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Proteinuria is independently associated with the incidence of primary cardiovascular events in diabetic patients
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Original article
Proteinuria is independently associated with the incidence of primary cardiovascular events in diabetic patients Hirofumi Soejima (MD, PhD, FJCC)a,b,*, Hisao Ogawa (MD, PhD, FJCC)c, Takeshi Morimoto (MD, PhD)d, Sadanori Okada (MD, PhD)e, Chisa Matsumoto (MD, PhD)f, Masafumi Nakayama (MD, PhD)g, Izuru Masuda (MD, PhD)h, Hideaki Jinnouchi (MD, PhD)i, Masako Waki (MD, PhD)j, Yoshihiko Saito (MD, PhD, FJCC)k, for the JPAD Trial Investigators a
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Health Care Center, Kumamoto University, Kumamoto, Japan c National Cerebral and Cardiovascular Center, Suita, Japan d Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan e Center for Postgraduate Training, Nara Medical University, Kashihara, Japan f Department of Cardiology, Preventive Medicine, Tokyo Medical University, Tokyo, Japan g Nakayama Cardiovascular Clinic, Amakusa, Japan h Medical Examination Center, Takeda Hospital, Kyoto, Japan i Diabetes Care Center, Jinnouchi Clinic, Kumamoto, Japan j Division of Endocrinology and Metabolism, Department of Internal Medicine, Shizuoka City Shizuoka Hospital, Shizuoka, Japan k Department of Cardiovascular Medicine, Nara Medical University, Kashihara, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 April 2019 Received in revised form 13 August 2019 Accepted 26 August 2019 Available online xxx
Background: Albuminuria is a risk factor for cardiovascular events in diabetic patients, but it is unknown whether proteinuria is also a risk factor for cardiovascular events in these patients. Methods: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was performed between 2002 and 2008 to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetes patients. After the JPAD trial was completed, we continued to follow up the patients until 2015. Among the 2536 patients participating in the JPAD study, 42 were excluded because proteinuria was not checked at registration. We divided the patients into two groups: proteinuria group (n = 446; proteinuria or greater) and non-proteinuria groups (n = 2048; proteinuria ). We compared the incident rate of cardiovascular events between the two groups. Results: During the observation period [median, 10.3 (10.2–10.5) years], 332 patients had a first cardiovascular event. Among 332 patients, 136 patients had cerebrovascular events and 54 patients had acute myocardial infarction. The incidence rate of cardiovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group (HR 1.75, 95%CI 1.36–2.23, p < 0.0001). The incidence rate of cerebrovascular events was also significantly higher in the proteinuria group than in the non-proteinuria group (HR 1.71, 95%CI 1.14–2.49, p = 0.0064). The Cox proportional hazards model revealed that proteinuria was independently associated with cardiovascular events in diabetic patients without a history of cardiovascular events after adjusting for age, gender, body mass index, hemoglobin A1c level, duration of diabetes, and estimated glomerular filtration rate. Conclusions: Proteinuria was independently associated with the incidence of primary cardiovascular events in diabetic patients. Proteinuria detected by the dipstick test, which is simple and inexpensive, is useful as a first step in the risk assessment of diabetic patients. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Cardiovascular events Diabetes mellitus Proteinuria
Introduction * Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556 Japan. E-mail address: [email protected] (H. Soejima).
Diabetes mellitus is a strong risk factor for cardiovascular events [1–8]. Numerous studies have described a strong independent association between the level of urinary protein excretion and
https://doi.org/10.1016/j.jjcc.2019.08.021 0914-5087/© 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Soejima H, et al. Proteinuria is independently associated with the incidence of primary cardiovascular events in diabetic patients. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.021
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the risk of death in populations with and without diabetes mellitus [9–15]. There are few reports that demonstrate a significant relationship between the dipstick proteinuria and cardiovascular events in diabetic patients. Urinary dipstick is a relatively simple and clinically easy-to-use tool to detect proteinuria, and it may identify patients who are at a high risk of mortality. We undertook the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetic patients [16]. Our data showed that low-dose aspirin therapy did not increase adverse events and although the efficacy results were not statistically significantly different, the point estimate of the effect on the primary composite cardiovascular outcome was a 20% reduction [16]. We also reported the results of the JPAD2 extension study using the data that were obtained until 2015 [17]. This mean observation during and after the trial which comprised more than one decade, indicated that long-term therapy with low-dose aspirin is not associated with lower cardiovascular events in Japanese patients with type 2 diabetes mellitus in a primary prevention setting. However, low-dose aspirin therapy was associated with, and significantly increased, the incidence of gastrointestinal bleeding [17]. By using these data, we sought to investigate whether dipstick proteinuria was a significant risk factor for cardiovascular events in patients without a history of cardiovascular events. Materials and methods JPAD trial and JPAD2 study The study protocol for the JPAD trial was registered at clinicaltrials.gov with the identifier NCT00110448.The JPAD trial design and overall findings have been reported previously [16]. The study protocol is in agreement with the guidelines of the ethics committees at Kumamoto University (Rinri 956) and Nara Medical University (No. 236-3), and the study complies with the Declaration of Helsinki.Briefly, this multicenter, prospective, randomized, open, blinded-end-point study was conducted at 163 institutions throughout Japan, and it enrolled 2536 patients with type 2 diabetes, who had no history of cardiovascular disease. The institutional review board at each participating hospital approved this trial, and written informed consent was obtained from each patient. In the JPAD trial, the inclusion criteria were diagnosis of type 2 diabetes mellitus, 30–85 years of age, and the ability to provide informed consent. The exclusion criteria were electrocardiographic ischemic changes, a history of coronary heart disease, cerebrovascular disease, arteriosclerotic disease, atrial fibrillation, use of antiplatelet or antithrombotic therapy, a history of severe gastric or duodenal ulcer, severe liver dysfunction, severe renal dysfunction, or allergy to aspirin [16]. There were 2536 patients who were randomly assigned and the median follow-up period until 2008 was 4.37 years. Cardiovascular events analyses and subgroup analyses of the follow-up for the following cardiovascular events were performed: cerebrovascular events including stroke events and transient ischemic attack; coronary events including acute myocardial infarction and angina; aortic and peripheral vascular events; and sudden death. Urinalysis Urinalysis using the dipstick method was performed on a single spot urine specimen that was collected. Urine dipstick results were interpreted by the medical staff at each local medical institution and recorded as ( ), (), (+), (1+), (2+), or (3+). In Japan, it is a
widely adopted policy of the Japanese Committee for Clinical Laboratory Standards (http://jccls.org/) that all urine dipstick tests should be manufactured so that a urine dipstick result of will correspond to a urinary protein level of 15 mg/dL. Serum creatinine was assayed using an enzymatic method. Estimated glomerular filtration rate (eGFR) was determine based on the chronic kidney disease (CKD)-epidemiology collaboration equation for Japanese people as follows [18]: Men : 194 Cre
1:094
Women : 194 Cre
age
1:094
0:287
age
0:287
0:739
Proteinuria and non-proteinuria groups Among the 2536 JPAD patients, 42 patients were excluded for lack of proteinuria data at registration. Based on the result of the dipstick test at registration, we divided the patients into two groups: a proteinuria group (n = 446; proteinuria ); and a nonproteinuria group (n = 2048; proteinuria ). We compared the incident rates of cardiovascular events between the proteinuria group and the non-proteinuria group. Therefore, this study was not a randomized study based on proteinuria. Definition of cardiovascular events The primary endpoint was any cardiovascular event, that was a composite of sudden death; death from coronary, stroke, and aortic causes; nonfatal myocardial infarction; unstable angina; newly developed exertional angina; nonfatal ischemic and hemorrhagic stroke; transient ischemic attack; and/or nonfatal aortic and peripheral vascular disease (arteriosclerosis obliterans, aortic dissection, mesenteric arterial thrombosis) during the follow-up period. Stroke events were a combination of death from cerebrovascular causes and nonfatal ischemic and hemorrhagic stroke. Heart events were a combination of death from coronary causes and nonfatal myocardial infarction; unstable angina; and newly developed exertional angina. All potential endpoints were adjudicated by an independent committee for validation of data and events, and they were unaware of the group assignments. Statistical analyses Patient characteristics are presented as the mean standard deviation (SD), median (interquartile range) or number (%). Comparisons of variables between the proteinuria and nonproteinuria groups were conducted using a t-test or the Wilcoxon rank sum test for continuous variables or the Chi-square test for categorical variables. Comparisons of cardiovascular events were performed based on the time to the first event. Cumulative incidences of primary end points were estimated using the KaplanMeier method and differences between groups were then assessed using the log-rank test. We constructed multivariate Cox proportional hazard models to estimate the hazards ratios (HRs) of proteinuria , with a 95% CI. We included the clinically relevant factors of age 65 years, gender, body mass index (BMI) 24 kg/m2, duration of diabetes mellitus 7 years, hemoglobin A1c level 7.2%, use of angiotensin II receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI), categorized eGFR level (60, 60> to 30, <30 ml/min/1.73 m2), and use of aspirin as confounders. Patients with missing values for any selected variable were excluded from the analyses that used this variable. All statistical analyses were conducted using JMP version 13.1 (SAS Institute Inc, Cary, NC, USA). Two-tailed p-values of less than 0.05 were considered statistically significant.
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Table 1 Baseline characteristics. Characteristics
Proteinuria group (n = 446)
Non-proteinuria group (n = 2048)
p-Value
Age, Mean SD, Years Male Past or current smoker, n (%) Body mass index, Mean SD, kg/m2 Dyslipidemia, n (%) Hypertension, n (%) Duration of diabetes, median, (IQR), years Diabetic retinopathy Diabetic nephropathy Diabetic neuropathy Dermal ulcer Hemoglobin A1c level, Mean SD, % Fasting plasma glucose level, Mean SD, mg/dl Serum creatinine levels, Mean SD, mg/dl Estimated glomerular filtration rate, Mean SD, ml/min/1.73 m2 Treatment for hypertension Calcium channel blockers Angiotensin II receptor blockers Angiotensin converting enzyme inhibitors b-blockers a-blockers Treatment for diabetes and dyslipidemia Sulfonylureas a-Glucosidase inhibitors Biguanides Insulin Thiazolidines Statins Family history Ischemic heart disease Stroke
64 11 267 (60) 209 (47) 25 4 247 (55) 309 (69) 8.1 (3.3–13.7) 111 (25) 246 (55) 85 (19) 5 (1.1) 7.7 1.5 152 50 0.9 0.5 70.8 25.2
64 10 1089 (53) 830 (41) 24 4 1080 (53) 1138 (56) 6.6 (2.9–12.1) 253 (12) 74 (4) 210 (10) 7 (0.3) 7.4 1.3 146 48 0.8 0.2 74.6 19.5
0. 96 0.01 0.01 0.004 0.3 <0.001 0.02 <0.0001 <0.0001 <0.0001 0.047 0.0006 0.02 <0.0001 0.003
203 (46) 132 (30) 77 (17) 31 (7) 23 (5)
655 (32) 393 (19) 290 (14) 129 (6) 68 (3)
<0.0001 <0.0001 0.09 0.6 0.06
263 (59) 146 (33) 77 (17) 75 (17) 27 (6) 119 (27)
1149 (56) 679 (33) 273 (13) 250 (12) 95 (5) 522 (25)
0.3 0.9 0.03 0.009 0.2 0.6
48 (11) 98 (22)
238 (12) 442 (21)
0.6 0.5
Proteinuria is a risk factor for cardiovascular events in diabetic patients
Results Baseline clinical characteristics The baseline clinical characteristics are shown in Table 1. There were significant differences in gender, BMI, hemoglobin A1c levels, and eGFR, and in the frequency of smoking, hypertension, diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy between the proteinuria and non-proteinuria groups. The use of calcium channel blockers and ARBs was significantly higher in the proteinuria group compared with the non-proteinuria group. The use of biguanide and insulin was significantly higher in the proteinuria compared with the non-proteinuria group. Clinical characteristics such as age, the frequency of dyslipidemia, and use of ACEIs, statins, and b-blockers were similar between the proteinuria and non-proteinuria groups.
Primary cardiovascular events that occurred are presented in Table 2. There was a significant difference in the incidence of the primary cardiovascular events between the proteinuria and non-proteinuria groups. The incidence rates of primary cardiovascular events were significantly higher in the proteinuria group (84 events, 19%) compared with the non-proteinuria group (248 events, 12%) (HR, 1.75; 95% CI, 1.36–2.23; log-rank test, p < 0.0001) as shown in Fig. 1. We compared the difference of cardiovascular event rate among the proteinuria , , 1+, 2+, and 3+ groups as shown in Fig. 2. The cardiovascular event rate (event number/patient number) was 0.12 (248/2048) in the proteinuria – group, 0.16 (16/100) in the proteinuria group, 0.20 (41/208) in the proteinuria + group, 0.17
Table 2 Cardiovascular events.
Cardiovascular events Coronary artery events Fatal myocardial infarction Nonfatal myocardial infarction Stroke events Fatal stroke Nonfatal stroke Ischemic Hemorrhagic Transient ischemic attack Vascular events Sudden death
Proteinuria group (n = 446)
Non-proteinuria group (n = 2048)
n (%)
No. per 1000 person-years
n (%)
No. per 1000 person-years
84 (19) 29 (7) 1 (0.2) 10 (2) 29 (7) 5 (1.1) 24 (5) 20 (4) 4 (0.9) 5 (1.1) 17 (4) 4 (0.9)
25.53 8.81 0.30 3.04 8.81 1.52 7.29 6.08 1.22 1.52 5.17 1.22
248 (12) 101 (5) 8 (0.4) 35 (1.7) 88 (4) 13 (0.6) 75 (4) 62 (3) 13 (0.6) 14 (0.7) 34 (1.7) 11 (0.5)
14.62 5.95 0.47 2.06 5.19 0.77 4.42 3.65 0.77 0.83 2.00 0.65
HR (95% CI)
p-Value
1.75 (1.36–2.23) 1.49 (0.97–2.22) 0.62 (0.03–3.41) 1.50 (0.70–2.91) 1.69 (1.09–2.54) 2.03 (0.65–5.39) 1.64 (1.01–2.55) 1.64 (0.97–2.67) 1.61 (0.45–4.55) 1.79 (0.58–4.68) 2.58 (1.41–4.55) 1.92 (0.53–5.63)
<0.0001 0.07 0.6 0.3 0.02 0.2 0.045 0.07 0.4 0.3 0.003 0.3
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Fig. 1. Comparison of primary cardiovascular events between the proteinuria and non-proteinuria groups. The incidence of primary cardiovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group. HR, hazard ratio.
Fig. 4. Comparison of primary acute myocardial infarction between the proteinuria and non-proteinuria groups. There was no significant difference in the incidence rate of primary acute myocardial infarction between the proteinuria group and the non-proteinuria group. HR, hazard ratio.
(17/98) in the proteinuria 2+ group, and 0.25 (10/40) in the proteinuria 3+ group. Subgroup analyses of cerebrovascular events and acute myocardial infarction Cardiovascular events are shown in Table 2. The incidence rates of primary cerebrovascular events were significantly higher in the proteinuria group (34 events, 8%) compared with the non-proteinuria group (102 events, 5%; HR, 1.71; 95% CI, 1.14–2.49; log-rank test, p = 0.0064; Fig. 3). There were no significant differences, however, in the incidence rate of primary acute myocardial infarction between the high proteinuria group (11 events, 2%) and the non-proteinuria group (43 events, 2%; HR, 1.33; 95% CI, 0.65–2.49; log-rank test, p = 0.40; Fig. 4). Fig. 2. Comparison of primary cerebrovascular events among each proteinuria level group. Although it seemed that there was a significant difference when it was divided into 5 groups, Kaplan-Meier curve overlapped in the proteinuria , 1+, and 2 + groups. The event rate seemed higher in the proteinuria 3+ group, but the proteinuria 3+ group had fewer patients and was less reliable.
Proteinuria was independently associated with cardiovascular events The Cox proportional hazards model including clinically important factors revealed that proteinuria, age, gender, and hemoglobin A1c level were independent predictive factors for cardiovascular events in diabetic patients (Table 3). However, eGFR and use of ARB or ACEI were not independently associated with cardiovascular events.
Table 3 Multivariate Cox proportional hazards model.
Fig. 3. Comparison of primary cerebrovascular events between the proteinuria and non-proteinuria groups. The incidence rate of primary cerebrovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group. HR, hazard ratio.
Factor
Hazard ratio
95% CI
p-Value
Proteinuria Age 65 years Men Body mass index 24 kg/m2 Duration of diabetes mellitus 7.0 years Hemoglobin A1c 7.2% Use of ARB or ACEI 60>eGFR30 ml/min/1.73 m2 30 ml/min/1.73 m2 > eGFR Use of aspirin
1.62 1.91 1.51 0.98 1.32 1.50 1.14 1.17 1.17 0.94
1.23–2.11 1.49–2.46 1.19–1.93 0.77–1.24 1.04–1.68 1.18–1.90 0.89–1.45 0.90–1.51 0.29–3.13 0.75–1.18
0.0005 <0.0001 0.0007 0.9 0.02 0.0008 0.3 0.2 0.8 0.6
ARB, angiotensin II receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; eGFR, estimated glomerular filtration rate.
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Discussion In this 10-year follow-up study, we demonstrated that the incidence rate of cardiovascular events including cerebrovascular events, coronary events, and aortic and peripheral vascular events, in type 2 diabetic patients in a primary prevention setting, was significantly higher in the proteinuria group compared with the non-proteinuria group. Thus, dipstick proteinuria results are useful for predicting the incidence of cardiovascular events in diabetic patients. Previously, several studies that showed the association between dipstick proteinuria results and cardiovascular events were reported [19–22]. Dipstick proteinuria results were significantly associated with the risk of cardiovascular events in patients with angiographic evidence of clinically significant coronary artery disease [19]. Dipstick proteinuria results were significantly associated with the risk of stent thrombosis in patients with acute myocardial infarction who underwent percutaneous coronary intervention with a stent [20]. Dipstick proteinuria results were significantly associated with the risk of all-cause mortality in patients with previous myocardial infarction [21]. Dipstick proteinuria was significantly associated with the risk of thromboembolism in patients with atrial fibrillation [22]. Our data showed, for the first time, the association between dipstick proteinuria results and primary cardiovascular events in patients with diabetes mellitus who had no history of cardiovascular events. Recently, dipstick proteinuria results were used to identify subjects with chronic kidney disease among the general population in several studies [23]. Dipstick proteinuria results were categorized as follows: , , and + or greater. The albuminuria level was categorized as follows: A1, <30 mg/gCr; A2, 30–300 mg/ gCr; and A3, >300 mg/gCr; Quantitative proteinuria was categorized as follows: P1, <150 mg/gCr; P2, 150–500 mg/gCr; and P3, >500 mg/ gCr. These categories are based on the recommendations of the Japanese Society of Nephrology [24] which were created by modifying the Kidney Disease: Improving Global Outcome (KDIGO) CKD guideline 2012 [25] for Japanese people. The National Kidney Foundation Kidney Disease Outcome Quality Initiative recommends screening high-risk groups, such as patients with diabetes or hypertension [26]. The United Kingdom’s National Institute for Health and Clinical Excellence also recommends screening high-risk groups [27]. Thus, the dipstick test is useful as a risk screening methods for diabetic patients. The dipstick test could fail to diagnose patients with microalbuminuria depending on the dipstick that is used [28]. Therefore, a highly accurate dipstick test should be chosen. In the present study, we considered proteinuria to be a proteinuria-positive result in the dipstick test. The proteinuria group was reported to contain a high proportion of albuminuriapositive patients [29]. It was reported that proteinuria means the presence of microalbuminuria and that proteinuria - means no presence of albuminuria [30]. Selvin et al. reported that proteinuria should be repeatedly measured because a proteinuria level in the same person often changes greatly in a short period of time [31]. The dipstick test is suitable for frequent testing because it is simple to use and has a low cost. In the present study, the Cox proportional hazards model including clinically important factors revealed that proteinuria was independently associated with primary cardiovascular events in diabetic patients. Previous reports also showed that proteinuria was an independent predictive factor of mortality and cardiovascular events [19–22]. Treatments that decreased proteinuria were shown to lead to decreased cardiovascular events during follow-up [32]. Sandsmark et al. showed that when adjusted for variables that were known to influence stroke risk, total proteinuria or albuminuria, but not eGFR, was associated with an increased risk
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of stroke [33]. Our data showed that eGFR was not an independent factor for cardiovascular events, as shown in Table 2. Several studies found that subjects with a decreased eGFR had an increased risk of stroke compared with subjects with normal eGFR (>60 ml/min per 1.73 m2).We suggest that eGFR did not become an independent predictive factor for cardiovascular events in the present study because most patients had a normal eGFR (n = 1868, 74.9%). The 2012 KDIGO clinical practice guideline for the evaluation and management of CKD [34] and the KDIGO clinical practice guideline for the management of blood pressure [35] have both recommended that renin-angiotensin system (RAS)-blocking drugs are used in adults with diabetes mellitus and albuminuria. In a recent randomized, double-blind, placebo-controlled trial, patients who were treated with sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor were reported to be more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria or from macroalbuminuria to microalbuminuria or normoalbuminuria, and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria [36]. The trial results support the clinical benefits of SGLT2 inhibitors in diabetic patients with urinary albumin excretion, irrespective of patients' albuminuria status. Possible mechanisms of renal cortex injury by hypoxia and protection of proximal tubular epithelial cells by SGLT2 inhibitor have been shown [37]. This study had some limitations. First, the JPAD trial was designed as a randomized controlled trial to evaluate the efficacy of low-dose aspirin in cardiovascular prevention, and not to evaluate the prognostic value of proteinuria. Second, this study included a small number of cardiovascular events. Because the present study was a sub-analysis of the JPAD trial, the number of patients and number of events were lower compared with the main study. We compared the difference of cardiovascular event rate among the proteinuria , , 1+, 2+, and 3 + groups. The proteinuria 3+ group is likely higher, but the significance is unreliable because the number of events was small. This point needs to be followed up and reconsidered. Conclusions In conclusion, proteinuria was independently associated with the incidence of cardiovascular events in diabetic patients without a history of cardiovascular events. Dipstick proteinuria testing is a simple, inexpensive, but significant predictive method for primary cardiovascular events in diabetic patients. Funding This study was supported by the Ministry of Health, Labour and Welfare, Japan (H16-Junkanki-004, and H27-Junkanki-Ippan-001) and Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENHI) grant 18K08521. Disclosures Dr Soejima reports research grant from Boehringer Ingelheim. Dr Morimoto reports lecturer's fees from AstraZeneca, Bayer, Daiichi Sankyo, Japan Lifeline, Kyocera, Mitsubishi Tanabe, Novartis, and Pfizer; a manuscript fee from Pfizer; and served advisory boards for Asahi Kasei, Bristol-Myers Squibb, and Boston Scientific. Dr Okada reports lecturer's fees from Novo Nordisk, Mitsubishi Tanabe, Sumitomo Dainippon, Arkray, Bayer, Eli Lilly, Boehringer Ingelheim, Ono, AstraZeneca, Sanofi, and Takeda. Dr Nakayama reports lecturer’s fees from Bayer, Shionogi, Takeda, Daiichi Sankyo, Sanofi, Boehringer Ingelheim, Sumitomo Dainip-
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pon, Fujifilm Medical, Kowa, Pfizer, and Astellas. Dr Masuda reports lecturer's fees from AstraZeneca, Ono, Takeda, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, Kowa, Kyowa Hakko Kirin, MSD, Novartis, Shionogi, and Mitsubishi Tanabe. Dr Jinnouchi reports research grants from MSD, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Takeda, Taisho Toyama, Astellas, Chugai, Bayer, Sanofi, GlaxoSmithKline, Sanwa Kagaku Kenkyusho, Ono, Eli Lilly, AstraZeneca, Pfizer, and Shionogi; lecturer's fees from MSD, AstraZeneca, Astellas, Abbott, Sanofi, Terumo, Novo Nordisk, Bayer, Sanwa Kagaku Kenkyusho, Kyowa Hakko Kirin, Taisho Toyama, Daiichi Sankyo, Teijin, Mitsubishi Tanabe, Eli Lilly, Boehringer Ingelheim, and Takeda; and manuscript fees from Novo Nordisk and Taisho Toyama. Dr Waki reports research grants from Sanofi and AstraZeneca; and lecturer's fees from MSD, Astellas, Amgen Astellas BioPharma, AstraZeneca, Otsuka, Ono, Kowa, Kyowa Hakko Kirin, Novartis, Sanofi, Sanwa Kagaku Kenkyusho, Johnson & Johnson, Daiichi Sankyo, Taisho Toyama, Sumitomo Dainippon, Takeda, Mitsubishi Tanabe, Teijin, Eli Lilly, Novo Nordisk, Bayer, Pfizer, Boehringer Ingelheim, and Abbott. Dr Saito reports research grants from Bayer, Terumo, Otsuka, Amgen Astellas BioPharma, Novartis, Ono, Shionogi, Teijin, St. Jude Medical, and Mitsubishi Tanabe; non-purpose research grants from Astellas, Asahi Kasei, Actelion, Boston Scientific, Chugai, Daiichi Sankyo, Sumitomo Dainippon, Eisai, Fuji Yakuhin, Kowa, Kyowa Hakko Kirin, Medtronic, Mitsubishi Tanabe, MSD, Nihon Medi-Physics, Ono, Otsuka, Sanofi, Shionogi, Takeda, Teijin, and Zeria; lecturer's fees from Asahi Kasei, Astellas, Bayer, Daiichi Sankyo, Sumitomo Dainippon, Fuji Yakuhin, Kowa, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Boehringer Ingelheim, Novartis, Ono, Otsuka, Pfizer, Sanofi, Taisho Toyama, Takeda, and Toa Eiyo; a manuscript fee from Pfizer; served advisory boards for Novartis, Pfizer, Mitsubishi Tanabe, Ono, Boehringer Ingelheim; and a sponsored office from MSD. The others declare no conflicts of interest. Acknowledgments The authors thank M. Ohtorii (Institute for Clinical Effectiveness, Kyoto, Japan) for her roles in data management and statistical analyses. The authors also thank M. Aoyama (Kumamoto University), Y. Wada, Y. Kamada, and M. Miyagawa (Nara Medical University) for their secretarial work. Additionally, we thank Jodi Smith, PhD, from Edanz Group for editing a draft of this manuscript.
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Long-term blood pressure variability, new-onset diabetes mellitus, and new-onset chronic kidney disease in the Japanese general population. Hypertension 2015;66:30–6. [24] Japanese Society of Nephrology. Evidence based clinical practice guideline for CKD 2018.. Tokyo: Toky-igakusha CO., Ltd.; 2018. [25] No author. Summary of KDIGO guideline: behind the scenes, need for guidance, and a framework for moving forward. Kidney Int 2013;84:627. [26] National Kidney Foundation. K/DOQI clinical guidelines practice for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–266. [27] National Collaborating Centre for Chronic Conditions. Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care. London: Royal College of Physicians; 2008. [28] Nagai K, Yamagata K. Quantitative evaluation of proteinuria for health checkups is more efficient than the dipstick method. Clin Exp Nephrol 2015;19:152–3. [29] Konta T, Hao Z, Takasaki S, Abiko H, Ishikawa M, Takahashi T, et al. Clinical utility of trace proteinuria for microalbuminuria screening in the general population. Clin Exp Nephrol 2007;11:51–5. [30] Sam R, Shaykh MS, Pegoraro AA, Khalili V, Hristea I, Singh AK, et al. The significance of trace proteinuria. Am J Nephrol 2003;23:438–41.
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[35] KDIGO Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease: summary of recommendation statements. Kidney Int Suppl 2012;2:341–2. [36] Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, et al. Effects of empagliflozin on the urinary albumin-tocreatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017;5:610–21. [37] Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol 2018;71:471–6.
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Original article
Proteinuria is independently associated with the incidence of primary cardiovascular events in diabetic patients Hirofumi Soejima (MD, PhD, FJCC)a,b,*, Hisao Ogawa (MD, PhD, FJCC)c, Takeshi Morimoto (MD, PhD)d, Sadanori Okada (MD, PhD)e, Chisa Matsumoto (MD, PhD)f, Masafumi Nakayama (MD, PhD)g, Izuru Masuda (MD, PhD)h, Hideaki Jinnouchi (MD, PhD)i, Masako Waki (MD, PhD)j, Yoshihiko Saito (MD, PhD, FJCC)k, for the JPAD Trial Investigators a
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Health Care Center, Kumamoto University, Kumamoto, Japan c National Cerebral and Cardiovascular Center, Suita, Japan d Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan e Center for Postgraduate Training, Nara Medical University, Kashihara, Japan f Department of Cardiology, Preventive Medicine, Tokyo Medical University, Tokyo, Japan g Nakayama Cardiovascular Clinic, Amakusa, Japan h Medical Examination Center, Takeda Hospital, Kyoto, Japan i Diabetes Care Center, Jinnouchi Clinic, Kumamoto, Japan j Division of Endocrinology and Metabolism, Department of Internal Medicine, Shizuoka City Shizuoka Hospital, Shizuoka, Japan k Department of Cardiovascular Medicine, Nara Medical University, Kashihara, Japan b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 19 April 2019 Received in revised form 13 August 2019 Accepted 26 August 2019 Available online xxx
Background: Albuminuria is a risk factor for cardiovascular events in diabetic patients, but it is unknown whether proteinuria is also a risk factor for cardiovascular events in these patients. Methods: The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was performed between 2002 and 2008 to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetes patients. After the JPAD trial was completed, we continued to follow up the patients until 2015. Among the 2536 patients participating in the JPAD study, 42 were excluded because proteinuria was not checked at registration. We divided the patients into two groups: proteinuria group (n = 446; proteinuria or greater) and non-proteinuria groups (n = 2048; proteinuria ). We compared the incident rate of cardiovascular events between the two groups. Results: During the observation period [median, 10.3 (10.2–10.5) years], 332 patients had a first cardiovascular event. Among 332 patients, 136 patients had cerebrovascular events and 54 patients had acute myocardial infarction. The incidence rate of cardiovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group (HR 1.75, 95%CI 1.36–2.23, p < 0.0001). The incidence rate of cerebrovascular events was also significantly higher in the proteinuria group than in the non-proteinuria group (HR 1.71, 95%CI 1.14–2.49, p = 0.0064). The Cox proportional hazards model revealed that proteinuria was independently associated with cardiovascular events in diabetic patients without a history of cardiovascular events after adjusting for age, gender, body mass index, hemoglobin A1c level, duration of diabetes, and estimated glomerular filtration rate. Conclusions: Proteinuria was independently associated with the incidence of primary cardiovascular events in diabetic patients. Proteinuria detected by the dipstick test, which is simple and inexpensive, is useful as a first step in the risk assessment of diabetic patients. © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Cardiovascular events Diabetes mellitus Proteinuria
Introduction * Corresponding author at: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556 Japan. E-mail address: [email protected] (H. Soejima).
Diabetes mellitus is a strong risk factor for cardiovascular events [1–8]. Numerous studies have described a strong independent association between the level of urinary protein excretion and
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the risk of death in populations with and without diabetes mellitus [9–15]. There are few reports that demonstrate a significant relationship between the dipstick proteinuria and cardiovascular events in diabetic patients. Urinary dipstick is a relatively simple and clinically easy-to-use tool to detect proteinuria, and it may identify patients who are at a high risk of mortality. We undertook the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial to examine the efficacy of low-dose aspirin therapy for the primary prevention of cardiovascular events in type 2 diabetic patients [16]. Our data showed that low-dose aspirin therapy did not increase adverse events and although the efficacy results were not statistically significantly different, the point estimate of the effect on the primary composite cardiovascular outcome was a 20% reduction [16]. We also reported the results of the JPAD2 extension study using the data that were obtained until 2015 [17]. This mean observation during and after the trial which comprised more than one decade, indicated that long-term therapy with low-dose aspirin is not associated with lower cardiovascular events in Japanese patients with type 2 diabetes mellitus in a primary prevention setting. However, low-dose aspirin therapy was associated with, and significantly increased, the incidence of gastrointestinal bleeding [17]. By using these data, we sought to investigate whether dipstick proteinuria was a significant risk factor for cardiovascular events in patients without a history of cardiovascular events. Materials and methods JPAD trial and JPAD2 study The study protocol for the JPAD trial was registered at clinicaltrials.gov with the identifier NCT00110448.The JPAD trial design and overall findings have been reported previously [16]. The study protocol is in agreement with the guidelines of the ethics committees at Kumamoto University (Rinri 956) and Nara Medical University (No. 236-3), and the study complies with the Declaration of Helsinki.Briefly, this multicenter, prospective, randomized, open, blinded-end-point study was conducted at 163 institutions throughout Japan, and it enrolled 2536 patients with type 2 diabetes, who had no history of cardiovascular disease. The institutional review board at each participating hospital approved this trial, and written informed consent was obtained from each patient. In the JPAD trial, the inclusion criteria were diagnosis of type 2 diabetes mellitus, 30–85 years of age, and the ability to provide informed consent. The exclusion criteria were electrocardiographic ischemic changes, a history of coronary heart disease, cerebrovascular disease, arteriosclerotic disease, atrial fibrillation, use of antiplatelet or antithrombotic therapy, a history of severe gastric or duodenal ulcer, severe liver dysfunction, severe renal dysfunction, or allergy to aspirin [16]. There were 2536 patients who were randomly assigned and the median follow-up period until 2008 was 4.37 years. Cardiovascular events analyses and subgroup analyses of the follow-up for the following cardiovascular events were performed: cerebrovascular events including stroke events and transient ischemic attack; coronary events including acute myocardial infarction and angina; aortic and peripheral vascular events; and sudden death. Urinalysis Urinalysis using the dipstick method was performed on a single spot urine specimen that was collected. Urine dipstick results were interpreted by the medical staff at each local medical institution and recorded as ( ), (), (+), (1+), (2+), or (3+). In Japan, it is a
widely adopted policy of the Japanese Committee for Clinical Laboratory Standards (http://jccls.org/) that all urine dipstick tests should be manufactured so that a urine dipstick result of will correspond to a urinary protein level of 15 mg/dL. Serum creatinine was assayed using an enzymatic method. Estimated glomerular filtration rate (eGFR) was determine based on the chronic kidney disease (CKD)-epidemiology collaboration equation for Japanese people as follows [18]: Men : 194 Cre
1:094
Women : 194 Cre
age
1:094
0:287
age
0:287
0:739
Proteinuria and non-proteinuria groups Among the 2536 JPAD patients, 42 patients were excluded for lack of proteinuria data at registration. Based on the result of the dipstick test at registration, we divided the patients into two groups: a proteinuria group (n = 446; proteinuria ); and a nonproteinuria group (n = 2048; proteinuria ). We compared the incident rates of cardiovascular events between the proteinuria group and the non-proteinuria group. Therefore, this study was not a randomized study based on proteinuria. Definition of cardiovascular events The primary endpoint was any cardiovascular event, that was a composite of sudden death; death from coronary, stroke, and aortic causes; nonfatal myocardial infarction; unstable angina; newly developed exertional angina; nonfatal ischemic and hemorrhagic stroke; transient ischemic attack; and/or nonfatal aortic and peripheral vascular disease (arteriosclerosis obliterans, aortic dissection, mesenteric arterial thrombosis) during the follow-up period. Stroke events were a combination of death from cerebrovascular causes and nonfatal ischemic and hemorrhagic stroke. Heart events were a combination of death from coronary causes and nonfatal myocardial infarction; unstable angina; and newly developed exertional angina. All potential endpoints were adjudicated by an independent committee for validation of data and events, and they were unaware of the group assignments. Statistical analyses Patient characteristics are presented as the mean standard deviation (SD), median (interquartile range) or number (%). Comparisons of variables between the proteinuria and nonproteinuria groups were conducted using a t-test or the Wilcoxon rank sum test for continuous variables or the Chi-square test for categorical variables. Comparisons of cardiovascular events were performed based on the time to the first event. Cumulative incidences of primary end points were estimated using the KaplanMeier method and differences between groups were then assessed using the log-rank test. We constructed multivariate Cox proportional hazard models to estimate the hazards ratios (HRs) of proteinuria , with a 95% CI. We included the clinically relevant factors of age 65 years, gender, body mass index (BMI) 24 kg/m2, duration of diabetes mellitus 7 years, hemoglobin A1c level 7.2%, use of angiotensin II receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI), categorized eGFR level (60, 60> to 30, <30 ml/min/1.73 m2), and use of aspirin as confounders. Patients with missing values for any selected variable were excluded from the analyses that used this variable. All statistical analyses were conducted using JMP version 13.1 (SAS Institute Inc, Cary, NC, USA). Two-tailed p-values of less than 0.05 were considered statistically significant.
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Table 1 Baseline characteristics. Characteristics
Proteinuria group (n = 446)
Non-proteinuria group (n = 2048)
p-Value
Age, Mean SD, Years Male Past or current smoker, n (%) Body mass index, Mean SD, kg/m2 Dyslipidemia, n (%) Hypertension, n (%) Duration of diabetes, median, (IQR), years Diabetic retinopathy Diabetic nephropathy Diabetic neuropathy Dermal ulcer Hemoglobin A1c level, Mean SD, % Fasting plasma glucose level, Mean SD, mg/dl Serum creatinine levels, Mean SD, mg/dl Estimated glomerular filtration rate, Mean SD, ml/min/1.73 m2 Treatment for hypertension Calcium channel blockers Angiotensin II receptor blockers Angiotensin converting enzyme inhibitors b-blockers a-blockers Treatment for diabetes and dyslipidemia Sulfonylureas a-Glucosidase inhibitors Biguanides Insulin Thiazolidines Statins Family history Ischemic heart disease Stroke
64 11 267 (60) 209 (47) 25 4 247 (55) 309 (69) 8.1 (3.3–13.7) 111 (25) 246 (55) 85 (19) 5 (1.1) 7.7 1.5 152 50 0.9 0.5 70.8 25.2
64 10 1089 (53) 830 (41) 24 4 1080 (53) 1138 (56) 6.6 (2.9–12.1) 253 (12) 74 (4) 210 (10) 7 (0.3) 7.4 1.3 146 48 0.8 0.2 74.6 19.5
0. 96 0.01 0.01 0.004 0.3 <0.001 0.02 <0.0001 <0.0001 <0.0001 0.047 0.0006 0.02 <0.0001 0.003
203 (46) 132 (30) 77 (17) 31 (7) 23 (5)
655 (32) 393 (19) 290 (14) 129 (6) 68 (3)
<0.0001 <0.0001 0.09 0.6 0.06
263 (59) 146 (33) 77 (17) 75 (17) 27 (6) 119 (27)
1149 (56) 679 (33) 273 (13) 250 (12) 95 (5) 522 (25)
0.3 0.9 0.03 0.009 0.2 0.6
48 (11) 98 (22)
238 (12) 442 (21)
0.6 0.5
Proteinuria is a risk factor for cardiovascular events in diabetic patients
Results Baseline clinical characteristics The baseline clinical characteristics are shown in Table 1. There were significant differences in gender, BMI, hemoglobin A1c levels, and eGFR, and in the frequency of smoking, hypertension, diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy between the proteinuria and non-proteinuria groups. The use of calcium channel blockers and ARBs was significantly higher in the proteinuria group compared with the non-proteinuria group. The use of biguanide and insulin was significantly higher in the proteinuria compared with the non-proteinuria group. Clinical characteristics such as age, the frequency of dyslipidemia, and use of ACEIs, statins, and b-blockers were similar between the proteinuria and non-proteinuria groups.
Primary cardiovascular events that occurred are presented in Table 2. There was a significant difference in the incidence of the primary cardiovascular events between the proteinuria and non-proteinuria groups. The incidence rates of primary cardiovascular events were significantly higher in the proteinuria group (84 events, 19%) compared with the non-proteinuria group (248 events, 12%) (HR, 1.75; 95% CI, 1.36–2.23; log-rank test, p < 0.0001) as shown in Fig. 1. We compared the difference of cardiovascular event rate among the proteinuria , , 1+, 2+, and 3+ groups as shown in Fig. 2. The cardiovascular event rate (event number/patient number) was 0.12 (248/2048) in the proteinuria – group, 0.16 (16/100) in the proteinuria group, 0.20 (41/208) in the proteinuria + group, 0.17
Table 2 Cardiovascular events.
Cardiovascular events Coronary artery events Fatal myocardial infarction Nonfatal myocardial infarction Stroke events Fatal stroke Nonfatal stroke Ischemic Hemorrhagic Transient ischemic attack Vascular events Sudden death
Proteinuria group (n = 446)
Non-proteinuria group (n = 2048)
n (%)
No. per 1000 person-years
n (%)
No. per 1000 person-years
84 (19) 29 (7) 1 (0.2) 10 (2) 29 (7) 5 (1.1) 24 (5) 20 (4) 4 (0.9) 5 (1.1) 17 (4) 4 (0.9)
25.53 8.81 0.30 3.04 8.81 1.52 7.29 6.08 1.22 1.52 5.17 1.22
248 (12) 101 (5) 8 (0.4) 35 (1.7) 88 (4) 13 (0.6) 75 (4) 62 (3) 13 (0.6) 14 (0.7) 34 (1.7) 11 (0.5)
14.62 5.95 0.47 2.06 5.19 0.77 4.42 3.65 0.77 0.83 2.00 0.65
HR (95% CI)
p-Value
1.75 (1.36–2.23) 1.49 (0.97–2.22) 0.62 (0.03–3.41) 1.50 (0.70–2.91) 1.69 (1.09–2.54) 2.03 (0.65–5.39) 1.64 (1.01–2.55) 1.64 (0.97–2.67) 1.61 (0.45–4.55) 1.79 (0.58–4.68) 2.58 (1.41–4.55) 1.92 (0.53–5.63)
<0.0001 0.07 0.6 0.3 0.02 0.2 0.045 0.07 0.4 0.3 0.003 0.3
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Fig. 1. Comparison of primary cardiovascular events between the proteinuria and non-proteinuria groups. The incidence of primary cardiovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group. HR, hazard ratio.
Fig. 4. Comparison of primary acute myocardial infarction between the proteinuria and non-proteinuria groups. There was no significant difference in the incidence rate of primary acute myocardial infarction between the proteinuria group and the non-proteinuria group. HR, hazard ratio.
(17/98) in the proteinuria 2+ group, and 0.25 (10/40) in the proteinuria 3+ group. Subgroup analyses of cerebrovascular events and acute myocardial infarction Cardiovascular events are shown in Table 2. The incidence rates of primary cerebrovascular events were significantly higher in the proteinuria group (34 events, 8%) compared with the non-proteinuria group (102 events, 5%; HR, 1.71; 95% CI, 1.14–2.49; log-rank test, p = 0.0064; Fig. 3). There were no significant differences, however, in the incidence rate of primary acute myocardial infarction between the high proteinuria group (11 events, 2%) and the non-proteinuria group (43 events, 2%; HR, 1.33; 95% CI, 0.65–2.49; log-rank test, p = 0.40; Fig. 4). Fig. 2. Comparison of primary cerebrovascular events among each proteinuria level group. Although it seemed that there was a significant difference when it was divided into 5 groups, Kaplan-Meier curve overlapped in the proteinuria , 1+, and 2 + groups. The event rate seemed higher in the proteinuria 3+ group, but the proteinuria 3+ group had fewer patients and was less reliable.
Proteinuria was independently associated with cardiovascular events The Cox proportional hazards model including clinically important factors revealed that proteinuria, age, gender, and hemoglobin A1c level were independent predictive factors for cardiovascular events in diabetic patients (Table 3). However, eGFR and use of ARB or ACEI were not independently associated with cardiovascular events.
Table 3 Multivariate Cox proportional hazards model.
Fig. 3. Comparison of primary cerebrovascular events between the proteinuria and non-proteinuria groups. The incidence rate of primary cerebrovascular events was significantly higher in the proteinuria group compared with the non-proteinuria group. HR, hazard ratio.
Factor
Hazard ratio
95% CI
p-Value
Proteinuria Age 65 years Men Body mass index 24 kg/m2 Duration of diabetes mellitus 7.0 years Hemoglobin A1c 7.2% Use of ARB or ACEI 60>eGFR30 ml/min/1.73 m2 30 ml/min/1.73 m2 > eGFR Use of aspirin
1.62 1.91 1.51 0.98 1.32 1.50 1.14 1.17 1.17 0.94
1.23–2.11 1.49–2.46 1.19–1.93 0.77–1.24 1.04–1.68 1.18–1.90 0.89–1.45 0.90–1.51 0.29–3.13 0.75–1.18
0.0005 <0.0001 0.0007 0.9 0.02 0.0008 0.3 0.2 0.8 0.6
ARB, angiotensin II receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; eGFR, estimated glomerular filtration rate.
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Discussion In this 10-year follow-up study, we demonstrated that the incidence rate of cardiovascular events including cerebrovascular events, coronary events, and aortic and peripheral vascular events, in type 2 diabetic patients in a primary prevention setting, was significantly higher in the proteinuria group compared with the non-proteinuria group. Thus, dipstick proteinuria results are useful for predicting the incidence of cardiovascular events in diabetic patients. Previously, several studies that showed the association between dipstick proteinuria results and cardiovascular events were reported [19–22]. Dipstick proteinuria results were significantly associated with the risk of cardiovascular events in patients with angiographic evidence of clinically significant coronary artery disease [19]. Dipstick proteinuria results were significantly associated with the risk of stent thrombosis in patients with acute myocardial infarction who underwent percutaneous coronary intervention with a stent [20]. Dipstick proteinuria results were significantly associated with the risk of all-cause mortality in patients with previous myocardial infarction [21]. Dipstick proteinuria was significantly associated with the risk of thromboembolism in patients with atrial fibrillation [22]. Our data showed, for the first time, the association between dipstick proteinuria results and primary cardiovascular events in patients with diabetes mellitus who had no history of cardiovascular events. Recently, dipstick proteinuria results were used to identify subjects with chronic kidney disease among the general population in several studies [23]. Dipstick proteinuria results were categorized as follows: , , and + or greater. The albuminuria level was categorized as follows: A1, <30 mg/gCr; A2, 30–300 mg/ gCr; and A3, >300 mg/gCr; Quantitative proteinuria was categorized as follows: P1, <150 mg/gCr; P2, 150–500 mg/gCr; and P3, >500 mg/ gCr. These categories are based on the recommendations of the Japanese Society of Nephrology [24] which were created by modifying the Kidney Disease: Improving Global Outcome (KDIGO) CKD guideline 2012 [25] for Japanese people. The National Kidney Foundation Kidney Disease Outcome Quality Initiative recommends screening high-risk groups, such as patients with diabetes or hypertension [26]. The United Kingdom’s National Institute for Health and Clinical Excellence also recommends screening high-risk groups [27]. Thus, the dipstick test is useful as a risk screening methods for diabetic patients. The dipstick test could fail to diagnose patients with microalbuminuria depending on the dipstick that is used [28]. Therefore, a highly accurate dipstick test should be chosen. In the present study, we considered proteinuria to be a proteinuria-positive result in the dipstick test. The proteinuria group was reported to contain a high proportion of albuminuriapositive patients [29]. It was reported that proteinuria means the presence of microalbuminuria and that proteinuria - means no presence of albuminuria [30]. Selvin et al. reported that proteinuria should be repeatedly measured because a proteinuria level in the same person often changes greatly in a short period of time [31]. The dipstick test is suitable for frequent testing because it is simple to use and has a low cost. In the present study, the Cox proportional hazards model including clinically important factors revealed that proteinuria was independently associated with primary cardiovascular events in diabetic patients. Previous reports also showed that proteinuria was an independent predictive factor of mortality and cardiovascular events [19–22]. Treatments that decreased proteinuria were shown to lead to decreased cardiovascular events during follow-up [32]. Sandsmark et al. showed that when adjusted for variables that were known to influence stroke risk, total proteinuria or albuminuria, but not eGFR, was associated with an increased risk
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of stroke [33]. Our data showed that eGFR was not an independent factor for cardiovascular events, as shown in Table 2. Several studies found that subjects with a decreased eGFR had an increased risk of stroke compared with subjects with normal eGFR (>60 ml/min per 1.73 m2).We suggest that eGFR did not become an independent predictive factor for cardiovascular events in the present study because most patients had a normal eGFR (n = 1868, 74.9%). The 2012 KDIGO clinical practice guideline for the evaluation and management of CKD [34] and the KDIGO clinical practice guideline for the management of blood pressure [35] have both recommended that renin-angiotensin system (RAS)-blocking drugs are used in adults with diabetes mellitus and albuminuria. In a recent randomized, double-blind, placebo-controlled trial, patients who were treated with sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor were reported to be more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria or from macroalbuminuria to microalbuminuria or normoalbuminuria, and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria [36]. The trial results support the clinical benefits of SGLT2 inhibitors in diabetic patients with urinary albumin excretion, irrespective of patients' albuminuria status. Possible mechanisms of renal cortex injury by hypoxia and protection of proximal tubular epithelial cells by SGLT2 inhibitor have been shown [37]. This study had some limitations. First, the JPAD trial was designed as a randomized controlled trial to evaluate the efficacy of low-dose aspirin in cardiovascular prevention, and not to evaluate the prognostic value of proteinuria. Second, this study included a small number of cardiovascular events. Because the present study was a sub-analysis of the JPAD trial, the number of patients and number of events were lower compared with the main study. We compared the difference of cardiovascular event rate among the proteinuria , , 1+, 2+, and 3 + groups. The proteinuria 3+ group is likely higher, but the significance is unreliable because the number of events was small. This point needs to be followed up and reconsidered. Conclusions In conclusion, proteinuria was independently associated with the incidence of cardiovascular events in diabetic patients without a history of cardiovascular events. Dipstick proteinuria testing is a simple, inexpensive, but significant predictive method for primary cardiovascular events in diabetic patients. Funding This study was supported by the Ministry of Health, Labour and Welfare, Japan (H16-Junkanki-004, and H27-Junkanki-Ippan-001) and Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENHI) grant 18K08521. Disclosures Dr Soejima reports research grant from Boehringer Ingelheim. Dr Morimoto reports lecturer's fees from AstraZeneca, Bayer, Daiichi Sankyo, Japan Lifeline, Kyocera, Mitsubishi Tanabe, Novartis, and Pfizer; a manuscript fee from Pfizer; and served advisory boards for Asahi Kasei, Bristol-Myers Squibb, and Boston Scientific. Dr Okada reports lecturer's fees from Novo Nordisk, Mitsubishi Tanabe, Sumitomo Dainippon, Arkray, Bayer, Eli Lilly, Boehringer Ingelheim, Ono, AstraZeneca, Sanofi, and Takeda. Dr Nakayama reports lecturer’s fees from Bayer, Shionogi, Takeda, Daiichi Sankyo, Sanofi, Boehringer Ingelheim, Sumitomo Dainip-
Please cite this article in press as: Soejima H, et al. Proteinuria is independently associated with the incidence of primary cardiovascular events in diabetic patients. J Cardiol (2019), https://doi.org/10.1016/j.jjcc.2019.08.021
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pon, Fujifilm Medical, Kowa, Pfizer, and Astellas. Dr Masuda reports lecturer's fees from AstraZeneca, Ono, Takeda, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, Kowa, Kyowa Hakko Kirin, MSD, Novartis, Shionogi, and Mitsubishi Tanabe. Dr Jinnouchi reports research grants from MSD, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Takeda, Taisho Toyama, Astellas, Chugai, Bayer, Sanofi, GlaxoSmithKline, Sanwa Kagaku Kenkyusho, Ono, Eli Lilly, AstraZeneca, Pfizer, and Shionogi; lecturer's fees from MSD, AstraZeneca, Astellas, Abbott, Sanofi, Terumo, Novo Nordisk, Bayer, Sanwa Kagaku Kenkyusho, Kyowa Hakko Kirin, Taisho Toyama, Daiichi Sankyo, Teijin, Mitsubishi Tanabe, Eli Lilly, Boehringer Ingelheim, and Takeda; and manuscript fees from Novo Nordisk and Taisho Toyama. Dr Waki reports research grants from Sanofi and AstraZeneca; and lecturer's fees from MSD, Astellas, Amgen Astellas BioPharma, AstraZeneca, Otsuka, Ono, Kowa, Kyowa Hakko Kirin, Novartis, Sanofi, Sanwa Kagaku Kenkyusho, Johnson & Johnson, Daiichi Sankyo, Taisho Toyama, Sumitomo Dainippon, Takeda, Mitsubishi Tanabe, Teijin, Eli Lilly, Novo Nordisk, Bayer, Pfizer, Boehringer Ingelheim, and Abbott. Dr Saito reports research grants from Bayer, Terumo, Otsuka, Amgen Astellas BioPharma, Novartis, Ono, Shionogi, Teijin, St. Jude Medical, and Mitsubishi Tanabe; non-purpose research grants from Astellas, Asahi Kasei, Actelion, Boston Scientific, Chugai, Daiichi Sankyo, Sumitomo Dainippon, Eisai, Fuji Yakuhin, Kowa, Kyowa Hakko Kirin, Medtronic, Mitsubishi Tanabe, MSD, Nihon Medi-Physics, Ono, Otsuka, Sanofi, Shionogi, Takeda, Teijin, and Zeria; lecturer's fees from Asahi Kasei, Astellas, Bayer, Daiichi Sankyo, Sumitomo Dainippon, Fuji Yakuhin, Kowa, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Boehringer Ingelheim, Novartis, Ono, Otsuka, Pfizer, Sanofi, Taisho Toyama, Takeda, and Toa Eiyo; a manuscript fee from Pfizer; served advisory boards for Novartis, Pfizer, Mitsubishi Tanabe, Ono, Boehringer Ingelheim; and a sponsored office from MSD. The others declare no conflicts of interest. Acknowledgments The authors thank M. Ohtorii (Institute for Clinical Effectiveness, Kyoto, Japan) for her roles in data management and statistical analyses. The authors also thank M. Aoyama (Kumamoto University), Y. Wada, Y. Kamada, and M. Miyagawa (Nara Medical University) for their secretarial work. Additionally, we thank Jodi Smith, PhD, from Edanz Group for editing a draft of this manuscript.
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