Acta Diabetologica

, Volume 55, Issue 4, pp 323–330 | Cite as

Levels of serum uric acid at admission for hypoglycaemia predict 1-year mortality

  • Aldo BonaventuraEmail author
  • Fiorenza Gallo
  • Federico Carbone
  • Luca Liberale
  • Davide Maggi
  • Giovanni Sacchi
  • Franco Dallegri
  • Fabrizio Montecucco
  • Renzo Cordera
Original Article



Hypoglycaemia represents a critical burden with clinical and social consequences in the management of diabetes. Serum uric acid (SUA) has been associated with cardiovascular diseases (CVD), but no conclusive findings are available nowadays in patients suffering from hypoglycaemia. We investigated whether SUA levels at the time of hypoglycaemia could predict all-cause mortality after 1-year follow-up.


In total, 219 patients admitted to the Emergency Department (ED) of Ospedale Policlinico S. Martino of Genoa (Italy) have been enrolled between January 2011 and December 2014. The primary endpoint of the study consisted in determining whether SUA levels at the time of ED admission could predict the occurrence of death after 1 year.


The majority of patients were diabetic, especially type 2. CVD and chronic kidney disease were prevalent comorbidities. By a cut-off value obtained by the receiver operating characteristic curve analysis, a Kaplan–Meier analysis demonstrated that patients with SUA levels > 5.43 mg/dL were more prone to death after 1 year compared to those with lower SUA levels. The risk of death increased with high SUA levels both in the univariate and the multivariate models including estimated glomerular filtration rate, C-reactive protein, type of diabetes, and age-adjusted Charlson comorbidity index.


SUA could be useful as a predictor of 1-year mortality in hypoglycaemic patients, irrespective of severe comorbidities notably increasing the risk of death in these frail patients.


Serum uric acid Cardiovascular disease Hypoglycaemia Diabetes mellitus Mortality Frailty 



This study has been supported by a grant from the European Commission (FP7-INNOVATION I HEALTH-F2-2013-602114; Athero-B-Cell: Targeting and exploiting B cell function for treatment in cardiovascular disease) and a grant from the Swiss National Science Foundation to Dr. F. Montecucco (#310030_152639/1).

Authors’ contribution

FG, GS, and RC collected data; AB, RC, and FM designed the study; AB, FC, LL, and FM performed statistical analyses; AB, FM, and RC prepared the manuscript. LL, FD, DM, and RC gave suggestions to enhance the manuscript. All authors approved the final version of the manuscript. AB is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Compliance with ethical standards

Conflict of interest


Ethical approval

The study has been approved by the local Ethics Committee in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all patients and/or their relatives at the time of their inclusion in the study.


  1. 1.
    Connelly KA, Yan AT, Leiter LA, Bhatt DL, Verma S (2015) Cardiovascular implications of hypoglycemia in diabetes mellitus. Circulation 132:2345–2350CrossRefPubMedGoogle Scholar
  2. 2.
    Feig DI, Kang DH, Johnson RJ (2008) Uric acid and cardiovascular risk. N Engl J Med 359:1811–1821CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ahola AJ, Sandholm N, Forsblom C, Harjutsalo V, Dahlstrom E, Groop PH et al (2017) The serum uric acid concentration is not causally linked to diabetic nephropathy in type 1 diabetes. Kidney Int 91:1178–1185CrossRefPubMedGoogle Scholar
  4. 4.
    Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC (2008) High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care 31:361–362CrossRefPubMedGoogle Scholar
  5. 5.
    Carnethon MR, Fortmann SP, Palaniappan L, Duncan BB, Schmidt MI, Chambless LE (2003) Risk factors for progression to incident hyperinsulinemia: the Atherosclerosis Risk in Communities Study, 1987–1998. Am J Epidemiol 158:1058–1067CrossRefPubMedGoogle Scholar
  6. 6.
    Zoppini G, Targher G, Negri C, Stoico V, Perrone F, Muggeo M et al (2009) Elevated serum uric acid concentrations independently predict cardiovascular mortality in type 2 diabetic patients. Diabetes Care 32:1716–1720CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Barranco RJ, Gomez-Peralta F, Abreu C, Delgado M, Palomares R, Romero F et al (2015) Incidence and care-related costs of severe hypoglycaemia requiring emergency treatment in Andalusia (Spain): the PAUEPAD project. Diabet Med 32:1520–1526CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wang J, Geiss LS, Williams DE, Gregg EW (2015) Trends in emergency department visit rates for hypoglycemia and hyperglycemic crisis among adults with diabetes, United States, 2006–2011. PLoS ONE 10:e0134917CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sako A, Yasunaga H, Matsui H, Fushimi K, Hamasaki H, Katsuyama H et al (2015) Hospitalization for hypoglycemia in Japanese diabetic patients: a retrospective study using a national inpatient database, 2008–2012. Medicine (Baltimore) 94:e1029CrossRefGoogle Scholar
  10. 10.
    Marchesini G, Veronese G, Forlani G, Forlani G, Ricciardi LM, Fabbri A et al (2014) The management of severe hypoglycemia by the emergency system: the HYPOTHESIS study. Nutr Metab Cardiovasc Dis 24:1181–1188CrossRefPubMedGoogle Scholar
  11. 11.
    Bonaventura A, Gallo F, Carbone F, Sacchi G, Liberale L, Dallegri F et al (2017) Low serum C-reactive protein levels predict 90-day mortality in hypoglycaemic patients. Diabetes Metab 43:554CrossRefPubMedGoogle Scholar
  12. 12.
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al (2013) Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 36:1384–1395CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Alderman MH, Cohen H, Madhavan S, Kivlighn S (1999) Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension 34:144–150CrossRefPubMedGoogle Scholar
  15. 15.
    Fang J, Alderman MH (2000) Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA 283:2404–2410CrossRefPubMedGoogle Scholar
  16. 16.
    Mohan V, Snehalatha C, Jayashree R, Ramachandran A, Viswanathan M, Kameswaran L et al (1984) Serum uric acid concentrations in offspring of conjugal diabetic parents. Metabolism 33:869–871CrossRefPubMedGoogle Scholar
  17. 17.
    Gotoh M, Li C, Yatoh M, Iguchi A, Hirooka Y (2005) Serum uric acid concentrations in type 2 diabetes: its significant relationship to serum 1,5-anhydroglucitol concentrations. Endocr Regul 39:119–125PubMedGoogle Scholar
  18. 18.
    Kim WJ, Kim SS, Bae MJ, Yi YS, Jeon YK, Kim BH et al (2014) High-normal serum uric acid predicts the development of chronic kidney disease in patients with type 2 diabetes mellitus and preserved kidney function. J Diabetes Complicat 28:130–134CrossRefPubMedGoogle Scholar
  19. 19.
    Qin L, Yang Z, Gu H, Lu S, Shi Q, Xing Y et al (2014) Association between serum uric acid levels and cardiovascular disease in middle-aged and elderly Chinese individuals. BMC Cardiovasc Disord 14:26CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Joy NG, Perkins JM, Mikeladze M, Younk L, Tate DB, Davis SN (2016) Comparative effects of acute hypoglycemia and hyperglycemia on pro-atherothrombotic biomarkers and endothelial function in non-diabetic humans. J Diabetes Complicat 30:1275–1281CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Gogitidze Joy N, Hedrington MS, Briscoe VJ, Tate DB, Ertl AC, Davis SN (2010) Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals. Diabetes Care 33:1529–1535CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bedenis R, Price AH, Robertson CM, Morling JR, Frier BM, Strachan MW et al (2014) Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh Type 2 Diabetes Study. Diabetes Care 37:3301–3308CrossRefPubMedGoogle Scholar
  23. 23.
    Alcaino H, Greig D, Chiong M, Verdejo H, Miranda R, Concepcion R et al (2008) Serum uric acid correlates with extracellular superoxide dismutase activity in patients with chronic heart failure. Eur J Heart Fail 10:646–651CrossRefPubMedGoogle Scholar
  24. 24.
    Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ et al (1998) Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J 19:1814–1822CrossRefPubMedGoogle Scholar
  25. 25.
    Zhao G, Huang L, Song M, Song Y (2013) Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis 231:61–68CrossRefPubMedGoogle Scholar
  26. 26.
    Kamei K, Konta T, Ichikawa K, Sato H, Suzuki N, Kabasawa A et al (2016) Serum uric acid levels and mortality in the Japanese population: the Yamagata (Takahata) study. Clin Exp Nephrol 20:904–909CrossRefPubMedGoogle Scholar
  27. 27.
    Lyngdoh T, Marques-Vidal P, Paccaud F, Preisig M, Waeber G, Bochud M et al (2011) Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study. PLoS ONE 6:e19901CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kanellis J, Watanabe S, Li JH, Kang DH, Li P, Nakagawa T et al (2003) Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. Hypertension 41:1287–1293CrossRefPubMedGoogle Scholar
  29. 29.
    Ma QQ, Yang XJ, Yang NQ, Liu L, Li XD, Zhu K et al (2016) Study on the levels of uric acid and high-sensitivity C-reactive protein in ACS patients and their relationships with the extent of the coronary artery lesion. Eur Rev Med Pharmacol Sci 20:4294–4298PubMedGoogle Scholar
  30. 30.
    Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J et al (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146–M156CrossRefPubMedGoogle Scholar
  31. 31.
    Ren Y, Ji L, Mu Y, Hong T, Ji Q, Guo L et al (2016) Uric acid, renal function and risk of hypoglycaemia in Chinese type 2 diabetes patients. Diabetes Metab Res Rev 32:875–882CrossRefPubMedGoogle Scholar
  32. 32.
    Borghi C, Rosei EA, Bardin T, Dawson J, Dominiczak A, Kielstein JT et al (2015) Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens 33:1729–1741 (discussion 41) CrossRefPubMedGoogle Scholar
  33. 33.
    Bombelli M, Ronchi I, Volpe M, Facchetti R, Carugo S, Dell’oro R et al (2014) Prognostic value of serum uric acid: new-onset in and out-of-office hypertension and long-term mortality. J Hypertens 32:1237–1244CrossRefPubMedGoogle Scholar
  34. 34.
    Mantovani A, Rigolon R, Pichiri I, Pernigo M, Bergamini C, Zoppini G et al (2016) Hyperuricemia is associated with an increased prevalence of atrial fibrillation in hospitalized patients with type 2 diabetes. J Endocrinol Invest 39:159–167CrossRefPubMedGoogle Scholar
  35. 35.
    Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ (2013) The role of uric acid in the pathogenesis of human cardiovascular disease. Heart 99:759–766CrossRefPubMedGoogle Scholar
  36. 36.
    Strasak AM, Kelleher CC, Brant LJ, Rapp K, Ruttmann E, Concin H et al (2008) Serum uric acid is an independent predictor for all major forms of cardiovascular death in 28,613 elderly women: a prospective 21-year follow-up study. Int J Cardiol 125:232–239CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.First Clinic of Internal Medicine, Department of Internal MedicineUniversity of GenoaGenoaItaly
  2. 2.Diabetology Unit, Department of Internal MedicineUniversity of GenoaGenoaItaly
  3. 3.Center for Molecular CardiologyUniversity of ZürichSchlierenSwitzerland
  4. 4.Emergency Department, Ospedale Policlinico San MartinoGenoaItaly
  5. 5.Ospedale Policlinico San MartinoGenoaItaly
  6. 6.Centre of Excellence for Biomedical Research (CEBR)University of GenoaGenoaItaly

Personalised recommendations