Analysis of alternatives for insulinizing patients to achieve glycemic control and avoid accompanying risks of hypoglycemia

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1 284 Anlysis of lterntives for izing ptients to chieve glycemic control nd void ccompnying risks of hypoglycemi JIALIN GAO 1,2*, QIANYIN XIONG 1,2*, JUN MIAO 1*, YAO ZHANG 2,3, LIBING XIA 1, MEIQIN LU 1, BINHUA ZHANG 1, YUEPING CHEN 1, ANSU ZHANG 1, CUI YU 1,2 nd LI ZHUO WANG 3 1 Deprtment of Endocrinology nd Genetic Metbolism, Yijishn Hospitl of Wnnn Medicl College, Wuhu, Anhui ; 2 Anhui Province Key Lbortory of Biologicl Mcro molecules Reserch, 3 Deprtment of Biochemistry nd Moleculr Biology, Wnnn Medicl College, Wuhu, Anhui , P.R. Chin Received December 4, 2014; Accepted Jnury 7, 2015 DOI: /br Abstrct. The ims of the present study were to explore the efficcy of glycemic control nd the risks of hypoglycemi with different methods of therpy, nd to provide reference dt for the clinicl tretment of dibetes. In this retrospective study, hospitlized ptients dignosed with type 2 dibetes between Mrch nd December 2014, in the Deprtment of Endocrinology in the First Affilited Hospitl of Wnnn Medicl College, were divided into three groups, including n intensive therpy group, premixed tretment group nd premixed humn therpy group. The efficcy of glycemic control nd the incidence of hypoglycemi were determined in ech of the tretment groups. Compred with the other tretment groups, the intensive therpy group ws ssocited with superior blood glucose control, shorter time to rech stndrd regimen, shorter hospitliztion time, fewer fluctutions in blood glucose levels nd lower dosge on dischrge from hospitl. However, this tretment ws lso ssocited with high risk of hypoglycemi. In conclusion, when combined with the effective prevention of hypoglycemi nd pproprite nursing cre (especilly in hospitl cre), intensive therpy my provide the gretest benefit to ptients. Correspondence to: Professor Jilin Go, Deprtment of Endocrinology nd Genetic Metbolism, Yijishn Hospitl of Wnnn Medicl College, 22 West Zheshn Rod, Wuhu, Anhui , P.R. Chin E mil: jiling.go@yhoo.com Mrs. Li-Zhuo Wng, Deprtment of Biochemistry nd Moleculr Biology, Wnnn Medicl College, Wuhu, 22 Wenchng West Rod, Anhui , P.R. Chin E mil: lizhuo.wng@yhoo.com * Contributed eqully Key words: glycemic control, hypoglycemi,, tretment method Introduction Dibetes is group of metbolic endocrine diseses tht re chrcterized by hyperglycemi. Due to its high incidence nd multiple complictions, dibetes is the third biggest disese thret to humn helth in disese burden nd morbidity, fter oncologicl nd crdiovsculr diseses (1). The dvent of tretment with ws revolution in the tretment of dibetes nd hs mde it possible to more effectively control dibetes nd hyperglycemi. The pthogenesis of type 1 nd type 2 dibetes involves the bsolute or reltive lck of islet function. Therefore, in type 1 dibetes nd dult onset type 2 dibetes, the dministrtion of exogenous is the most effective form of tretment. Furthermore, the erly use of therpy in type 2 dibetes is hypothesized to be importnt in slowing the course of this disese (2). Insulin s nd humn, nd the corresponding premixed preprtions re widely used in clinicl prctice. Blood glucose fluctution hs been perceived s n independent risk fctor tht contributes to vsculr complictions in ptients with dibetes, while hypoglycemi is the min risk ssocited with therpy (3). The present study investigted the effects of different therpies on glycemic control nd fluctutions of blood sugr levels, nd evluted the risks of hypoglycemi with these pproches, in order to provide reference for the selection of therpy in clinicl prctice. Subjects nd methods Ethics pprovl. This study ws pproved by the ethics committee of Yijishn Hospitl of Wnnn Medicl College (Wuhu, Chin). Ptient consent ws lso obtined. Witten informed consent ws obtined from the ptient. Relevnt stndrd. When mking the dignosis of dibetes, the 'WHO 1999 dibetes dignostic criteri' were referred to (4). Criteri for inclusion in the study were: i) ge yers nd body mss index (BMI) 30 kg/m 2 ; nd ii) no severe renl impirment, serum cretinine 133 µmol/l, nd no hypoglycemi, infection, ketocidosis or cute complictions, such s wter nd electrolyte disorders or cid bse imblnces. Exclusion criteri were: i) type 1 dibetes; ii) pregnncy; nd

2 GAO et l: EFFECTS AND RISKS OF DIFFERENT INSULIN TREATMENTS 285 iii) tretment with the orl hypoglycemic gents, sulfonylures or non sulfonylure secretgogues. Ptient selection nd tretment. In this retrospective study, conducted from Mrch to December 2012 t the Wnnn Medicl College (Wuhu, Chin), ptients requiring hospitl tretment for type 2 dibetes, were predominntly newly dignosed ptients with severe type 2 dibetes, in ddition to number of older ptients with type 2 dibetes (with prior use of sulfonylures or non sulfonylure secretgogues orl hypoglycemic drugs) who exhibited poor control of blood glucose. A totl of 145 ptients with type 2 dibetes were selected, ccording to the inclusion nd exclusion criteri, of which 89 were mle nd 85 were femle. A helthy diet nd exercise re dvised s n importnt component of dibetic cre. Subjects were divided into three groups ccording to tretment. The first group consisted of those given intensive therpy (55 cses), using sprt, new fst cting humn nlog [IAsp; Novo Nordisk (Chin) Phrmceuticls Co., Ltd., Tinjin, Chin], s subcutneous injection prior to mels, in ddition to the subcutneous long cting, glrgine (Lntus ; Snofi Aventis Phrmceuticls), t bedtime. The second group consisted of those given premixed (48 cses), with subcutneous injection of the two phse, sprt 30 [Novo Nordisk (Chin) Phrmceuticls Co.], prior to brekfst nd dinner, nd before lunch when required. The finl groups consisted of those given premixed humn (42 cses), Novolin 30R [Novo Nordisk (Chin) Phrmceuticls Co.]. Depending on blood glucose levels, ptients in the three groups took metformin nd dded crbose when required. The initil dosge of ptients ws estimted by n experienced senior doctor, ccording to the level of blood glucose nd the ptient's BMI s well s indictors such s present illness, pst history, eting hbits, ge, presence or bsence of complictions nd kidney function. Initilly, totl dily dose of units of ws prescribed. The lloction for the intensive group ws s follows: Before brekfst, qurter of the totl dose; before lunch nd dinner, fifth of the totl dose; with the residul dose t bedtime in the form of glrgine. For the premixed group, the initil lloction scheme ws s follows: Before brekfst, three fifths of the totl dose; before dinner, the remining two fifths of the totl. For the premixed humn group, the initil lloction ws s follows: Before brekfst, two thirds of the totl dose; before dinner, the remining dose. Blood glucose levels were mesured prior to brekfst in order to djust the dose of. If the pre mel blood glucose ws <3.9 mmol/l, subjects were dvised to et nd to reduce the corresponding pre dinner dose by 2 4 units. If the pre mel blood glucose ws mmol/l, the dose ws not ltered. If the pre mel blood glucose ws mmol/l, subjects were dvised to increse the corresponding pre dinner dose by 2 units. If the pre mel blood glucose ws >11.1 mmol/l, subjects were dvised to increse the corresponding pre dinner dose by 2 4 units nd djust the timing for the next dose to fter brekfst the following dy. Blood glucose monitoring. During hospitliztion, Johnson & Johnson stedy glucose meter [Johnson & Johnson Medicl (Chin) Ltd., Shnghi, Chin] ws used to monitor blood glucose levels prior to nd following mels, nd before going to bed (10 p.m.); totl of seven times per dy. A totl of 75 ptients, including lower blood sugr in 10 p.m. nd with previous history of hypoglycemi, were required to dd mesurements during the night (00:00 nd 03:00). Peripherl cpillry whole blood glucose ws monitored by fingertip smpling. Mesurement of trgets. Ech subject's height, weight, ge, durtion of dibetes nd BMI were recorded, together with fsting blood glucose, glycosylted hemoglobin, serum cretinine, nd totl cholesterol nd triglyceride levels, determined from blood smples collected on the second dy of dmission. Sttisticl grouping of ll peripherl cpillry blood glucose stndrd devitions reflected the overll blood sugr fluctutions. Sttisticl grouping of ll the vrition coefficients of peripherl cpillry blood sugr levels tken on n empty stomch gve the coefficient of vrition of fsting blood glucose (FBG CV; the rtio of the stndrd devition nd men), reflecting fsting blood glucose fluctutions. On two consecutive dys, fsting blood glucose of 7 mmol/l nd 2 h postprndil blood glucose of 10 mmol/l were designted s stndrd glucose control (5). The rtio of the number of hypoglycemi nd the totl number of peripherl blood glucose monitoring gve the hypoglycemi occurrence frequency t ech time point of the distribution sttistics of hypoglycemi: On n empty stomch, 2 h fter brekfst, 2 h fter lunch nd 2 h fter dinner, nd t nother five points in time (prior to lunch nd dinner, 10 p.m., 0 nd 3.m.). Dignostic criteri were s follows: For hypoglycemi, blood glucose 3.9 mmol/l; for severe hypoglycemi, blood glucose 2.8 mmol/l (5). The frequency of hypoglycemi were defined (clculted) s the rtio of the numbers of hypoglycemi nd the totl numbers of peripherl blood glucose monitoring, wheres the frequency of severe hypoglycemi were clculted s the rtio of the numbers of severe hypoglycemi nd the numbers of hypoglycemi. Sttisticl methods. SPSS 13.0 softwre (SPSS, Inc., Chicgo, IL, USA) ws used for sttisticl nlysis. If the dt conformed to norml distribution (men ± stndrd devition), groups were compred using the Student's t test. The constituent rtio of dt ws expressed s rtio. Groups were compred using the χ 2 squre (4x2) test. P<0.05 ws considered to indicte sttisticlly significnt difference. Results Comprison of generl chrcteristics. Three groups of ptients were included in the present study: An intensive group (group A), with 55 cses; premixed group (group B), with 48 cses; nd premixed humn group (group C), with 42 cses. The generl clinicl bseline dt for the three groups re shown in Tble I. From the generl dt pirwise comprison, no sttisticlly significnt differences were observed between the three sets of bseline dt. Glycemic control. A totl of 145 ptients monitored their blood sugr levels throughout the dy during hospitliztion, nd totl of 62 ptients mintined blood glucose control t the trget levels. Among these ptients, 28 cses were from the

3 286 Tble I. Generl clinicl dt for ech group. Group Age, BMI, Course of BG, CHOL, TG, LDL, SCr, HbA1c, (no. of cses) yers (kg/m 2) disese, (yers) (mmol/l) (mmol/l) (mmol/l) (mmol/l) (mmol/l) (%) A (55) 56.7± ± ± ± ± ± ± ± ±1.9 B (48) 53.6± ± ± ± ± ± ± ± ±1.85 C (42) 52.5± ± ± ± ± ± ± ± ±1.75 Group A, intensive group; group B, premixed group; group C, premixed group. No significnt differences were detected between the three groups for ny of the fctors. P>0.05 for ll comprisons. BMI, body mss index; BG, blood glucose; CHOL, cholesterol; TG, triglyceride; LDL, low density lipoprotein; SCr, serum cretinine; HbA1c, glycosylted hemoglobin. Tble II. Comprison of glycemic control between the three groups. Time to Number of Totl Stndrd glucose Stndrd glucose rech stndrd cses requiring Acrbose use Group ptients control ptients control rte, (%) (dys) crbose (percentge) Intensive ± Premixed ± Premixed humn ± P<0.01, compred with the premixed nd premixed humn groups. stndrd intensive group, in which the stndrd rte of glycemic control ws 50.9%; 18 cses were from the stndrd premixed group, in which the stndrd rte of glycemic control ws 37.5%; nd 16 cses were from the stndrd premixed group, in which the stndrd rte of control ws 38.1%. The intensive group chieved rte tht ws significntly higher thn tht of the other two groups (P<0.01). In ddition the time tken to chieve stndrd glucose control ws lso significntly shorter in the intensive group compred with the other groups (3.5±1.2 dys; P<0.01). Furthermore, the intensive group required less crbose in order to chieve postprndil blood glucose control; in this group, the crbose utiliztion rte ws only 9.09%. By contrst, the crbose utiliztion rtes for the premixed group nd the premixed humn group were nd 83.33%, respectively. These differences were significnt (P<0.01), s shown in Tble II. Insulin dosge t hospitl dischrge nd durtion of hospitliztion. In the intensive group, dosge ws 29.2±9.7 units t dischrge, nd hospitliztion ws 8.8±1.7 dys. For the premixed group, the dischrge dosge ws 35.5±12.3 units nd hospitliztion ws 10.6±2.1 dys. In the premixed humn group, the dischrge dosge ws 37.6±13.7 units nd hospitliztion ws 11.3±2.4 dys. At dischrge the dosge of ws lowest for the intensive group, with sttisticlly significnt difference (P<0.05). In ddition, this group hd Tble III. Insulin dosge t dischrge length of hospitliztion. Dischrge Hospitliztion Group Cses, (U/d) (dys) Intensive ± ±1.7 Premixed ± ±2.1 Premixed humn ± ±2.4 P<0.05 compred with the premixed group nd premixed humn group. the shortest hospitl sty, lso with sttisticlly significnt difference (P<0.05), s shown in Tble III. Comprison of the prevlence of hypoglycemi. Among the three groups of ptients, totl of 5,651 peripherl blood sugr monitoring dt points were collected, including 1,983 for the intensive group, 1,886 for the premixed group nd 1,782 for the premixed humn group. Of totl of 210 episodes of hypoglycemi, the number of episodes of severe hypoglycemi ws 64. The frequency of hypoglycemi for the intensive group ws higher thn the other groups, t 44.9% (P<0.05), nd the intensive group lso experienced the

4 GAO et l: EFFECTS AND RISKS OF DIFFERENT INSULIN TREATMENTS 287 Tble IV. Comprison of hypoglycemi between the tretment groups. Number of Number of Proportion peripherl Number of Frequency severe Frequency of ptients with blood glucose hypoglycemic of hypoglycemic of severe severe Group Cses redings episodes hypoglycemi (%) episodes hypoglycemi (%) hypoglycemi (%) Intensive 55 1, Premixed 48 1, Premixed 42 1, humn P<0.05, compred with the premixed nd premixed humn groups. Tble V. Comprison of blood glucose fluctution with ech form of therpy. Number of peripherl Blood Fsting Number of blood glucose sugr level stndrd cpillry blood fsting blood glucose Group Cses redings devition, (mmol/l) glucose vrition coefficient (%) Intensive 55 1, b nlogs Premixed 48 1, Premixed humn 42 1, P<0.01 nd b P<0.05, compred with the premixed nd premixed humn groups. 11.9%, respectively. Therefore, the intensive group exhibited the highest incidence of hypoglycemi nd severe hypoglycemi (P<0.05). No significnt differences were detected between the other two groups, s shown in Fig. 1. Figure 1. Percentge of ptients experiencing hypoglycemi nd severe hypoglycemi in the three therpy groups. ** P<0.01, compred with premixed nd premixed humn group groups. highest occurrence of severe hypoglycemi (16.1%; P<0.05), s shown in Tble IV. The proportion of ptients who hd t lest one episode of hypoglycemi in individuls within the three groups ws lso exmined. In the intensive group (55 cses), there were 41 cses of hypoglycemi, including 12 cses of severe hypoglycemi. Thus the incidence of hypoglycemi nd severe hypoglycemi ws 74.5 nd 21.8%, respectively. In the premixed group the incidence ws 45.8 nd 12.5%, respectively. In the premixed humn group the incidence ws 42.8 nd Blood glucose fluctutions ssocited with different therpies. The blood glucose level stndrd devition is good representtion of blood glucose fluctutions. For the three groups of ptients, sttisticl nlysis reveled stndrd devitions of 3.95 mmol/l for the intensive group, 5.76 mmol/l for the premixed group nd 5.82 mmol/l for the premixed humn group. Since the fsting blood glucose is reltively stble, FBG CV cn reflect the blood glucose fluctutions. FBG CV ws 37.1% for the intensive group, 43.7% for the premixed group nd 44.6% for the premixed humn group. Therefore, the intensive group hd the lowest vrition coefficient, compred with the other two groups (P<0.01; Tble V). Discussion Strict glycemic control is n importnt mesure by which to prevent nd reduce the numerous complictions of dibetes. Insulin hs vitl role in the tretment of dibetes. In ddition,

5 288 the functioning of pncretic β cells is ffected, to different degrees, in the mjority of ptients with type 2 dibetes. There re vrying degrees of defects in the phses of secretion. In the first phse, defect in secretion is the primry cuse of postprndil hyperglycemi. Therefore, the pproprite use of my simulte the reconstruction of the physiologicl secretion phse, promptly control blood sugr levels nd reduce toxicity resulting from high sugr levels, which cuses dmge to the islet cells, thereby restoring the function of islet β cells (6,7). However, excessively strict glucose control lso increses the risk of crdiovsculr events in dibetic ptients, which is clerly counter productive (8). Therefore, determining how to sfely nd effectively utilize, nd fmilirity with the dvntges nd disdvntges of vrious therpies, helps to provide clinicl stff with pproprite guidelines for the dignosis, tretment nd nursing cre of ptients with dibetes. The present study selected three widely used types of in order to control blood sugr levels: An intensive, premixed nd premixed humn. Among these options, the intensive included sprt, with proline mino cid t humn B28 replced by sprtic cid. Due to the substitution of the B28 proline residue for sprtte, the tendency of humn soluble to form hexmers is gretly reduced in sprt. Therefore, sprt hs number of dvntges, including fster subcutneous bsorption rte nd nd cn be given closer to mel times. Its durtion of ction is shorter nd it is therefore effective t reducing postprndil blood glucose, lthough it often requires combintion with long or intermedite cting, in order to chieve good control of fsting blood glucose. However, s result of the higher frequency of dministrtion, the complince of ptients ws generlly poorer with this preprtion. The premixed group received sprt 30 injections, which contined biphsic sprt, composed of 30% soluble sprt nd 70% protmine sprt ( short cting gent). This is usully dministered twice per dy (prior to brekfst nd dinner). It my lso be tken three times dy (before ech mel) in order to chieve better control of blood glucose. As fewer injection were required in this group reltive to the intensive tretment group, long term complince ws generlly better. The premixed humn tretment group received protmine zinc recombinnt humn (Novolin 30R). It contined 30% soluble humn nd 70% isophne. The speed of onset is hlf n hour; thus the dose is given min prior to mels. Anlysis of glycemic control nd the risk of hypoglycemi in the different groups ws performed. The results showed tht the intensive tretment groups ws superior in terms of glycemic control s well s the time tken to chieve the blood glucose trget. Tht is, the stndrd rte of glycemic control ws higher, the time tken to chieve control ws shorter nd blood glucose fluctutions were smller. These fctors my ll help to reduce the length of hospitl dmissions. Compred with the other tretment groups, ptients in the intensive group required significntly lower dose of t dischrge. This suggests tht good recovery of islet function hd occurred following short term intensive tretment. Furthermore, the intensive group exhibited better control of postprndil glucose levels, with significntly lower percentge of ptients in this group requiring tretment with crbose drugs, compred with ptients in the premixed sprt 30R nd premixed humn groups. The minly reson for this phenomen my be the different diet hbits between Chin nd the west. the lrger proportion of crbohydrte were intook in Chinese wheres sprt 30R nd humn Novolin 30R only include 30% vilble or short cting components, which could be more effective on postprndil blood glucose. However, the Chinese diet is chrcterized by crbohydrtes tht given priority to. Therefore, it is chllenging to effectively control the postprndil blood glucose pek, nd the use of α glycosidse inhibitors is frequently required. However, lthough good blood glucose control nd improved islet function were chieved using the intensive tretment, more hypoglycemic events nd significntly higher frequency of hypoglycemi were recorded in this group. In prticulr, the proportion of severe hypoglycemic events incresed significntly. Severe hypoglycemi my induce detrimentl crdiovsculr events (8,9), nd is thus significnt dverse rection of this method of tretment. Therefore, intensive tretment should be combined with n wreness of the risk of hypoglycemi, nd the use of preventive nd ctive mesures in order to reduce the likelihood of ptients experiencing this problem. Using this pproch, intensive tretment my provide the gretest benefit to ptients. Acknowledgements The uthors would like to thnk the prticipnts for their involvement in the study. This study ws supported by the Ntionl Nturl Science Foundtion of Chin (grnt no ), the Nturl Science Foundtion of Anhui, Chin (grnt no QH134) nd the Introduction of Tlents Foundtion of Yijishn Hospitl (grnt no. YR201104). References 1. Wild S, Roglic G, Green A, Sicree R nd King H: Globl prevlence of dibetes: estimtes for the yer 2000 nd projections for Dibetes Cre 27: , Jones S, Benroubi M, Cstell C, et l: Chrcteristics of ptients with type 2 dibetes mellitus inititing therpy: bseline dt from the INSTIGATE study. Curr Med Res Opin 25: , Arbi YM, Tmim HM nd Rishu AH: Hypoglycemi with intensive therpy in criticlly ill ptients: predisposing fctors nd ssocition with mortlity. Crit Cre Med 37: , Bennett PH: Impct of the new WHO clssifiction nd dignostic criteri. Dibetes Obes Metb 1 (Suppl 2): S1 S6, Chinese Dibetes Assocition: Chin guideline for type 2 dibetes (2010). Chin J Dib 20: 1-9, Grg R, Hurwitz S, Turchin A nd Trivedi A: Hypoglycemi, with or without therpy, is ssocited with incresed mortlity mong hospitlized ptients. Dibetes Cre 36: , Cook D nd McIntyre L: Intensive therpy nd strch (HES 200/0.5) hd some risk nd no cler benefit in severe sepsis. ACP J Club 148: 4, Retnkrn R, Qi Y, Opsteen C, Vivero E nd Zinmn B: Initil short term intensive therpy s strtegy for evluting the preservtion of bet cell function with orl ntidibetic medictions: pilot study with sitgliptin. Dibetes Obes Metb 12: , Diley G: Erly nd intensive therpy for mngement of hyperglycemi nd crdiovsculr risk fctors in ptients with type 2 dibetes. Clin Ther 33: , 2011.