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Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE

Efficacy and Safety of Once Weekly Versus , , and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 (DURATION-4) A 26-week double-blind study

1 6 DAVID RUSSELL-JONES, MD MELANIE CHAN, PHD he 2009 consensus algorithm from 2 6 ROBERT M. CUDDIHY, MD ANNE M. WOLKA, PHD 3 6 the American Diabetes Association MARKOLF HANEFELD, MD MARILYN K. BOARDMAN, PHARMD T 4 (ADA)/European Association for the AJAY KUMAR, MD ON BEHALF OF THE DURATION-4 STUDY 5 Study of Diabetes (EASD) recommends JOSE G. GONZÁLEZ, MD GROUP* lifestyle changes and metformin (MET) as the initial (tier one, well-validated) treat- ment at diagnosis of (1). OBJECTIVEdTo test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally Common adjunctive treatments not associ- treated (diet and exercise) drug-naive patients with type 2 diabetes. ated with an increased risk of when used as monotherapy include the RESEARCH DESIGN AND METHODSdPatients were randomized to subcutaneous , pioglitazone (PIO), the (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n =246),PIO45 dipeptidyl peptidase-4 inhibitor, sitagliptin mg/day + SC placebo (n =163),orSITA100mg/day+SCplacebo(n =163)for26weeks. (SITA), and the -like peptide-1 re- MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW ceptor agonist exenatide twice daily (BID) or placebo were administered weekly, while oral medication or placebo was administered – daily. (2 5). PIO and exenatide BID are included in the second tier (less well-validated) of RESULTSdBaseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 preferred agents in the ADA/EASD algo- years, HbA1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes du- rithm. SITA is not indentified, but may be ration 2.7 years. HbA1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, 2 2 2 2 , an appropriate choice for selected patients PIO, and SITA were 1.53 vs. 1.48 (P =0.620), 1.63 (P = 0.328), and 1.15 (P 0.001), (1). These agents, commonly used only respectively. Weight changes (kg) were 22.0 vs. 22.0 (P = 0.892), +1.5 (P , 0.001), and 20.8 , in MET-intolerant patients as monother- (P 0.001), respectively. Common adverse events were as follows: EQW, (11.3%) and fi diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) apy, have unique risks, bene ts, and mech- and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (con- anisms. firmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. Effective and safe monotherapy treat- ment options for patients unable to toler- d CONCLUSIONS EQW was noninferior to MET but not PIO and superior to SITA with ate MET are limited. In the United States, regard to HbA1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar exenatide BID is indicated as an adjunct improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia. to diet and exercise to improve glycemic control in adults with type 2 diabetes. A new formulation of exenatide (exenatide once weekly [EQW]) has been shown to result in greater improvements in glyce- mic control, with no increased risk of ccccccccccccccccccccccccccccccccccccccccccccccccc hypoglycemia and similar weight reduc- tion compared with exenatide BID (6,7). From the 1Department of Diabetes and Endocrinology, Royal Surrey County Hospital, University of Surrey, Guildford, U.K.; the 2International Diabetes Center, Park Nicollet Clinic, Minneapolis, Minnesota; the This randomized trial (Diabetes Therapy 3Center for Clinical Studies, Technical University Dresden, Dresden, Germany; the 4Diabetes Care and Utilization: Researching Changes in A1C, Research Center, Patna, India; the 5Department of Endocrinology, University Hospital, Monterrey, Mexico; Weight and Other Factors Through In- 6 and the Eli Lilly and Company, Indianapolis, Indiana. tervention with Exenatide Once-Weekly Corresponding author: Marilyn Boardman, [email protected]. Received 13 June 2011 and accepted 9 November 2011. [DURATION-4]) directly compared the DOI: 10.2337/dc11-1107. reg. no. NCT00676338, clinicaltrials.gov. safety and efficacy of EQW monotherapy This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 versus MET, PIO, and SITA monotherapy .2337/dc11-1107/-/DC1. in patients with type 2 diabetes who were *A complete list of study group participants can be found in the Supplementary Data. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly suboptimally treated with diet and exer- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ cise but naive to antihyperglycemic licenses/by-nc-nd/3.0/ for details. drugs. care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online December 30, 2011 Exenatide once-weekly monotherapy

RESEARCH DESIGN AND Patients All scheduled postbaseline measurements METHODS A total of 820 patients in 22 countries were included, with no imputation of participated between November 2008 and missing data. Least-squares (LS) estimates Outcomes June 2010. Adults with type 2 diabetes met and CIs of the treatment differences be- The aim of this study was to assess the the following inclusion criteria: HbA1c tween EQW and the three oral comparators efficacy of EQW compared with MET, PIO, 7.1–11.0%, BMI 23–45 kg/m2, and history were presented. The differences were based and SITA, as measured by change in HbA1c of stable weight. Patients were excluded if ontheestimateat26weeksofEQWminus after 26 weeks. Secondary and exploratory treated with any antihyperglycemic drug the estimate for each comparator at 26 measures included the proportion of pa- for .7 days within 3 months of screening. weeks. SEs were also presented. Secondary tients achieving HbA1c ,7.0 and #6.5%, Antihypertensive and lipid-lowering medi- end points were tested using similar MMRM changes in fasting serum glucose, seven- cation changes were only made if medically analyses. Analyses of patient-reported out- point self-monitoring of blood glucose required. comes were performed without adjustment (SMBG), weight, serum lipids, homeostasis for multiple statistical testing. model assessment of pancreatic b-cell Study design The original primary analysis excluded function (HOMA-B) and sensitivity Randomization was determined by unscheduled postbaseline observations (HOMA-S), and safety and tolerability. computer-generated random sequence for unexpected early discontinuations; Patient-reported outcomes were collected, using an interactive voice response system. therefore, a modified analysis was com- including Impact of Weight on Quality of Treatment assignments were stratified by pleted, including all postbaseline observa- Life Questionnaire-Lite (IWQOL-Lite), country. MET and PIO dosages were in- tions. This modified MMRM analysis was Binge Eating Scale (BES), the Diabetes Treat- creased in weekly increments up to target performed after database lock when it was ment Satisfaction Questionnaire (DTSQ), doses of 2,000 and 45 mg/day, respec- determined that the original analysis ex- and EuroQol-5 dimensions (EQ-5D). tively. MET could be increased up to cluded patients who discontinued before Safety end points were adverse events, 2,500 mg/day based on glycemic control. week 8. All statistical analyses were per- clinical laboratory assessments, vital signs, Standard diet and exercise counseling was formed using SAS Version 9.1 (SAS In- hypoglycemia, and antibodies to exenatide. provided in each treatment group. Fol- stitute, Cary, NC). Treatment-emergent adverse events were lowing 26 weeks, patients stopped study defined as those occurring or worsening treatment and were allowed to follow RESULTS after the first dose of study drug. Minor diabetes regimens deemed appropriate hypoglycemia was defined as signs or by the investigator, with the exception of Patients symptoms associated with blood glucose exenatide BID. Patients returned to the Of 820 intent-to-treat patients, 696 ,3.0 mmol/L (either self-treated or re- study sites 10 weeks after study end for (84.9%) completed the 26-week treat- solved independently). Major hypoglyce- collection of additional safety data. ment period and 736 (89.8%) returned for mia was classified as symptoms resulting 10-week safety follow-up (Fig. 1). Patient in loss of consciousness or seizure that Statistical analysis characteristics at baseline were similar showed prompt recovery after administra- Data were reported for randomized pa- among the treatment groups (Supplemen- tion of glucose, or documented blood glu- tients who received at least one dose of the tary Table 1). By week 12, 87% of patients cose ,3.0 mmol/L that required the study drug (intent-to-treat population). taking MET and 75% taking PIO had been assistance of another person because of To control family-wise error within 0.05, titrated to or above target doses for each severe impairment in consciousness or be- the Bonferroni-Hommel gate-keeping agent (PIO 45 mg/day, MET 2,000 mg/day, havior. A subset, defined as symptoms of procedure was used to test hypotheses. respectively). At week 16–26, patients were hypoglycemia, was not confirmed by Three noninferiority hypotheses (EQW is on stable doses: PIO ($45 mg/day) 88% blood glucose measurement. inferior to MET, PIO, and SITA) were and MET ($2,000 mg/day) 76%. tested first using the Bonferroni test (non- Sample size determination inferiority margin 0.3%, Bonferroni- Glycemic control and weight fi fi The protocol speci ed that 822 patients adjusted signi cance of 0.0167). If Mean baseline HbA1c values ranged from be enrolled, with at least 740 patients any null hypothesis was rejected (i.e., 8.4 to 8.6% across treatment groups. fi (10% dropout before rst HbA1c collec- noninferiority was established), the corre- Figure 2A presents the time course of fi tion) available for primary analysis. A sponding superiority hypothesis was tested HbA1c change from modi ed MMRM sample of 740 patients (222 EQW and using the Hommel test (8) and decision ma- analysis (intent-to-treat sample; all post- MET, 148 PIO and SITA) would provide trix algorithm (9). The nominal significance baseline observations included). This ;90% power to detect true differences in level based on Hommel adjustment was be- modified analysis demonstrated LS mean HbA1c change of 0.4% (EQW vs. MET), tween 0.0167 and 0.05 depending on the (SE) reductions in HbA1c at 26 weeks of 0.5% (EQW vs. PIO), and 0.5% (EQW vs. noninferiority hypotheses rejected. 21.53% (0.07%) with EQW; 21.48% SITA), respectively (two-sided t test sig- The primary end point was tested (0.07%) with MET (P = 0.620 vs. EQW; nificance of 0.05 and common SD of using a maximum likelihood-based 98.3% CI was 20.26 to 0.17); 21.63% 1.2%) (6). A predefined noninferiority mixed-model repeated-measures (MMRM) (0.08%) with PIO (P = 0.328 vs. EQW; 2 margin of 0.3% and sample size of 444 ANCOVA with change in HbA1c as the de- 98.3% CI was 0.15 to 0.35); and patients would provide 74% power to pendent variable; treatment, baseline 21.15% (0.08%) with SITA (P , 0.001 test the noninferiority of EQW versus HbA1c, country, week of visit, and treat- vs. EQW; 98.3% CI was 20.62 to 20.13). MET, and a sample size of 370 would pro- ment by week interaction as fixed effects; TheLSmean(SE)HbA1c at end point vide 65% power to test the noninferiority patient and error as random effects; and an was 6.94 (0.07), 6.99 (0.07), 6.84 (0.08), of EQW versus PIO (and SITA). unstructured variance/covariance matrix. and 7.32 (0.08) for EQW, MET, PIO, and

2 DIABETES CARE care.diabetesjournals.org Russell-Jones and Associates

Figure 1dDisposition of all randomized patients. Data are presented as n or n (%) of patients.

SITA, respectively. The original primary fasting serum glucose at 16 and 26 weeks significantly different between EQW ver- analysis, which excluded post-baseline ob- were significantly greater in patients treated sus PIO and SITA starting at 4 and 8 weeks, servations from patients who discontinued with EQW versus SITA (both P , 0.001). respectively, and continued through 26 before week 8, showed LS mean (SE) reduc- LS mean (SE) reductions in fasting serum weeks (all P # 0.003). At 26 weeks, LS 2 tions in HbA1c of 21.56% (0.07%) with glucose at 26 weeks were 2.3 mmol/L mean (SE) body weight changes were EQW; 21.52% (0.06%) with MET (P = (0.1 mmol/L) in patients treated with 22.0 kg (0.2 kg) with EQW; 22.0 kg (0.2 0.609 vs. EQW; 98.3% CI was 20.26 to EQW; 22.0 mmol/L (0.1 mmol/L) with kg) with MET (P = 0.892 vs. EQW); +1.5 kg 0.17); 21.73% (0.08%) with PIO (P = MET (P =0.155vs.EQW);22.6 mmol/L (0.3 kg) with PIO (P , 0.001 vs. EQW); and 0.107 vs. EQW; 98.3% CI was 20.08 to (0.2 mmol/L) with PIO (P =0.153vs. 20.8 kg (0.3 kg) with SITA (P , 0.001 vs. 0.41); and 21.17% (0.08%) with SITA EQW); and 21.1 mmol/L (0.2 mmol/L) EQW). The percentage of patients with re- , (P , 0.001 vs. EQW; 98.3% CI was with SITA (P 0.001 vs. EQW). ductions in both body weight and HbA1c 20.63 to 20.16). Findings from original Mean seven-point SMBG profiles was similar for EQW and MET; percentages and modified primary analyses were consis- showed similar reductions in blood glu- were comparably lower with PIO and SITA tent and demonstrated that EQW was non- cose from baseline to 26 weeks in EQW, (Supplementary Figs. 2A–D). inferior to MET and SITA, but did not reach MET, and PIO treatment groups (Supple- the noninferiority measure with PIO. Sub- mentary Figs. 1A–C). There were no sig- Pancreatic b-cell function and sequent hypothesis testing concluded that nificant differences between EQW versus insulin sensitivity EQW was superior to SITA, but not to MET. MET or PIO treatment groups with regard b-Cell function, as measured by geomet- Similar percentages of EQW-, MET-, to changes from baseline for any of the ric mean HOMA-B (C-peptide), at base- and PIO-treated patients reached a target seven time points or for daily mean line ranged from 51.0 to 54.4%. Mean HbA1c ,7.0% (Fig. 2B). Significantly SMBG; however, EQW was associated (SE) HOMA-B (ratio of end point [last ob- more patients treated with EQW versus with greater mean reductions at all time servation carried forward] to baseline) fi , SITA (P , 0.001) achieved HbA1c points compared with SITA. Mean reduc- was signi cantly (all P 0.001) im- ,7.0% after 26 weeks. Moreover, signif- tions in SMBG postmeal excursions after proved in patients treated with EQW icantly more patients treated with EQW 26 weeks were similar among all treat- [+1.8 (0.06)] compared with MET [+1.4 achieved HbA1c #6.5% after 26 weeks, ment groups. (0.04)], PIO [+1.3 (0.05)], and SITA [+1.3 versus MET- and SITA-treated patients LS mean baseline weight values (0.04)]. Insulin sensitivity, as measured by (P = 0.004 and P , 0.001, respectively). ranged from 85.9 to 88.6 kg. Weight geometric mean HOMA-S (C-peptide), at LS mean baseline fasting serum glucose decreased with EQW, MET, and SITA baseline ranged from 36.4 to 39.5%. Mean values ranged from 9.7 to 9.9 mmol/L treatment, but increased with PIO treat- (SE) HOMA-S (ratio of end point [last ob- across treatment groups. Reductions in ment (Fig. 2C). Weight changes were servation carried forward] to baseline) was care.diabetesjournals.org DIABETES CARE 3 Exenatide once-weekly monotherapy

during the treatment period. No serious adverse event was reported by more than one patient. One death, due to gastric ad- enocarcinoma, was reported during the 10-week follow-up in a patient receiving MET and was not considered by the in- vestigator to be related to the study drug. One MET-treated patient experienced an adverse event of injection site nodule, con- sidered serious for other medically sig- nificant reasons (i.e., psychological). The event was of mild severity and resolved without treatment. Treatment-emergent adverse events re- ported by $5% of patients in any group during the treatment period are shown in Table 1. All patients received injection, ei- ther with active EQW or placebo micro- sphere injection. Injection site nodules were more commonly reported with active EQW and placebo injection administered intheMETarmcomparedwithplaceboin- jection administered in the PIO and SITA arms. Nausea, the most common treat- ment-emergent adverse event with EQW, occurred in 11.3% of patients in this group. One EQW-treated patient withdrew be- cause of nausea. Vomiting was reported in ,5% of patients in all treatment groups, with incidences of 4.8% (12/248), 3.3% (8/246), 3.1% (5/163), and 1.8% (3/163) in EQW-, MET-, PIO-, and SITA-treated patients, respectively. Most treatment- emergent adverse events had resolved by the end of the 10-week follow-up period (Supplementary Table 2). No patient had a major hypoglycemic episode during the treatment period of the study. The incidence of hypoglycemia unconfirmed by glucose measurement was low in all treatment groups: 5.2% (13/248), 4.1% (10/246), 3.7% (6/163), and 3.1% (5/163) of EQW-, MET-, PIO-, and SITA-treated patients, respectively. Minor (confirmed) hypoglycemia was lim- ited to a small group of EQW-treated pa- tients (5/248, 2.0%). Figure 2dA: Changes in HbA1c over 26 weeks. *Significant difference between MET and No clinically significant changes in EQW (all P # 0.002). †Significant difference between PIO and EQW (all P # 0.003). fasting serum lipids were observed during ‡Significant difference between SITA and EQW (all P , 0.001). B: Percentages of patients the treatment period. LS mean (SE) sys- achieving HbA1c ,7.0%, and #6.5% at end point (last observation carried forward). tolic blood pressure reductions of 21.3 *Significant difference between MET and EQW (P = 0.004). ‡Significant difference between mmHg (0.8 mmHg), 21.7 mmHg (1.0 SITA and EQW (all P , 0.001). C: Changes in weight over 26 weeks. †Significant difference 2 # ‡ fi mmHg), and 1.8 mmHg (1.0 mmHg) between PIO and EQW (all P 0.003). Signi cant difference between SITA and EQW (all were observed with EQW, PIO, and P # 0.002). SITA treatment, respectively. Additionally, a reduction in diastolic blood pressure of 22.5 mmHg (0.6 mmHg) was observed significantly (both P , 0.001) improved in Safety and tolerability with PIO treatment. Mean (SD) heart rate patients treated with MET [+1.3 (0.04)] and Serious adverse events were reported in (bpm) increases were observed in the EQW PIO [+1.5 (0.06)] compared with EQW 1.6% (4/248), 5.3% (13/246), 5.5% (9/163), [+1.5 (10.0)], MET [+0.3 (9.5)], and SITA [+1.0 (0.03)]; change with EQW was sim- and 1.8% (3/163) of EQW-, MET-, PIO-, [+0.5 (9.7)] groups; mean heart rate de- ilar to SITA [+1.0 (0.04), P = 0.329]. and SITA-treated patients, respectively, creased in the PIO group [–1.7 (8.7)].

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Table 1dTreatment-emergent adverse events reported in ‡5% of patients in any are added in stepwise fashion with disease treatment group progression after MET failure (1). Find- ings from DURATION-4 demonstrate EQW MET PIO SITA that both EQW and PIO offer similar im- provements in glycemia as MET, with one n 248 246 163 163 key difference between these agents being Headache 20 (8.1) 30 (12.2) 13 (8.0) 15 (9.2) the effect on body weight. Thus, health Diarrhea 27 (10.9) 31 (12.6) 6 (3.7) 9 (5.5) care practitioners have more treatment Injection site nodule 26 (10.5) 25 (10.2) 6 (3.7) 11 (6.7) choices for drug-naive patients. Nasopharyngitis 19 (7.7) 11 (4.5) 14 (8.6) 16 (9.8) Clinicians are advised to consider mul- Nausea 28 (11.3) 17 (6.9) 7 (4.3) 6 (3.7) tiple factors when treating patients with Dyspepsia 18 (7.3) 8 (3.3) 8 (4.9) 3 (1.8) type 2 diabetes. Similar to previous studies Constipation 21 (8.5) 8 (3.3) 3 (1.8) 4 (2.5) evaluating PIO as monotherapy (3,13), Back pain 6 (2.4) 14 (5.7) 7 (4.3) 5 (3.1) patients treated with PIO in the current Arthralgia 13 (5.2) 3 (1.2) 5 (3.1) 3 (1.8) study gained weight. EQW and MET led Hypertension 3 (1.2) 3 (1.2) 12 (7.4) 3 (1.8) to similar significant reductions in body Peripheral edema 0 (0) 1 (0.4) 12 (7.4) 1 (0.6) weight after 26 weeks, whereas SITA led Data are n (%) of intent-to-treat population. to a lesser reduction. Although variability based on study design and patient charac- teristics was expected, weight reduction No clinically significant changes in treatment decisions for type 2 diabetes observed in this study with EQW was on mean amylase, lipase, or calcitonin were (1), a disease for which there are numerous the lower end of the range (22.0 to 23.7 observed during the treatment period. One treatment options. This study evaluated the kg)observedinpreviousDURATION SITA-treated patient with elevated lipase at efficacy and safety of EQW monotherapy, studies (6,7,10,17). Conversely, reduc- screening experienced moderate chronic in comparison with MET, PIO, and SITA tionsobservedwithSITAandMETin after 8 days of treatment and monotherapy, in drug-naive patients with the current study tended to be greater discontinued from study treatment. type 2 diabetes. Treatment with EQW, than results from meta-analyses and recent Lower-titer (,1/125) and higher-titer MET, and PIO all resulted in improve- monotherapy trials of similar duration ($1/625) antibodies to exenatide at end ments in glycemic control, achieving (5,18–20). The potential for improve- point were observed in 43.1% (107/248) mean HbA1c concentrations at 26 weeks ments in HbA1c and body weight in stud- and 11.3% (28/248) of EQW-treated of ,7%. EQW demonstrated superiority ies with placebo injection therapy has patients, respectively. Mean HbA1c was to SITA and noninferiority to MET but been noted in a previous study of exenatide reduced irrespective of antibody status: not to PIO with regard to HbA1c reduction therapy (21). These data show that EQW negative (21.33%), positive lower at 26 weeks. The lack of noninferiority of and MET provided the best profile in (21.51%), and positive higher (21.02%) EQW monotherapy compared with PIO terms of improving glycemic control as (Supplementary Table 3). Events with monotherapy was unexpected based on well as reducing weight, without increased higher incidence in antibody-positive pa- DURATION-2 study results, where EQW risk of hypoglycemia, particularly impor- tients included injection site–related was superior to PIO on a background of tant for treatment of overweight or obese events (i.e., injection site erythema, injec- MET (10), and the fact that the HbA1c re- patients with type 2 diabetes. tion site extravasation, injection site hema- duction with PIO was greater than that re- The findings with respect to safety toma, injection site nodule, injection site ported in other PIO studies with a similar and tolerability were consistent with pre- pruritus, and injection site reaction). In- baseline HbA1c (2,3,11–14). Several dispa- vious studies, including the observance of jection site nodules are expected with mi- rate factors could have contributed to the gastrointestinal adverse events in patients crosphere injection and were not reported incongruent outcomes, including differen- treated with EQW and MET, and hyper- as an adverse event unless accompanied ces in background therapy and mean dura- tension and peripheral edema with PIO by symptoms such as pain, erythema, or tion of type 2 diabetes. (3,5,6,10,17,20,22–24). Most notably, pruritus. SITA treatment led to comparatively the safety profile of EQW in the current Patients in all treatment groups had lesser glycemic improvement than the other trial was consistent with previous DURA- mean improvements from baseline in agents, which supports the contention that TION studies (6,10,17), with low rates of perceived treatment satisfaction, weight- the increase in plasma glucagon-like peptide- confirmed minor hypoglycemia and few related quality of life, and binge-eating 1 associated with dipeptidyl peptidase-4 patients discontinuing treatment due to behavior (Supplementary Tables 4–9). All inhibition is not as effective as pharmaco- nausea (one patient) and vomiting (zero treatments with the exception of PIO logical concentrations achieved with re- patients). Less nausea and vomiting with were associated with significant mean im- ceptor agonism (15,16). The similar EQW have previously been reported in provements in health status. Significant effects obtained with EQW monotherapy head-to-head studies versus exenatide improvements in weight-related quality and MET monotherapy in terms of HbA1c BID. In general, hypoglycemia incidence of life, binge-eating behavior, and health and body weight reductions support the and incidence of serious adverse events status were reported for patients treated appropriateness of considering MET as were low across all treatment groups dur- with EQW compared with PIO. the first-line antihyperglycemic agent in ing the current study. The small percent- type 2 diabetes. For example, the ADA/ age (2%) of patients experiencing minor CONCLUSIONSdHead-to-head com- EASD recommends MET as a first-line hypoglycemia with EQW monotherapy parative studies are needed to better inform agent; other antihyperglycemic agents was similar to that observed with EQW care.diabetesjournals.org DIABETES CARE 5 Exenatide once-weekly monotherapy adjunct to MET in previous clinical trials Daiichi-Sankyo, Dexcom, Edwards Life- Association for the Study of Diabetes. (0–3%) (6,7,10,17). Most treatment- sciences, Eli Lilly, Hygeia, Intarcia, Johnson Diabetes Care 2009;32:193–203 emergent adverse events in this study & Johnson, Mannkind, Medtronic, Merck, 2. Schernthaner G, Matthews DR, Charbonnel Novo Nordisk, Quotient Diagnostics, Re- B, Hanefeld M, Brunetti P; Quartet [cor- had resolved by the end of the 10-week fi fi safety follow-up period, with few treatment- sMed, Roche, sano -aventis, Schering-Plough, rected] Study Group. Ef cacy and safety of Takeda, and Valeritas. R.M.C. was an advisory pioglitazone versus metformin in patients emergent adverse events starting during board member for Abbott, Bayer, CeQur, Eli with type 2 diabetes mellitus: a double- the safety follow-up. Lilly, Novo Nordisk, and Roche and has re- blind, randomized trial. J Clin Endocrinol There were several limitations to this ceived education grant support from Johnson Metab 2004;89:6068–6076 study. First, patients were enrolled based & Johnson, Eli Lilly, Merck, Novartis, sanofi- 3. Pavo I, Jermendy G, Varkonyi TT, et al. on specific criteria and were followed aventis, and Schering-Plough. All honoraria, Effect of pioglitazone compared with met- according to the study schedule, which speaking fees, consulting fees, and research and formin on glycemic control and indicators may not reflect real-world use. Second, no educational support were paid directly to the of insulin sensitivity in recently diagnosed specific compliance data were collected; nonprofit International Diabetes Center, of patients with type 2 diabetes. J Clin Endo- which R.M.C. was a salaried employee. In 2011, crinol Metab 2003;88:1637–1645 however, patient-reported outcomes in- fi dicated that both oral and injectable R.M.C. became an employee of sano -aventis. 4. Moretto TJ, Milton DR, Ridge TD, et al. M.H. is an advisory board member for sanofi- fi therapies were associated with increases Ef cacy and tolerability of exenatide mon- aventis and Novartis and has received hono- otherapy over 24 weeks in antidiabetic in treatment satisfaction and quality of life raria from Astra Zeneca, Bayer, Boehringer In- drug-naive patients with type 2 diabetes: in these previously drug-naive patients. gelheim, Eli Lilly, Merck Sharp & Dohme Idea, a randomized, double-blind, placebo- Additionally, 26 weeks is too short a Novartis, and sanofi-aventis. A.K. has received controlled, parallel-group study. Clin Ther study duration to evaluate long-term gly- education grant support from Boeringher In- 2008;30:1448–1460 cemic control, weight loss, and b-cell gelheim, Eli Lilly, Johnson & Johnson, Merck, 5. Aschner P, Katzeff HL, Guo H, et al. Efficacy preservation (25). For example, potential Novo Nordisk, Spherix, and Takeda. A.K. has and safety of monotherapy of sitagliptin received speaking fees, honoraria, or travel implications of the upward shift in HbA1c, compared with metformin in patients with observed in the EQW group between support from Intas Pharmaceuticals, Ltd., Novo type 2 diabetes. Diabetes Obes Metab 2010; – weeks 16 and 26 (Fig. 2A), cannot be as- Nordisk, Merck, and USV. M.C., A.M.W., and 12:252 261 M.K.B. are employees and/or shareholders of Eli sessed further without additional data 6. Drucker DJ, Buse JB, Taylor K, et al. Ex- Lilly. No other potential conflicts of interest enatide once weekly versus twice daily points. relevant to this article were reported. for the treatment of type 2 diabetes: In conclusion, in these patients with D.R.-J., R.M.C., M.H., A.K., and J.G.G. were a randomised, open-label, non-inferiority type 2 diabetes who were naive to anti- principal clinical investigators for this trial. M.C. study. Lancet 2008;372:1240–1250 hyperglycemic therapy, all four treatments was the lead statistician. A.M.W. was the project 7. Blevins T, Pullman J, Malloy J, et al. resulted in improvements in HbA1c, and a manager, performed literature searches, and DURATION-5: exenatide once weekly re- majority of EQW-, MET-, and PIO-treated drafted sections of the manuscript. M.K.B. was sulted in greater improvements in glycemic involved in the study design and protocol de- patients achieved a target HbA1c of control compared with exenatide twice ,7.0%. This study recognizes that guide- velopment. All coauthors contributed to the daily in patients with type 2 diabetes. J Clin – lines typically recommend MET as the first interpretation of data, critically revised the Endocrinol Metab 2011;96:1301 1310 manuscript for important intellectual content, agent used, because it is inexpensive and 8. Hommel G. A stagewise rejective multi- and approved the version to be published. ple test procedure based on a modified supported by long-term data. Of the Parts of this study were presented at the Bonferroni test. Biometrika 1988;75:383–386 agents studied, EQW and MET provided 71st Scientific Sessions of the American Di- 9. Dmitrienko A, Molenberghs G, Chuang- similar improvements in glycemic control abetes Association, San Diego, CA, 24–28 Stein C, Offen W. Analysis of Clinical Trials along with the benefit of weight reduction June 2011. Using SAS: A Practical Guide.Cary,NC, and no increased risk of hypoglycemia. The authors thank Michael Trautmann, MD SAS Institute Inc, 2005 There were no unexpected findings with (Eli Lilly), Justin Northrup, MPT (Eli Lilly), 10. Bergenstal RM, Wysham C, Macconell L, regard to safety or tolerability. Based on Matt Reaney, MSc (Eli Lilly), Jaret Malloy, PhD et al. Efficacy and safety of exenatide once these 26-week data, EQW is a once- ( Pharmaceuticals), and Dr. Luis de weekly versus sitagliptin or pioglitazone as an weekly dosing option for initial therapy. Teresa (Clínica Mediterránea de Neurociencias, adjunct to metformin for treatment of type Medicina Innovadora, Alicante, Spain), who 2 diabetes (DURATION-2): a randomised Longer-term studies will be required to provided medical, scientific, and writing sup- – assess the durability of the observations trial. Lancet 2010;376:431 439 port for this article. The authors thank the pa- 11. Tan MH, Johns D, Strand J, et al. Sustained in this study. tients, investigators, and staffs at the 124 sites in effects of pioglitazone vs. on the 22 participating countries (Argentina, insulin sensitivity, glycaemic control, and Belgium, Brazil, Canada, France, Germany, lipid profiles in patients with type 2 di- AcknowledgmentsdThis study was funded Hungary, India, Israel, Italy, South Korea, Mexico, abetes. Diabet Med 2004;21:859–866 by Amylin Pharmaceuticals (San Diego, CA) Poland, Romania, the Russian Federation, 12. Tan MH, Baksi A, Krahulec B, et al. and Eli Lilly (Indianapolis, IN). In 2011, R.M.C. Slovakia, South Africa, Spain, Taiwan, Turkey, Comparison of pioglitazone and became an employee of sanofi-aventis. M.K.B. the United Kingdom, and the United States). in sustaining glycemic control over 2 years is the designated guarantor for this publication. in patients with type 2 diabetes. Diabetes D.R.-J. served as an investigator on clinical Care 2005;28:544–550 trials sponsored by Eli Lilly and Amylin Phar- References 13. Rosenstock J, Kim SW, Baron MA, et al. maceuticals; is an advisory board member for 1. Nathan DM, Buse JB, Davidson MB, et al. Efficacy and tolerability of initial com- Eli Lilly, Novo Nordisk, GlaxoSmithKline, and Medical management of hyperglycemia in bination therapy with and Takeda; and has received education grant type 2 diabetes: a consensus algorithm for pioglitazone compared with component support from Eli Lilly. R.M.C. has served as the initiation and adjustment of therapy: monotherapy in patients with type 2 an investigator on clinical trials sponsored a consensus statement of the American diabetes. Diabetes Obes Metab 2007;9: by Amylin, Abbott, Bayer, Calibra Medical, Diabetes Association and the European 175–185

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14. Charbonnel BH, Matthews DR, Schernthaner an open-label randomised trial. Lancet 22. Schweizer A, Dejager S, Bosi E. Compar- G, Hanefeld M, Brunetti P; QUARTET 2010;375:2234–2243 ison of vildagliptin and metformin mon- Study Group. A long-term comparison of 18. Schweizer A, Couturier A, Foley JE, otherapy in elderly patients with type 2 pioglitazone and gliclazide in patients with Dejager S. Comparison between vildagliptin diabetes: a 24-week, double-blind, ran- type 2 diabetes mellitus: a randomized, and metformin to sustain reductions in domized trial. Diabetes Obes Metab 2009; double-blind, parallel-group comparison HbA(1c) over 1 year in drug-naïve patients 11:804–812 trial. Diabet Med 2005;22:399–405 with type 2 diabetes. Diabet Med 2007;24: 23. Goldstein BJ, Feinglos MN, Lunceford JK, 15. DeFronzo RA, Okerson T, Viswanathan P, 955–961 Johnson J, Williams-Herman DE; Sitagliptin Guan X, Holcombe JH, MacConell L. Ef- 19. Johansen K. Efficacy of metformin in the 036 Study Group. Effect of initial combi- fects of exenatide versus sitagliptin on treatment of NIDDM: meta-analysis. Di- nation therapy with sitagliptin, a dipeptidyl postprandial glucose, insulin and glucagon abetes Care 1999;22:33–37 peptidase-4 inhibitor, and metformin on secretion, gastric emptying, and caloric in- 20. Jadzinsky M, Pfützner A, Paz-Pacheco E, glycemic control in patients with type 2 take: a randomized, cross-over study. Curr et al. given in combination diabetes. Diabetes Care 2007;30:1979– Med Res Opin 2008;24:2943–2952 with metformin as initial therapy improves 1987 16. Pratley RE, Nauck M, Bailey T, et al. glycemic control in patients with type 2 di- 24. DeFronzo RA, Goodman AM; The Mul- versus sitagliptin for patients abetes compared with either monotherapy: ticenter Metformin Study Group. Effi- with type 2 diabetes who did not have ade- a randomized controlled trial. Diabetes cacy of metformin in patients with non- quate glycemic control with metformin: a 26- Obes Metab 2009;11:611–622 insulin-dependent diabetes mellitus. N week,randomised, parallel-group, open- 21. Liutkus J, Rosas Guzman J, Norwood P, Engl J Med 1995;333:541–549 label trial. Lancet 2010;375:1447–1456 et al. A placebo-controlled trial of exenatide 25. Bunck MC, Cornér A, Eliasson B, et al. 17. Diamant M, Van Gaal L, Stranks S, et al. twice-daily added to Effects of exenatide on measures of Once weekly exenatide compared with alone or in combination with metfor- b-cell function after 3 years in metformin- titrated to target in pa- min. Diabetes Obes Metab 2010;12: treated patients with type 2 diabetes. Di- tients with type 2 diabetes (DURATION-3): 1058–1065 abetes Care 2011;34:2041–2047

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