Dysglycemia and Cardiovascular Risk in the General Population
2009; Lippincott Williams & Wilkins; Volume: 119; Issue: 6 Linguagem: Inglês
10.1161/circulationaha.108.834408
ISSN1524-4539
Autores Tópico(s)Diabetes and associated disorders
ResumoHomeCirculationVol. 119, No. 6Dysglycemia and Cardiovascular Risk in the General Population Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDysglycemia and Cardiovascular Risk in the General Population Hertzel C. Gerstein Hertzel C. GersteinHertzel C. Gerstein From the Department of Medicine and the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada. Originally published17 Feb 2009https://doi.org/10.1161/CIRCULATIONAHA.108.834408Circulation. 2009;119:773–775Diabetes is a metabolic disorder that is diagnosed when the fasting and/or postload glucose level rises above well-established thresholds. These thresholds were chosen because they identified people at particularly high risk for retinopathy based on epidemiological data. These data also have shown that people with diabetes and poorly controlled glucose levels have higher risks of retinopathy than people with diabetes and well-controlled glucose levels.1,2 Moreover, recent studies have shown that the relationship between chronically elevated glucose levels (as measured by A1c) and retinal disease is not confined to people with diabetes and is apparent (although less marked) in people with high glucose levels that are below the diabetes cutoffs such as those with impaired glucose tolerance and/or impaired fasting glucose.3–5 Thus, there is a progressive relationship between glycemia and retinopathy that extends below glucose thresholds for diabetes.Article p 812Clearly, diabetes also is a risk factor for many other serious chronic diseases, including cardiovascular disease.6 Indeed, a recent meta-analysis of large prospective studies comprising 450 000 people showed that men and women with diabetes are 2 and 3 times more likely, respectively, to die of coronary heart disease than men and women without diabetes.7 Other studies have shown that the degree of glucose elevation measured by A1c, fasting glucose, or postload glucose is progressively related to the incidence of cardiovascular outcomes in people with established diabetes and in people without diabetes after adjustment for age and varying numbers of other risk factors.8–15 Moreover, several studies that recruited people from both ambulatory and hospitalized settings suggest that there may be a stronger relationship between glycemia and incident cardiovascular outcomes in people without diabetes than in people with diabetes.8,9,15–17 Such a discrepancy may occur because in people with established diabetes, markers of glycemia are a measure of both adequacy of therapy and exposure to hyperglycemia, whereas they reflect only exposure to hyperglycemia in people without diabetes (in whom glucose and A1c levels are not targets for therapy).Retinopathy and cardiovascular disease are clearly not the only outcomes related to progressively higher glucose levels. This is perhaps best illustrated by epidemiological analyses of prospective data from the United Kingdom Prospective Diabetes Study (UKPDS), which recruited people with a fasting plasma glucose level >6 mmol/L18 and which therefore included individuals with newly diagnosed diabetes as well as some individuals who would be classified as having impaired fasting glucose and not diabetes based on today's diagnostic criteria for diabetes (ie, fasting glucose level ≥7 mmol/L). As noted in the Figure, these analyses showed that progressively higher A1c levels predicted progressively higher hazards of severe retinal or renal disease, cataracts, myocardial infarction, heart failure, amputation or peripheral vascular disease, stroke, and death. They also showed that the risk relationship differed with respect to outcome, with a stronger relationship to some outcomes and a weaker relationship to others (the Figure). Thus, organ systems may vary in their susceptibility to damage related to glucometabolic abnormalities, a conclusion strongly supported by the epidemiological analysis reported in this issue of Circulation.19Download figureDownload PowerPointFigure. The relationship between updated A1c and the multivariable adjusted hazard of various chronic consequences of diabetes in participants in the UKPDS based on the reported difference per 1% higher A1c level.1 The hazard ratio of an A1c of 6% was set at 1.0. Line A, Amputation or death resulting from peripheral vascular disease (43% per 1%); B, retinal or renal disease (37% per 1%); C, cataract extraction (19% per 1%); D, heart failure (16% per 1%); E, myocardial infarction (14% per 1%) and all-cause death (14% per 1%); and F, stroke (12% per 1%). The same results are shown on a linear scale (left) and a log scale (right).Sung et al19 report an analysis of 652 901 Korean men 30 to 64 years of age who were followed up over a 9-year period with biannual health examinations within the Korean National Health Insurance system. They calculated average glucose levels for participants followed up during this interval of time and grouped them within clinically relevant categories. They did not analyze fasting glucose level as a continuous measure; instead, they analyzed the relationship between categories of average fasting serum glucose levels and incident myocardial infarction, ischemic stroke, and hemorrhagic stroke in 570 453 men without any missing data and reported the hazard after adjustment for age and for other cardiovascular risk factors. As reported in other studies, they found a progressive age-adjusted relationship between fasting glucose levels and both myocardial infarction and stroke that extended to normal fasting serum glucose levels. The relationship persisted with adjustment for several risk factors but was attenuated after additional adjustment for blood pressure, body mass index, and cholesterol levels. Moreover, the relationship was stronger for ischemic stroke than for either myocardial infarction or hemorrhagic stroke. Notably, their analysis detected an interaction between age and fasting glucose category in that older men had a stronger relationship between fasting glucose levels and these cardiovascular outcomes than younger men. Moreover, for stroke but not myocardial infarction, there was an interaction between body mass index and fasting glucose level category.The large number of participants and outcomes is a clear strength of this study. First, it allowed the investigators to examine the relationship between fasting glucose levels and different types of cardiovascular disease. Their observation of different relationships to myocardial infarction, ischemic stroke, and hemorrhagic stroke clearly supports the conclusion that the impact of glycemia on outcomes varies according to the outcome being assessed and extends it to different subtypes of stroke and to the general population. Second, the weaker relationship to myocardial infarction than to ischemic stroke may not have been apparent in smaller studies that did not have sufficient numbers of strokes to divide people according to the type of stroke. This finding should lead to further analyses in women and in other populations. Third, the large sample facilitated exploration of the role of confounders. The fact that adjusting for blood pressure cholesterol and body mass index attenuates the relationship between glucose and myocardial infarction to a greater extent than between glucose and ischemic stroke is interesting but unexplained. If anything, one would expect that adjustment for blood pressure would attenuate the relationship with stroke, which tends to be more strongly associated with blood pressure than myocardial infarction.Of note, this study was conducted in relatively healthy men within the general Korean population whose 9-year incidence of myocardial infarction and stroke was quite low at 0.6% and 1.7%, respectively (ie, 5.5 mmol/L and myocardial infarction in older versus younger people suggests that the importance of dysglycemia as a cardiovascular risk factor may be greater in people at higher risk of cardiovascular disease. It would also have been very interesting if the risk for cardiovascular outcomes across progressively higher fasting glucose levels (measured as a continuous variable) had been presented in addition to the risk across discrete categories of fasting glucose. Such an analysis would be relevant in light of the spline distribution of the data (Data Supplement Figure I in the article by Sung et al19), which is consistent with a progressive versus a threshold relationship between fasting glucose levels and both myocardial infarction and ischemic stroke.In summary, a fasting glucose level above normal is a progressive risk factor for cardiovascular outcomes, and the magnitude of the risk rises with age and is greater for ischemic stroke than for myocardial infarction or hemorrhagic stroke. Whether specifically targeting lower fasting glucose levels can reduce cardiovascular outcomes remains unknown. Some clues may reside in the 10-year-long UKPDS, which randomized people with newly diagnosed diabetes and few other cardiovascular risk factors to a policy of targeting a fasting plasma glucose <6 mmol/L versus a conventional policy targeting a fasting plasma glucose 12 500 people with impaired fasting glucose, impaired glucose tolerance, or early diabetes to 1 injection of insulin glargine that is titrated to a fasting plasma glucose ≤5.3 mmol/L versus standard care.25 Data from this and other trials underway will clarify the therapeutic implications of epidemiological observations such as those published in this issue.19The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.DisclosuresDr Gerstein's institution receives funding from Sanofi-Aventis to conduct the ORIGIN trial of the effect of lowering fasting glucose levels with glargine insulin on cardiovascular outcomes. Dr Gerstein holds the McMaster Population Health Research Institute Chair in Diabetes (sponsored by Aventis).FootnotesCorrespondence to Dr H.C. Gerstein, Department of Medicine, Room 3V38, 1200 Main St W, Hamilton, Ontario, L8N 3Z5, Canada. E-mail [email protected] References 1 Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000; 321: 405–412.CrossrefMedlineGoogle Scholar2 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997; 20: 1183–1197.CrossrefMedlineGoogle Scholar3 Wong TY, Liew G, Tapp RJ, Schmidt MI, Wang JJ, Mitchell P, Klein R, Klein BE, Zimmet P, Shaw J. Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studies. Lancet. 2008; 371: 736–743.CrossrefMedlineGoogle Scholar4 Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007; 24: 137–144.CrossrefMedlineGoogle Scholar5 Gerstein HC, Pogue J, Mann JF, Lonn E, Dagenais GR, McQueen M, Yusuf S. The relationship between dysglycaemia and cardiovascular and renal risk in diabetic and non-diabetic participants in the HOPE study: a prospective epidemiological analysis. Diabetologia. 2005; 48: 1749–1755.CrossrefMedlineGoogle Scholar6 Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364: 937–952.CrossrefMedlineGoogle Scholar7 Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ. 2006; 332: 73–78.CrossrefMedlineGoogle Scholar8 Selvin E, Coresh J, Golden SH, Brancati FL, Folsom AR, Steffes MW. Glycemic control and coronary heart disease risk in persons with and without diabetes: the Atherosclerosis Risk in Communities Study. Arch Intern Med. 2005; 165: 1910–1916.CrossrefMedlineGoogle Scholar9 Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European Prospective Investigation Into Cancer in Norfolk. Ann Intern Med. 2004; 141: 413–420.CrossrefMedlineGoogle Scholar10 Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ. 2001; 322: 1–6.CrossrefMedlineGoogle Scholar11 Danaei G, Lawes CM, Vander HS, Murray CJ, Ezzati M. Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment. Lancet. 2006; 368: 1651–1659.CrossrefMedlineGoogle Scholar12 Lawes CM, Parag V, Bennett DA, Suh I, Lam TH, Whitlock G, Barzi F, Woodward M. Blood glucose and risk of cardiovascular disease in the Asia Pacific region. Diabetes Care. 2004; 27: 2836–2842.CrossrefMedlineGoogle Scholar13 Brunner EJ, Shipley MJ, Witte DR, Fuller JH, Marmot MG. Relation between blood glucose and coronary mortality over 33 years in the Whitehall Study. Diabetes Care. 2006; 29: 26–31.CrossrefMedlineGoogle Scholar14 Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, Sleight P, Teo K. Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk. Circulation. 2007; 115: 1371–1375.LinkGoogle Scholar15 Gerstein HC, Swedberg K, Carlsson J, McMurray JJ, Michelson EL, Olofsson B, Pfeffer MA, Yusuf S. The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program. Arch Intern Med. 2008; 168: 1699–1704.CrossrefMedlineGoogle Scholar16 Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y, Havranek EP, Krumholz HM. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation. 2005; 111: 3078–3086.LinkGoogle Scholar17 Goyal A, Mahaffey KW, Garg J, Nicolau JC, Hochman JS, Weaver WD, Theroux P, Oliveira GB, Todaro TG, Mojcik CF, Armstrong PW, Granger CB. Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study. Eur Heart J. 2006; 27: 1289–1297.CrossrefMedlineGoogle Scholar18 UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352: 837–853.CrossrefMedlineGoogle Scholar19 Sung J, Song Y-M, Ebrahim S, Lawlor D. Fasting blood glucose and the risk of stroke and myocardial infarction. Circulation. 2009; 119: 812–819.LinkGoogle Scholar20 UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998; 352: 854–865.CrossrefMedlineGoogle Scholar21 Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359: 1577–1589.CrossrefMedlineGoogle Scholar22 Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358: 2545–2559.CrossrefMedlineGoogle Scholar23 Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD, for the VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360: 129–139.CrossrefMedlineGoogle Scholar24 ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358: 2560–2572.CrossrefMedlineGoogle Scholar25 Origin Trial Investigators. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction With an Initial Glargine Intervention). 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February 17, 2009Vol 119, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.108.834408PMID: 19221229 Originally publishedFebruary 17, 2009 Keywordsmyocardial infarctionEditorialsglucosestrokerisk factorsepidemiologyPDF download Advertisement SubjectsDiabetes, Type 2EpidemiologyIntracranial HemorrhageIschemic StrokeMyocardial Infarction
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