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

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

We investigated the relationship between complications development and estimated glomerular filtration rate (eGFR), in a cohort of type 2 diabetes mel...
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