Effects of a 6-Month Exenatide Therapy on HbA1c and Weight in Korean Patients with Type 2 Diabetes: A Retrospective Cohort Study

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1 Originl Article Clinicl Cre/Eduction Dibetes Metb J 20;3: pissn eissn D I A B E T E S & M E T A B O L I S M J O U R N A L Effects of -Month Exentide Therpy on HbA1c nd Weight in Koren Ptients with Type 2 Dibetes: A Retrospective Cohort Study Juyoung Shin, Jin-Sun Chng, Hun-Sung Kim, Sun-Hee Ko, Bong-Yun Ch, Ho-Young Son, Kun-Ho Yoon, Je-Hyoung Cho Division of Endocrinology nd Metbolism, Deprtment of Internl Medicine, College of Medicine, The Ctholic University of Kore, Seoul, Kore Bckground: While mny studies hve shown the good efficcy nd sfety of exentide in ptients with dibetes, limited informtion is vilble bout exentide in clinicl prctice in Koren popultions. Therefore, this retrospective cohort study ws designed to nlyze the effects of exentide on blood glucose level nd body weight in Koren ptients with type 2 dibetes mellitus. Methods: We reviewed the records of the ptients with dibetes who visited Seoul St. Mry s Hospitl nd for whom exentide ws prescribed from June 200 to October 20. After excluding subjects bsed on their rce/ethnicity, medicl history, whether or not they chnged more thn 2 kinds of orl hypoglycemic gents with exentide tretment, loss to follow-up, or whether they stopped exentide therpy within months, totl of 2 subjects were included in the finl nlysis. Results: The men glycted hemoglobin (HbA1c) level nd weight remrkbly decresed from.±1.% to.±1.0% (P<0.001) nd from 2.3±1. kg to.±1.3 kg (P<0.001), respectively. The multiple regression nlysis indicted tht the reduction in HbA1c level ws significntly ssocited with shorter durtion of dibetes, higher bseline HbA1c level, nd greter weight reduction, wheres weight loss hd no significnt correltion with other fctors. No severe dverse events were observed. Conclusion: These results suggest tht -month exentide injection therpy significntly improved ptients HbA1c levels nd body weights without cusing serious dverse effects in Koren ptients with type 2 dibetes. Keywords: Dibetes mellitus, type 2; Exentide; Glucgon-like peptide 1; Tretment outcome INTRODUCTION The prevlence of obesity in Asi is now n epidemic thret, followed by n exponentil increse in the incidence of dibetes [1]. As result, type 2 dibetes mellitus (T2DM) hs become one of the most common metbolic diseses in Kore. Since mny epidemiologic, interventionl, nd lbortory studies hve reveled tht dequte blood glucose control delys the onset of complictions [2-], there hve been continuous efforts towrd chieving nd mintining pproprite glucose levels. However, only hlf of dibetic ptients re known to rech glycemic control gols []. The highest contributing fctor to tretment filure is nondherence to medictions, which is ssumed to come from fer of weight gin nd hypoglycemi [-]. The weight gin nd hypoglycemic events re unfortuntely common side effects of stndrd medictions. Exentide is recently developed incretin-bsed mediction tht is n nlog of glucgon-like peptide 1 (GLP-1). GLP-1 is gut hormone tht not only lowers glucose levels by promoting insulin secretion nd inhibiting glucgon relese, but lso controls weight by inducing stiety nd slowing gstric emptying time [,]. Exentide chieves better physiologicl glucose control with low risk of weight gin nd hypoglycemi. Therefore, clinicins hve turned their ttention to exentide. 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 13-1, Kore E-mil: drhopper@ctholic.c.kr Received: My 14, 20; Accepted: Jun. 4, 20 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 20 Koren Dibetes Assocition

2 The effectiveness of exentide in Korens Although mny exentide studies hve shown good efficcy nd sfety in dibetic ptients, limited informtion is vilble from rel clinicl prctice in Kore. Therefore, this retrospective study ws designed to nlyze the effects of exentide on blood glucose level nd body weight in Koren ptients with T2DM. METHODS Study subjects The medicl records of the ptients who visited Seoul St. Mry s Hospitl between June 200 nd October 20 were screened. The ptients were eligible for inclusion in the study if they were Koren, ged 20 to yers, nd hd T2DM for minimum of 3 months. Subjects were enrolled if their glycted hemoglobin (HbA1c).% nd if they did not hve ny chnges in their orl hypoglycemic gents (OHA) for t lest 3 months before exentide ws prescribed. Ptients were excluded if they hd type 1 dibetes with positivity for utontibodies ginst glutmic cid decrboxylse, islet cell or insulin, or C-peptide <0. ng/ml, gesttionl dibetes, or dibetes with secondry cuses. We lso excluded the ptients who hd significnt renl impirment (estimted cretinine clernce <0 ml/min), elevted (more thn two-fold the upper limit of norml) lmine minotrnsferse or sprtte minotrnsferse, or concomitnt conditions such s surgery, hospitliztion, or cncer, or hd used insulin within the previous 3 months. Additionl exclusion criteri included switching more thn two kinds of OHAs with exentide tretment, follow-up loss, or discontinution of exentide tretment within months. The ptients were subdivided into 4 groups: group 1, n exentide monotherpy group of tretment-nive ptients; group 2, group of ptients who continued their OHA tretments; group 3, switching group of ptients who used exentide s substitute for one kind of OHAs; nd group 4, combintion group of ptients took exentide long with OHAs. All ptients initilly received μg of exentide twice dy. After 1 month of tretment, the exentide dosge ws incresed to μg twice dy. The initil OHAs were mintined for months. Dietitins in the sme institute provided individulized medicl nutrition therpy nd physicins recommended t lest 10 min/wk of regulr moderte-intensity exercise in their out-ptient clinics. Ptients were informed of dverse effects of exentide including dizziness, hedche, norexi, nuse, vomiting, or symptoms of pncretitis nd monitored by physicins. The ptients returned t 1, 3, nd months for follow-up. Mesurement of the nthropometric nd biochemicl prmeters The bseline ssessments included mesurements of height, weight, blood pressure, nd fsting blood glucose (FBG), nd HbA1c levels. The weights nd the HbA1c levels were mesured t ech visit. Height nd weight were mesured without shoes nd with light indoor clothes by trined helth-cre personnel. Body mss index (BMI) ws clculted s weight in kilogrms divided by height in meter squred (kg/m 2 ). After -minute rest in the outptient clinic, systolic nd distolic blood pressures were mesured in sitting position, using n utomtic device. Blood ws drwn fter overnight fsting. FBG levels were mesured in serum, using modified glucose oxidse/ peroxidse method (Sekisui Medicl Co., Tokyo, Jpn). HbA1c levels were mesured using G Glycohemoglobin Anlyzer (Tosoh Co., Tokyo, Jpn). Sttisticl nlysis The ctegoricl dt re expressed s number nd percentge of subjects. The continuous vribles re expressed s men nd stndrd devition. The chnges in HbA1c level nd weight over time were estimted by repeted mesures nlysis of vrince. To obtin the best-fit eqution for the reltionship between the bseline HbA1c levels nd the chnges in the HbA1c levels with the tretment, liner model of regression nlysis ws used. We then nlyzed the dt using liner-by-liner ssocition to identify the vribles ssocited with the chnges in HbA1c level nd weight. Multiple regression nlysis ws used to determine the independent fctors for predicting reductions in HbA1c level nd weight. A P vlue of less thn 0.0 ws considered sttisticlly significnt. The sttisticl nlyses were performed using SPSS for Windows version 1.0 (SPSS Inc., Chicgo, IL, USA). RESULTS Study subjects clinicl chrcteristics Among the 14 ptients given exentide, were excluded for vrious resons (Fig. 1). The finl nlysis included 2 subjects (2 mles, 2 femles), which were divided into group 1 (ex- Dibetes Metb J 20;3:34-3 3

3 Shin J, et l. 14 Ptients given exentide from June 200 to October 20 were screened Were excluded 4 Were foreigners Were ineligible owing to medicl history 3 Used insulin 20 Hd initil HbA1c<.% Were reviewed 3 Were excluded 1 Chnged more thn 2 kinds of OHAs Were lost to follow-up Stopped exentide therpy within months fter the onset of tretment Quit by themselves becuse of dverse effects 3 Stopped ccording to clinicin s recommendtion owing to remrkbly improved glucose levels 2 Were included in the finl nlysis Group 1 (n=) Group 2 (n=) Group 3 (n=23) Group 4 (n=) Exentide only for tretment-nive ptients Adding exentide on previous OHAs Substituting exentide for 1 kind of OHA Adding exentide nd OHAs Fig. 1. Selection of the study prticipnts. OHA, orl hypoglycemic gent. Tble 1. Bseline chrcteristics of the study subjects Chrcteristic Group 1 (n=) Group 2 (n=) Group 3 (n=23) Group 4 (n=) Totl (n=2) M/F 3/ 3/ / /1 2/2 Age, yr 44.±.4 4.4±. 4.±.2 3.±.1 4.1±. Durtion of dibetes, yr 0.4± ±4..0± ± ±3. SBP, mm Hg.3±.0 2.0±..± ±13.2.±13. DBP, mm Hg 1.±..±.4.±14. 4.±..±. BMI, kg/m 2 2.± ±.3 2.±4.0 2.± ±4.1 HbA1c, %.±2.1.3±1..0±1.3.±2.0.±1. FBG, mg/dl 1.±4. 10.± ± ±. 1.2±.3 Vlues re presented s men±stndrd error of the men. SBP, systolic blood pressure; DBP, distolic blood pressure; BMI, body mss index; HbA1c, glycted hemoglobin; FBG, fsting blood glucose. entide monotherpy for tretment nive ptients, n=/2), group 2 (ddition of exentide to ongoing OHA tretment, n=/2), group 3 (substitution of exentide for one kind of OHA, n=23/2), nd group 4 (ddition of exentide nd OHAs, n=/2). Bseline chrcteristics of the study subjects re summrized in Tble 1. Of the 2 ptients, 2 ptients were mle (4%), the men ge ws 4.1±. yers, the men dibetes durtion ws 3.2±3. yers, the men BMI ws 30.0±4.1 kg/m 2, the men HbA1c ws.±1.%, nd the men FBG ws 1.2±.3 mg/dl. Subjects in group 4 hd the highest 3 Dibetes Metb J 20;3:34-3

4 The effectiveness of exentide in Korens Group 1 Group 2 Group 3 Group 4 HbA1c (%) A Group 1 Group 2 Group 3 Group 4 Body weight (kg) B Fig. 2. Chnges in glycted hemoglobin (HbA1c) level (A) nd body weight (B) fter the exentide tretment. The vlues re presented s men±stndrd error of the men. Sttisticl significnces were tested by repeted mesures nlysis of vrince. P<0.0. men vlues for HbA1c nd FBG, while they hd the lowest men vlue for ge. Effects of exentide on HbA1c level nd body weight Fig. 2 nd Tble 2 show the chnges in HbA1c level nd weight from the bseline to fter -month exentide tretment. Exentide tretment led to significnt improvements in HbA1c in ech group: the reductions of HbA1c were 3.1±2.3% (P= 0.003) in group 1, 1.3±1.2% (P=0.004) in group 2, 0.±0.% (P<0.001) in group 3, 3.±2.3% (P=0.004) in group 4, nd 1.±1.% (P<0.001) overll. Weight chnges hd similr ptterns to those of HbA1c. However, group 4 didn t hve significnt differences in weight between mesurements tken t bseline nd fter the -month tretment. The reductions of weight were.±. kg (P=0.004) in group 1, 2.±2. kg (P= 0.00) in group 2, 2.±4.2 kg (P=0.00) in group 3, 2.0±3. kg (P=0.1) in group 4, nd 3.±4. kg (P<0.001) overll. Tble 2. Efficcy of the -month exentide tretment on HbA1c nd weight chnge depending on the subgroups HbA1c, % Δ HbA1c P vlue Bseline Bseline Weight, kg Δ Weight P vlue Group ± ± Group ± ± Group ±0. < ± Group ± ± Totl. -1.±1. < ±4. <0.001 Vlues re presented s men±stndrd error of the men. Δ HbA1c, chnge in HbA1c level from the bseline to fter the - month tretment; Δ Weight, chnge in weight from the bseline to fter the -month tretment. Fctors ffecting the response in HbA1c nd weight The ptients who hd higher bseline HbA1c levels hd greter reductions in HbA1c level fter the exentide tretment, s Dibetes Metb J 20;3:34-3 3

5 Shin J, et l Initil HbA1c (%) Tble 3. Multiple regression nlysis of the potentil vribles for predicting chnges in HbA1c level s dependent vribles Vrible β P vlue Age, yr BMI, kg/m Δ HbA1c (%) R 2 =0.0 P<0.001 Durtion of dibetes Bseline HbA1c, % <0.001 Δ Weight, kg β, regression coefficient; BMI, body mss index; HbA1c, glycted hemoglobin; Δ Weight, chnge in weight from the bseline to fter the -month tretment. - - Fig. 3. The reltionship between the initil glycted hemoglobin (HbA1c) vlues nd the chnge in the HbA1c vlues (Δ HbA1c). indicted by the liner model of the regression nlysis (β = -0., P<0.001) (Fig. 3). A multiple regression nlysis ws performed to evlute the independent fctors tht might predict HbA1c chnges (R 2 =0., P<0.001) (Tble 3). Shorter durtion of dibetes (P=0.004), higher bseline HbA1c level (P<0.001), nd greter reduction in body weight (P=0.001) were the clinicl vribles tht independently suggested greter decreses in HbA1c level with the -month exentide injection therpy. Age nd BMI were insignificnt fctors. On the other hnd, the weight chnges hd no sttisticlly significnt reltionships with the other vribles such s ge, BMI, nd dibetes durtion (R 2 = 0.0, P=0.) (Tble 3). Sfety nd tolerbility There were no serious dverse effects relted to the exentide tretment (Tble 4). Among the 143 Koren ptients who used exentide, 23 ptients (1.1%) hd nuse, 1 ptients (.%) suffered from vomiting, 3 ptients (2.1%) complined of dizziness, nd 2 ptients (1.4%) hd erythem on the injection site. Among the ptients with T2DM nd HbA1c.%, who hd not used insulin for previous 3 months nd did not chnge more thn 2 kinds of OHAs when exentide ws strted, ptients (.4%) stopped tking exentide by themselves due to norexi or vomiting. Among the 2 study subjects, (1.4%) lso hd mild nuse, but their symptoms ttenuted over time. Tble 4. Adverse effects of exentide tretment Adverse effect Neither hypoglycemic events nor the occurrence of pncretitis ws reported during the -month tretment. DISCUSSION T2DM Korens with exentide tretment (n=143) Study subjects (n=2) Nuse 23 (1.1) (1.4) Vomiting 1 (.) 0 (0) Dizziness 3 (2.1) 0 (0) Erythem on injection site 2 (1.4) 0 (0) Vlues re presented s number (%) of ptients. T2DM, type 2 dibetes mellitus. The objective of this study ws to investigte the effects of exentide on HbA1c levels nd weight in Koren ptients with dibetes. To dte, the effectiveness of exentide in Koren T2DM ptients hs not been evluted in rel clinicl prctice. The present study shows tht exentide therpy reduced the verge HbA1c levels nd weights by 1.% nd 3. kg, respectively. Depending on the prescription regimen, the decreses rnged 0.% to 3.% nd 2.0 to. kg. Group 4, the group tht strted both exentide nd OHAs, hd the gretest reduction in HbA1c nd group 1, the exentide monotherpy group, hd the gretest reduction in body weight. All four groups showed similr ptterns in HbA1c chnges. Weight chnge seemed to follow the trend of HbA1c chnges. However, group 4 hd insignificnt chnges between mesurements t bseline nd fter the -month tretment, which is ssumed to come from the smll smple size. There re erlier rndomized controlled trils tht show the efficcy of exentide tretment either s 3 Dibetes Metb J 20;3:34-3

6 The effectiveness of exentide in Korens monotherpy or combined therpy with OHAs including metformin, sulfonylure, nd thizolidinedione. Drucker proved tht -μg injections of exentide dministered twice dily for 30 weeks resulted in reductions of pproximtely 1.% in HbA1c level nd 3. kg in weight in DURATION-1 study []. Blevins et l. [13] documented tht 24-week exentide tretment reduced HbA1c nd weight by 0.% nd 1.4 kg, respectively. Bseline HbA1c, the durtion of dibetes, nd weight chnges re importnt confounders to nlyze chnges in HbA1c. Bseline HbA1c hd negtive liner reltionship with chnges in HbA1c fter exentide tretment. These results correspond well with those found in recent met-nlysis, which reported tht the effect of incretin-bsed therpy on reduction in HbA1c depended on initil vlues [14]. Ptients with shorter dibetes durtions hd greter decreses in HbA1c. Those with shorter dibetes durtions would hve higher possibilities of mintining the number nd function of pncretic β-cells. It is lredy well-known fct tht the function of insulin-secreting β-cells is lredy hlved t the time of dignosis nd continues declining therefter [1,1]. Therefore, some experts insist tht erly intervention should be strted to ttenute this chnge. There re some lbortory experiments tht report exentide-induced β-cell prolifertion, possible neogenesis, nd reduced poptosis [1-1]. The degree of weight loss hd cler correltion with chnges in HbA1c levels. One possible hypothesis is tht weight loss cn induce greter HbA1c reductions. Improving insulin resistnce through weight loss cn hve synergic effect on HbA1c chnges by mplifying the function of insulin. However, we cnnot confirm if the weight loss ctully cused the greter HbA1c reduction or if it ws just n independent finding due to decresed food intke. Unfortuntely, we hd no dt to ssess β-cell function, insulin resistnce, or cloric intke. The results of the multiple regression nlysis showed tht ge nd BMI re insignificnt vribles for HbA1c chnges. However, it might be unresonble to conclude tht ge nd BMI do not ffect it since most ptients in this study were young nd obese. In contrst to HbA1c levels, weight chnge hd no correltion with other fctors. Previous studies hve lso shown no correltion between bseline body weight nd chnge in body weight [14]. Interpreting the chnges in body weight, we must consider lifestyle confounding fctor. It is possible tht greter lifestyle modifiction induces greter weight reduction. Even though ll the ptients were recommended helthy lifestyle chnges, their responses could hve been vrible. This study hs some limittions. First, there ws no control group. Therefore, we cnnot estimte the effects of other fctors like lifestyle modifiction. The ct of injecting exentide my hve reminded ptients to control their lifestyle, including eting helthy diet nd exercising dily. In other trils, the control group tht received plcebo injections lso hd weight reduction, even though the study group tht received exentide injections hd more prominent reduction [20,21]. Second, it is especilly difficult to determine whether the effect on HbA1c nd weight cme from the direct or indirect effects of exentide becuse we cnnot clculte its effects on hormonl chnges such s insulin nd glucgon or the subjects food intke. Neither insulin nor C-peptide ws mesured before nd fter the -month tretment. In ddition, whether ptients followed the medicl nutrition therpy nd exercise recommendtion ws not evluted in stndrdized mnner. Third, the smple size is smll nd most of the ptients in the current study were young nd obese. The men ge nd BMI were 4.1 yers nd 30.0 kg/m 2. Therefore, we suggest tht future studies monitor subjects with wide rnge of ge nd BMI to provide more ccurte evlution. Exentide-induced improvements in glucose level nd body weight re expected to bring long-term dvntges. However, there is some concern tht the use of exentide might increse the risk of pncretitis, thyroid cncer, or unexpected dverse effects [22]. Future studies re needed to evlute the long-term effects of exentide. To our knowledge, this is the first study to report the effectiveness of exentide in clinicl setting. The -month exentide therpy demonstrted significnt improvements in HbA1c level nd body weight without displying serious dverse effects in Koren ptients with T2DM. CONFLICTS OF INTEREST No potentil conflict of interest relevnt to this rticle ws reported. REFERENCES 1. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, Zimmet P, Son HY. Epidemic obesity nd type 2 dibetes in Asi. Lncet 200;3: Holmn RR, Pul SK, Bethel MA, Mtthews DR, Neil HA. - Dibetes Metb J 20;3:34-3 3

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