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The Prediction of Atherosclerotic Cardiovascular Disease in Type 1 Diabetes Mellitus

2016; Lippincott Williams & Wilkins; Volume: 133; Issue: 11 Linguagem: Inglês

10.1161/circulationaha.116.021654

1524-4539

Robert H. Eckel, John E. Hokanson,

Diabetes Treatment and Management

HomeCirculationVol. 133, No. 11The Prediction of Atherosclerotic Cardiovascular Disease in Type 1 Diabetes Mellitus Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Prediction of Atherosclerotic Cardiovascular Disease in Type 1 Diabetes MellitusDo We Just Stop Here? Robert H. Eckel, MD and John E. Hokanson, MPH, PhD Robert H. EckelRobert H. Eckel From University of Colorado School of Medicine (R.H.E.) and University of Colorado School of Public Health (J.E.H.), Anschutz Medical Campus, Aurora. and John E. HokansonJohn E. Hokanson From University of Colorado School of Medicine (R.H.E.) and University of Colorado School of Public Health (J.E.H.), Anschutz Medical Campus, Aurora. Originally published17 Feb 2016https://doi.org/10.1161/CIRCULATIONAHA.116.021654Circulation. 2016;133:1051–1053Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 15, 2016: Previous Version 1 Type 1 diabetes mellitus (T1D) is well recognized to be associated with a higher incidence and prevalence of atherosclerotic cardiovascular disease (ASCVD).1 However, randomized clinical trials in which risk factors for ASCVD (blood pressure, lipids, glycemia) have been modified are nonexistent for T1D patients. Thus, any model that is developed must be based on observational data only. The Steno Risk Engine, as described in this issue of Circulation,2 is the second attempt at estimating ASCVD risk in T1D patients and differs somewhat in design and application from that previously created from the Swedish National Diabetes Register (NDR).3Article, see p 1058The Swedish NDR study was based on a model derived from 3661 T1D patients, with >90% having no history of ASCVD over a 5-year interval wherein 197 fatal/nonfatal ASCVD events (myocardial infarction or stroke) occurred. Nonfatal coronary heart disease was defined as nonfatal myocardial infarction, unstable angina, percutaneous coronary intervention, and/or coronary artery bypass grafting, whereas stroke was defined as fatal or nonfatal cerebral infarction or subarachnoid hemorrhage, or was unspecified. In the Swedish study, the hazard ratios for significant predictors of an ASCVD event were previous cardiovascular disease, 3.51; diabetes duration, 2.76; smoking, 1.76; macroalbuminuria (>200 μg/min), 1.52; age of onset of T1D, 1.47; log ratio total cholesterol:high-density lipoprotein cholesterol, 1.26; log hemoglobin A1c (HbA1c), 1.19; and log systolic blood pressure, 1.17. With the use of all 8 variables, the predicted 5-year risk was 5.4±7.9% with a C-statistic of 0.83.In contrast, the Steno Risk Engine was entirely a primary prevention model of first fatal/nonfatal cardiovascular disease (CVD) events that included ischemic heart disease, ischemic stroke, heart failure, and peripheral arterial disease from 4306 T1D patients, and it included ASCVD risk factors similar to the Swedish study + lifestyle. Over a median follow-up of 6.8 years, a much higher percentage of patients experienced an event, 793 or 18.4% of the cohort. The predictive model for ASCVD after postestimate shrinkage identified risk factors similar to the Swedish T1D Study (Table) with significant predictor rate ratios estimated for macroalbuminuria (≥300 mg/g creatinine), 2.09; microalbuminuria (30–299 mg/g creatinine), 1.55; age, 1.50; estimated glomerular filtration rate age 30 years, almost one-third of the population assessed. Is an absolute need for insulin therapy in patients with a low C-peptide or GAD65-positive antibodies sufficient to define T1D? Not infrequently, type 2 diabetes mellitus results in insulinopenia with inadequate basal insulin secretion (low C-peptide) and the need for insulin therapy,6 and GAD65-positive autoantibodies alone are less diagnostic for T1D than the presence of 2 to 4 autoantibodies.7 In addition, an inquiry relates to the reliability of spot versus 24 urine collections to assess the quantity of proteinuria. Although a spot urine is reasonably accurate in the microalbuminuric range, the reliability becomes less when protein excretion is in the higher range8; herein, 5.2% of the cohort had macroalbuminuria. Despite the limitations of assessing lifestyle at 1 point in time on future events, the Steno group deserves credit in addressing levels of physical activity in addition to alcohol consumption and tobacco. Unfortunately, nutrient intake patterns, an important part of ASCVD prevention,9 were not evaluated. What was so surprising was the relatively small risk ratio of tobacco use on ASCVD events (1.23 with 64.1% current smokers), in particular, in comparison with the Swedish cohort (1.76 with 24.4% smokers).Another risk that differed between the 2 studies was the duration of T1D with the Steno and Swedish studies quite discrepant, 1.14 versus 2.76, respectively. The average duration of diabetes mellitus in the Swedish study, however, was much longer (mean, 28.0 years) than in the Steno study (mean, 15.6 years). This is of interest in that the means for age were not that different, 44.6 versus 42.2, respectively, for the Swedish and Steno studies. Importantly, this builds on a previous point, there were many more patients in the Swedish study that developed diabetes mellitus at a younger age, thus, a longer duration.An interesting theme in T1D that appears to be developing is the relative weakness of relationships between conventional risk factors for ASCVD, eg, levels of glycemia, lipids, and blood pressure, on the measured outcome. Although a gradient relationship between HbA1c and ischemic heart disease incidence was seen in patients with 30 years of T1D, the only significant difference in data provided by the Danish Civil Registration System, the Danish Causes of Death Registry, and the Danish National Patient Registry was between the first quartile (5.5%–8.0%) and the fourth quartile (9.7%–14.0%).10 A similar statistical trend and first and fourth quartile comparison was seen for total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (inverse), and ischemic heart disease. In addition, another analysis from the Swedish NDR examined the cause of death in patients with T1D in comparison with age- and sex-matched controls and related the outcome to the importance of glycemia.11 Again, a gradient relationship for all-cause and CVD-related mortality was identified, but only the fifth quintile of HbA1c (≥9.7%) was significantly different from the other 4 quintiles for CVD death. A subsequent analysis demonstrated a reduced rate of fatal coronary heart disease in T1D patients managed with an insulin infusion pump versus multiple daily injections, but there was no relationship to levels of glycosylated hemoglobin.12 Moreover, despite recent evidence from the Diabetes Control and Complications Trial that demonstrated a legacy effect on all-cause mortality of being randomly assigned to the intensive versus control group (107 deaths, 22% from CVD), the impact of glycemic control was at best moderate (hazard ratio=1.56 per 10% relative increase in HbA1c; P<0.001).13 Although there were modest yet significant higher baseline levels of blood pressure, total cholesterol, and triglycerides in the dead versus alive, these numbers would all be considered normal: HbA1c, 9.5% versus 9.0%; blood pressure, 117/74 versus 114/72 mm Hg; total cholesterol, 182 versus 176; triglycerides, 90 versus 81 mg/dL.Clearly, macroalbuminuria and chronic renal disease incidence can be reduced by more aggressive glycemic and blood pressure control in patients with T1D, and this may be, at least in part, responsible for the stabilization of diabetic nephropathy in patients with T1D over the past 20 years.14 The Steno predictive model now demonstrates the importance of more exercise in addition to no tobacco use as modifiable risk factors. The modest importance of systolic blood pressure and low-density lipoprotein cholesterol cannot be ignored, but randomized, controlled trials in T1D with more aggressive blood pressure and lipid lowering have not been accomplished and appear unlikely with current evidence-based guidelines focused on type 2 diabetes mellitus.9,15,16 There's much still to be learned about T1D and ASCVD; however, the Steno Risk Engine does support a healthy lifestyle and improving blood pressure and glycemia optimally and, of course, including prevention of severe hypoglycemia. However, at present, it seems timely to address how much benefit versus risk relates to earlier and more aggressive control of blood pressure and lipids/lipoproteins in the prevention of ASCVD events and related mortality in patients with T1D.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Robert H. Eckel, MD, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045. E-mail [email protected]References1. de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, Magge SN, Marx N, McGuire DK, Orchard TJ, Zinman B, Eckel RH. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association.Circulation. 2014; 130:1110–1130. doi: 10.1161/CIR.0000000000000034.LinkGoogle Scholar2. Vistisen D, Andersen GS, Hansen CS, Hulman A, Henriksen JE, Bech-Nielsen H, Jørgensen ME. Prediction of first cardiovascular disease event in type 1 diabetes mellitus: the Steno type 1 risk engine.Circulation. 2016; 133:1058–1066. doi: 10.1161/CIRCULATIONAHA.115.018844.LinkGoogle Scholar3. Cederholm J, Eeg-Olofsson K, Eliasson B, Zethelius B, Gudbjörnsdottir S; Swedish National Diabetes Register. 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March 15, 2016Vol 133, Issue 11 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.021654PMID: 26888766 Originally publishedFebruary 17, 2016 Keywordsdiabetes mellitusmyocardial infarctionstrokerisk factorsEditorialstype 1risk assessmentcardiovascular diseasesPDF download Advertisement SubjectsCardiovascular DiseaseDiabetes, Type 1EpidemiologyPrimary PreventionRisk Factors