{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:13:35Z","timestamp":1787858015390,"version":"build-2784847793"},"reference-count":48,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T00:00:00Z","timestamp":1609286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Atherosclerotic cardiovascular disease (CVD) is the major cause of morbidity and mortality in individuals with diabetes mellitus (DM). Preclinical models have suggested that excessive oxidative stress and hyperglycemia are directly responsible for this pathological association. However, numerous clinical trials involving the administration of high doses of the antioxidant vitamin E or attempts at strict glycemic control have failed to show a significant reduction of CVD in DM patients. We describe here a possible explanation for the failure of these trials, that being their lack of proper patient selection. The haptoglobin (Hp) genotype is a major determinant of the risk of CVD in the setting of DM. Treatment of individuals with the high-risk Hp genotype with antioxidants or aggressive glycemic control has shown benefit in several small studies. These studies suggest a precision medicine-based approach to preventing diabetes complications. This approach would have a profound effect on the costs of diabetes care and could dramatically reduce morbidity from diabetes.<\/jats:p>","DOI":"10.3390\/ijms22010287","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T09:35:23Z","timestamp":1609320923000},"page":"287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The Role of Haptoglobin Polymorphism in Cardiovascular Disease in the Setting of Diabetes"],"prefix":"10.3390","volume":"22","author":[{"given":"Shmuel","family":"Somer","sequence":"first","affiliation":[{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 1 Efron st. Bat Galim, Haifa 3525433, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Levy","sequence":"additional","affiliation":[{"name":"Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 1 Efron st. Bat Galim, Haifa 3525433, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.4239\/wjd.v6.i13.1246","article-title":"Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research","volume":"6","author":"Leon","year":"2015","journal-title":"World J. Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/S0140-6736(10)60484-9","article-title":"Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies","volume":"375","author":"Sarwar","year":"2010","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s11892-017-0868-1","article-title":"Interaction between the haptoglobin genotype and vitamin E on cardiovascular disease in diabetes","volume":"17","author":"Hochberg","year":"2017","journal-title":"Curr. Diab. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1001\/archinte.158.6.668","article-title":"Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease","volume":"158","author":"Virtamo","year":"1998","journal-title":"Arch. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1056\/NEJMoa0802987","article-title":"ADVANCE collaborative group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes","volume":"358","author":"Patel","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.jacc.2019.11.051","article-title":"Haptoglobin phenotype modifies the influence of intensive glycemic control on cardiovascular outcomes","volume":"75","author":"Carew","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"649","DOI":"10.3233\/JAD-191294","article-title":"Vitamin E intake is associated with lower brain volume in haptoglobin 1-1 elderly with type 2 diabetes","volume":"74","author":"Livny","year":"2020","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3389\/fcvm.2018.00141","article-title":"Precision healthcare of type 2 diabetic patients through implementation of haptoglobin genotyping","volume":"5","author":"Bale","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s12933-019-0867-4","article-title":"Association of haptoglobin phenotype with incident acute myocardial infarction in Chinese patients with type 2 diabetes","volume":"18","author":"Gurung","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.cca.2019.03.1617","article-title":"Genetic determinants of circulating haptoglobin concentration","volume":"494","author":"Kazmi","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"148","DOI":"10.2337\/diaclin.34.3.148","article-title":"Role of haptoglobin in health and disease: A focus on diabetes","volume":"34","author":"MacKellar","year":"2016","journal-title":"Clin. Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1093\/clinchem\/42.10.1589","article-title":"Biological and clinical significance of haptoglobin polymorphism in humans","volume":"42","author":"Langlois","year":"1996","journal-title":"Clin. Chem."},{"key":"ref_13","first-page":"71","article-title":"Meta-analysis of the association of the haptoglobin genotype with cardiovascular outcomes and the pharmacogenomic interactions with vitamin E supplementation","volume":"11","author":"Asleh","year":"2018","journal-title":"Pharmgenomics Pers. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3317\/jraas.2000.002","article-title":"The HOPE Study (Heart Outcomes Prevention Evaluation)","volume":"1","author":"Sleight","year":"2000","journal-title":"J. Renin. Angiotensin Aldosterone Syst."},{"key":"ref_15","first-page":"154","article-title":"Vitamin E supplementation and cardiovascular events in high-risk patients","volume":"20","author":"Yusuf","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1093\/oxfordjournals.aje.a115757","article-title":"The Strong Heart Study. A study of cardiovascular disease in American Indians: Design and methods","volume":"132","author":"Lee","year":"1990","journal-title":"Am. J. Epidemiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.2337\/diacare.26.9.2628","article-title":"Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes","volume":"26","author":"Roguin","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1159\/000492329","article-title":"In a nutshell: Findings from the Bruneck study","volume":"65","author":"Kiechl","year":"2019","journal-title":"Gerontology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1007\/s00125-007-0797-7","article-title":"Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mellitus: Findings from the Pittsburgh Epidemiology of diabetes complications study (EDC)","volume":"50","author":"Prince","year":"2007","journal-title":"Diabetologia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1001\/jama.294.1.56","article-title":"Vitamin E in the primary prevention of cardiovascular disease and cancer. The Women\u2019s Health Study: A Randomized Controlled Trial","volume":"294","author":"Lee","year":"2005","journal-title":"JAMA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1111\/j.1572-0241.2008.02188.x","article-title":"Hepatic steatosis and subclinical cardiovascular disease in a cohort enriched for type 2 diabetes: The Diabetes Heart Study","volume":"103","author":"McKimmie","year":"2008","journal-title":"Am. J. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.2337\/dc13-2112","article-title":"The diabetes control and complications trial\/epidemiology of diabetes interventions and complications study at 30 years: Overview","volume":"37","author":"Nathan","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1016\/S2213-8587(18)30137-2","article-title":"Transition from metabolic healthy to unhealthy phenotypes and association with cardiovascular disease risk across BMI categories in 90,257 women (the Nurses\u2019 Health Study): 30-year follow-up from a prospective cohort study","volume":"6","author":"Eckel","year":"2018","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_24","first-page":"m513","article-title":"Egg consumption and risk of cardiovascular disease: Three large prospective US cohort studies, systematic review, and updated meta-analysis","volume":"368","author":"Chen","year":"2020","journal-title":"BMJ"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1177\/2047487318794521","article-title":"Haptoglobin and haptoglobin genotypes in diabetes: A silver bullet to identify the responders to antioxidant therapy?","volume":"25","year":"2018","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1007\/s12975-017-0535-5","article-title":"CD163, a hemoglobin\/haptoglobin scavenger receptor, after intracerebral hemorrhage: Functions in microglia\/macrophages versus neurons","volume":"8","author":"Garton","year":"2017","journal-title":"Transl. Stroke Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.2337\/db08-0450","article-title":"Corrections of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype","volume":"57","author":"Asleh","year":"2008","journal-title":"Diabetes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1161\/CIRCRESAHA.107.149435","article-title":"Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2-2 genotype: Implications for the response to intraplaque hemorrhage and plaque vulnerability","volume":"101","author":"Levy","year":"2007","journal-title":"Circ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1016\/j.jacc.2016.03.533","article-title":"Haptoglobin genotype as a determinant of benefit or harm from niacin for participants with diabetes","volume":"67","author":"Asleh","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Goldenstein, H., Levy, N.S., Ward, J., Costacou, T., and Levy, A.P. (2018). Haptoglobin genotype is a determinant of hemoglobin adducts and vitamin E content in HDL. J. Diabetes Res.","DOI":"10.1155\/2018\/6125420"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1161\/ATVBAHA.118.312232","article-title":"Haptoglobin phenotype is associated with high-density lipoprotein-bound hemoglobin content and coronary endothelial dysfunction in patients with mild nonobstructive coronary artery disease","volume":"39","author":"Asleh","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1177\/2047487318776829","article-title":"The protean role of haptoglobin and haptoglobin genotypes on vascular complications in diabetes mellitus","volume":"25","author":"Dalan","year":"2018","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/0005-2736(86)90501-8","article-title":"Vitamin E in young and old human red blood cells","volume":"860","author":"Burton","year":"1986","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41387-020-0116-7","article-title":"Impact of vitamin E supplementation on vascular function in haptoglobin genotype stratified diabetes patients (EVAS Trial): A randomised controlled trial","volume":"10","author":"Dalan","year":"2020","journal-title":"Nutr. Diabetes"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3904\/kjim.2015.30.5.571","article-title":"Evidence for beneficial effects of vitamin E","volume":"30","author":"Niki","year":"2015","journal-title":"Korean J. Intern. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ijcme.2016.06.003","article-title":"Is vitamin E supplementation effective in reducing mortality related to cardiovascular events in people with type 2 diabetes mellitus? A systematic review","volume":"12","author":"Patel","year":"2016","journal-title":"IJC Metab. Endocr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.diabres.2017.06.026","article-title":"Anti-oxidative treatment with vitamin E improves peripheral vascular function in patients with diabetes mellitus and Haptoglobin 2-2 genotype: A double-blinded cross-over study","volume":"131","author":"Alshiek","year":"2017","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"37","DOI":"10.7326\/0003-4819-142-1-200501040-00110","article-title":"Meta-analysis: High dosage vitamin E supplementation may increase all-cause mortality","volume":"142","author":"Miller","year":"2005","journal-title":"Ann. Intern. Med."},{"key":"ref_39","first-page":"95","article-title":"Clinical importance of haptoglobin testing in diabetes","volume":"6","author":"Vigerust","year":"2016","journal-title":"Diabetes Manag."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2767","DOI":"10.2337\/diacare.27.11.2767","article-title":"The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes","volume":"27","author":"Levy","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1161\/ATVBAHA.107.153965","article-title":"Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: A prospective double-blinded clinical trial","volume":"28","author":"Milman","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"s28","DOI":"10.2337\/diacare.26.2007.S28","article-title":"American Diabetes Association. Implications of the United Kingdom prospective diabetes study","volume":"26","author":"Genuth","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.jacc.2019.11.052","article-title":"Should the haptoglobin be considered in setting glycemic goals for diabetes patients?","volume":"75","author":"Costacou","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2337\/dc08-9026","article-title":"Intensive glycemic control and the prevention of cardiovascular events: Implications of the accord, advance, and va diabetes trials","volume":"32","author":"Skyler","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_45","first-page":"2545","article-title":"Action to control cardiovascular risk in diabetes study group","volume":"12","author":"Gerstein","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.jacc.2012.09.063","article-title":"Haptoglobin genotype is a consistent marker of coronary heart disease risk among individuals with elevated glycosylated hemoglobin","volume":"61","author":"Cahill","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_47","first-page":"158","article-title":"DNA polymorphisms in the controlling region of the human haptoglobin genes: A molecular explanation for the haptoglobin 2-1 modified phenotype","volume":"49","author":"Maeda","year":"1991","journal-title":"Am. J. Hum. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"169","DOI":"10.2147\/DMSO.S61438","article-title":"Importance of cardiovascular disease risk management in patients with type 2 diabetes mellitus","volume":"7","author":"Lorber","year":"2014","journal-title":"Diabetes Metab. Syndr. Obes."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:47:44Z","timestamp":1760179664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,30]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010287"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010287","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,30]]}}}