A possible relationship between renal impairment and complications development in type 2 diabetes mellitus: a prospective, observational study in Italy

    A possible relationship between renal impairment and complications development in type 2 diabetes mellitus: a prospective, observational study in Italy Fabio Fabbian, Alfredo De Giorgi, Marcello Monesi, Marco Pala, Ruana Tiseo, Silvia Forcellini, Alda Storari, Roberto Graziani, Riccardo Volpi, Dimitri P. Mikhailidis, Roberto Manfredini PII: DOI: Reference:

S1056-8727(15)00178-6 doi: 10.1016/j.jdiacomp.2015.05.003 JDC 6450

To appear in:

Journal of Diabetes and Its Complications

Received date: Revised date: Accepted date:

26 January 2015 26 March 2015 6 May 2015

Please cite this article as: Fabbian, F., De Giorgi, A., Monesi, M., Pala, M., Tiseo, R., Forcellini, S., Storari, A., Graziani, R., Volpi, R., Mikhailidis, D.P. & Manfredini, R., A possible relationship between renal impairment and complications development in type 2 diabetes mellitus: a prospective, observational study in Italy, Journal of Diabetes and Its Complications (2015), doi: 10.1016/j.jdiacomp.2015.05.003

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ACCEPTED MANUSCRIPT A possible relationship between renal impairment and complications development in type 2 diabetes mellitus: a prospective, observational study in Italy

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Fabio Fabbian1 MD, Alfredo De Giorgi1 MD, Marcello Monesi2 MD, Marco Pala1 MD,

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Ruana Tiseo1, MD, Silvia Forcellini3, MD, Alda Storari3, MD, Roberto Graziani2 MD,

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Riccardo Volpi4, MD, Dimitri P. Mikhailidis5 MD, Roberto Manfredini1 MD. 1. Clinica Medica, Department of Medical Sciences, University Hospital St. Anna, Ferrara

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2. Diabetes and Clinical Nutrition, University Hospital St. Anna, Ferrara 3. Nephrology and Dialysis, University Hospital St. Anna, Ferrara

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4. Department of Internal Medicine and Biomedical Science, University of Parma, Parma 5. Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), University

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College London Medical School, University College London (UCL), London, UK

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Short title: GFR and complications in type 2 DM

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Author for correspondence: Fabio Fabbian, MD; Unit of Clinica Medica, Department of Medical Sciences, University Hospital St. Anna, Via Aldo Moro, 8; I-44124, Ferrara, Italy e-mail: [email protected] - tel. #39 0532 239008; fax. #39 0532 238539 Financial support: This paper is supported, in part, by a scientific grant (FAR – Fondo Ateneo Ricerca) from the University of Ferrara, Italy. Conflict of interest: FF, ADG, MM, MP, RT, SF, AS, RG, RV, and RM had no conflict of interest; DPM has given talks, attended conferences and participated in advisory boards and trials sponsored by Merck, Sharp & Dohme.

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ACCEPTED MANUSCRIPT Author Contribution FF, ADG, MM, MP, RT, SF, AS, RG, RV, and RM participated in study’s conception and

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design; FF, ADG, MM, MP, RT, SF, AS, RG, handled the original database, collected and

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analyzed the data, and drafted the article; FF, ADG, MM, MP, RT, SF, AS, RG, RV DPM, and RM, participated in the interpretation of data, and revised it critically for important

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intellectual content, and final approval. All authors read and approved the final manuscript.

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ACCEPTED MANUSCRIPT Abstract Background: We investigated the relationship between complications development and

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estimated glomerular filtration rate (eGFR), in a cohort of type 2 diabetes mellitus (T2DM)

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outpatients.

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Methods: This observational study considered 1284 T2DM outpatients, who had been followed-up for 4.5 ± 1.6 years. eGFR was estimated using Chronic Kidney Disease

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Epidemiology Collaboration equation. The independent relationship between development of complications and clinical data was evaluated, and Hazard Ratio (HR) by Cox regression analysis calculated.

Results: Mean age of the population was 66.8 ± 10.4 years, mean serum creatinine and

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eGFR were 1.05 ± 0.36 mg/dl and 71.6 ± 21.6 ml/min/1.73 m2, respectively. Complications

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including death (14.2% of the whole population) were recorded in 504 subjects (39.3%). Patients with complications were older and more frequently male with history of

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hypertension, coronary heart disease, congestive heart disease, retinopathy, nephropathy

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and had higher levels of glycated hemoglobin. At Cox regression analysis, eGFR was the major risk factor for development of complications and the HR increased according with lower eGFR (HR 1.53 and 1.86, for eGFR < 45 and < 30 ml/min/1.73 m2, respectively)

Conclusions: In our cohort of T2DM outpatients, a reduced eGFR was associated with an increased the risk of complications development.

Keywords: Type 2 diabetes mellitus, glomerular filtration rate, complications, outpatients, kidney.

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ACCEPTED MANUSCRIPT Introduction Type 2 diabetes mellitus (T2DM) is a widely accepted risk factor for development of percentage

of CKD

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chronic kidney disease (CKD) and, at the same time, a high

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patients suffers T2DM. Moreover, the burden of atherosclerotic vascular damage is more evident in uraemic subjects with DM than in those without this metabolic derangement

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[Fabbian et al., 2003]. Renal dysfunction has been reported to be related with diagnosed,

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undiagnosed and pre-DM, besides more than one third of subjects with CKD have been reported to have DM [Plantinga et al., 2010]. The estimation of the prevalence of diabetic nephropathy shows wide variations, ranging from 10 - 40% depending on type of DM, proportion and definition of the disease [Gross et al., 2005; Ritz et al., 1999]. As for Italy,

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DM is the cause of end-stage renal disease (ESRD) in 20% of incident dialysis subjects [Registro Italiano Dialisi e Trapianto. http://www.sin-ridt.org/italia/report 2010 Accessed

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02/02/2014]. Complications due to DM have been reported to be particularly frequent in

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T2DM patients with renal failure [Ritz et al., 1999], and well accepted guidelines define CKD as failing kidney function when estimated glomerular filtration rate (eGFR) is lower 60

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ml/min/1.73m2 [National Kidney Foundation, 2002; American Diabetes Association, 2013]. On the other hand, in a previous study our group reported that calculation of eGFR, performed with different formulae, could differently classify CKD stages in T2DM patients [Fabbian et al., 2013a]. Although the pathophysiology of the relationship between renal dysfunction and complications development is still a matter of debate, renal dysfunction in T2DM could be a marker of generalized atherosclerotic disease [Kramer et al., 2003]. The aim of this study was to prospectively investigate the relationship between degree of renal failure and development of complications in a cohort of T2DM outpatients.

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Patients and methods

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This prospective, longitudinal, observational study, was approved by the local ethic committee and was conducted in agreement with the Declaration of Helsinki. It included a

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cohort of Caucasian T2DM outpatients consecutively evaluated at the diabetic clinic of the University Hospital of Ferrara between January 2008 and December 2013. Missing data,

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non-diabetic renal disease and being on renal replacement therapy (RRT) were exclusion criteria. At the time of enrollment, the following parameters were recorded: age, sex, presence of history of hypertension, nephropathy, coronary artery disease (CHD), congestive heart failure (CHF), peripheral arterial disease (PAD), cerebrovascular disease

decreasing

glomerular

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(CeVD), peripheral neuropathy and retinopathy. Nephropathy was defined by filtration

below

60

m/min/1.73m2,

development

of

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microalbuminuria in subjects who hadn’t had it, progression of microalbuminuria to

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overt macroalbuminuria, and beginning of renal replacement therapy (RRT). Antidiabetic drugs prescribed in the enrolled patients were: metformin (n= 458, 35.7%),

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metformin and sulfonylurea (n= 35.5%), sulfonylurea (n= 5.7%), glitazones (n= 10, 0.8%), repaglinide (n= 66, 5.1%) and dipeptidyl peptidase-4 inhibitors (n= 0.2%) patients. None of the patients were treated with insulin. Values of serum creatinine (SCr) (Jaffe method on a Hitachi Modular, Roche Diagnostics, Mannheim, Germany), and glycated hemoglobin (Variant II HbA2/HbA1c Dual Program, Hercules, California) were also recorded. Patients with pre-existing diagnosis of nephropathy, including presence or absence of microalbuminuria and macroalbuminuria were

enrolled.

The

latter

variable

was

analyzed

as

categorical

ones

(i.e.

presence/absence), normal urinary albumin excretion rate was below 30 mg/24 h. For each patient, renal function was evaluated by eGFR using the following equation: 5

ACCEPTED MANUSCRIPT  Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [Levey et al., 2009]:

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- If female and if SCr ≤ 0.7 mg/dl: GFR CKD-EPI = 144 x SCr/0.7 –0.329 x 0.993 age - If female and if SCr > 0.7 mg/dl: GFR CKD-EPI = 144 x SCr/0.7 –1.209 x 0.993 age

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- If male and if SCr ≤ 0.9 mg/dl: GFR CKD-EPI = 141 x SCr/0.9 –0.411 x 0.993 age

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- If male and if SCr > 0.9 mg/dl: GFR CKD-EPI = 141 x SCr/0.9 –1.209 x 0.993 age Duration of follow-up of 4.5±1.6 years, and development of new complications including all-cause mortality and cardiovascular (CV) mortality, non-fatal CV events, episodes of CHF, cerebrovascular events, new diagnosis of proliferative retinopathy, neuropathy,

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diabetic foot and beginning of RRT were considered as single composite end-point.

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The presence of CV disease was recorded by diabetologists as a history of cerebrovascular accidents such as bleeding or infarction, admission because of CHF and

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CHD. CHD was defined as history of typical angina, myocardial infarction of coronary

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bypass surgery or percutaneous revascularization. All data of events during the follow-up period were drawn from the database of the Emilia-Romagna region of Italy. Statistical Analysis Data were expressed as mean ± SD or as percentage. The primary composite outcome was development of all complications. Subjects with and without complications were compared using the Chi-square test for estimating the occurrence of categorical variables and t-test and Mann-Whitney for parametric and non-parametric continuous variables, respectively. In order to analyze the relationship between complications development and different clinical characteristics, Cox regression analysis for Hazard ratios (HRs) calculation was performed. Age, anthropometric parameters, biochemical variables, eGFR, 6

ACCEPTED MANUSCRIPT presence or absence of microalbuminuria, macroalbuminuria, clinical history were the independent variables. eGFR was analyzed as a dichotomous variable using different cut-

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off, lower than 60, 45 and 30 ml/min/1.73m 2. All p-values were two-tailed, with significance

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defined as p <0.05. SPSS for Windows was used as a statistical system (SPSS, Version 13, SPSS Inc., Chicago, IL, USA).

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Results

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The clinical and biochemical data of the 1,284 patients enrolled, as recorded at the start of the study, are shown in Table 1. The mean age of the population was 66.8 ± 10.4 years, mean SCr and eGFR were 1.05 ± 0.36 mg/dl and 71.6 ± 21.6 ml/min/1.73 m2, respectively; 292 (22.7%) had CKD stage 1 Kidney Disease Outcomes Quality Initiative (K/DOQI), 612

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(47.7%) had CKD stage 2 K/DOQI, 342 (26.6%) had CKD stage 3 K/DOQI, 38 (2.9%) had

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CKD stage 4-5 K/DOQI. Complications including death (14.2% of the whole population) were recorded in 504 subjects (39.3%) (Table 2). Only three patients (0.2%) started

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RRT. Complications of patients with eGFR < and ≥ 60 ml/min/1.73 m2 are shown in Table 3. Comparisons between subjects with and without complications are shown in Table 4.

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Patients with complications were older, more frequently male, with history of hypertension, CHD, CHF, retinopathy, nephropathy and had higher levels of glycated hemoglobin. During follow-up 517 (40.2%) started insulin therapy, while 78 subjects (6.1%) were on diet therapy only. In order to evaluate the relationship between development of complications and clinical data including therapy, we calculated HR and 95% CI by Cox regression analysis. Complications development was the dependent variable, and eGFR and age, anthropometric parameters, biochemical variables, eGFR, presence or absence of microalbuminuria, macroalbuminuria, and history of hypertension, nephropathy, 7

ACCEPTED MANUSCRIPT coronary artery disease, congestive heart failure, peripheral arterial disease, cerebrovascular disease, peripheral neuropathy, retinopathy) were the independent

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ones. eGFR was the major risk factor for development of complications and the risk was

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higher for eGFR < 30 ml/min/1.73 m2 than for eGFR < 45 ml/min/1.73m2 (Figure 1). In contrast, complications development was not independently related with less serious

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degree of renal dysfunction as demonstrated by the lack of relationship with eGFR < 60

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ml/min/1.73 m2.

Discussion

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The main result of the present study is that low eGFR predicts T2DM complications. It has to be emphasized that we did not aim to precisely evaluate risk factors for development of

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single complications in different organs, but rather to evaluate the prognostic impact of eGFR on the development of complications in T2DM outpatients. Evaluation of renal

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function is a well established medical action in T2DM as suggested by major scientific

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societies; the American Diabetes Association (ADA) suggests using the MDRD equation to evaluate eGFR [American Diabetes Association, 2013]. Even calculators created for the evaluation of mortality risk in T2DM, included eGFR as one of the variables [Wells et al., 2008]. Although T2DM is an independent risk factor for mortality, its impact is greatly reduced if the eGFR is normal [Vaccaro et al., 2004]. In hospitalized patients, renal impairment is an independent risk factor for mortality due to myocardial infarction and stroke [Fabbian et al., 2013b; Fabbian et al., 2014], and in subjects with CV disease, DM did not change mortality risk associated with renal dysfunction [Selvarajah et al., 2013]. It could be possible that renal dysfunction is a major factor responsible for high mortality risk secondary to DM; in fact, renal impairment is associated with 5-fold higher risk of mortality [Amin et al., 2013]. 8

ACCEPTED MANUSCRIPT More than 15,000 Caucasian patients with T2DM were studied aiming at assessing the CV disease burden associated with CKD [Pugliese et al., 2011]. In that study, CKD was

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defined as an eGFR <60 mL/min/1.73m2 and/or micro/macroalbuminuria. The authors

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concluded that evaluation of eGFR provides a better definition of CV disease burden associated with CKD [Pugliese et al., 2011].

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A recent Italian study followed 2,823 T2DM outpatients for a period of 6 years, and found

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that eGFR < 60 mL/min/1.73 m2, detected in more that 20% of patients, was associated with an increased risk of all-cause and CV mortality [Targher et al., 2012]. A Swedish study including more than 66,000 patients with T2DM recorded in the National Diabetes Register (NDR) with a follow-up of 5.7 years, evaluated the relationship between

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reduced renal function, albuminuria and CV events. Renal impairment was defined as

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eGFR < 60 mL/min/1.73 m2 and reported in 17% of cases. A total of 10% of patients experienced a CV event and 3.7% of these were fatal. Increasing levels of albuminuria and

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renal impairment were independently associated with increasing risk of CV events and allcause mortality also when adjusting for CHF. Moreover, in normoalbuminuric patients, a

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reduction in renal function was an important predictor of CV events and all-cause mortality [Svensson et al., 2013]. A smaller study from Taiwan enrolled 646 T2DM subjects, followed-up for about 10 years. One hundred and fifty-eight subjects died (59 from cancer). Subjects with proteinuria had a hazard ratio (HR) of 2.77 (95% CI 1.82-4.21) for all-cause mortality and 1.99 (95% CI 1.00-3.94) for cancer-related mortality, after adjustment for demographic factors and medical conditions. However, if eGFR was < 60 mL/min/1.73 m 2, HR for all-cause mortality was higher than patients with proteinuria only [Yu et al., 2013]. Barkoudah et al. selected all the published randomized control trials including T2DM patients from August 1980 through March 2011. Selection included studies enrolling adults with T2DM of at least 1,000 patients, reporting all-cause mortality and having follow-up 9

ACCEPTED MANUSCRIPT duration of at least 1 year. The analysis cohort included 91,842 patients and 6,837 deaths. Mortality rates ranged from 0.28 to 8.24 per 100 patient-years. Patients enrolled in the

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highest mortality category were more likely to be older and had longer DM duration and

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higher blood pressure. Although the mortality rates were higher in randomized controlled trials with prior CV morbidity, the selection of subjects with CKD, defined by either higher

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SCr or lower eGFR and/or the presence of proteinuria, was associated with the highest

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mortality rates [Barkoudah et al., 2012].

Yap et al. investigated the relationship between peripheral artery disease and renal dysfunction in 236 elderly T2DM patients. eGFR <60 ml/min/1.73m2 was independently associated with peripheral artery disease and considering the presence or absence of

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albuminuria did not result in a significant variation of the relationship. It could be that reduced renal function better reflected the burden of vascular damage than albuminuria

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[Yap et al., 2014].

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In our study eGFR <60 mL/min/1.73 m2 was not independently related to complications development, while worse degree of renal impairment, i.e. eGFR <45 mL/min/1.73 m 2 and

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eGFR <30 mL/min/1.73 m2 were the major predictors of decreasing clinical conditions. In contrast, all the other clinical parameters investigated, including patient history, were not related to complications development. As well as in the reported studies, in our one, low eGFR appears to behave as a negative biomarker. Our single-center study has limitations. First, we used a composite outcome (development of all complications including mortality rate) because the number of new different complications was low. This suggests the possibility that either the population studied was small and/or the duration of follow-up short. Also, we evaluated eGFR only at the first visit, and we did not consider variation during the study period. The mean age of our population was about 67 years and the proportion of subjects with different complications at the start 10

ACCEPTED MANUSCRIPT of the study was considerable; about 10% of subjects had diabetic nephropathy and 10% had microalbuminuria. As stated before, Yu et al. [Yu et al., 2013] reported that in subjects

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with T2DM even if proteinuria predicted mortality, both proteinuria and GFR <60

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ml/min/1.73m2 had a stronger relationship with all-cause mortality than proteinuria only. Moreover, Barkoudah et al. [Barkoudah et al., 2012] suggested that decreasing renal

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function was probably stronger than microalbuminuria in predicting death. On the other hand renal dysfunction could represent a predictor of clinical outcome [Fox et al., 2012],

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and this relationship could be the main explanation of our results. Considering everyday clinical practice, an evaluation of eGFR in T2DM patients seems to be a biomarker for complications development. Our results regarding the relationship

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between eGFR and complications development agree only in part with from the National Diabetes Register in North of Europe [Svensson et al, 2013]. In the Swedish study,

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increasing levels of albuminuria and renal impairment were independently

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associated with increasing risk of CV events and all-cause mortality. In our study,

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microalbuminuria was not independently associated with complications development. CKD prevalence is rapidly increasing worldwide, and this figure is particularly worrying, especially if physicians realize that decreasing GFR is associated with CVD independently of other risk factors. In fact standardized CV mortality is much higher in patients starting dialysis than in the general population [Reiner et al., 2011]. Therefore, from the clinician’s point of view, detection of low eGFR in T2DM patients could suggest development of complications independently from all the other data. We suggest that combined T2DM and renal dysfunction constitute a vicious circle leading to poor outcome, independently from the evaluation of the classic risk factors leading to widespread atherosclerotic vascular damage. In our study we focused on renal dysfunction ‘per se’ in subjects with T2DM without considering the evolution of nephropathy. Evaluation of renal dysfunction by 11

ACCEPTED MANUSCRIPT GFR calculation should represent a crucial clinical action to better identify high risk

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patients, and arrange the most appropriate management.

Acknowledgement

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We thank Dr Cinzia Ghirardello for her precious work in managing the database.

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ACCEPTED MANUSCRIPT References American Diabetes Association. Standard of medical care in diabetes – 2013. Diabetes

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Care 2013;36(Suppl.1):S11-S66 Amin AP, Whaley-Connell AT, Li S, Chen SC, McCullough PA, Kosiborod MN. (2013). The

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synergistic relationship between estimated GFR and microalbuminuria in predicting long-term progression to ESRD or death in patients with diabetes: results from the

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Kidney Early Evaluation Program (KEEP). Am J Kidney Dis, 61, S12-23. Barkoudah E, Skali H, Uno H, Solomon SD, Pfeffer MA. (2012). Mortality rates in trials of subjects with type 2 diabetes. J Am Heart Assoc, 1, 8-15.

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Fabbian F, Benussi P, Cacici G, Cavallini L, Loschiavo C, Ortalda V, et al. (2003). Relationship between diabetes mellitus and degree of coronary artery disease in

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uraemic patients investigated with coronary angiography. Int J Artif Organs, 26,

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196-199.

Fabbian F, Gallerani M, Pala M, De Giorgi A, Salmi R, Dentali F, et al. (2014). Association

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between in-hospital mortality and renal dysfunction in 186 219 patients hospitalized for acute stroke in the Emilia-Romagna Region of Italy. Angiology, 65, 906-910. Fabbian F, Pala M, Monesi M, De Giorgi A, Mallozzi Menegatti A, Tomasi F, et al. (2013a) The estimation of glomerular filtration rate in type 2 diabetic patients may depend on the equation used. Eur Rev Med Pharmacol Sci, 17(:2791-2797 Fabbian F, Pala M, De Giorgi A, Manfredini F, Mallozzi Menegatti A, Salmi R, et al. (2013b). In-hospital mortality in patients with renal dysfunction admitted for myocardial infarction: the Emilia-Romagna region of Italy database of hospital admissions. Int Urol Nephrol, 45, 769-775. 13

ACCEPTED MANUSCRIPT Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, et al. (2012). Associations of kidney disease measures with mortality and end-stage renal

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disease in individuals with and without diabetes: a meta-analysis. Lancet, 380,

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1662-1673.

Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. (2005).

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Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes care, 28, 164-

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Kramer HJ, Nguyen QD, Curhan G, Hsu CY. (2003). Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA, 289,

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Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. (2009). A

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new equation to estimate glomerular filtration rate. Ann Intern Med, 150, 604-612.

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National Kidney Foundation. (2002). K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis, 39,

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Plantinga LC, Crews DC, Coresh J, Miller ER, Saran R, Yee J, et al. (2010). Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol, 5, 673-682. Pugliese G, Solini A, Bonora E, Orsi E, Zerbini G, Giorgino F, et al. (2011). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation provides a better definition of cardiovascular burden associated with CKD than the Modification of Diet in Renal Disease (MDRD) Study formula in subjects with type 2 diabetes. Atherosclerosis, 218, 194-199.

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ACCEPTED MANUSCRIPT Registro Italiano Dialisi e Trapianto. http://www.sin-ridt.org/italia/report 2010 Accessed 02/02/2014

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Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. (2011).

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Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and

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the European Atherosclerosis Society (EAS). Eur Heart J, 32, 1769-818.

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Ritz E, Orth SR. (1999). Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med, 341, 1127-1133.

Selvarajah S, Uiterwaal CS, Haniff J, van der Graaf Y, Visseren FL, Bots ML. (2013).

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Renal impairment and all-cause mortality in cardiovascular disease: effect modification by type 2 diabetes mellitus. Eur J Clin Invest, 43, 198-207.

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Svensson MK, Cederholm J, Eliasson B, Zethelius B, Gudbjörnsdottir S; Swedish National

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Diabetes Register. (2013). Albuminuria and renal function as predictors of cardiovascular events and mortality in a general population of patients with type 2

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diabetes: a nationwide observational study from the Swedish National Diabetes Register. Diab Vasc Dis Res, 10, 520-529. Targher G, Zoppini G, Mantovani W, Chonchol M, Negri C, Stoico V, et al. (2012). Comparison of two creatinine-based estimating equations in predicting all-cause and cardiovascular mortality in patients with type 2 diabetes. Diabetes Care, 35, 2347-2353. Vaccaro O, Eberly LE, Neaton JD, Yang L, Riccardi G, Stamler J. (2004). Impact of diabetes and previous myocardial infarction on long-term survival: 25-year mortality follow-up of primary screenees of the Multiple Risk Factor Intervention Trial. Arch Intern Med, 164, 1438-1443. 15

ACCEPTED MANUSCRIPT Wells BJ, Jain A, Arrigain S, Yu C, Rosenkrans WA Jr, Kattan MW. (2008). Predicting 6year mortality risk in patients with type 2 diabetes. Diabetes Care, 31, 2301-2306.

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Yap YS, Chuang HY, Chien CM, Tai YK. (2014). Relationship between peripheral artery

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disease and combined albuminuria and low estimated glomerular filtration rate

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among elderly patients with type 2 diabetes mellitus. Diab Vasc Dis Res, 11, 41-47. Yu TY, Li HY, Jiang YD, Chang TJ, Wei JN, Chuang LM. (2013). Proteinuria predicts 10-

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Complications, 27, 201-207.

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year cancer-related mortality in patients with type 2 diabetes. J Diabetes

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ACCEPTED MANUSCRIPT Figure 1. Complication development in type 2 diabetes mellitus outpatients with different degrees of renal failure. Hazard ratios (HR) and 95% CI related to estimated glomerular

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filtration rate (eGFR) <45 and 30 ml/min/1.73m2 are reported.

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ACCEPTED MANUSCRIPT Table 1. Clinical and biochemical characteristics of the 1284 patients investigated at the time of enrolment (eGFR: estimated glomerular filtration rate; 737 (57.4)/547 (42.6)

Age (years)

66.8±10.4

Serum creatinine (mg/dl)

1.05±0.36

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Male/female (n(%))

eGFR (ml/min/1.72m2)

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71.6±21.6

Patients with eGFR < 60 ml/min/1.72m2 (n(%))

380 (29.6)

Patients with microalbuminuria (n(%))

126 (9.8)

919 (71.5)

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History of hypertension (n(%))

8.06±1.33

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Glycated haemoglobin (%)

213 (16.6)

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History of nephropathy (n (%))

174 (13.6)

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History of coronary artery disease (n (%)) History of congestive heart failure (n (%))

49 (3.8)

History of peripheral vascular disease (n (%))

154 (12)

History of cerebrovascular disease (n (%))

71 (5.5)

History of peripheral neuropathy (n (%))

101 (7.9)

History of retinopathy (n (%))

200 (15.6)

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504 (39.3)

Death (n (%))

182 (14.2)

Nephropathy (n (%))*

132 (10.3)

Myocardial infarction (n (%))

55 (4.3)

Stroke (n (%))

37 (2.9)

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38 (3)

163 (12.7) 62 (4.8) 92 (7.2)

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Retinopathy (n (%))

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Peripheral arterial disease (n (%))

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Congestive heart failure (n (%))

Peripheral neuropathy (n (%))

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All complications (n (%))

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Table 2. Complications developed during the study

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*Nephropathy was defined by decreasing glomerular filtration below 60 m/min/1.73m2, development of microalbuminuria in subjects who hadn’t had

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it, progression of microalbuminuria to overt macroalbuminuria; only 3 patients (0.2%) started renal replacement therapy

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ACCEPTED MANUSCRIPT Table 3. Complications of patients with eGFR < and ≥ 60 ml/min/1.73 m2 eGFR ≥60

ml/min/1.72m2

ml/min/1.72m2

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(n=380)

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eGFR<60

219 (57.6)

285 (31.5)

<0.001

Death (n (%))

98 (25.8)

84 (9.3)

<0.001

23 (6.1)

32 (3.5)

0.042

13 (3.4)

24 (2.7)

ns

24 (6.3)

14 (1.5)

<0.001

115 (12.7)

48 (12.6)

ns

16 (4.2)

46 (5.1)

ns

25(6.6)

67 (7.4)

ns

Myocardial infarction (n (%)) Stroke (n (%))

ED

Congestive heart failure (n (%))

MA NU

SC

All complications (n (%))

PT

Peripheral arterial disease (n (%))

(n=904)

CE

Peripheral neuropathy (n (%))

AC

Retinopathy (n (%))

20

ACCEPTED MANUSCRIPT Table 4. Clinical data of patients with and without complications With

complications

complications

RI P

(n=780)

T

Without

425 (55.5)

SC

Male (n(%))

355 (45.5)

MA NU

Female (n(%)) Age (years)

P

(n=504) 312 (61.9) 0.009 192 (38.1)

62.9±9.6

67.1±8.4

<0.001

0.97±0.27

1.09±0.39

<0.001

77.6±19.3

69.7±8.4

<0.001

161 (20.6)

219 (43.5)

<0.001

8.05±1.2

8.4±1.3

0.003

History of hypertension (n(%))

25(6.6)

67 (7.4)

ns

History of nephropathy (n (%))

534 (68.5)

383 (76)

0.004

History of coronary artery disease (n (%))

83 (10.6)

91 (18.1)

<0.001

History of congestive heart failure (n (%))

17 (2.2)

32 (6.3)

<0.001

History of peripheral arterial disease (n (%))

90 (11.5)

64 (12.7)

ns

History of cerebrovascular disease (n (%))

37 (4.7)

34 (6.7)

ns

History of peripheral neuropathy (n (%))

60 (7.7)

41 (8.1)

ns

History of retinopathy (n (%))

94 (12.1)

106 (21)

<0.001

Serum creatinine (mg/dl)

ED

eGFR (ml/min/1.72m2)

AC

CE

Glycated haemoglobin (%)

PT

Patients with eGFR < 60 ml/min/1.72m2 (n(%))

21

MA NU

SC

RI P

T

ACCEPTED MANUSCRIPT

AC

CE

PT

ED

Figure 1

22