Exenatide versus Insulin Lispro Added to Basal Insulin in a Subgroup of Korean Patients with Type 2 Diabetes Mellitus

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1 Original Artile Others Diaetes Meta J 217;41: pissn eissn DIABETES & METABOLISM JOURNAL Exenatide versus Insulin Lispro Added to Basal Insulin in a Sugroup of Korean Patients with Type 2 Diaetes Mellitus Kun-Ho Yoon 1, Elise Hardy 2, Jenny Han 3 1 Division of Endorinology and Metaolism, Department of Internal Mediine, Seoul St. Mary s Hospital, College of Mediine, The Catholi University of Korea, Seoul, Korea, 2 AstraZenea, Gaithersurg, MD, 3 Pharmapae, San Diego, CA, USA Bakground: The prevalene of type 2 diaetes mellitus (T2DM) and oesity is inreasing in Korea. Clinial studies in patients with T2DM have shown that omining the gluagon-like peptide-1 reeptor agonist exenatide twie daily with asal insulin is an effetive gluose-lowering strategy. However, these studies were predominantly onduted in non-asian populations. Methods: We onduted a sugroup analysis of data from a multinational, 3-week, randomized, open-lael trial to ompare the effets of exenatide twie daily (n=1) or three times daily mealtime insulin lispro (n=13) among Korean patients with T2DM inadequately ontrolled (glyosylated hemogloin [HA1] >7.%) on metformin plus optimized insulin glargine. Results: Exenatide twie daily and insulin lispro oth redued HA1 (mean 1.5% and 1.%, respetively; P<.1 vs. aseline). Fasting gluose and weight numerially dereased with exenatide twie daily (.7 mmol/l and.7 kg, respetively) and numerially inreased with insulin lispro (.9 mmol/l and 1. kg, respetively). Minor hypoglyemia ourred in four patients reeiving exenatide twie daily and three patients reeiving insulin lispro. Gastrointestinal adverse events were the most ommon with exenatide twie daily treatment. Conlusion: This analysis found treatment with exenatide twie daily improved glyemi ontrol without weight gain in Korean patients with T2DM unale to ahieve glyemi ontrol on metformin plus asal insulin. Keywords: Diaetes mellitus, type 2; Exenatide; Insulin lispro INTRODUCTION The prevalene of type 2 diaetes mellitus (T2DM) is inreasing in Asian ountries, with some reporting omparale or higher rates of diaetes than Western ountries [1]. In Korea, diaetes prevalene inreased from 7.2% in 1993 to 9.9% over 27 to 29 [2]. The World Health Organization notes that inreased T2DM risk is seen at a lower ody mass index (BMI) for Asian ompared with European populations [3]; however, the prevalene of oesity (BMI 25 kg/m 2 ) is also inreasing in Korea, and 4% to 5% of Korean people with diaetes are now oese [4,5]. Although postprandial gluose (PPG) and fasting gluose (FG) levels oth play an important role in the development of hyperglyemia in patients with T2DM, elevated PPG appears to e a greater ontriutor to hyperglyemia than FG among Asian patients [6,7]. For patients unale to ahieve glyemi targets with oral gluose-lowering agents or a single injetale, international guidelines reommend omination injetale therapy [8]. One suh option inludes the omination of asal Corresponding author: Kun-Ho Yoon Division of Endorinology and Metaolism, Department of Internal Mediine, Seoul St. Mary s Hospital, College of Mediine, The Catholi University of Korea, 222 Banpodaero, Seoho-gu, Seoul 6591, Korea yoonk@atholi.a.kr This is an Open Aess artile distriuted under the terms of the Creative Commons Attriution Non-Commerial Liense ( whih permits unrestrited non-ommerial use, distriution, and reprodution in any medium, provided the original work is properly ited. Reeived: Apr. 9, 216; Aepted: Jul. 18, 216 Copyright 217 Korean Diaetes Assoiation

2 Yoon KH, et al. insulin and a gluagon-like peptide-1 reeptor agonist (GLP- 1RA). GLP-1RAs improve glyemi ontrol through inreased gluose-dependent insulin seretion, gluose-dependent suppression of gluagon, delayed gastri emptying, and inreased satiety [9]. The short-ating GLP-1RA exenatide twie daily is dosed with reakfast and dinner, speifially reduing the PPG exursions that our with these meals [1]. The gluose-lowering effetiveness of omining exenatide twie daily with asal insulin has previously een demonstrated without the weight gain and hypoglyemia assoiated with omplex asalolus insulin regimens [11,12]. However, treatment responses to gluose-lowering mediations may vary aross populations with different disease phenotypes and/or regional praties, and the addition of exenatide twie daily to asal insulin has een primarily studied in non-asian populations [11,12]. Furthermore, to our knowledge, there is no pulished evidene of the effiay and safety of exenatide twie daily speifially in Korean patients reeiving asal insulin. In the Basal Insulin Glargine plus Exenatide twie daily versus Basal Insulin Glargine plus Bolus Insulin Lispro (4B) study, addition of exenatide twie daily or mealtime insulin lispro to treatment among patients with T2DM and insuffiient glyemi ontrol on titrated insulin glargine resulted in omparale redutions in glyosylated hemogloin (HA1) [12]. However, ompared with insulin lispro, exenatide twie daily treatment resulted in weight loss rather than weight gain and fewer nonnoturnal hypoglyemia episodes [12]. Here, we report the results of a sugroup analysis examining the effiay and toleraility of exenatide twie daily among patients enrolled in the 4B study at enters in South Korea. METHODS Study design and patients The protool was approved y Ethis and Regulatory Committees, the Institutional Review Boards, and was ompleted in aordane with the Delaration of Helsinki and Good Clinial Pratie Guidelines. All patients provided written informed onsent [12]. The methods of the randomized, ontrolled, open-lael, noninferiority 4B study (NCT96661) were reported previously [12]. Briefly, eligile patients were males and females aged 18 years with T2DM treated with insulin glargine and metformin, with an HA1 of 7.% to 1.%. Eligile South Korean patients had a BMI of 23. kg/m 2 (vs. 25. kg/m 2 for all others) to 45. kg/m 2. The study omprised a 12-week asal insulin optimization phase, during whih insulin glargine was titrated to an FG of 5.6 mmol/l without hypoglyemia. Patients who were unale to reah HA1 7.% were randomized to reeive exenatide (5 µg twie daily for 4 weeks, then 1 µg twie daily) efore the two largest meals with 6 hours etween dosing or three times daily mealtime insulin lispro (titrated to ahieve preprandial lood gluose <6.1 mmol/l without hypoglyemia), oth added to insulin glargine and metformin, for the 3-week intervention phase. Insulin glargine dose was redued y 1% for patients with an HA1 of 8.% reeiving exenatide twie daily or y one-half or onethird for patients reeiving insulin lispro. Thereafter, insulin glargine was titrated as in the asal insulin optimization phase. Study outome measures The primary outome was the hange in HA1 from randomization to 3 weeks [12]. Key seondary outomes inluded ahievement of HA1 targets ( 6.5%, 7.%), total insulin dose, seven-point self-monitored lood gluose profiles, and hanges in FG and weight. Safety outomes inluded hypoglyemia and adverse events (AEs). Statistial analysis Patient harateristis and effiay outomes were reported for the per-protool population, defined as all randomized patients ompleting the study who met the inlusion, exlusion, and disontinuation riteria [12]. Safety analyses were reported for the as-treated population, defined as all randomized patients who reeived at least one dose of study mediation, aording to treatment reeived. Statistial analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA). Categorial variales were reported as frequeny (perentage) of patients, and ontinuous variales as arithmeti mean± standard deviation (SD), for eah treatment group. Endpoint data were generated using the last oservation arried forward method, and P values were derived from omparisons to aseline using paired t-tests. RESULTS Patient disposition and demographis Thirty Korean patients were randomized to reeive exenatide twie daily (n=15) or insulin lispro (n=15). In the per-protool population, 1 Korean patients reeived exenatide twie 7 Diaetes Meta J 217;41:

3 Exenatide versus insulin lispro in Korean patients Tale 1. Demographis and aseline harateristis of Korean patients randomized to treatment with exenatide twie daily or insulin lispro added to titrated insulin glargine and metformin who ompleted the study (per-protool population) Parameter Sex Exenatide twie daily (n=1) Insulin lispro (n=13) Female 6 (6.) 7 (53.8) Male 4 (4.) 6 (46.2) Age, yr 48.2± ±9.2 Weight, kg 75.8± ±16.9 BMI, kg/m ± ±4.4 HA1, % 8.2±1. 8.2±.6 Fasting gluose, mmol/l 5.7±2. 5.3±1.4 Duration of diaetes at sreening, yr 11.1± ±5.8 Values are presented as numer (%) or mean±standard deviation. BMI, ody mass index; HA1, glyosylated hemogloin. daily and 13 reeived three times daily mealtime insulin lispro. Numerially, aseline harateristis were well alaned etween the two treatment groups; however, statistial omparisons were not onduted (Tale 1). Reasons for disontinuation with exenatide twie daily were AE (n=1), protool violation (n=3), and sponsor deision (n=1). Two patients reeiving insulin lispro disontinued due to patient deision. Effiay Signifiant (P<.5) redutions from aseline in HA1 were oserved for oth groups from week 2 onwards (Fig. 1A); at endpoint, the mean±sd hange from aseline was 1.5%± 1.2% with exenatide twie daily (P=.4) and 1.%±1.% with insulin lispro (P=.2). HA1 goals of 7.% and 6.5% were ahieved y 6% and 5% of exenatide twie daily-treated patients, respetively, and y 46% and 23% of insulin lispro-treated patients, respetively. Insulin glargine dose was redued from aseline throughout the study in oth treatment groups ut was onsistently higher in the exenatide twie daily group (Fig. 1B). Mean±SD daily insulin glargine doses were 42.3±1.1 units/day with exenatide twie daily and 42.±19. units/day with insulin lispro at aseline, and 39.2±13.9 units/ day with exenatide twie daily and 35.5±16.1 units/day with insulin lispro at endpoint. Compared with aseline, FG numerially dereased with exenatide twie daily and numerially inreased with insulin lispro, with signifiant inreases at weeks 6 and 18 (Fig. 1C). The mean±sd hange in FG from aseline was.7±1.6 mmol/l with exenatide twie daily (P=.23) and.9±1.9 mmol/l with insulin lispro (P=.11). PPG tended to derease from aseline in oth treatment groups (Fig. 1D). Relative to aseline, weight numerially dereased in exenatide twie daily-treated patients, with signifiant redutions at weeks 6 and 8 (P<.5) (Fig. 1E). At endpoint, there was a.7±3.3 kg hange in weight from aseline with exenatide twie daily (P=.5) and a 1.±2.7 kg hange in weight with insulin lispro (P=.21). Safety and toleraility The most ommon AEs were gastrointestinal. In the exenatide twie daily and insulin lispro groups, this inluded nausea (five patients [33%] and, respetively), onstipation ( and two [13%]), and vomiting (two [13%] and ). Serious AEs were reported y one patient in eah group (exenatide twie daily: fall and lower-lim frature leading to study disontinuation; insulin lispro: aute pyelonephritis and nephrolithiasis). The investigators judged oth serious AEs as not related to study mediation. No major hypoglyemia events ourred in either group. Four patients reeiving exenatide twie daily and three patients reeiving insulin lispro experiened minor hypoglyemia events (12 events vs. eight events, respetively). More noturnal than daytime hypoglyemia events ourred with exenatide twie daily (four patients vs. two patients [1 events vs. two events]) and more daytime than noturnal hypoglyemia ourred with insulin lispro (three patients vs. one patient [seven events vs. one event]). DISCUSSION In this analysis of the supopulation of Korean patients partiipating in the 4B study, we found that exenatide twie daily administered efore the two largest meals and prandial insulin lispro oth effetively redued HA1 in patients with poor glyemi ontrol despite titrated asal insulin. FG and weight oth numerially dereased in patients treated with exenatide twie daily and numerially inreased in patients reeiving insulin lispro. Minor daytime and minor noturnal hypoglyemi events ourred most frequently in the insulin lispro and exenatide twie daily groups, respetively. Gastrointestinal AEs were most frequently reported: nausea and vomiting were most ommon with exenatide twie daily, and onstipation o- Diaetes Meta J 217;41:

4 Yoon KH, et al. Change in HA1 (%) a Exenatide BID Insulin lispro Daily insulin dose (units/day) Total insulin (insulin lispro group) Insulin glargine (exenatide BID group) Insulin glargine (insulin lispro group) 2.5 A B Change in fasting gluose (mmol/l) Change in weight (kg) a Exenatide BID Insulin lispro C Exenatide BID Insulin lispro a a E Blood gluose (mmol/l) Pre-reakfast Post-reakfast Exenatide BID-Baseline Exenatide BID-Week 3 Insulin lispro-baseline Insulin lispro-week 3 Pre-lunh Post-lunh Pre-dinner Post-dinner Bedtime Fig. 1. Primary and seondary outomes over 3 weeks for the per-protool population: (A) hange in glyosylated hemogloin (HA1) values (primary outome measure); (B) insulin glargine dose in the exenatide twie daily (BID) treatment group (open squares) and the insulin lispro treatment group (losed triangles), and total insulin dose in the insulin lispro group (losed irles); (C) hange in fasting gluose; (D) selfmonitored lood gluose values at randomization (gray lines) and 3 weeks (lak lines); and (E) hange in weight. Values are presented as mean±standard error. a P<.5, P.1, P<.1. D urred most often with insulin lispro. Colletively, hanges in indies of glyemi ontrol in the Korean supopulation were onsistent with the findings of the overall 4B study, whih predominantly enrolled white patients (88%) [12]. The primary study reported a redution in HA1 of 1.13% with exenatide twie daily and 1.1% with insulin lispro. Despite similar redutions in HA1, there was a signifiant etween group differene regarding the hange in FG (.5 mmol/l for exenatide twie daily vs..2 mmol/l for insulin lispro). Similarly, among Korean patients, HA1 and FG dereased with exenatide twie daily, HA1 dereased with insulin lispro, and FG inreased with insulin lispro. Additionally, among the primary study population, treatment with exenatide twie daily resulted in weight loss ( 2.5 kg), whereas 72 Diaetes Meta J 217;41:

5 Exenatide versus insulin lispro in Korean patients treatment with insulin lispro resulted in weight gain (2.1 kg) [12]. Likewise, patients in the Korean sugroup reeiving exenatide twie daily lost weight and patients reeiving insulin lispro gained weight. For the Korean sugroup, this small derease in weight ould e important over time, espeially as the prevalene of severe oesity has inreased among Korean patients with diaetes [4]. In the primary study, noturnal hypoglyemia ourred at a similar frequeny among exenatide twie daily- and insulin lispro-treated patients [12]. Noturnal hypoglyemia was likely attriutale to insulin glargine, as oth exenatide twie daily and insulin lispro have short half-lives and are administered during the day, whereas insulin glargine is administered at edtime [12]. In the Korean supopulation randomized to exenatide twie daily, the derease in FG, relatively small insulin glargine dose redution at randomization, relatively high insulin glargine dose at endpoint, and the relatively high frequeny of noturnal hypoglyemia olletively suggest that physiians may have aggressively titrated insulin glargine when given with exenatide twie daily. The findings of the urrent study are also onsistent with the effets of other studies of GLP-1RAs. A study of exenatide twie daily added to insulin glargine versus insulin glargine alone also found add-on exenatide twie daily to improve HA1 and ody weight without any additional risk for hypoglyemia [11]. In an additional systemati review examining the omined use of insulin with the GLP-1RAs exenatide twie daily, liraglutide (one daily), or lixisenatide (one daily) aross 19 studies, the omination onsistently resulted in an improvement in HA1 and ody weight [13]. Gastrointestinal AEs, partiularly nausea, were the most ommon AEs ut were generally mild and temporary. Furthermore, the authors noted that the onveniene of adding a GLP-1RA, whih does not require arohydrate ounting or adjustments for meal size, may lead to improved ompliane and patient satisfation. Other studies of exenatide twie daily treatment in Asian patients have also demonstrated improved glyemi ontrol, without an inreased risk for hypoglyemia. In a study of 52 Korean patients, exenatide twie daily treatment was used in patients who were treatment-naïve (group 1), on additional oral gluose-lowering mediation (group 2), who were sustituting exenatide twie daily for one of their urrent oral mediations (group 3), or adding exenatide twie daily and oral mediations to their regimen (group 4) [14]. Over 6 months, all groups reported a signifiant derease in HA1. Body weight was signifiantly redued after 3 months for all groups and after 6 months for all groups exept group 4. Nausea was the most ommon AE and there were no reports of hypoglyemia. In an additional single-arm study of exenatide twie daily, HA1 and ody weight were oth signifiantly redued among 73 Korean patients with T2DM reeiving exenatide twie daily treatment for 22 weeks [15]. The patients did not report any major hypoglyemi events. Plaeo-ontrolled studies onduted in Japanese and Taiwanese populations have also found exenatide twie daily to redue HA1 with the additional enefit of weight loss among patients who had inadequate glyemi ontrol with oral gluose-lowering therapy [16,17]. These redutions in HA1 and weight oserved with exenatide twie daily were maintained in the long term (52 weeks) in Japanese patients partiipating in an open-lael extension study [18]. Additionally, the findings of a retrospetive analysis of pooled data from the exenatide linial development program support exenatide twie daily as an appropriate injetale treatment option in Asian patients, providing redutions in HA1, FG, and PPG, as well as weight loss and low risk of hypoglyemia [19]. Of note, these studies did not utilize asal insulin with exenatide twie daily. As suh, this sugroup analysis adds important insight into a new approah to exenatide twie daily therapy among Asian patients. Limitations of the urrent analysis are the small sample size and the retrospetive nature of the analysis. Therefore, the findings of this study should e onsidered in onjuntion with the results from the overall 4B study population. In onlusion, in this sugroup analysis of Korean patients with T2DM, exenatide twie daily or three times daily mealtime insulin lispro added to insulin glargine eah redued HA1. FG and weight tended to derease with exenatide twie daily and inrease with insulin lispro. Four patients reeiving exenatide twie daily experiened minor hypoglyemia, and nausea and vomiting were the most ommon gastrointestinal AEs. These results suggest exenatide twie daily may e appropriate for Korean patients unale to ahieve glyemi ontrol with asal insulin plus metformin. CONFLICTS OF INTEREST K.H.Y has served on advisory oards for AstraZenea, Eli Lilly, Merk, and Pfizer; has reeived researh support from Astra- Zenea, Bayer, Merk, and Takeda; and has reeived speaker Diaetes Meta J 217;41:

6 Yoon KH, et al. fees from Boehringer Ingelheim, Eli Lilly, Merk, Novartis, Novo Nordisk, and Takeda. E.H. is an employee and stokholder of AstraZenea. J.H. is an employee of Pharmapae, In. and was an employee of Bristol-Myers Squi at the time of data olletion. ACKNOWLEDGMENTS The analysis was supported y AstraZenea. Mollie Marko, PhD, of insiene Communiations, Springer Healthare (New York, NY, USA), provided medial writing support, whih was funded y AstraZenea. REFERENCES 1. Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH, Hu FB. Diaetes in Asia: epidemiology, risk fators, and pathophysiology. JAMA 29;31: Kim DJ. The epidemiology of diaetes in Korea. Diaetes Meta J 211;35: WHO Expert Consultation. Appropriate ody-mass index for Asian populations and its impliations for poliy and intervention strategies. Lanet 24;363: Kim CS, Ko SH, Kwon HS, Kim NH, Kim JH, Lim S, Choi SH, Song KH, Won JC, Kim DJ, Cha BY; Taskfore Team of Diaetes Fat Sheet of the Korean Diaetes Assoiation. Prevalene, awareness, and management of oesity in Korea: data from the Korea National Health and Nutrition Examination Survey ( ). Diaetes Meta J 214;38: Son JW, Park CY, Kim S, Lee HK, Lee YS; Insulin Resistane as Primary Pathogenesis in Newly Diagnosed, Drug Naïve Type 2 Diaetes Patients in Korea (SURPRISE) Study Group. Changing linial harateristis aording to insulin resistane and insulin seretion in newly diagnosed type 2 diaeti patients in Korea. Diaetes Meta J 215;39: Shimizu H, Uehara Y, Okada S, Mori M. Contriution of fasting and postprandial hyperglyemia to hemogloin A1 in insulintreated Japanese diaeti patients. Endor J 28;55: Venn BS, Williams SM, Mann JI. Comparison of postprandial glyaemia in Asians and Cauasians. Diaet Med 21;27: Inzuhi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauk M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglyemia in type 2 diaetes, 215: a patient-entered approah: update to a position statement of the Amerian Diaetes Assoiation and the European Assoiation for the Study of Diaetes. Diaetes Care 215;38: Nielsen LL, Young AA, Parkes DG. Pharmaology of exenatide (syntheti exendin-4): a potential therapeuti for improved glyemi ontrol of type 2 diaetes. Regul Pept 24;117: Meier JJ. GLP-1 reeptor agonists for individualized treatment of type 2 diaetes mellitus. Nat Rev Endorinol 212;8: Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, Hoogwerf BJ, Rosenstok J. Use of twie-daily exenatide in asal insulin-treated patients with type 2 diaetes: a randomized, ontrolled trial. Ann Intern Med 211;154: Diamant M, Nauk MA, Shaginian R, Malone JK, Cleall S, Reaney M, de Vries D, Hoogwerf BJ, MaConell L, Wolffenuttel BH; 4B Study Group. Gluagon-like peptide 1 reeptor agonist or olus insulin with optimized asal insulin in type 2 diaetes. Diaetes Care 214;37: Balena R, Hensley IE, Miller S, Barnett AH. Comination therapy with GLP-1 reeptor agonists and asal insulin: a systemati review of the literature. Diaetes Oes Meta 213;15: Shin J, Chang JS, Kim HS, Ko SH, Cha BY, Son HY, Yoon KH, Cho JH. Effets of a 6-month exenatide therapy on HA1 and weight in Korean patients with type 2 diaetes: a retrospetive ohort study. Diaetes Meta J 212;36: Song SO, Kim KJ, Lee BW, Kang ES, Cha BS, Lee HC. Toleraility, effetiveness and preditive parameters for the therapeuti usefulness of exenatide in oese, Korean patients with type 2 diaetes. J Diaetes Investig 214;5: Lu CH, Wu TJ, Shih KC, Ni E, Reed V, Yu M, Sheu WH, Chuang LM. Safety and effiay of twie-daily exenatide in Taiwanese patients with inadequately ontrolled type 2 diaetes mellitus. J Formos Med Asso 213;112: Kadowaki T, Nama M, Imaoka T, Yamamura A, Goto W, Boardman MK, Sowa H. Improved glyemi ontrol and redued odyweight with exenatide: a doule-lind, randomized, phase 3 study in Japanese patients with suoptimally ontrolled type 2 diaetes over 24 weeks. J Diaetes Investig 211; 2: Inagaki N, Ueki K, Yamamura A, Saito H, Imaoka T. Longterm safety and effiay of exenatide twie daily in Japanese patients with suoptimally ontrolled type 2 diaetes. J Diaetes Investig 211;2: Sheu WH, Brunell SC, Blase E. Effiay and toleraility of exenatide twie daily and exenatide one weekly in Asian versus White patients with type 2 diaetes mellitus: a pooled analysis. Diaetes Res Clin Prat 216;114: Diaetes Meta J 217;41: