atheroscler. Rep. 7, 351–357 (2005).

    Article  CAS  Google Scholar 

  37. Law, M. & Rudnicka, A. R. Statin safety: a systematic review. Am. J. Cardiol. 97 (Suppl. 1), 52C–60C (2006).

    Article  CAS  Google Scholar 

  38. Ozsoy, R. C., van Leuven, S. I., Kastelein, J. J., Arisz, L. & Koopman, M. G. The dyslipidemia of chronic renal disease: effects of statin therapy. Curr. Opin. Lipidol. 17, 659–666 (2006).

    Article  CAS  Google Scholar 

  39. Wanner, C. et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 353, 238–248 (2005).

    Article  CAS  Google Scholar 

  40. Smulders, Y. M. et al. Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus? Eur. J. Clin. Invest. 27, 997–1002 (1999).

    Article  Google Scholar 

  41. Nagai, T., Tomizawa, T., Nakajima, K. & Mori, M. Effect of bezafibrate or pravastatin on serum lipid levels and albuminuria in NIDDM patients. J. Atheroscler. Thromb. 7, 91–96 (2000).

    Article  CAS  Google Scholar 

  42. Ansquer, J. C. et al. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am. J. Kidney Dis. 45, 485–493 (2005).

    Article  CAS  Google Scholar 

  43. Hottleart, C., El Esper, N., Rose, F., Achard, J. M. & Fournier, A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine. Nephron 92, 536–541 (2002).

    Article  Google Scholar 

  44. Rossing, P. et al. Fish oil in diabetic nephropathy. Diabetes Care 19, 1214–1219 (1996).

    Article  CAS  Google Scholar 

  45. Tesfaye, S. et al. Vascular risk factors and diabetic neuropathy. N. Engl. J. Med. 352, 341–350 (2005).

    Article  CAS  Google Scholar 

  46. Kempler, P. et al. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabet. Med. 19, 900–909 (2002).

    Article  CAS  Google Scholar 

  47. Davis, T. M., Yeap, B. B., Davis, W. A. & Bruce, D. G. Lipid-lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study. Diabetologia 51, 562–566 (2008).

    Article  CAS  Google Scholar 

  48. Welzig, C. M. et al. Lipid lowering by pravastatin increases parasympathetic modulation of heart rate: Galpha(i2), a possible molecular marker for parasympathetic responsiveness. Circulation 108, 2743–2746 (2003).

    Article  CAS  Google Scholar 

  49. Rajamani, K. et al. Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial. Lancet 373, 1780–1788 (2009).

    Article  CAS  Google Scholar 

  50. Corrao, G. et al. Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases. J. Epidemiol. Community Health 58, 1047–1051 (2004).

    Article  Google Scholar 

  51. Okuda, Y. et al. Long-term effects of eicosapenaenoic acid on diabetic peripheral neuropathy and serum lipids in patients with type II diabetes mellitus. J. Diabetes Complications 10, 280–287 (1996).

    Article  CAS  Google Scholar 

  52. Lee, B. K. et al. Microcirculatory dysfunction in cardiac syndrome X: role of abnormal blood rheology. Microcirculation 15, 451–459 (2003).

    Article  Google Scholar 

  53. Kayikcioglu, M. et al. Benefits of statin treatment in cardiac syndrome-X1. Eur. Heart J. 24, 1999–2005 (2003).

    Article  CAS  Google Scholar 

  54. Bonetti, P. O. et al. Simvastatin preserves myocardial perfusion and coronary microvascular permeability in experimental hypercholesterolemia independent on lipid lowering. J. Am. Coll. Cardiol. 40, 546–554 (2002).

    Article  CAS  Google Scholar 

  55. Rim, S. J. et al. Decrease in coronary blood flow reserve during hyperlipidemia is secondary to an increase in blood viscosity. Circulation 104, 2704–2709 (2001).

    Article  CAS  Google Scholar 

  56. Labios, M. et al. Effect of a modified fibrate (Biniwas Retard) on hemorheological alterations in hyperlipemic patients. Clin. Hemorheol. Microcirc. 21, 79–85 (1999).

    CAS  PubMed  Google Scholar 

  57. Frost, R. J., Otto, C., Geiss, H. C., Schwandt, P. & Parhofer, K. G. Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia. Am. J. Cardiol. 87, 44–48 (2001).

    Article  CAS  Google Scholar 

  58. Rosenson, R. S. & Helenowski, I. B. Fenofibrate abrogates postprandial blood viscosity among hypertriglyceridemia subjects with the metabolic syndrome. Diabetes Met. Syndrome Clin. Res. Rev. 3, 17–23 (2009).

    Article  Google Scholar 

  59. Zheng, F. & Guan, Y. Thiazolidinediones: a novel class of drugs for the prevention of diabetic nephropathy? Kidney Int. 72, 1301–1303 (2007).

    Article  CAS  Google Scholar 

  60. Nakamura, T. et al. Pioglitazone reduces urinary podocyte excretion in type 2 diabetes patients with microalbuminuria. Metabolism 50, 1193–1196 (2001).

    Article  CAS  Google Scholar 

  61. Ohga, S. et al. Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation. Am. J. Physiol. Renal Physiol. 292, F1141–F1150 (2007).

    Article  CAS  Google Scholar 

  62. Fong, D. S. & Contreras, R. Glitazone use associated with diabetic macular edema. Am. J. Ophthalmol. 147, 583e1–586e1 (2009).

    Article  Google Scholar 

  63. Martin, P. M. et al. Expression and localization of GPR109A (PUMA-G/HM74A) mRNA and protein in mammalian retinal pigment epithelium. Mol. Vis. 15, 362–372 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. R3i studies. Microvascular residual risk epidemiological study. [online] (2009).

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Acknowledgements

The authors thank Jane Stock (Residual Risk Reduction Initiative [R3i]) for editorial assistance. R3i is an independent non-profit educational organization of basic and clinical scientists, cardiologists, endocrinologists and diabetologists that has been formed to address the high risk of macrovascular and microvascular complications in patients with atherogenic dyslipidemia.

Author information

Authors and Affiliations

  1. Department of Medical and Surgical Sciences, University of Padova, Via Giustiniani 2, Padova, Italy

    Paola Fioretto

  2. Heart of England Foundation Trust, Birmingham, UK

    Paul M. Dodson

  3. Institute for Clinical Diabetology, German Diabetes Center at the Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany

    Dan Ziegler

  4. Division of Endocrinology, Department of Medicine, Diabetes and Metabolism, State University of New York, Brooklyn, NY, USA

    Robert S. Rosenson

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Corresponding author

Correspondence to Paola Fioretto.

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Competing interests

Paul M. Dodson declares associations with the following companies: AstraZeneca (advisory board), Eli Lilly (research support), Pfizer (advisory board), Solvay (advisory board) and Takeda (advisory board).

Dan Ziegler declares associations with the following companies: Eli Lilly (consultant and speakers bureau), Eisai (consultant and speaker's bureau), Meda (consultant and speaker's bureau), Nycomed (consultant and speaker's bureau) and Pfizer (consultant, speaker's bureau and research support).

Robert S. Rosenson declares associations with the following companies: Abbott Laboratories (speaker's bureau and research support), Anthera (research support), Astra Zeneca (speaker's bureau and research support) and LipoScience (ownership interest and serves on the advisory board).

Paola Fioretto declares no competing interests.

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Fioretto, P., Dodson, P., Ziegler, D. et al. Residual microvascular risk in diabetes: unmet needs and future directions. Nat Rev Endocrinol 6, 19–25 (2010). https://doi.org/10.1038/nrendo.2009.213

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