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Impact of Lipoprotein(a) on Long-term Outcomes in Patients With Diabetes Mellitus Who Underwent Percutaneous Coronary Intervention
Impact of Lipoprotein(a) on Long-term Outcomes in Patients With Diabetes Mellitus Who Underwent Percutaneous Coronary Intervention Hirokazu Konishi, MD, PhDa, Katsumi Miyauchi, MDb,*, Jun Shitara, MDa, Hirohisa Endo, MDb, Hideki Wada, MDb, Shinichiro Doi, MDb, Ryo Naito, MDb, Shuta Tsuboi, MD, PhDa, Manabu Ogita, MD, PhDa, Tomotaka Dohi, MD, PhDb, Takatoshi Kasai, MD, PhDb, Shinya Okazaki, MDb, Kikuo Isoda, MDb, Satoru Suwa, MDa, and Hiroyuki Daida, MDb Patients with diabetes mellitus (DM) are at twofold to fourfold higher cardiovascular risk than those without DM. Serum levels of lipoprotein(a) (Lp(a)) can be risk factors for adverse events. However, the clinical implications of Lp(a) in patients with DM who underwent percutaneous coronary intervention (PCI) is unknown. The aim of the study was to determine the role of Lp(a) in patients with DM who underwent PCI. A total of 3,508 patients were treated by PCI from 1997 to 2011 at our institution. Among them, we analyzed consecutive 1,546 patients with DM. Eligible 1,136 patients were divided into 2 groups (high Lp(a) [n [ 575] and low Lp(a) [n [ 561]) by the median of Lp(a) levels. The number of chronic kidney disease, multivessel disease, and the level of LDL-C were higher in the group with high Lp(a) than with low Lp(a). The median follow-up period was 4.7 years. Event rate of all-cause death was same between the 2 groups (p [ 0.37). However, cumulative incidence of cardiac death and acute coronary syndrome was significantly higher in the high Lp(a) than in the low Lp(a) group (p [ 0.03). Multivariable analysis selected a high Lp(a) level as an independent predictor of cardiac death and acute coronary syndrome (hazard ratio 1.20; 95% confidence interval 1.00 to 1.42; p [ 0.04). In conclusion, a high Lp(a) value could be associated with advanced cardiac events after PCI for patients with DM. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;-:-e-)
Patients with diabetes mellitus (DM) are at twofold to fourfold higher cardiovascular risk compared with those without DM.1 Patients with DM who underwent PCI have worse outcomes compared with those without DM even in the era of drug-eluting stent.2 Therefore, it is important for patients with DM to investigate some residual risk factors of cardiovascular events to reduce these events. Lipoprotein(a) (Lp(a)) is a modified form of low-density lipoprotein in which the large glycoprotein apolipoprotein(a) is covalently bound to apolipoprotein B by a disulfide bridge.3 Consequently, elevated serum levels of Lp(a) are associated with increased risk of major adverse cardiac events in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI).4,5 However, it remains unclear whether Lp(a) contributes to increased cardiovascular disease in patients with DM. We, therefore, investigated the
a Department of Cardiology, Juntendo University Shizuoka Hospital, Shizuoka, Japan; and bDepartment of Cardiology, Juntendo University School of Medicine, Tokyo, Japan. Manuscript received May 7, 2016; revised manuscript received and accepted August 19, 2016. This study was supported in grant-in-aid for scientific research from Ministry of Health, Labor, and Welfare (23591063). See page 4 for disclosure information. *Corresponding author: Tel: (þ81) 3-5802-1056; fax: (þ81) 3-56890627. E-mail address: [email protected] (K. Miyauchi).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.08.067
impact of Lp(a) on long-term outcomes of patients with DM who underwent PCI. Methods This study was single-center observational cohort study at the Juntendo University Hospital (Tokyo, Japan). Consecutive Japanese patients who underwent PCI in our institution from January 1997 to October 2011 were considered for this analysis. We enrolled diabetic patients, where DM was defined as fasting plasma glycemic levels 126 mg/dl, medication with oral hypoglycemic drugs, or insulin injections. The exclusion criteria were as follows: (1) missing Lp(a) data and (2) the patients who undergo dialysis because Lp(a) plasma levels are obviously increased in such patients due to kidney dysfunction.6 The patients were divided into 2 groups by the median of Lp(a) levels. The internal review board of the Juntendo University Hospital approved this study, and written informed consent to participate was obtained from all patients. Baseline data included age, gender, body mass index (BMI), blood pressure (BP), total cholesterol, HDL-C, LDLC, triglycerides, Lp(a), fasting blood glucose at the time of PCI, smoking status, family history of CAD, medication use, revascularization procedure-related factors, and comorbidities were prospectively collected from each patients. Blood samples were collected during the early morning after an overnight fast. Hypertension was defined as systolic BP 140 mm Hg, diastolic BP 90 mm Hg, www.ajconline.org
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Table 1 Baseline characteristics of the patients
Age (years) Male Current smoker Hypertension Body mass index (kg/m2) Low-density lipoprotein High-density lipoprotein Triglycerides Lipoprotein(a) eGFR<60mL/min/1.73m2 HbA1c Left ventricular ejection fraction Acute coronary syndrome Multivessel disease Type B2/C lesion Left anterior descending lesion Drug eluting stent Use of medication Aspirin Antiplatelet drug b-blocker ACE-I/ARB Calcium channel blocker Statin Oral hypoglycemic agents Insulin
Low Lp (a) (< 20.4mg/dl) (n ¼ 561)
High Lp (a) (20.4mg/dl) (n ¼ 575)
P
65.610.0 481 (85.7%) 130 (23.2%) 407 (72.6%) 24.53.5 105.031.9mg/dl 42.911.5mg/dl 146.883.6mg/dl 11 (6.0-15.3) mg/dl 120 (21.4%) 7.21.2% 62.712.6% 157 (27.9%) 316 (56.3%) 481 (85.8%) 255 (45.4%) 239 (42.6%)
65.09.6 468 (81.4%) 133 (23.1%) 405 (70.4%) 24.53.6 112.632.1mg/dl 42.414.2mg/dl 136.3106.1mg/dl 33 (26.4-50.8) mg/dl 167 (29.0%) 7.43.4% 61.413.3% 127 (22.1%) 362 (62.9%) 515 (89.5%) 250 (43.5%) 177 (30.8%)
0.30 0.06 0.97 0.43 0.93 <0.01 0.51 0.07 <0.01 <0.01 0.19 0.08 0.02 0.02 0.11 0.50 <0.01
527 447 252 296 241 281 280 102
(93.9%) (79.7%) (44.9%) (52.8%) (42.9%) (50.2%) (49.9%) (18.2%)
542 461 266 293 227 316 261 128
(94.2%) (80.2%) (46.4%) (51.1%) (39.5%) (54.9%) (45.4%) (22.2%)
0.34 0.45 0.62 0.65 0.23 0.10 0.16 0.09
ACE-I ¼ angiotensin-converting enzyme inhibitors; ARB ¼ angiotensin-receptor blockers; eGFR ¼ estimated glomerular filtration rate.
or medication with antihypertensive drugs. DM was defined as fasting plasma glycemic levels 126 mg/dl, medication with oral hypoglycemic drugs, or insulin injections. A current smoker was defined as a person who smoked at the time of PCI or had quit smoking within the year before PCI. Indications for PCI were based on objective evidence of myocardial ischemia (positive stress test), ischemic symptoms, or signs associated with significant angiographic stenosis. Levels of Lp(a) were measured using latex agglutination immunoassays (Special Reference Laboratories, Hachioji, Japan). The follow-up period ended on December 31, 2011. Survival data and information about incident acute coronary syndrome (ACS) were collected by serial contact with the patients or their families and were assessed from the medical records of patients who had died or of those who were followed up at our hospital. Information about the circumstances and date of death were obtained from the families of patients who died at home, and details of events of the cause of death were supplied by other hospitals or clinics where the patients had been admitted. All data were collected by blinded investigators. ACS was defined as ST-elevation myocardial infarction (STEMI), noneST-elevation myocardial infarction (NSTEMI), or unstable angina. We determined STEMI based on symptoms of ischemia with ST-segment elevation on the electrocardiogram and increased serum levels of cardiac enzymes (troponin, CKMB, and creatine kinase of twofold increase or more)7,8
and NSTEMI based on symptoms of ischemia without STsegment elevation on the electrocardiogram and increased serum levels of cardiac enzymes. Unstable angina pectoris was determined based on symptoms of ischemia at rest or with a crescendo of symptoms or new-onset symptoms associated with transient ischemic ST-segment shifts and normal serum levels of cardiac enzymes.9 Cardiac death was defined as death caused by myocardial infarction, heart failure, and sudden death. The end points of this study were all-cause death and a composite of cardiac death and incident ACS. The results are expressed as mean SD or medians (interquartile range) for continuous variables and as ratio (%) for categorical variables. Baseline data were compared using an unpaired t test or the Mann-Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Kaplan-Meier event-free survival curves were compared using the log-rank test. Factors associated with outcomes were determined using univariable Cox regression analysis including age, gender, BMI, hypertension, HbA1c, LDL-C, HDL-C, triglycerides, high or low Lp(a) levels, current smoker, estimated glomerular filtration rate (eGFR), ACS, left ventricular ejection fraction, multivessel disease, type B2/C lesion, left anterior descending lesion, insulin, b blockers, angiotensinconverting enzyme inhibitors/angiotensin-receptor blockers, and statins as independent variables. Variables with significant or borderline significant associations (p <0.10) with
Coronary Artery Disease/Lipoprotein(a) as Coronary Risk for Diabetes
3
Figure 1. Kaplan-Meier curve for all-cause death (A) and composite end point of cardiac death and ACS (B). The incident of all-cause death was same between the 2 groups (p ¼ 037; log-rank test) (A). Cardiac outcomes were significantly worse for patients with high than low Lp(a) (p ¼ 0.03; log-rank test) (B).
Table 2 Cox proportional hazards models for predictors of composite endpoint Univariate
Age Gender (F/M) Body mass index Hypertension HbA1c Low-density lipoprotein High-density lipoprotein Triglycerides Lipoprotein(a) (high / low) Current smoker eGFR Acure coronary syndrome Left ventricular ejection fraction Multivessel disease Type B2/C lesion Left anterior descending lesion Insulin b-blockers ACE-I/ARB Statins Log Lipoprotein(a)
Multivariate
HR
95%CI
P
HR
95%CI
P
1.03 1.25 0.95 1.09 1.02 1.00 1.00 1.00 1.27 1.09 0.99 1.18 0.98 1.68 1.49 1.05 1.45 0.90 0.92 0.77 1.29
1.02-1.04 0.93-1.66 0.91-0.98 0.85-1.40 0.98-1.04 0.99-1.01 0.99-1.01 0.99-1.00 1.01-1.61 0.82-1.48 0.98-0.99 0.92-1.51 0.97-0.99 1.32-2.15 0.88-2.77 0.93-1.32 1.09-1.90 0.71-1.14 0.73-1.17 0.61-0.98 1.09-1.53
<0.01 0.13 <0.01 0.52 0.15 0.80 0.98 0.42 0.04 0.56 0.01 0.19 <0.01 <0.01 0.14 0.70 0.01 0.40 0.49 0.03 <0.01
1.03
1.01-1.04
<0.01
0.98
0.94-1.02
0.40
1.20
1.00-1.42
0.04
0.99
0.98-0.99
0.04
0.98 1.65
0.97-0.99 1.28-2.15
<0.01 <0.01
1.52
1.13-2.02
<0.01
0.80 1.32*
0.63-1.04 1.02-1.62*
0.09 0.01*
ACE-I ¼ angiotensin-converting enzyme inhibitors; ARB ¼ angiotensin-receptor blockers; CI ¼ confidence interval; eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio. * Adjusted for age, BMI, eGFR, LVEF, multivessel disease, insulin, statins.
outcomes were then included in multivariable Cox regression analyses. The assumption of proportional hazards was assessed using a log-minus-log survival graph. p <0.05 was considered to indicate significance, unless otherwise indicated. All data were analyzed using JMP 10.0 MDSU statistical software (SAS Institute, Cary, North Carolina). Results Of the 3,508 patients who underwent PCI, 1,546 patients with DM were analyzed. We excluded patients with dialysis and those who did not have Lp(a) data at the time of PCI. Table 1 lists the baseline characteristics of these patients. The number of chronic kidney disease (eGFR
<60 ml/min/1.73 m2), multivessel disease, and the level of LDL-C were higher in the group with high Lp(a) than with low Lp(a). The number of use of drug-eluting stents and ACS was higher in the group with low than with high Lp(a). Other characteristics were similar between the 2 groups. Outcome data were fully documented during the followup period (median 4.7 years, interquartile range 1.2 to 6.4). Figure 1 shows event-free survival curves. Event rate of allcause death was same between 2 groups. However, the incidence of cardiac death and/or ACS was significantly higher in the group with high than with low Lp(a). Univariate analysis identified age, BMI, Lp(a) (high/low), eGFR, left ventricular ejection fraction, multivessel disease, insulin, and statins as significant variables as for the
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predictors of cardiac death and ACS (Table 2). Multivariate Cox proportional hazards regression analysis revealed that age, Lp(a) (high/low), left ventricular ejection fraction, multivessel disease, eGFR, and insulin were significant independent predictors of a worse cardiac outcome (Table 2). We made further analysis about Lp(a). Because Lp(a) (high/ low) is a categorical variable, we used log Lp(a) (natural logarithm), which is a continuous variable, in this analysis. Multivariable analysis adjusted by same variables (Table 2) also selected log Lp(a) as a significant independent predictor of a worse cardiac outcome (hazard ratio 1.32; 95% CI 1.02 to 1.62; p ¼ 0.01). Discussion We assessed the prognostic value of Lp(a) in the patients with DM after PCI. The major findings of the present study are as follows: (1) an elevated Lp(a) level is an independent risk factor for cardiac death and/or ACS recurrence in the patients with DM who underwent PCI; (2) serum levels of Lp(a) are associated with a worse prognosis in the patients with DM after PCI; and (3) an elevated Lp(a) as a categorical and as a continuous variable was associated with worse cardiac prognosis in patients with DM after PCI. These are notable because there are no data about the relation between serum levels of Lp(a) and cardiovascular events in terms of secondary prevention after PCI in patients with DM. Lp(a) is a modified form of low-density lipoprotein in which the large glycoprotein apolipoprotein(a) is covalently bound to apolipoprotein B by a disulfide bridge.3 There is evidence that elevated levels of Lp(a) contribute significantly to the incidence of cardiovascular diseases.10e12 Several previous studies have already indicated relation between an elevated Lp(a) and increased risk of cardiovascular disease in patients with CAD.13e15 In the field of a primary prevention of CAD in patients with DM, several studies found that high serum levels of Lp(a) were associated with increased risk for CAD16 and cardiovascular disease,17,18 whereas others did not find any significant association.19,20 Therefore, it remains unclear whether serum levels of Lp(a) predicts for increased cardiovascular disease risk in patients with DM as primary prevention of cardiovascular disease. Furthermore, there are no reports about secondary prevention of cardiovascular disease in diabetic patients with CAD. In addition, patients with DM have 4% to 17% lower Lp(a) levels than those without DM.11 To our knowledge, our present study is the first one to demonstrate the prognostic value of an elevated Lp(a) level in patients with DM who underwent PCI. The pathophysiological role of Lp(a) in CAD progression is explained by the atherogenic and inhibitory effects of Lp(a) on fibrinolysis. Accumulating Lp(a) in atherosclerotic plaques promotes cholesterol accumulation in macrophages that form foam cells21 and the proliferation and migration of smooth muscle cells in atherosclerotic lesions.22 Because of structural similarity with plasminogen, binding to fibrin, and exerting anti-fibrinolytic actions, Lp(a) causes thrombosis.23 Endothelial dysfunction and prothrombotic and proinflammatory states are important features of the accelerated atherosclerotic process observed in patients with DM.24
Serum Lp(a) concentrations enhance inflammation and lead to insulin resistance as a result of autoimmune response.25 These might have contributed to the significantly worse cardiac outcomes of the group with high Lp(a) in the present study. Serum levels of Lp(a) are genetically determined; >90% of the variance in Lp(a) concentrations can be explained by genetics and it cannot be altered by diet or exercise.23,26 However, some new drugs were reported to modify Lp(a) levels. For example, the cholesterol ester transfer protein inhibitor anacetrapib decreased Lp(a) by 38.8% after 76 weeks.27 Proprotein convertase subtilisin/ kexin 9 inhibitor also decreased Lp(a) levels by 10% to 30% after 12 weeks.28 Drug therapy that targets Lp(a) reduction might have potential for secondary prevention of CAD to patients with DM. The potential benefit of Lp(a)-directed drugs in development, and the prognostic utility of Lp(a) as a surrogate marker, awaits the results of clinical trials. Our findings suggest that an elevated Lp(a) level may contribute to the worse prognosis in patients with DM who underwent PCI and that serum levels of Lp(a) is an important clinical consideration in those with DM after PCI. Serum levels of Lp(a) could predict worse clinical outcomes for patients with DM who underwent PCI. Confirming Lp(a) might help to reduce cardiovascular morbidity and mortality in patients with DM after PCI. The present observational study has some limitations. The study was conducted in a single institution, and the subjects were only Japanese. Although we applied multivariable Cox proportional hazards models including several known confounding variables, other unknown confounders might have played more roles. Acknowledgments: The authors gratefully acknowledge Yumi Nozawa and Ayako Onodera for data collection and management.
Disclosures None of the authors has any relation with industry that could influence the impartiality of this study. 1. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 2002;287: 2570e2581. 2. Roffi M, Angiolillo DJ, Kappetein AP. Current concepts on coronary revascularization in diabetic patients. Eur Heart J 2011;32:2748e2757. 3. Steyrer E, Durovic S, Frank S, Giessauf W, Burger A, Dieplinger H, Zechner R, Kostner GM. The role of lecithin: cholesterol acyltransferase for lipoprotein (a) assembly. Structural integrity of low density lipoproteins is a prerequisite for Lp(a) formation in human plasma. J Clin Invest 1994;94:2330e2340. 4. Ikenaga H, Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Miura F, Nakama Y, Dai K, Otani T, Ejiri K, Oda N, Nakamura M, Miki T. Usefulness of lipoprotein (a) for predicting progression of non-culprit coronary lesions after acute myocardial infarction. Circ J 2011;75: 2847e2852. 5. Kardys I, Oemrawsingh RM, Kay IP, Jones GT, McCormick SP, Daemen J, Van Geuns RJ, Boersma E, Van Domburg RT, Serruys PW. Lipoprotein(a), interleukin-10, C-reactive protein, and 8-year outcome after percutaneous coronary intervention. Clin Cardiol 2012;35: 482e489. 6. Kronenberg F, Utermann G, Dieplinger H. Lipoprotein(a) in renal disease. Am J Kidney Dis 1996;27:1e25.
Coronary Artery Disease/Lipoprotein(a) as Coronary Risk for Diabetes 7. Thygesen K, Alpert JS, White HD, Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction; Jaffe AS, Apple FS, Galvani M, Katus HA, Newby LK, Ravkilde J, Chaitman B, Clemmensen PM, Dellborg M, Hod H, Porela P, Underwood R, Bax JJ, Beller GA, Bonow R, Van der Wall EE, Bassand JP, Wijns W, Ferguson TB, Steg PG, Uretsky BF, Williams DO, Armstrong PW, Antman EM, Fox KA, Hamm CW, Ohman EM, Simoons ML, PooleWilson PA, Gurfinkel EP, Lopez-Sendon JL, Pais P, Mendis S, Zhu JR, Wallentin LC, Fernández-Avilés F, Fox KM, Parkhomenko AN, Priori SG, Tendera M, Voipio-Pulkki LM, Vahanian A, Camm AJ, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Morais J, Brener S, Harrington R, Morrow D, Lim M, Martinez-Rios MA, Steinhubl S, Levine GN, Gibler WB, Goff D, Tubaro M, Dudek D, Al-Attar N. Universal definition of myocardial infarction. Circulation 2007;116: 2634e2653. 8. Jaffe AS, Ravkilde J, Roberts R, Naslund U, Apple FS, Galvani M, Katus H. It’s time for a change to a troponin standard. Circulation 2000;102:1216e1220. 9. Cannon CP, Brindis RG, Chaitman BR, Cohen DJ, Cross JT Jr, Drozda JP Jr, Fesmire FM, Fintel DJ, Fonarow GC, Fox KA, Gray DT, Harrington RA, Hicks KA, Hollander JE, Krumholz H, Labarthe DR, Long JB, Mascette AM, Meyer C, Peterson ED, Radford MJ, Roe MT, Richmann JB, Selker HP, Shahian DM, Shaw RE, Sprenger S, Swor R, Underberg JA, Van de Werf F, Weiner BH, Weintraub WS. 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on clinical data standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). Circulation 2013;127:1052e1089. 10. Kostner KM, März W, Kostner GM. When should we measure lipoprotein (a)? Eur Heart J 2013;34:3268e3276. 11. Emerging Risk Factors Collaboration; Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412e423. 12. Emerging Risk Factors Collaboration; Di Angelantonio E, Gao P, Pennells L, Kaptoge S, Caslake M, Thompson A, Butterworth AS, Sarwar N, Wormser D, Saleheen D, Ballantyne CM, Psaty BM, Sundström J, Ridker PM, Nagel D, Gillum RF, Ford I, Ducimetiere P, Kiechl S, Koenig W, Dullaart RP, Assmann G, D’Agostino RB Sr, Dagenais GR, Cooper JA, Kromhout D, Onat A, Tipping RW, Gómez-de-la-Cámara A, Rosengren A, Sutherland SE, Gallacher J, Fowkes FG, Casiglia E, Hofman A, Salomaa V, Barrett-Connor E, Clarke R, Brunner E, Jukema JW, Simons LA, Sandhu M, Wareham NJ, Khaw KT, Kauhanen J, Salonen JT, Howard WJ, Nordestgaard BG, Wood AM, Thompson SG, Boekholdt SM, Sattar N, Packard C, Gudnason V, Danesh J. Lipidrelated markers and cardiovascular disease prediction. JAMA 2012;307:2499e2506. 13. Dangas G, Ambrose JA, D’Agate DJ, Shao JH, Chockalingham S, Levine D, Smith DA. Correlation of serum lipoprotein(a) with the
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angiographic and clinical presentation of coronary artery disease. Am J Cardiol 1999;83:583e585. Schwartzman RA, Cox ID, Poloniecki J, Crook R, Seymour CA, Kaski JC. Elevated plasma lipoprotein(a) is associated with coronary artery disease in patients with chronic stable angina pectoris. J Am Coll Cardiol 1998;31:1260e1266. Kwon SW, Lee BK, Hong BK, Kim JY, Choi EY, Sung JM, Rhee JH, Park YM, Ma DW, Chung H, Mun HS, Lee SJ, Park JK, Min PK, Yoon YW, Rim SJ, Kwon HM. Prognostic significance of elevated lipoprotein(a) in coronary artery revascularization patients. Int J Cardiol 2013;167:1990e1994. Shai I, Schulze MB, Manson JE, Stampfer MJ, Rifai N, Hu FB. A prospective study of lipoprotein(a) and risk of coronary heart disease among women with type 2 diabetes. Diabetologia 2005;48: 1469e1476. Hiraga T, Kobayashi T, Okubo M, Nakanishi K, Sugimoto T, Ohashi Y, Murase T. Prospective study of lipoprotein(a) as a risk factor for atherosclerotic cardiovascular disease in patients with diabetes. Diabetes Care 1995;18:241e244. Hernández C, Francisco G, Chacón P, Simó R. Lipoprotein(a) as a risk factor for cardiovascular mortality in type 2 diabetic patients: a 10-year follow-up study. Diabetes Care 2005;28:931e933. Haffner SM, Moss SE, Klein BE, Klein R. Lack of association between lipoprotein (a) concentrations and coronary heart disease mortality in diabetes: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Metabolism 1992;41:194e197. Abu-Lebdeh HS, Hodge DO, Nguyen TT. Predictors of macrovascular disease in patients with type 2 diabetes mellitus. Mayo Clin Proc 2001;76:707e712. Maher VM, Brown BG. Lipoprotein (a) and coronary heart disease. Curr Opin Lipidol 1995;6:229e235. Grainger DJ, Kirschenlohr HL, Metcalfe JC, Weissberg PL, Wade DP, Lawn RM. Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science 1993;260:1655e1658. Loscalzo J, Weinfeld M, Fless GM, Scanu AM. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis 1990;10: 240e245. Biondi-Zoccai GG, Abbate A, Liuzzo G, Biasucci LM. Atherothrombosis, inflammation, and diabetes. J Am Coll Cardiol 2003;41: 1071e1077. Onat A1, Dönmez I, Karadeniz Y, Cakır H, Kaya A. Type-2 diabetes and coronary heart disease: common physiopathology, viewed from autoimmunity. Expert Rev Cardiovasc Ther 2014;12:667e679. Boerwinkle E, Leffert CC, Lin J, Lackner C, Chiesa G, Hobbs HH. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest 1992;90:52e60. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB, Zafarino J, Mitchel Y, Barter P. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406e2415. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/ REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59: 2344e2353.
Patients with diabetes mellitus (DM) are at twofold to fourfold higher cardiovascular risk compared with those without DM.1 Patients with DM who underwent PCI have worse outcomes compared with those without DM even in the era of drug-eluting stent.2 Therefore, it is important for patients with DM to investigate some residual risk factors of cardiovascular events to reduce these events. Lipoprotein(a) (Lp(a)) is a modified form of low-density lipoprotein in which the large glycoprotein apolipoprotein(a) is covalently bound to apolipoprotein B by a disulfide bridge.3 Consequently, elevated serum levels of Lp(a) are associated with increased risk of major adverse cardiac events in patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI).4,5 However, it remains unclear whether Lp(a) contributes to increased cardiovascular disease in patients with DM. We, therefore, investigated the
a Department of Cardiology, Juntendo University Shizuoka Hospital, Shizuoka, Japan; and bDepartment of Cardiology, Juntendo University School of Medicine, Tokyo, Japan. Manuscript received May 7, 2016; revised manuscript received and accepted August 19, 2016. This study was supported in grant-in-aid for scientific research from Ministry of Health, Labor, and Welfare (23591063). See page 4 for disclosure information. *Corresponding author: Tel: (þ81) 3-5802-1056; fax: (þ81) 3-56890627. E-mail address: [email protected] (K. Miyauchi).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.08.067
impact of Lp(a) on long-term outcomes of patients with DM who underwent PCI. Methods This study was single-center observational cohort study at the Juntendo University Hospital (Tokyo, Japan). Consecutive Japanese patients who underwent PCI in our institution from January 1997 to October 2011 were considered for this analysis. We enrolled diabetic patients, where DM was defined as fasting plasma glycemic levels 126 mg/dl, medication with oral hypoglycemic drugs, or insulin injections. The exclusion criteria were as follows: (1) missing Lp(a) data and (2) the patients who undergo dialysis because Lp(a) plasma levels are obviously increased in such patients due to kidney dysfunction.6 The patients were divided into 2 groups by the median of Lp(a) levels. The internal review board of the Juntendo University Hospital approved this study, and written informed consent to participate was obtained from all patients. Baseline data included age, gender, body mass index (BMI), blood pressure (BP), total cholesterol, HDL-C, LDLC, triglycerides, Lp(a), fasting blood glucose at the time of PCI, smoking status, family history of CAD, medication use, revascularization procedure-related factors, and comorbidities were prospectively collected from each patients. Blood samples were collected during the early morning after an overnight fast. Hypertension was defined as systolic BP 140 mm Hg, diastolic BP 90 mm Hg, www.ajconline.org
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Table 1 Baseline characteristics of the patients
Age (years) Male Current smoker Hypertension Body mass index (kg/m2) Low-density lipoprotein High-density lipoprotein Triglycerides Lipoprotein(a) eGFR<60mL/min/1.73m2 HbA1c Left ventricular ejection fraction Acute coronary syndrome Multivessel disease Type B2/C lesion Left anterior descending lesion Drug eluting stent Use of medication Aspirin Antiplatelet drug b-blocker ACE-I/ARB Calcium channel blocker Statin Oral hypoglycemic agents Insulin
Low Lp (a) (< 20.4mg/dl) (n ¼ 561)
High Lp (a) (20.4mg/dl) (n ¼ 575)
P
65.610.0 481 (85.7%) 130 (23.2%) 407 (72.6%) 24.53.5 105.031.9mg/dl 42.911.5mg/dl 146.883.6mg/dl 11 (6.0-15.3) mg/dl 120 (21.4%) 7.21.2% 62.712.6% 157 (27.9%) 316 (56.3%) 481 (85.8%) 255 (45.4%) 239 (42.6%)
65.09.6 468 (81.4%) 133 (23.1%) 405 (70.4%) 24.53.6 112.632.1mg/dl 42.414.2mg/dl 136.3106.1mg/dl 33 (26.4-50.8) mg/dl 167 (29.0%) 7.43.4% 61.413.3% 127 (22.1%) 362 (62.9%) 515 (89.5%) 250 (43.5%) 177 (30.8%)
0.30 0.06 0.97 0.43 0.93 <0.01 0.51 0.07 <0.01 <0.01 0.19 0.08 0.02 0.02 0.11 0.50 <0.01
527 447 252 296 241 281 280 102
(93.9%) (79.7%) (44.9%) (52.8%) (42.9%) (50.2%) (49.9%) (18.2%)
542 461 266 293 227 316 261 128
(94.2%) (80.2%) (46.4%) (51.1%) (39.5%) (54.9%) (45.4%) (22.2%)
0.34 0.45 0.62 0.65 0.23 0.10 0.16 0.09
ACE-I ¼ angiotensin-converting enzyme inhibitors; ARB ¼ angiotensin-receptor blockers; eGFR ¼ estimated glomerular filtration rate.
or medication with antihypertensive drugs. DM was defined as fasting plasma glycemic levels 126 mg/dl, medication with oral hypoglycemic drugs, or insulin injections. A current smoker was defined as a person who smoked at the time of PCI or had quit smoking within the year before PCI. Indications for PCI were based on objective evidence of myocardial ischemia (positive stress test), ischemic symptoms, or signs associated with significant angiographic stenosis. Levels of Lp(a) were measured using latex agglutination immunoassays (Special Reference Laboratories, Hachioji, Japan). The follow-up period ended on December 31, 2011. Survival data and information about incident acute coronary syndrome (ACS) were collected by serial contact with the patients or their families and were assessed from the medical records of patients who had died or of those who were followed up at our hospital. Information about the circumstances and date of death were obtained from the families of patients who died at home, and details of events of the cause of death were supplied by other hospitals or clinics where the patients had been admitted. All data were collected by blinded investigators. ACS was defined as ST-elevation myocardial infarction (STEMI), noneST-elevation myocardial infarction (NSTEMI), or unstable angina. We determined STEMI based on symptoms of ischemia with ST-segment elevation on the electrocardiogram and increased serum levels of cardiac enzymes (troponin, CKMB, and creatine kinase of twofold increase or more)7,8
and NSTEMI based on symptoms of ischemia without STsegment elevation on the electrocardiogram and increased serum levels of cardiac enzymes. Unstable angina pectoris was determined based on symptoms of ischemia at rest or with a crescendo of symptoms or new-onset symptoms associated with transient ischemic ST-segment shifts and normal serum levels of cardiac enzymes.9 Cardiac death was defined as death caused by myocardial infarction, heart failure, and sudden death. The end points of this study were all-cause death and a composite of cardiac death and incident ACS. The results are expressed as mean SD or medians (interquartile range) for continuous variables and as ratio (%) for categorical variables. Baseline data were compared using an unpaired t test or the Mann-Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. Kaplan-Meier event-free survival curves were compared using the log-rank test. Factors associated with outcomes were determined using univariable Cox regression analysis including age, gender, BMI, hypertension, HbA1c, LDL-C, HDL-C, triglycerides, high or low Lp(a) levels, current smoker, estimated glomerular filtration rate (eGFR), ACS, left ventricular ejection fraction, multivessel disease, type B2/C lesion, left anterior descending lesion, insulin, b blockers, angiotensinconverting enzyme inhibitors/angiotensin-receptor blockers, and statins as independent variables. Variables with significant or borderline significant associations (p <0.10) with
Coronary Artery Disease/Lipoprotein(a) as Coronary Risk for Diabetes
3
Figure 1. Kaplan-Meier curve for all-cause death (A) and composite end point of cardiac death and ACS (B). The incident of all-cause death was same between the 2 groups (p ¼ 037; log-rank test) (A). Cardiac outcomes were significantly worse for patients with high than low Lp(a) (p ¼ 0.03; log-rank test) (B).
Table 2 Cox proportional hazards models for predictors of composite endpoint Univariate
Age Gender (F/M) Body mass index Hypertension HbA1c Low-density lipoprotein High-density lipoprotein Triglycerides Lipoprotein(a) (high / low) Current smoker eGFR Acure coronary syndrome Left ventricular ejection fraction Multivessel disease Type B2/C lesion Left anterior descending lesion Insulin b-blockers ACE-I/ARB Statins Log Lipoprotein(a)
Multivariate
HR
95%CI
P
HR
95%CI
P
1.03 1.25 0.95 1.09 1.02 1.00 1.00 1.00 1.27 1.09 0.99 1.18 0.98 1.68 1.49 1.05 1.45 0.90 0.92 0.77 1.29
1.02-1.04 0.93-1.66 0.91-0.98 0.85-1.40 0.98-1.04 0.99-1.01 0.99-1.01 0.99-1.00 1.01-1.61 0.82-1.48 0.98-0.99 0.92-1.51 0.97-0.99 1.32-2.15 0.88-2.77 0.93-1.32 1.09-1.90 0.71-1.14 0.73-1.17 0.61-0.98 1.09-1.53
<0.01 0.13 <0.01 0.52 0.15 0.80 0.98 0.42 0.04 0.56 0.01 0.19 <0.01 <0.01 0.14 0.70 0.01 0.40 0.49 0.03 <0.01
1.03
1.01-1.04
<0.01
0.98
0.94-1.02
0.40
1.20
1.00-1.42
0.04
0.99
0.98-0.99
0.04
0.98 1.65
0.97-0.99 1.28-2.15
<0.01 <0.01
1.52
1.13-2.02
<0.01
0.80 1.32*
0.63-1.04 1.02-1.62*
0.09 0.01*
ACE-I ¼ angiotensin-converting enzyme inhibitors; ARB ¼ angiotensin-receptor blockers; CI ¼ confidence interval; eGFR ¼ estimated glomerular filtration rate; HR ¼ hazard ratio. * Adjusted for age, BMI, eGFR, LVEF, multivessel disease, insulin, statins.
outcomes were then included in multivariable Cox regression analyses. The assumption of proportional hazards was assessed using a log-minus-log survival graph. p <0.05 was considered to indicate significance, unless otherwise indicated. All data were analyzed using JMP 10.0 MDSU statistical software (SAS Institute, Cary, North Carolina). Results Of the 3,508 patients who underwent PCI, 1,546 patients with DM were analyzed. We excluded patients with dialysis and those who did not have Lp(a) data at the time of PCI. Table 1 lists the baseline characteristics of these patients. The number of chronic kidney disease (eGFR
<60 ml/min/1.73 m2), multivessel disease, and the level of LDL-C were higher in the group with high Lp(a) than with low Lp(a). The number of use of drug-eluting stents and ACS was higher in the group with low than with high Lp(a). Other characteristics were similar between the 2 groups. Outcome data were fully documented during the followup period (median 4.7 years, interquartile range 1.2 to 6.4). Figure 1 shows event-free survival curves. Event rate of allcause death was same between 2 groups. However, the incidence of cardiac death and/or ACS was significantly higher in the group with high than with low Lp(a). Univariate analysis identified age, BMI, Lp(a) (high/low), eGFR, left ventricular ejection fraction, multivessel disease, insulin, and statins as significant variables as for the
4
The American Journal of Cardiology (www.ajconline.org)
predictors of cardiac death and ACS (Table 2). Multivariate Cox proportional hazards regression analysis revealed that age, Lp(a) (high/low), left ventricular ejection fraction, multivessel disease, eGFR, and insulin were significant independent predictors of a worse cardiac outcome (Table 2). We made further analysis about Lp(a). Because Lp(a) (high/ low) is a categorical variable, we used log Lp(a) (natural logarithm), which is a continuous variable, in this analysis. Multivariable analysis adjusted by same variables (Table 2) also selected log Lp(a) as a significant independent predictor of a worse cardiac outcome (hazard ratio 1.32; 95% CI 1.02 to 1.62; p ¼ 0.01). Discussion We assessed the prognostic value of Lp(a) in the patients with DM after PCI. The major findings of the present study are as follows: (1) an elevated Lp(a) level is an independent risk factor for cardiac death and/or ACS recurrence in the patients with DM who underwent PCI; (2) serum levels of Lp(a) are associated with a worse prognosis in the patients with DM after PCI; and (3) an elevated Lp(a) as a categorical and as a continuous variable was associated with worse cardiac prognosis in patients with DM after PCI. These are notable because there are no data about the relation between serum levels of Lp(a) and cardiovascular events in terms of secondary prevention after PCI in patients with DM. Lp(a) is a modified form of low-density lipoprotein in which the large glycoprotein apolipoprotein(a) is covalently bound to apolipoprotein B by a disulfide bridge.3 There is evidence that elevated levels of Lp(a) contribute significantly to the incidence of cardiovascular diseases.10e12 Several previous studies have already indicated relation between an elevated Lp(a) and increased risk of cardiovascular disease in patients with CAD.13e15 In the field of a primary prevention of CAD in patients with DM, several studies found that high serum levels of Lp(a) were associated with increased risk for CAD16 and cardiovascular disease,17,18 whereas others did not find any significant association.19,20 Therefore, it remains unclear whether serum levels of Lp(a) predicts for increased cardiovascular disease risk in patients with DM as primary prevention of cardiovascular disease. Furthermore, there are no reports about secondary prevention of cardiovascular disease in diabetic patients with CAD. In addition, patients with DM have 4% to 17% lower Lp(a) levels than those without DM.11 To our knowledge, our present study is the first one to demonstrate the prognostic value of an elevated Lp(a) level in patients with DM who underwent PCI. The pathophysiological role of Lp(a) in CAD progression is explained by the atherogenic and inhibitory effects of Lp(a) on fibrinolysis. Accumulating Lp(a) in atherosclerotic plaques promotes cholesterol accumulation in macrophages that form foam cells21 and the proliferation and migration of smooth muscle cells in atherosclerotic lesions.22 Because of structural similarity with plasminogen, binding to fibrin, and exerting anti-fibrinolytic actions, Lp(a) causes thrombosis.23 Endothelial dysfunction and prothrombotic and proinflammatory states are important features of the accelerated atherosclerotic process observed in patients with DM.24
Serum Lp(a) concentrations enhance inflammation and lead to insulin resistance as a result of autoimmune response.25 These might have contributed to the significantly worse cardiac outcomes of the group with high Lp(a) in the present study. Serum levels of Lp(a) are genetically determined; >90% of the variance in Lp(a) concentrations can be explained by genetics and it cannot be altered by diet or exercise.23,26 However, some new drugs were reported to modify Lp(a) levels. For example, the cholesterol ester transfer protein inhibitor anacetrapib decreased Lp(a) by 38.8% after 76 weeks.27 Proprotein convertase subtilisin/ kexin 9 inhibitor also decreased Lp(a) levels by 10% to 30% after 12 weeks.28 Drug therapy that targets Lp(a) reduction might have potential for secondary prevention of CAD to patients with DM. The potential benefit of Lp(a)-directed drugs in development, and the prognostic utility of Lp(a) as a surrogate marker, awaits the results of clinical trials. Our findings suggest that an elevated Lp(a) level may contribute to the worse prognosis in patients with DM who underwent PCI and that serum levels of Lp(a) is an important clinical consideration in those with DM after PCI. Serum levels of Lp(a) could predict worse clinical outcomes for patients with DM who underwent PCI. Confirming Lp(a) might help to reduce cardiovascular morbidity and mortality in patients with DM after PCI. The present observational study has some limitations. The study was conducted in a single institution, and the subjects were only Japanese. Although we applied multivariable Cox proportional hazards models including several known confounding variables, other unknown confounders might have played more roles. Acknowledgments: The authors gratefully acknowledge Yumi Nozawa and Ayako Onodera for data collection and management.
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