Original Paper. Med Princ Pract 2017;26: DOI: /

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1 Originl Pper Med Princ Prct 2017;26: Received: Mrch 28, 2016 Accepted: December 6, 2016 Published online: December 6, 2016 The Assocition of Vitmin D Sttus nd Vitmin D Replcement Therpy with Glycemic Control, Serum Uric Acid Levels, nd Microlbuminuri in Ptients with Type 2 Dibetes nd Chronic Kidney Disese Svs Siphi Seyyid Bill Acikgoz b Ahmed Bill Genc b Mehmet Yildirim b Ylcin Solk Ali Tmer b Division of Nephrology, Deprtment of Internl Medicine nd b Deprtment of Internl Medicine, Fculty of Medicine, Skry University, Skry, Turkey Keywords Type 2 dibetes Chronic kidney disese Vitmin D sttus Vitmin D replcement therpy Glycemic control Serum uric cid Microlbuminuri Abstrct Objective: To evlute the reltionship of vitmin D sttus nd vitmin D replcement therpy with glycemic control, serum uric cid (SUA) levels, nd microlbuminuri (MAU) in ptients with type 2 dibetes (T2DM) nd chronic kidney disese (CKD). Subjects nd Methods: A totl of 1,463 ptients with T2DM nd CKD (ged yers), 927 femles nd 536 mles, were included in this study. The serum dt of 25-hydroxyvitmin D, i.e., 25(OH)D, level, SUA, hemoglobin (Hb) A1 c, cretinine, estimted glomerulr filtrtion rte, nd urine lbumin-to-cretinine rtio (UACR) were obtined from the medicl records. The Mnn-Whitney U test, the χ 2 test, the Mntel-Henszel test, nd liner regression models were used for dt nlysis. Results: Vitmin D deficiency nd insufficiency were evident in 770 (52.0%) nd 357 (24.0%) ptients, respectively. Medin HbA1 c levels (7.3 [IQR 3.9] vs. 6.5 [IQR 2.3]%; p < 0.01) were significntly higher in ptients deficient in vitmin D thn in those with norml vitmin D sttus. A significntly low level of vitmin D ws noted with high UACR (β 0.01; 95% CI 0.01 to 0.001; p = 0.017) nd HbA1 c (β 1.1; 95% CI 1.6 to 0.6; p < 0.001), but with low levels of SUA (β 1.3; 95% CI ; p = 0.002). Vitmin D replcement ws ssocited with significntly low level of HbA1 c (7.4 [2.7] vs. 6.7 [1.9]%; p < 0.001]. Conclusion: In this study, there ws high prevlence of hypovitminosis D mong T2DM ptients with CKD, with higher UACR, higher HbA1 c, nd lower SUA being noted s plying role in predicting decrese in vitmin D levels nd potentil benefits of vitmin D replcement therpy on glycemic control in T2DM mngement S. Krger AG, Bsel Introduction In clcium-phosphte homeostsis nd bone physiology, it is well known tht vitmin D sttus is ssocited with number of nonskeletl functions including glucose homeostsis, pthophysiology, nd the progression of type 2 dibetes mellitus (T2DM) [1 3]. The serum 25-hydroxyvitmin D, i.e., 25(OH)D, level is considered to be the most stble nd relible indictor of vitmin D sttus [4, 5]. It reflects vitmin D exposure bsed on the sum of endogenous synthesis nd dietry intke from foods, for- E-Mil krger@krger.com S. Krger AG, Bsel This is n Open Access rticle licensed under the terms of the Cretive Commons Attribution-NonCommercil 3.0 Unported license (CC BY-NC) ( pplicble to the online version of the rticle only. Distribution permitted for non-commercil purposes only. Svs Siphi, MD Division of Nephrology, Deprtment of Internl Medicine, Fculty of Medicine Skry University, Adnn Menderes Cd. Sglik Sok. 195 TR Adpzri, Skry (Turkey) E-Mil skry.edu.tr

2 tified products, nd/or supplements [4, 5]. Most ptients with T2DM hve low 25(OH)D levels, while high levels re ssocited with lower risk of incident dibetes [6, 7]. Reduced nephron mss nd/or 1-α hydroxylse enzyme ctivity hs been shown to be ssocited with decline in 1.25 dihydroxyvitmin D, i.e., 1.25(OH) 2 D, levels in ptients with chronic kidney disese (CKD) [8]. Hence, it hs been suggested tht renl sttus be considered in studies involving vitmin D sttus mong T2DM ptients [7]. Serum uric cid (SUA) hs been shown to be ssocited with reduced levels of 1.25(OH) 2 D vi the inhibition of 1-α hydroxylse ctivity [9, 10] s well s with microlbuminuri (MAU) [11]. This seems notble, since MAU is considered to be biomrker for dignosing dibetic kidney disese, nd is predictive fctor for the progression to end-stge renl disese (ESRD) nd incresed crdiovsculr risk mong dibetic ptients [12, 13]. Vitmin D supplementtion for dibetic ptients is of prticulr interest, with regrd to its role in glucose hemostsis nd thus its use s potentil cost-effective djunct therpy in T2DM mngement [14, 15]. However, dt on the impct of mintining n dequte vitmin D sttus or supplementing with vitmin D on clinicl outcomes in dibetic ptients re inconsistent, probbly reflecting the differences cross studies in bseline vitmin D levels nd replcement therpy dosge [14 16]. This study ws therefore designed to evlute the reltionship of vitmin D sttus nd vitmin D replcement therpy with glycemic control, SUA levels, nd MAU in ptients with T2DM nd CKD. Subjects nd Methods Study Popultion A totl of 1,463 ptients with T2DM nd CKD (ge rnge yers), 927 femles nd 536 mles, who hd their serum 25(OH)D levels mesured during follow-up t our dibetes outptient clinic between Jnury 2010 nd Jnury 2015, were included in this retrospective study. Exclusion criteri were n ge of <18 yers, pregnncy, chnge in ntidibetic tretment during the study, nd no dt on concomitntly ssessed vitmin D levels. The study ws conducted in full ccordnce with the locl Good Clinicl Prctice guideline nd current legisltion, nd permission ws obtined from the Institutionl Ethics Committee for the use of ptient dt for publiction purposes. Study Assessments Dt on ptient demogrphics, lbortory prmeters including nlysis for 25(OH)D, SUA, HbA1 c, cretinine, estimted glomerulr filtrtion rte (egfr), nd urine lbumin-to-cretinine rtio (UACR) were obtined from medicl records. Demogrphic chrcteristics nd lbortory prmeters were evluted with respect to vitmin D sttus, while estimtors of bseline vitmin D levels nd the effect of vitmin D replcement therpy on the vitmin D, glycemic, nd renl function prmeters were lso nlyzed. Overll, 383 of 1,463 ptients received vitmin D replcement therpy ( units weekly). Pretretment nd posttretment lbortory prmeters were compred in these ptients. Blood Biochemistry Anlysis 25(OH)D, cretinine, uric cid, HbA1 c, nd hemogrm were mesured using centrl lbortory biochemistry nlyzer (ICT [ISE] Module of ARCHITECT c16000, Abbott Lbortories, Abbott Prk, IL, USA). 25(OH)D levels were mesured using high-performnce liquid chromtogrphy, nd were clssified s deficient (<20 ng/ml), insufficient (20 30 ng/ml) or optiml (>30 ng/ml) [17]. Estimtion of the Glomerulr Filtrtion Rte The GFR ws estimted ccording to the Modifiction of Diet in Renl Disese (MDRD) eqution, which includes 4 vribles: egfr (ml/min/1.73 m 2 ) = 175 (serum cretinine) (ge) (0.742 if femle) (conventionl units) [18]. The ptients were then clssified into 5 CKD stges: stge 1 (egfr >90 ml/min/1.73 m 2 ); stge 2, mild CKD (egfr ml/min/ 1.73 m 2 ); stge 3, moderte CKD (egfr ml/min/1.73 m 2 ); stge 4, severe CKD (egfr ml/min/1.73 m 2 ); nd stge 5, end-stge CKD (egfr <15 ml/min/1.73 m 2 ). Sttisticl Anlysis Ctegoricl vribles were summrized s n (%) nd continuous vribles s medin (IQR) due to nonnorml distribution ptterns. Bseline vitmin D level groups were compred by mens of the Mnn-Whitney U test for continuous vribles, the χ 2 test for nominl vribles, nd the Mntel-Henszel test for ordinl vribles. The estimtors of bseline vitmin D levels were evluted by using univrite nd multivrite (djusted for ge nd gender) liner regression models. The effect of vitmin D replcement therpy during follow-up ws evluted by the Wilcoxon or McNemr-Bowker test depending on the vribles. Type 1 error level ws set t 5% nd the Bonferroni djustment for type 1 error ws used, where pproprite. Sttisticl nlysis ws conducted with Sttisticl Pckge for the Socil Sciences softwre (v21.0, relesed 2012, IBM Corp., Armonk, NY, USA). Results Demogrphic Chrcteristics nd Lbortory Findings The medin (IQR) 25(OH)D level ws 18.1 (15.5) ng/ ml; vitmin D deficiency nd insufficiency were evident in 770 (52.6%) nd 357 (24.4%) ptients, respectively. Stge 1 2 CKD ws noted in 1,308 (91.9%) ptients. The medin (IQR) level of HbA1 c ws 7.0 (3.9%) nd tht of uric cid ws 4.9 (1.9) mg/dl in the overll study popultion ( Tble 1 ). Vitmin D deficiency ws ssocited with significntly higher number of femles ( n = 527; 68.4% vs. n = 197; 58.6%; p = 0.003) nd higher (medin [IQR]) HbA1 c Vitmin D Sttus nd T2DM Med Princ Prct 2017;26:

3 Tble 1. Demogrphics, medicl chrcteristics, nd lbortory findings in the overll study popultion nd ccording to bseline vitmin D sttus Deficiency (n = 770) p vlue Insufficiency (n = 357) p vlue Norml (n = 336) All ptients (n = 1,463) Demogrphics Age, yers 54.0 (17.0) (17.0) (20.0) 54.0 (17.0) Femle gender, n 527 (68.4%) b 203 (56.9%) b 197 (58.6%) 927 (63.4%) Medicl chrcteristics d CKD stge, n Stge (59.5%) c 212 (60.4%) c 193 (59.9%) 851 (59.8%) Stge (31.9%) 112 (31.9%) 106 (32.9%) 457 (32.1%) Stge 3 59 (7.9%) 25 (7.1%) 23 (7.1%) 107 (7.5%) Stge 4 6 (0.8%) 1 (0.3%) 0 (0%) 7 (0.5%) Stge 5 0 (0%) 1 (0.3%) 0 (0%) 1 (0.1%) Lbortory findings d Serum cretinine, mg/dl 0.8 (0.2) (0.2) (0.2) 0.8 (0.2) egfr, ml/min/1.73 m (31.9) (28.7) (29.2) 92.7 (30.4) UACR, mg/mmol 14.9 (42.9) (41.7) (19.6) 13.9 (40.0) SUA, mg/dl 4.7 (2) (1.7) (1.9) 4.9 (1.9) HbA1 c, % 7.3 (3.2) < (3.0) (2.3) 7.0 (3.9) Vlues re expressed s medin (IQR), unless otherwise indicted. CKD, chro nic kidney disese; egfr, estimted glomerulr filtrtion rte; HbA1 c, glycted hemoglobin A1 c ; SUA, serum uric cid; UACR, urine lbumin-to-cretinine rtio. Deficiency: serum vitmin D level <20 ng/ml; insufficiency: serum vitmin D level 20 nd <30 ng/ml; norml: serum vitmin D level 30 ng/ml. Comprisons mde by Mnn-Whitney U test nd results djusted by the Bonferroni method. b Comprisons mde by χ 2 test nd results djusted by the Bonferroni method. c Comprisons mde by Mntel-Henszel test nd results djusted by the Bonferroni method. d Dt for some ptients re missing, so results re bsed on vilble dt. levels (7.3 [3.2] vs. 6.5 [2.3]%; p < 0.01) compred with norml vitmin D sttus. Ptients with vitmin D deficiency nd insufficiency hd significntly lower levels for SUA (4.7 [2.0] nd 4.7 [1.7] vs. 5.1 [1.9] mg/dl, respectively; p < for ech), nd higher UACR (14.9 [42.9] nd 15.2 [41.7] vs. 9.5 [19.6] mg/mmol; p < 0.01 for ech) when compred to ptients with norml vitmin D sttus ( Tble 1 ). Estimtors of Bseline Vitmin D Levels Univrite liner regression nlyses reveled lower vitmin D levels with higher UACR (β 0.01; 95% CI 0.01 to 0.001; p = 0.017) nd HbA1 c (β 1.1; 95% CI 1.6 to 0.6; p < 0.001) levels but lower SUA (β 1.3; 95% CI ; p = 0.002), even fter djusting for ge nd gender ( p = 0.023, p = 0.013, nd p < 0.001, respectively; Tble 2 ). Effect of Vitmin D Replcement Therpy on Lbortory Findings Among ptients who hd vitmin D replcement therpy ( n = 383), fter medin (IQR) 6.0 (5.0) months, there ws significnt increse in (medin [IQR]) 25(OH) D levels (from 18.1 [15.5] ng/ml pretretment to 25.5 [19.1] ng/ml posttretment; p < 0.001) nd the percentge of ptients with norml vitmin D sttus (from 19.8 to 37.1%; p < 0.001) ( Tble 3 ). When compred to pretretment vlues, posttretment vlues showed significnt decrese (medin [IQR]) in HbA1 c (7.4 [2.7] vs. 6.7 [1.9]%; p < 0.001) nd egfr (92.3 [30.3] vs [30.4] ml/min/1.73 m 2 ; p < 0.001). Anlysis of dt djusted for follow-up durtion lso reveled significnt decrese in men (95% CI) HbA1 c levels from bseline to follow-up (7.8 [ ] vs. 7.1 [ ]%; p < 0.001) ( Tble 3 ). Discussion Our findings in cohort of ptients with T2DM nd CKD reveled high prevlence (pprox. 70%) of hypovitminosis D, prticulrly mong femles, in cses of vitmin D deficiency. Higher levels of HbA1 c nd UACR, 148 Med Princ Prct 2017;26: Siphi/Acikgoz/Genc/Yildirim/Solk/ Tmer

4 Tble 2. Estimtors of bseline vitmin D levels UnivriteAdjusted β (95% CI) p vlue β (95% CI) p vlue Serum cretinine, mg/dl 1.3 ( 2.9 to 5.5) ( 5.9 to 3.6) egfr, ml/min/1.73 m ( 0.07 to 0.02) ( 0.07 to 0.03) UACR, mg/mmol 0.01 ( 0.01 to 0.001) ( 0.01 to 0.001) SUA, mg/dl 1.3 ( ) ( ) HbA1 c, % 1.1 ( 1.6 to 0.6) < ( 1.7 to 0.8) <0.001 Dt on some ptients re missing, so the results re bsed on the vilble dt. β, liner regression coefficient; egfr, estimted glomerulr filtrtion rte; HbA1 c, glycted hemoglobin A1 c ; SUA, serum uric cid; UACR, urine lbumin-to-cretinine rtio. Results of liner regression model which ws djusted for ptients ge nd gender. Tble 3. Effect of vitmin D replcement therpy on renl function nd glycemic prmeters nd vitmin D sttus Prmeters Ptients, n At bseline After tretment p vlue Renl function b Serum vitmin D, ng/ml (15.5) 25.5 (19.1) <0.001 Serum cretinine, mg/dl (0.2) 0.8 (0.2) egfr, ml/min/1.73 m (30.3) 91.4 (30.4) <0.001 SUA, mg/dl (2.0) 5.0 (1.5) HbA1 c, % b (2.7) 6.7 (1.9) <0.001 Men (95% CI) 7.8 ( ) 7.1 ( ) <0.001 Vitmin D sttus, n (%) Deficiency 224 (58.5) 140 (36.6) <0.001 Insufficiency 83 (21.7) 101 (26.4) Norml 76 (19.8) 142 (37.1) egfr, estimt ed glomerulr filtrtion rte; HbA1 c, glycted hemoglobin A1 c ; SUA, serum uric cid; UACR, urine lbumin-to-cretinine rtio. Results of comprison to norml vitmin D group. b Medin (IQR). nd lower levels of SUA were shown to predict lower vitmin D levels. Vitmin D replcement reveled n increse in ptients with norml vitmin D sttus, long with significnt decrese in HbA1 c levels. The high 76.0% prevlence of hypovitminosis D in our cohort, prticulrly mong femles, in cses of vitmin D deficiency, ws similr to the previously published dt indicting, overll, 73.0% prevlence of hypovitminosis D (higher in femles) mong Turkish T2DM ptients [19, 20]. This lower level of 25(OH)D mong dibetic ptients nd higher HbA1 c in cses of hypovitminosis D thn with vitmin D sufficiency ws lso reported in other studies on dibetic ptients with vrious stges of CKD [7, 19, 21, 22]. Our findings lso reveled significnt role of higher HbA1 c in predicting decrese in vitmin D levels, in greement with previous studies [7, 23, 24]. In this cohort, vitmin D replcement therpy enbled significnt improvement in HbA1 c levels. In n nlysis of insulin-nïve T2DM ptients with vitmin D deficiency who received vitmin D supplementtion, ll ptients were reported to chieve serum levels of 25(OH)D >20 ng/ml, long with significnt reduction in fsting blood glucose, but nonsignificnt reductions in HbA1 c, fsting insulin, nd HOMA-IR [16]. Vitmin D Sttus nd T2DM Med Princ Prct 2017;26:

5 In this cohort, the increse in medin 25(OH)D level, from 18.1 to 25.5 ng/ml, long with n increse in the rte of norml vitmin D sttus, from 19.8 to 37.1%, due to the vitmin D replcement, could hve produced extrskeletl benefits of vitmin D s suggested previously [25]. The significnt improvement in HbA1 c levels fter vitmin D replcement therpy tht we observed emphsizes the ssocition of vitmin D levels with glucose hemostsis in T2DM, nd the potentil therpeutic implictions of this ssocition in chieving improved glycemic control in T2DM mngement [21]. Similr to our findings, the likely benefit of vitmin D substitution for better T2DM prognosis ws suggested in 15-yer longitudinl study mong T2DM ptients [26]. Clinicl trils, however, hve reveled inconsistent findings on the impct of mintining dequte vitmin D sttus nd/or high-dose vitmin replcement on long-term glycemic control in T2DM ptients [14 16, 27]. Thus, the need for vlidtion by further lrge-scle, cross-sectionl, nd interventionl clinicl studies is emphsized [15]. Given tht renl sttus is covrint influencing vitmin D sttus [7], it seems worth noting tht the mjority of our ptients hd stge 1 2 CKD nd no difference ws noted in the CKD stge of the ptients with respect to vitmin D sttus. A decrese in SUA ws mongst the predictors of hypovitminosis D in our study. This seems to contrst with pst studies tht indicted n ssocition between hyperuricemi nd hypovitminosis D in gout, dibetes, nd CKD ptient popultions [10, 19, 28]. In ddition, no ssocition ws shown between reduced 25(OH)D levels nd elevted SUA in premenopusl women, regrdless of concomitnt T2DM nd hypertension [29]. This seems to indicte the likelihood of multifceted pthogenesis of the interction between vitmin D sttus nd SUA, with the contribution of severl endocrine fctors [9, 30]. In this cohort, higher UACR ws shown to predict decrese in vitmin D levels. This seems to support the liner reltion between vitmin D deficiency nd progression of MAU reported in T2DM ptients [13, 27], while lso emphsizing the potentil benefit of the normliztion of vitmin D levels in the reduction of renl nd crdiovsculr risks ssocited with MAU in these ptients [12, 13]. Certin limittions to this study include its retrospective, single-center design nd thus n inbility to generlize our findings to the overll dibetic popultion, the lck of dt on prthyroid hormone levels nd sesonl chnges in vitmin D levels, nd lso the fct tht there ws no stndrd durtion of vitmin D tretment. Conclusion Our findings in cohort of ptients with T2DM nd CKD reveled high prevlence (70%) of hypovitminosis D, prticulrly mong femles, in cses of vitmin D deficiency. Higher UACR, higher HbA1 c, nd lower SUA were shown to predict decrese in vitmin D levels. Vitmin D replcement therpy hd beneficil effect on glucose hemostsis vi significnt reduction in HbA1 c ; this emphsizes the potentil therpeutic implictions of vitmin D supplementtion s promising preventtive nd therpeutic gent for improved glycemic control mong T2DM ptients with CKD. We recommend n evlution of the reltionship between hypovitminosis D nd SUA nd of the impct of longer-term vitmin D replcement therpy on glycemic control nd renl function mong dibetic ptients in lrge-scle clinicl study. Disclosure Sttement There were no conflicts of interest. References 1 Mtyjszek-Mtuszek B, Lenrt-Lipińsk M, Woźnikowsk E: Clinicl implictions of vitmin D deficiency. Prz Menopuzlny 2015; 14: Adms JS, Hewison M: Updte in vitmin D. J Clin Endocrinol Metb 2010; 95: Thoms GN, ó Hrtigh B, Bosch JA, et l: Vitmin D levels predict ll-cuse nd crdiovsculr disese mortlity in subjects with the metbolic syndrome: the Ludwigshfen Risk nd Crdiovsculr Helth (LURIC) Study. Dibetes Cre 2012; 35: Ross AC, Mnson JE, Abrms SA, et l: The 2011 report on dietry reference intkes for clcium nd vitmin D from the Institute of Medicine: wht clinicins need to know. J Clin Endocrinol Metb 2011; 96: Thcher TD, Clrke BL: Vitmin D insufficiency. Myo Clin Proc 2011; 86: 50 60; review. 6 Pitts AG, Nelson J, Mitri J, et l: Plsm 25-hydroxyvitmin D nd progression to dibetes in ptients t risk for dibetes: n ncillry nlysis in the Dibetes Prevention Progrm. Dibetes Cre 2012; 35: Kjbf F, Mentverri R, Diouf M, et l: The ssocition between 25-hydroxyvitmin D nd hemoglobin A1 c levels in ptients with type 2 dibetes nd stge 1 5 chronic kidney disese. Int J Endocrinol 2014; 2014: Med Princ Prct 2017;26: Siphi/Acikgoz/Genc/Yildirim/Solk/ Tmer

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