Original Article Clinical Care/Education INTRODUCTION DIABETES & METABOLISM JOURNAL

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1 Originl Article Clinicl Cre/Eduction Dibetes Metb J 216;4: pissn eissn DIABETES & METABOLISM JOURNAL Reduction of Sulfonylure with the Initition of Bsl Insulin in Ptients with Indequtely Controlled Type 2 Dibetes Mellitus Undergoing Long-Term Sulfonylure-Bsed Tretment Yeoree Yng 1, Jeong-Ah Shin 2, He Kyung Yng 1, Seung-Hwn Lee 1, Seung-Hyun Ko 3, Yu-Be Ahn 3, Kun-Ho Yoon 1, Je-Hyoung Cho 1 1 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Seoul St. Mry s Hospitl, College of Medicine, The Ctholic University of Kore, Seoul, 2 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Serim Hospitl, Incheon, 3 Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, St. Vincent s Hospitl, College of Medicine, The Ctholic University of Kore, Suwon, Kore Bckground: There were limited number of studies bout β-cell function fter insulin initition in ptients exposed to long durtions of sulfonylure tretment. In this study, we imed to evlute the recovery of β-cell function nd the efficcy of concurrent sulfonylure use fter the strt of long-cting insulin. Methods: In this rndomized controlled study, ptients with type 2 dibetes mellitus (T2DM), receiving sulfonylure for t lest 2 yers with glycosylted hemoglobin (HbA1c) >7%, were rndomly ssigned to two groups: sulfonylure mintennce (SM) nd sulfonylure reduction (SR). Following 75-g orl glucose tolernce test (OGTT), we dministered long-cting bsl insulin to the two groups. After 6-month follow-up, we repeted the OGTT. Results: Among 69 enrolled ptients, 57 completed the study nd were nlyzed: 31 in the SM nd 26 in the SR group. At bseline, there ws no significnt difference except for the longer durtion of dibetes nd lower triglycerides in the SR group. After 6 months, the HbA1c ws similrly reduced in both groups, but there ws little difference in the insulin dose. In ddition, insulin secretion during OGTT ws significntly incresed by 2% to 3% in both groups. A significnt weight gin ws observed in the SM group only. The insulinogenic index ws more significntly improved in the SR group. Conclusion: Long-cting bsl insulin replcement could improve the glycemic sttus nd restore β-cell function in the T2DM ptients undergoing sulfonylure-bsed tretment, irrespective of the sulfonylure dose reduction. The dose reduction of the concurrent sulfonylure might be beneficil with regrd to weight grin. Keywords: Bsl insulin; Bet-cell; Dibetes mellitus, type 2; Recovery; Sulfonylure INTRODUCTION Insulin resistnce nd defective β-cell function re well-known pthophysiologicl mechnisms for the development of type 2 dibetes mellitus (T2DM) [1]. β-cell dysfunction comprises both secretory dysfunction nd decresed mss. Studies hve reported tht, rther thn insulin resistnce, defective β-cell function is n importnt fctor in Asin people, including Korens [2-4]. As one of the oldest hypoglycemic gents, sulfonylure stim- Corresponding uthor: Je-Hyoung Cho Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, Seoul St. Mry s Hospitl, College of Medicine, The Ctholic University of Kore, 222 Bnpo-dero, Seocho-gu, Seoul 6591, Kore E-mil: drhopper@ctholic.c.kr Received: Dec. 9, 215; Accepted: Aug. 8, 216 This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. Copyright 216 Koren Dibetes Assocition

2 Sulfonylure efficcy with bsl insulin ultes pncretic β-cells to relese insulin in rther glucoseindependent mnner. With the introduction of new orl hypoglycemic gents, the use of sulfonylure hs rpidly declined. Nevertheless, this drug remins one of the most commonly prescribed second-line orl gents in combintion with metformin [5], nd n option when the combintion of bsl insulin nd orl hypoglycemi gent is considered [6-8]. Although the efficcy of sulfonylure is strong, Khn et l. [9] showed tht the glycemic durbility of sulfonylures ws not persistent for long periods. In ddition, sulfonylure showed higher secondry therpeutic filure rte nd more rpid loss of β-cell function compred with metformin nd rosiglitzone. There re severl hypotheses concerning the mechnisms of sulfonylure-induced β-cell dysfunction. For exmple, ccelerted β-cell poptosis resulting from endoplsmic reticulum stress, decresed functionl expression of denosine triphosphte sensitive K + chnnels, nd reduced insulin content could induce secondry β-cell filure [-12]. Therefore, the long-term use of sulfonylure in Koren people with T2DM could induce erly β-cell filure nd further ggrvte dibetes. The protection of β-cell function through pproprite insulin replcement is generlly ccepted tretment guideline in ptients with T2DM [13-18]. Evidence is well-estblished of the beneficil effect of insulin on β-cell function nd glycemic control compred with the sulfonylure in ptients recently dignosed with T2DM [16,17,19]. However, there is limited number of studies bout β-cell recovery fter insulin therpy in ptients lredy exposed to long durtions of sulfonylure tretment or who showed secondry filure of sulfonylure [2-22]. Krm et l. [23] reported unresponsiveness of β-cells to cute sulfonylure stimultion during long sulfonylure tretment in dibetic ptients. Once sustined therpy with sulfonylure ws discontinued, β-cell response to cute sulfonylure stimultion ws restored. Bsed on such bckground, we hypothesized tht bsl insulin replcement relieves loding on β-cells for insulin secretion nd reduces β-cell stress in subjects with T2DM bsed on previous long-term sulfonylure tretment, nd this relief could improve β-cell function. Moreover, dditionl effects could occur with sulfonylure dose reduction. The im of the present study ws to reserch the recovery of β-cell function through long-cting bsl insulin replcement in ptients with indequtely controlled T2DM, receiving long-term sulfonylure-bsed tretment. In ddition, we evluted the efficcy of concurrent sulfonylure with the strt of bsl insulin by compring the sulfonylure mintennce (SM) nd sulfonylure reduction (SR) groups. METHODS Subjects In the present study, we enrolled subjects who visited the dibetes center of St. Vincent s Hospitl. Eligible ptients hd T2DM with indequte glycemic control (glycosylted hemoglobin [HbA1c] >7%). The ptients were over 35 yers old nd hd been treted with stble dose of sulfonylure for t lest 2 yers, with or without metformin. Ptients tking α-glucosidse inhibitors, thizolidinediones, nd other orl hypoglycemic gents rther thn sulfonylure nd metformin were excluded. Other exclusion criteri consisted of renl impirment (serum cretinine >133 μmol/l), heptic dysfunction (sprtte minotrnsminse [AST] nd lnine minotrnsminse [ALT] >3 times the upper norml level), mjor severe dibetic complictions, severe medicl illnesses, nd previous insulin tretment. Informed consent ws obtined from ll prticipnts, nd this study ws pproved through the Interntionl Review Bord of St. Vincent s Hospitl (VIRB-34-2). Study design At enrollment, we performed bsic nthropometric mesurements nd bseline lbortory tests, including HbA1c, lipid profiles (totl cholesterol, triglyceride, high density lipoprotein nd low density lipoprotein cholesterol), blood ure nitrogen, cretinine, AST, nd ALT. To exmine β-cell function, we performed 75-g orl glucose tolernce test (OGTT) nd mesured plsm glucose nd insulin t, 3, 6, 9, nd 12 minutes fter glucose loding. The HbA1c ws mesured using high-performnce liquid chromtogrphy instruments (BIO- RAD Vrint II; Bio-Rd, Hercules, CA, USA). Plsm glucose levels were ssyed using the glucose oxidse method. Plsm insulin vlues were tested using chemiluminescent immunossy (IMMULITE; Siemens, Berlin nd Munich, Germny). After the bseline study, the ptients were rndomly ssigned in 1:1 rtio to two groups: SM nd SR groups. While mintining ntidibetic medictions, ll prticipnts in both groups were treted with long-cting insulin (insulin glrgine) immeditely fter rndomiztion. The initil doses were.1 to.2 unit/kg/dy, nd the ptients self-djusted the insulin dose ccording to self-monitoring blood glucose (SMBG) levels until Dibetes Metb J 216;4:

3 Yng Y, et l. fsting blood glucose levels were less thn 6.7 mmol/l (12 mg/ dl). When hypoglycemi ws experienced, the insulin doses were reduced two units. The subjects visited the dibetes center t 1, 3, nd 6 months fter insulin dministrtion ws initited, nd we ppropritely modified the insulin doses. At every visit, the body weight ws ssessed. For the SR group, we reduced the mounts of sulfonylure more thn 5% when the fsting SMBG level ws less thn 6.7 mmol/l t the 1- or 3-month visit. We did not chnge the metformin dose during the study period. At the 3-month visit, we followed up the HbA1c level. At the 6-month visit, we repeted the bseline lbortory studies, including the 75-g OGTT. Insulin tretment ws discontinued for 48 hours prior to the OGTT t the 6-month visit. We clculted severl indices to evlute insulin secretion nd resistnce. The insulinogenic index ws defined s the rtio of the 3-minute increment in insulin concentrtion (pmol/l) to the 3-minute increment in glucose concentrtion (mmol/l) following orl glucose loding [24]. The homeosttic model ssessment of insulin resistnce (HOMA-IR) ws clculted bsed on the index from the product of the fsting plsm insulin (μu/ml) nd plsm glucose (mmol/l) divided by 22.5 [25]. In ccordnce with Mtsud nd DeFronzo [26], the insulin sensitivity index (ISI) ws clculted using the following eqution: ISI composite=,/squre root of [(men plsm insulin [μu/ml] men plsm glucose [mg/dl] during OGTT) (fsting plsm glucose fsting plsm insulin)]. The re under the curve (AUC) ws clculted using trpezoidl integrtion. Smple size We expected more increments of insulin secretion fter glucose loding in the SR group (25%) compred with the SM group (5%) [21]. Therefore, the clcultion of the smple size ws bsed on n expected difference of 2% in the increment of insulin secretion fter glucose loding with α of.5 nd β of.2. By multipliction of the ssumed withdrwl rte of %, smple size of 55 in ech group ws obtined. Sttisticl nlysis The bseline chrcteristics of the subjects enrolled in the present study re expressed s the men±stndrd devition or number (%). The dt for the results re expressed s the men±stndrd error. A chi-squre nlysis ws used for discontinuous vribles. The distinction between the two study groups ws nlyzed using n independent t-test. In the sme group, differences between pretretment nd posttretment of bsl insulin were exmined using pired t-test. Repeted mesurements of nlysis of vrince were used to compre the chnge of the β-cell function between the two groups. All dt were nlyzed using PASW sttistics version 18. (SPSS Inc., Chicgo, IL, USA). Sttisticlly significnt differences were considered t P<.5. RESULTS Chrcteristics of the subjects A totl of 69 ptients underwent rndomiztion. Among these ptients, 35 subjects were ssigned to the SM group, nd 34 subjects were ssigned to the SR group. After 6 months, four ptients from the SM group nd eight ptients from the SR group were excluded due to the refusl of OGTT or the followup loss. Thus, totl of 31 ptients in the SM group nd 26 ptients in the SR group were nlyzed in the present study. The clinicl chrcteristics nd biochemicl prmeters of the ptients in both groups re shown in Tble 1. The men ge ws 54.6±11.1 yers, nd the men durtion of dibetes ws 9.3±5.7 yers. There ws no significnt difference in ge, sex, body mss index, nd blood pressure between the two groups. However, the men durtion of dibetes in the SR group ws significntly higher thn tht in the SM group. The bseline lbortory evlutions showed no sttisticl differences between the two groups, except the triglyceride level. The most commonly used sulfonylure in ll prticipnts ws glimepiride. The verge dose of glimepiride ws 3.5±1.3 mg in the SM group nd 4.1±1.3 mg in the SR group. Other sulfonylures used were gliclzide, gliclzide MR, nd glibenclmide. Chnges in the glucose level nd body weight In both study groups, the HbA1c level ws significntly decresed t the first follow-up t 3 months fter inititing longcting insulin tretment. However, the HbA1c vlues were only slightly chnged during the lst 3 months of the study period (Fig. 1A). The initil HbA1c vlues of 9.3%±.2% in the SM group nd 9.%±.2% in the SR group decresed to 8.1%±.2% (P<.1) nd 7.9%±.2% (P=.3) t the 6-month follow-up, respectively. Fig. 1B shows the chnges in body weight during the follow-up period. At the 6-month follow-up, the verge body weight significntly incresed from 68.1±1.9 to 7.4±2.5 kg in the SM group (P=.3) but showed no differ- 456 Dibetes Metb J 216;4:

4 Sulfonylure efficcy with bsl insulin Tble 1. Bseline chrcteristics of the subjects Chrcteristic Totl (n=57) Sulfonylure-mintennce (1) Sulfonylure-reduction (n=26) Age, yr 54.6± ± ± Mle sex 33 (57.9) 18 (58.1) 15 (57.7).977 Weight, kg 66.7± ± ± BMI, kg/m ± ± ± Durtion of dibetes, yr 9.3± ± ±5.8.2 SBP, mm Hg 131.9± ± ± DBP, mm Hg 74.7± ± ± HbA1c, % 9.2± ±1.2 9.± Totl cholesterol, mmol/l 4.7±.9 4.9±.9 4.5± Triglyceride, mmol/l 1.8± ± ±.7.7 HDL-C, mmol/l 1.1±.2 1.1±.2 1.1± LDL-C, mmol/l 2.9±.8 2.9±.9 2.8± Insulin t min, pmol/l b 45.9± ± ± Insulin t 12 min, pmol/l b 132.5± ± ± Insulinogenic index 5.±5. 4.5± ± HOMA-IR 3.± ± ± ISI composite (Mtsud index) 7.5± ± ± Metformin dose, mg 1,21.7± ±58.1 1,115.4± Types of sulfonylure.536 Glimepiride 39 (7.2) 23 (74.2) 17 (65.4) Dose, mg 3.7± ± ±1.3 Gliclzide 4 (7.) 1 (3.2) 3 (11.5) Dose, mg 14± ±. Gliclzide MR 5 (8.8) 2 (6.5) 3 (11.5) Dose, mg 6.± ±21.2 7±17.3 Glibenclmide 8 (14.) 5 (16.1) 3 (11.5) Dose, mg 9.8± ± ±5.5 P vlue Vlues re presented s men±stndrd devition or number (%). BMI, body mss index; SBP, systolic blood pressure; DBP, distolic blood pressure; HbA1c, glycosylted hemoglobin; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; HOMA-IR, homeosttic model ssessment of insulin resistnce; ISI, insulin sensitivity index; OHA, orl hypoglycemic gents; MR, modified relese. The BMI ws clculted s the weight in kilogrms divided by the squre of the height in meters, b Insulin level during the 75-g orl glucose tolernce test. ence from 65.±2.3 to 65.7±2.2 kg in the SR group (P=.74). The verge weight gin in the SM group ws significntly higher thn tht in the SR group. Fig. 1C shows the dily dosge of insulin dministered to the subjects. During the study period, the insulin dose ws incresed from 9.4±.3 to 17.1±1.2 IU/dy in the SM group nd from 9.5±.5 to 16.±1.3 IU/dy in the SR group, nd there ws no significnt difference in the insulin dose between the two groups (P=.55). At the end of the investigtion, 11 ptients (42.3%) discontinued sulfonylure tretment in the SR group, nd the drug dosge ws reduced more thn 5% in the remining 15 ptients (57.7%) (Fig. 1D). Chnge in β-cell function nd insulin resistnce The levels of glucose nd insulin fter 75-g glucose loding t bseline nd the 6-month follow-up re illustrted in Fig. 2. Compred with the levels prior to insulin tretment, plsm Dibetes Metb J 216;4:

5 Yng Y, et l. SU mintence SU reduction HbA1c (%) Body weight (kg) Time (mo) A Time (mo) B Time (mo) C Does of insulin (IU/dy) 2 15 Dose (mg) n=17 n=14 n=2 3 6 Time (mo) n= Glimepiride Glibenclmide Gliclzide ( ) Gliclzide MR ( ) n=2 n=1 n=2 D Fig. 1. Chnges in the glucose levels, body weight, nd insulin nd sulfonylure (SU) doses over 6 months. Chnges in the (A) glycosylted hemoglobin (HbA1c) levels, (B) body weight, nd (C) injected insulin dose in the SU mintennce nd SU reduction groups during the study period. (D) Dose reduction of SU in the SU reduction group. The dt re presented s the men±stndrd error. Tble 2. Chnges in β-cell function nd insulin resistnce Prmeter Sulfonylure-mintennce (1) Sulfonylure-reduction (n=26) Between-group P vlue Bseline 6 Months P vlue Bseline 6 Months P vlue AUCg, mmol/l hr 37.± ± ± ± AUCi, pmol/l hr 29.± ± ± ± AUCi/AUCg 5.6±.7 7.4± ±.6 7.5± HOMA-IR 3.4±.4 2.9± ±.4 2.1± Insulinogenic index 4.6±.8 6.9± ± ± <.1 ISI composite (Mtsud index) 7.4± ± ± ± Vlues re presented s men±stndrd error. AUCg, re under the response curve of glucose; AUCi, re under the response curve of insulin; HOMA-IR, homeosttic model ssessment of insulin resistnce; ISI, insulin sensitivity index. glucose t OGTT ws significntly decresed, nd plsm insulin ws significntly incresed 2% to 3% fter the dministrtion of insulin in both groups. Tble 2 revels the chnges in the biochemicl mesures of the study groups. Almost ll prmeters representing β-cell function in the OGTT were improved fter 6 months of insulin therpy in both groups. The AUC insulin/glucose rtio ws significntly incresed in both groups, nd the insulinogenic index, reflecting first-phse insulin secretion, lso mrkedly incresed in both groups. Although the sulfonylure dose ws reduced in the SR group, the insulinogenic index ws more significntly improved in the SR group. The HOMA-IR nd 458 Dibetes Metb J 216;4:

6 Sulfonylure efficcy with bsl insulin Bseline After insulin tretment Plsm glucose (mmol/l) Plsm glucose (mmol/l) Time (min) A Time (min) B 2 2 Plsm insulin (pmol/l) 15 5 Plsm insulin (pmol/l) Time (min) C Time (min) D Fig. 2. Chnges in β-cell function nd insulin resistnce. Results of the 75-g orl glucose tolernce test. (A) The plsm glucose levels in the sulfonylure (SU) mintennce nd (B) SU reduction groups. (C) The plsm insulin levels in the SU mintennce nd (D) SU reduction groups. The dt re presented s the men±stndrd error. P<.5 before nd fter insulin tretment. ISI, representing insulin resistnce, showed no significnt chnges from bseline to the end of the follow-up period in the two study groups. Hypoglycemi The number of symptomtic hypoglycemi events during the tretment ws similr between the two groups (SM group, 9.7%; SR group, 11.5%); no event of severe hypoglycemi occurred. DISCUSSION In the present study, we demonstrted tht bsl insulin replcement in ptients undergoing long-term sulfonylurebsed tretment improved not only glycemic control sttus but lso β-cell function, irrespective of the sulfonylure dose reduction. Although the use of sulfonylures hs rpidly decresed, this drug remins the preferred orl gent when ptients show reltively high glucose levels or refuse insulin therpy. These gents will likely initilly improve the hyperglycemic stte. However, hyperglycemi could prdoxiclly worsen with time becuse these drugs could induce the exhustion of pncretic β-cells, prticulrly in subjects with predominnt β-cell dysfunction [9]. Thus, we evluted the recovery of insulin secretory function prticulrly in ptients receiving long durtions of sulfonyl- Dibetes Metb J 216;4:

7 Yng Y, et l. ure-bsed tretments. We thought tht reduction of the sulfonylure dose would increse the insulin requirement compred with SM. Interestingly, the decrement in HbA1c ws similr between these two conditions, nd there ws no difference in insulin requirement, despite reduction in the sulfonylure dose or even the termintion of sulfonylure tretment. Prior studies hve reported beneficil effects of bsl insulin on insulin secretion by glucgon stimultion, compred with the sulfonylure in ptients with recently dignosed T2DM [16,17,19]. In our study, there ws little difference in the insulin secretion fter glucose loding in both groups, irrespective of the sulfonylure dose reduction. These findings indirectly suggested tht there might be reltively similr self-relint insulin secretion between SM nd SR. Ptients presenting with significnt hyperglycemi could benefit from the initition of insulin tretment, which restores the deleterious effects of excessive glucose (glucotoxicity) nd lipid (lipotoxicity) exposure on β-cell function nd insulin ction [27-29]. In the present study, we considered n dded effect of improved glucose toxicity, resulting in more improvements in insulin secretion fter glucose loding. However, the insulinogenic index, mrker for β-cell function, ws more significntly improved in SR group. This result hs thred of connection with results in Krm s study [23]. As mentioned in introduction, Krm et l. [23] reported recovery of β-cell response to cute sulfonylure stimultion when sustined therpy with sulfonylure ws discontinued. In ddition, ptients body weight significntly incresed in the SM group t 6 months fter bsl insulin replcement, wheres there ws no chnge in body weight in the SR group. Thus, we concluded tht when bsl insulin ws replced, n dditionl effect of sulfonylure ws not observed; therefore, sulfonylure could be reduced or discontinued without n increse in the bsl insulin dose. Previous studies hve reveled tht erly insuliniztion could more effectively chieve dequte glycemic trget levels nd improve β-cell function compred with the use of orl hypoglycemic gents in newly dignosed ptients or subjects with short disese durtions [14,16,17]. In the present study, the ptients hd reltively longer verge dibetes durtions, nd the glucose control sttus ws poorer thn in previously reported studies. Although the HbA1c levels were decresed nd the insulin secretory function ws slightly recovered in the present study, we expect tht if the dibetes durtion hd been shorter, the results would hve been better. We did not observe ny improvements in HbA1c fter the 3- nd 6-month follow-ups, likely reflecting the fct tht the glucose increment levels fter OGTT did not sufficiently decrese to trget levels, despite dequte control of fsting blood glucose levels. This finding suggests tht nother pproch, such s glucgon-like peptide-1 gonists or rpid-cting insulin, is needed for postprndil glucose control in combintion with bsl insulin replcement, lthough bsl insulin replcement could normlize fsting blood glucose levels nd slightly restore postprndil insulin secretion in ptients undergoing sulfonylure-bsed tretment. There re severl limittions in the present study. First, the smple size ws smll. We were unble to fulfill the plnned 1 ptients, mking this study n underpowered nlysis. In dditionlly, the follow-up durtion ws short. To evlute sulfonylure durbility nd the long-term effect of β-cell dysfunction recovery, longer studies re needed. Moreover, diet nd exercise were not monitored during the 6-month tretment period. However, the present study ws prospective, rndomized, controlled study tht evluted the efficcy of SR with bsl insulin replcement in ptients receiving sulfonylurebsed tretment over 2 yers. In conclusion, bsl insulin replcement in Koren ptients with T2DM receiving long durtions of sulfonylure-bsed tretment is beneficil to restore β-cell function. Indeed, when bsl insulin is replced, sulfonylure-bsed tretment cn be reduced or even discontinued without ffecting glycemic control sttus nd insulin requirements. Moreover, the dose reduction of the concurrent sulfonylure might be beneficil with regrd to weight gin. Further studies re needed to trget lrge number of subjects over longer period. CONFLICTS OF INTEREST No potentil conflict of interest relevnt to this rticle ws reported. REFERENCES 1. DeFronzo RA. Lilly lecture The triumvirte: bet-cell, muscle, liver. A collusion responsible for NIDDM. Dibetes 1988;37: Kim DJ, Lee MS, Kim KW, Lee MK. Insulin secretory dysfunction nd insulin resistnce in the pthogenesis of Koren type 2 dibetes mellitus. Metbolism 21;5: Dibetes Metb J 216;4:

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