Emerging Treatments and Technologies ORIGINAL ARTICLE

Treatment With the Human Once-Weekly -Like -1 Analog Taspoglutide in Combination With Improves Glycemic Control and Lowers Body Weight in Patients With Inadequately Controlled With Metformin Alone A double-blind placebo-controlled study

1 4 MICHAEL A. NAUCK, MD RACHELE BERRIA, MD pproximately 50% of patients with 2 4 ROBERT E. RATNER, MD MARK BOLDRIN type 2 diabetes fail to achieve the 3 5 CHRISTOPH KAPITZA, MD RAFFAELLA BALENA, MD, PHD A American Diabetes Association– recommended target A1C level of 7% (1), indicating the need for additional treatment OBJECTIVE — To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a options. A new class of antidiabetic agents is human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inade- the glucagon-like peptide-1 (GLP-1) recep- quately controlled with metformin. tor agonists, which act through multiple mechanisms (2), similar to the RESEARCH DESIGN AND METHODS — Type 2 diabetic (n ϭ 306) patients who hormone GLP-1 (3–6). Taspoglutide failed to obtain glycemic control (A1C 7–9.5%) despite 1,500 mg metformin daily were ran- (R1583/BIM51077) is a human GLP-1 domly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspo- analog with a pharmacokinetic profile glutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin suitable for weekly subcutaneous admin- throughout the study. Glycemic control was assessed by change in A1C (percent) from istration, through two amino acid substi- baseline. tutions in positions 8 and 35 with aminoisobutyric acid and a sustained re- RESULTS — Significantly greater (P Ͻ 0.0001) reductions in A1C from a mean Ϯ SD baseline lease formulation. Taspoglutide has 93% of 7.9 Ϯ 0.7% were observed in all taspoglutide groups compared with placebo after 8 weeks of homology with endogenous GLP-1 and treatment: –1.0 Ϯ 0.1% (5 mg once weekly), –1.2 Ϯ 0.1% (10 mg once weekly), –1.2 Ϯ 0.1% comparable in vitro potency. Taspo- (20 mg once weekly), –0.9 Ϯ 0.1% (10 mg Q2W), and –1.0 Ϯ 0.1% (20 mg Q2W) vs. –0.2 Ϯ glutide is resistant to degradation by 0.1% with placebo. After 8 weeks, body weight loss was significantly greater in the 10 mg (–2.1 Ϯ dipeptidyl peptidase-4 and other pro- 0.3 kg, P ϭ 0.0035 vs. placebo) and 20 mg (–2.8 Ϯ 0.3 kg, P Ͻ 0.0001) once-weekly groups and Ϯ ϭ Ϯ teases, resulting in a 12-fold increase in the 20 mg once every 2 weeks (–1.9 0.3 kg, P 0.0083) group than with placebo (–0.8 0.3 stability over the native GLP-1 when in- kg). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea; the incidence of hypoglycemia was very low. cubated in rat serum (7). Taspoglutide has been shown to enhance the rate of CONCLUSIONS — Taspoglutide used in combination with metformin significantly im- glucose-induced secretion from proves fasting and postprandial glucose control and induces weight loss, with a favorable toler- isolated, cultured rat islets and the per- ability profile. fused ZDF rat pancreas (7,8). Further- more, in vivo studies with taspoglutide in Diabetes Care 32:1237–1243, 2009 Sprague-Dawley rats and diabetic db/db mice have shown a dose-related enhance- ment of glucose-dependent insulin re- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● lease, which lowered blood glucose in the From the 1Diabeteszentrum, Bad Lauterberg im Harz, Germany; the 2Medstar Research Institute, Hyattsville, db/db mouse model of type 2 diabetes (9). Maryland; the 3Profil Institute, Neuss, Germany; the 4Roche Laboratories, Nutley, New Jersey; and Thus, the biological activity of taspo- 5Hoffmann-La Roche, Basel, Switzerland. glutide is similar to that of native GLP-1, Corresponding author: Raffaella Balena, [email protected]. Received 30 October 2008 and accepted 23 March 2009. with the added benefit of a prolonged ac- Published ahead of print at http://care.diabetesjournals.org on 14 April 2009. DOI: 10.2337/dc08-1961. tion profile. Clinical trial reg. no. NCT00423501, clinicaltrials.gov. The sustained release formulation of © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly taspoglutide showed a release profile up cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. to 26 days in dogs, making it an attractive org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby candidate for human investigation (10). marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Of note, in patients with type 2 diabetes

DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009 1237 Phase 2 dose ranging study of taspoglutide

Figure 1—Patient flow diagram. DB, database; QW, once weekly; Q2W, once every 2 weeks. not well controlled with metformin, a sin- and additional parameters of glycemic once weekly or one of the following doses gle 30-mg dose of the same 10% formu- and lipid control. and regimens of taspoglutide: 5 mg once lation of taspoglutide improved fasting The study population comprised men weekly; 10 mg once weekly; 20 mg once and postprandial glucose for up to 14 and postmenopausal or surgically steril- weekly; 10 mg once every 2 weeks; or 20 days in nearly all subjects treated (11). ized women with type 2 diabetes, treated mg once every 2 weeks. Patients were The aim of the current study was to eval- with a daily dose of metformin (Ն1,500 asked to follow their prestudy diet and uate the efficacy, safety, and tolerability of mg/day) monotherapy for at least 3 exercise plan and metformin regimen a range of doses of taspoglutide, given ei- months before screening. Key inclusion throughout the study. Patients reported ther once weekly or once every 2 weeks, criteria at screening were age 18–75 to the study site for weekly visits. At each in patients with type 2 diabetes inade- years, A1C between 7.0 and 9.5% (inclu- visit the lyophilized peptide was reconsti- quately controlled with metformin alone. sive), fasting plasma glucose (FPG) Ͼ126 tuted at the study site with the diluent mg/dl (7.0 mmol/l) and Յ240 mg/dl (zinc chloride solution). Patients in the RESEARCH DESIGN AND (13.3 mmol/l), BMI Ͼ25 and Յ45 kg/m2, placebo group received 0.9% NaCl. Study METHODS — This was a random- and stable weight (Ϯ10%) for at least 3 was administered by person- ized, double-blind, parallel group, place- months before screening. nel not involved with the preparation of bo-controlled, multicenter, phase 2b Key exclusion criteria were history of study drug to maintain the blinding and clinical study, consisting of a screening type 1 diabetes; treatment with any anti- injected subcutaneously in the abdomen (up to 3 weeks), a treatment (8 weeks), hyperglycemic medication other than in a different site each time, according to a and a follow-up period (4 weeks). The metformin during the prior 3 months (ex- given scheme. study was conducted in accordance with cept insulin use in acute situations or dur- Patients measured their fasting blood guidelines of all the institutional review ing surgery for up to 7 days); previous glucose levels using a glucometer (ACCU- boards, with the principles of the Decla- exposure to GLP-1, GLP-1 analogs, or ex- CHEK) while at home in the morning at ration of Helsinki, and with the laws and enatide; weight-lowering in least once weekly or more frequently if they regulations of the countries where the re- the prior 3 months; impaired liver or kid- felt unwell or had any symptoms of hypo- search was conducted. ney function, clinically significant gastro- or hyperglycemia or if requested by local The primary objectives of this study intestinal disease, or uncontrolled guidelines. A subset of patients (n ϭ 118, were to determine the efficacy, safety, and hypertension at screening; or a stroke or ϳ20 per group) consumed a mixed-meal tolerability of multiple doses and regi- myocardial infarction within 6 months test with Ensure (350 kcal; 50 g carbohy- mens of taspoglutide, when added to met- before screening. drate, 13 g protein, and 11 g fat) at baseline formin therapy. Secondary objectives Patients were randomly assigned by a and after 8 weeks of treatment. Central lab- were to compare the effects of taspo- central randomization system (interactive oratories (Covance, Geneva, Switzerland; glutide versus placebo on body weight voice response system) to either placebo Harrogate, U.K.; Indianapolis, IN) were

1238 DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009 Nauck and Associates

Table 1—Baseline demographics, disease characteristics, and changes after the 8-week treatment

Once weekly Once every 2 weeks Placebo 5 mg 10 mg 20 mg 10 mg 20 mg n 49* 50* 49* 50* 50* 49* Sex (female/male) 57/43 48/52 39/61 64/36 48/52 55/45 Age (years) 56 Ϯ 657Ϯ 756Ϯ 856Ϯ 853Ϯ 11 56 Ϯ 7 BMI (kg/m2) 31.8 Ϯ 4.9 33.2 Ϯ 5.3 32.6 Ϯ 4.7 32.4 Ϯ 5.2 33.1 Ϯ 5.1 33.2 Ϯ 5.1 Duration of diabetes (years) 5 Ϯ 46Ϯ 65Ϯ 55Ϯ 45Ϯ 46Ϯ 5 Metformin dose (mg/day) 2,019 Ϯ 63 1,897 Ϯ 51 1,888 Ϯ 53 1,998 Ϯ 57 2,011 Ϯ 68 1,934 Ϯ 56 Systolic blood pressure (mmHg) 129 Ϯ 13 127 Ϯ 13 128 Ϯ 14 131 Ϯ 14 132 Ϯ 13 132 Ϯ 13 Diastolic blood pressure (mmHg) 77 Ϯ 978Ϯ 878Ϯ 880Ϯ 981Ϯ 881Ϯ 7 A1C (%) 8.0 Ϯ 0.1 7.9 Ϯ 0.1 7.9 Ϯ 0.1 7.8 Ϯ 0.1 8.0 Ϯ 0.1 7.9 Ϯ 0.1 ⌬Ϫ0.2 Ϫ1.0 Ϫ1.2 Ϫ1.2 Ϫ0.9 Ϫ1.0 P Ͻ0.0001 Ͻ0.0001 Ͻ0.0001 Ͻ0.0001 Ͻ0.0001 Fructosamine (␮mol/l) 310 Ϯ 6 310 Ϯ 6 300 Ϯ 6 292 Ϯ 6 309 Ϯ 6Ϫ 290 Ϯ 6 ⌬Ϫ5 Ϯ 4 Ϫ44 Ϯ 4 Ϫ51 Ϯ 4 Ϫ48 Ϯ 4 Ϫ35 Ϯ 4 Ϫ40 Ϯ 4 P Ͻ0.0001 Ͻ0.0001 Ͻ0.0001 Ͻ0.0001 Ͻ0.0001 Fasting glucose (mg/dl) 173 Ϯ 5 187 Ϯ 5 175 Ϯ 5 164 Ϯ 5 175 Ϯ 5 171 Ϯ 5 ⌬Ϫ14 Ϫ33 Ϫ45 Ϫ45 Ϫ22 Ϫ26 P 0.0002 Ͻ0.0001 Ͻ0.0001 0.13 0.02 Proinsulin-to-insulin ratio 0.590 Ϯ 0.032 0.579 Ϯ 0.032 0.594 Ϯ 0.032 0.550 Ϯ 0.032 0.606 Ϯ 0.031 0.613 Ϯ 0.032 ⌬ 0.002 Ϫ0.079 Ϫ0.120 Ϫ0.166 Ϫ0.091 Ϫ0.055 P 0.0738 0.0076 0.0003 0.0372 0.2054 Lipid parameters Total cholesterol (mg/dl) 211 Ϯ 6 201 Ϯ 6 195 Ϯ 6 194 Ϯ 6 196 Ϯ 6 200 Ϯ 6 ⌬ϩ7 Ϫ8 Ϫ12 Ϫ9 Ϫ7 Ϫ12 LDL cholesterol (mg/dl) 127 Ϯ 5 117 Ϯ 5 116 Ϯ 5 113 Ϯ 5 114 Ϯ 5 114 Ϯ 5 ⌬ϩ5 Ϫ3 Ϫ8 ϩ1 Ϫ0 Ϫ6 HDL cholesterol (mg/dl) 47 Ϯ 245Ϯ 245Ϯ 245Ϯ 244Ϯ 243Ϯ 2 ⌬ϩ0 Ϫ1 Ϫ2 Ϫ1 Ϫ10 Triglycerides (mg/dl) 224 Ϯ 27 220 Ϯ 27 188 Ϯ 28 199 Ϯ 27 220 Ϯ 27 256 Ϯ 27 ⌬ϩ9 Ϫ22 Ϫ26 Ϫ48 Ϫ28 Ϫ27 Data are means Ϯ SD for baseline characteristics and mean Ϯ SEM for disease characteristics. used to measure all laboratory parameters Ն8%) and participation in the meal RESULTS including drug concentrations of test. The sample size of 264 patients (44 taspoglutide. patients per group) was calculated to Baseline demographics and clinical provide 90% power to detect a 1% dif- characteristics Study end points ference in the change of A1C from base- Of 572 patients screened, 306 of them The primary efficacy end point was the line in the individual comparison of all were randomly assigned into six treat- change from baseline in A1C (percent), five active dose groups versus placebo, ment arms. Of the 306 randomly assigned assessed 1 week after 8 consecutive weeks assuming a common SD of 1.2%, two- patients, 297 received at least one dose of of treatment. Secondary end points in- sided ␣ϭ0.05, and 20% dropout rate. study medication and were included in cluded the percentage of patients achiev- the safety database (Fig. 1). There were no Ͻ ANCOVA with fixed-effect terms for re- ing the treatment goals of A1C 7% and gion, treatment, and baseline A1C as covari- clinically meaningful differences in baseline Ͻ6.5% and the absolute changes from demographic, anthropometric, or disease ates was used to assess possible differences baseline in FPG, body weight, fruc- characteristics among treatment groups in the changes in A1C among the treatment tosamine, C-peptide, fasting insulin, pro- (Table 1). Patients were treated with com- insulin, proinsulin-to-insulin molar ratio, groups. mon medications for a diabetic population fasting glucagon, and lipid parameters. The intent-to-treat population con- including ACE inhibitors, thiazide diuret- Safety assessments included vital signs, sisted of all patients who were randomly ics, angiotensin receptor blockers, statins, physical examination, clinical laboratory assigned, received at least one dose of and ␤-blockers (data not shown). tests, electrocardiogram, local tolerance at study medication, and had a baseline and the injection site, anti-taspoglutide anti- at least one postbaseline A1C assessment. bodies, and adverse event reporting. Missing data were handled using the last The taspoglutide mean plasma concentra- observation carried forward method. The tions, based on the trough levels between Statistical methods safety population consisted of all patients weeks 3 and 8, were 41.2, 77.5, and 96.6 Randomization was stratified based on who received at least one dose of study pmol/l for the 5, 10, and 20 mg once- severity of disease (A1C Ͻ8% and medication. weekly groups and 29.7 and 51.8 pmol/l in

DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009 1239 Phase 2 dose ranging study of taspoglutide

Figure 2—Effects of taspoglutide and placebo on A1C. All taspoglutide doses were statistically significant (P Ͻ 0.0001) (A). Percentage of patients achieving target A1C, *P Ͻ 0.0001 vs. placebo (B); fasting plasma glucose (C); and body weight (D). Black, placebo; magenta, 5 mg once weekly; green, 10 mg once weekly; yellow, 20 mg once weekly; purple, 10 mg once every 2 weeks; orange, 20 mg once every 2 weeks. the 10 and 20 mg once every 2 weeks cantly (P Ͻ 0.0001) decreased in all treat- the 20 mg once weekly group showing a group. ment groups, consistent with the A1C trend (P ϭ 0.069) and the 10 mg once data (Table 1). every 2 weeks group achieving statistical Glycemic control Reductions in FPG were apparent significance (P ϭ 0.009) after 8 weeks of After 8 weeks of treatment, the reductions within 1 week after initiation of treat- treatment. in A1C from baseline were statistically ment. At the end of the treatment period, The fasting proinsulin-to-insulin mo- significant compared with placebo in all weekly administration of taspoglutide re- lar ratio ranged between 0.5 and 0.6 at groups that received taspoglutide (P Ͻ sulted in a statistically significant decrease baseline and decreased in all treatment 0.0001) (Fig. 2A, Table 1). Reductions in of FPG by 33 mg/dl (P ϭ 0.0002) with 5 arms (Table 1). A placebo-corrected, sta- A1C were apparent after 1 week of treat- mg and 45 mg/dl (P Ͻ 0.0001) with both tistically significant decline from baseline ment with taspoglutide, with the greatest 10 and 20 mg doses versus a decrease of could be shown for the 10 mg (P ϭ 0.008) reductions observed in the 10 and 20 mg 14 mg/dl in the placebo group (Fig. 2C; and 20 mg (P ϭ 0.0003) once-weekly once weekly dose groups at the end of Table 1). When only four doses of taspo- groups as well as for the 10 mg once every treatment. As expected, patients with glutide were administered every 2 weeks 2 weeks (P ϭ 0.037) group. The mean higher baseline A1C values (Ն8.0%) (i.e., 10 and 20 mg taspoglutide once ev- fasting glucagon concentration ranged showed greater reductions in all treat- ery 2 weeks), FPG rebounded during the between 6.9 and 7.8 pg/ml at baseline and ment groups, including placebo; the second week after drug administration, as showed a decrease in all treatment groups change from baseline was –1.3%, –1.5%, shown in Fig. 2C. Nevertheless, the de- without reaching statistical significance and –1.4% in the 5, 10, and 20 mg once- crease in FPG (–26 mg/dl) in the 20 mg (data not shown). weekly groups and –1.2% and –1.3% in once every 2 weeks group was statistically the 10 and 20 mg once every 2 weeks significant (Table 1). Lipid profile group vs. –0.3% in the placebo group. Baseline levels of fasting lipid parameters More than 44% reached a target A1C ␤-Cell function and glucagon and changes after 8 weeks are shown in Ͻ7% in all active doses and regimens, Mean fasting C-peptide concentrations Table 1. All active treatment groups with 79 and 81% achieving this goal with ranged from 0.8 to 1.0 nmol/l at baseline showed a decline in triglycerides after the 10 and 20 mg taspoglutide once weekly, and increased in all treatment arms after 8 treatment, compared with a slight in- respectively, versus 17% with placebo weeks of treatment. All treatment arms crease in the placebo control group. Pla- (Fig. 2B). Serum fructosamine signifi- showed an increase from baseline, with cebo-corrected changes ranged from –32

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Table 2—Most frequently reported adverse events ratory parameters after treatment with taspoglutide. Once every 2 Once weekly weeks CONCLUSIONS — This study dem- onstrates that taspoglutide in patients Placebo 5 mg 10 mg 20 mg 10 mg 20 mg with type 2 diabetes inadequately con- n 49* 50* 49* 50* 50* 49* trolled with metformin produced statisti- Nausea 3 (6) 11 (22) 12 (24) 26 (52) 16 (32) 20 (10) cally significant and clinically meaningful Diarrhea 4 (8) 4 (8) 5 (10) 5 (10) 8 (16) 9 (18) improvements in glycemic control in all Vomiting 2 (4) 2 (4) 2 (4) 11 (22) 6 (12) 12 (24) treatment groups, compared with pla- Headache 3 (6) 1 (2) 3 (6) 6 (12) 7 (14) 6 (12) cebo. This magnitude of improvement in Decreased appetite — — 5 (10) 3 (6) 4 (8) 3 (6) glycemic control observed with taspo- glutide after 8 weeks (–1.1% decrease in Dyspepsia — — 4 (8) 6 (12) 3 (6) 2 (4) Ϯ Abdominal distension — — 2 (4) 2 (4) 3 (6) 6 (12) A1C from a baseline of 7.9 0.7%) com- pares favorably with that seen with other Data are n (%). *All patients who received at least one dose of study drug treatment (n ϭ 297) were included in the safety database. GLP-1 receptor agonists, such as ex- enatide (12–14) and (15). Both fasting and postprandial glucose levels mg/dl in the 5 mg once weekly group to a Safety and tolerability were reduced by taspoglutide. Improve- maximum decrease of –58 mg/dl in the 20 Table 2 summarizes the most frequent ad- ment in glucose control during postpran- mg once weekly group. verse events. Nausea and vomiting tended dial as well as fasting periods is important Placebo-corrected changes in total to occur during the first day after study for reaching goal A1C (16). Our data in- cholesterol levels varied from –15 to –20 drug administration, was associated with dicate that four of five patients treated mg/dl. Placebo-corrected changes in LDL peak plasma drug concentration, and re- with 10 and 20 mg taspoglutide once cholesterol levels ranged from –4 to –13 solved within 1 day. Subsequent admin- weekly achieved the treatment target A1C mg/dl, with no clear dose response. There istrations of taspoglutide were less likely Ͻ7% recommended by the American Di- was a trend for a minimal decrease of HDL to induce nausea. The highest dose of ta- abetes Association (17). cholesterol levels during this treatment spoglutide (20 mg once weekly) was as- In addition, in type 2 diabetic patients period. sociated with nausea and vomiting in 52 in whom metformin monotherapy had and 22% of patients, respectively. failed, taspoglutide treatment produced Body weight Hypoglycemia occurred infrequently progressive, dose-dependent weight loss Body weight decreased progressively and (only seven events in six patients, two of with no evidence of a plateau after four or dose dependently throughout the 8-week which were asymptomatic). No cases of eight injections at 8 weeks. The weight treatment period, with clinically mean- severe hypoglycemia occurred in the tas- loss is consistent with published clinical ingful and statistically significant reduc- poglutide-treated patients. No cases of trial data with other GLP-1 receptor ago- tions in the 10 mg once weekly (–2.1 Ϯ pancreatitis were identified. nists (12–15). It is notable that the ob- 0.3 kg, P ϭ 0.0035), 20 mg once weekly Six patients experienced serious ad- served weight loss occurred without any (–2.8 Ϯ 0.3 kg, P Ͻ 0.0001), and 20 mg verse events, including two in the placebo specific diet or weight management once every 2 weeks (–1.9 Ϯ 0.3 kg, P ϭ group, all considered by the investigators regimen. 0.0083) groups compared with the pla- to be unrelated to the study drug. These The beneficial effects of taspoglutide cebo group (–0.8 Ϯ 0.3 kg) (Fig. 2D). were perineal fibroma and otitis media in on glycemic control and body weight loss the placebo group and colonic polyp, were accompanied by a meaningful im- Postprandial glucose and insulin wrist fracture, coronary artery occlusion, provement of the proinsulin-to-insulin After treatment with taspoglutide, the me- and unstable angina in the treated groups. molar ratio. An elevation of this ratio is dian percent decrease from baseline in The last two led to withdrawal from the predictive of subsequent development of plasma glucose 120 min after a mixed study. Eight patients discontinued pre- type 2 diabetes (18), and its decrease is meal was 21.6, 22.0, and 18% in the 5, maturely because of adverse events. These considered a sign of improved ␤-cell 10, and 20 mg once-weekly groups and were nausea (n ϭ 3, one patient in the 10 function (19). In addition, the observed 12.0 and 5.5% in the 10 and 20 mg once mg once weekly and two in the 20 mg increase in postprandial insulin coupled every 2 weeks groups vs. 10.5% in the once weekly groups), vomiting (n ϭ 1), with reduced postprandial glucose after placebo group (complete postprandial hyperglycemia (n ϭ 1), hepatic cirrhosis taspoglutide treatment is suggestive of en- glucose data are shown in supplementary (n ϭ 1), unstable angina (n ϭ 1), and hanced glucose-dependent insulin secre- Table 1, available in an online appendix coronary artery occlusion (n ϭ 1). He- tion. These results are consistent with the at http://care.diabetesjournals.org/cgi/ patic cirrhosis, unstable angina, and cor- mechanism of action of the class of incre- content/full/dc08-1961/DC1). Further- onary artery occlusion were all deemed by tin-based treatments (6,12,20). more, the median percent change in the investigators to be unrelated to treat- Type 2 diabetes is typically accom- plasma insulin levels at 120 min was ment. Mild and moderate injection site panied by cardiovascular and metabolic ϩ22.2, ϩ28.5, and ϩ44.9% in the 5, 10, reactions were observed, which did not disorders, including hypertension, dys- and 20 mg once-weekly groups and –0.6 result in treatment discontinuation. There lipidemia, and obesity (21). Despite re- and –13% in the 10 and 20 mg once every were no clinically relevant abnormalities cent advances in therapy, diabetes is still 2 weeks group vs. –15.3% in the placebo in scheduled electrocardiograms, vital associated with excess cardiovascular group. signs (including heart rate), or any labo- morbidity and mortality (21,22), medi-

DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009 1241 Phase 2 dose ranging study of taspoglutide ated in part by exacerbation of risk fac- cgi/content/full/dc08-1961/DC1) for their as- hanced in vivo efficacy (Abstract P1-360). tors, including obesity. The salutary sistance in the conduct, reporting, and quality Proceedings of the Endocrine Society Meet- effects of 8 weeks of taspoglutide treat- control of the study, as well as the patients who ing, Denver, CO, 2001. Chevy Chase, MD, ment on glycemic control, body weight, volunteered to participate in the study. We The Endocrine Society and lipid profile may improve the overall also thank F. Leigh from Cheshire, U.K., for 10. Ramis J, Menargues A, Allue JA, Peraire C, her assistance in the editing and formatting of Cordero JA, Cherif-Cheikh R. Pharmaco- metabolic and cardiovascular risk profile this manuscript. kinetic profile of a SRF formulation of of type 2 diabetic patients. However, fur- BIM51077, a novel GLP-1 analog, in the ther studies of longer duration, involving beagle dog (Abstract). Diabetes 2006;55 a large number of patients, will be re- References (Suppl. 1):AP-547 quired to fully assess long-term cardio- 1. Resnick HE, Foster GL, Bardsley J, Ratner 11. Kapitza C, Klein O, Obach R, Birman P, metabolic effects of taspoglutide. RE. Achievement of American Diabetes Jallet K, Balena R. Long acting human Consistent with the available data on Association clinical practice recommen- GLP-1 analogue R1583: safety, pharma- other GLP-1 receptor agonists, the most dations among U.S. adults with diabetes, cokinetic and pharmacodynamic proper- frequent adverse event seen with taspo- 1999–2002: the National Health and Nu- ties after a single administration in glutide treatment was dose-dependent, trition Examination Survey. Diabetes subjects with type 2 diabetes (Abstract). Care 2006;29:531–537 Diabetes 2008;57 (Suppl. 1):506-P transient, mild-to-moderate nausea (12). 12. DeFronzo RA, Ratner RE, Han J, Kim DD, However, the majority of gastrointestinal 2. Drucker DJ, Nauck MA. The incretin sys- tem: glucagon-like peptide-1 receptor Fineman MS, Baron AD. Effects of ex- events were transient and resolved spon- agonists and dipeptidyl peptidase-4 in- enatide (exendin-4) on glycemic control taneously without sequelae. Moreover, it hibitors in type 2 diabetes. Lancet 2006; and weight over 30 weeks in metformin- should be noted that the present study 368:1696–1705 treated patients with type 2 diabetes. Di- was performed with fixed doses. There is 3. Nauck MA, Bartels E, Orskov C, Ebert R, abetes Care 2005;28:1092–1100 evidence with both (23) and li- Creutzfeldt W. Additive insulinotropic ef- 13. Buse JB, Henry RR, Han J, Kim DD, Fine- raglutide (15) that gradual and progres- fects of exogenous synthetic human gas- man MS, Baron AD, Exenatide-113 Clin- sive dose escalation can reduce the tric inhibitory polypeptide and glucagon- ical Study Group. Effects of exenatide incidence of nausea (these adverse like peptide-1-(7-36) amide infused at (exendin-4) on glycemic control over 30 events). To reduce the incidence of gas- near-physiological insulinotropic hor- weeks in -treated patients with type 2 diabetes. Diabetes Care 2004; trointestinal events, an uptitration mone and glucose concentrations. J Clin Endocrinol Metab 1993;76:912–917 11:2628–2635 scheme has been included in the ongoing 4. Na¨slund E, Bogefors J, Skogar S, Gryba¨ck 14. Kendall DM, Riddle MC, Rosenstock J, phase 3 program. P, Jacobsson H, Holst JJ, Hellstro¨m PM. Zhuang D, Kim DD, Fineman MS, Baron In summary, taspoglutide, given GLP-1 slows solid gastric emptying and AD. Effects of exenatide (exendin-4) on weekly or every 2 weeks in combination inhibits insulin, glucagon, and PYY re- glycemic control over 30 weeks in pa- with metformin, resulted in significant im- lease in humans. Am J Physiol 1999;277: tients with type 2 diabetes treated with provements in glycemic control and weight R910–R906 metformin and a sulfonylurea. Diabetes loss after four to eight injections and was 5. Gutzwiller JP, Drewe J, Go¨ke B, Schmidt Care 28:1083–1091, 2005 well tolerated in the vast majority of pa- H, Rohrer B, Lareida J, Beglinger C. Glu- 15. Nauck M, Frid A, Hermansen K, Shah NS, tients. Thus, taspoglutide (10 and 20 mg cagon-like peptide-1 promotes satiety Tankova T, Mitha IH, Zdravkovic M, Du¨r- ing M, Matthews DR, LEAD-2 Study weekly) appears to offer the benefits of a and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol Group. Efficacy and safety comparison of weekly GLP-1 analog: potent glycemic con- 1999;276:R1541–R1544 liraglutide, , and placebo, all trol, weight loss, and a low risk of 6. Holst JJ, Deacon CF, Vilsbøll T, Krarup T, in combination with metformin, in type 2 hypoglycemia. Madsbad S. Glucagon-like peptide-1, glu- diabetes: the LEAD (Liraglutide Effect and cose homeostasis and diabetes. Trends Action in Diabetes)-2 study. Diabetes Mol Med 2008;14:161–168 Care 2009;32:84–90 Acknowledgments— This trial was sup- 7. Woon CW, Taylor JE, Dong JZ, Shen Y, 16. Monnier L, Lapinski H, Colette C. Contri- ported by F. Hoffmann-La Roche, Basel, Swit- Skinner S, Carlile L, Sullivan T, Nolan butions of fasting and postprandial zerland. M.A.N. and R.E.R. have received AL, Morgan BA, Cawthorne MA, Culler plasma glucose increments to the overall consulting and advisory board honoraria from M. BIM 51077, a stable glucagon-like diurnal hyperglycemia of type 2 diabetic Roche as well as from other pharmaceutical peptide-1 (GLP-1) analogue with pre- patients: variations with increasing levels companies developing incretin-based antidia- served gluco-incretin property in vitro of A1C. Diabetes Care 2003;26:881–885 betic medications whose products may be per- (Abstract P1-359). In Proceedings of the 17. Nathan DM, Buse JB, Davidson MB, Fer- ceived as being competitive to taspoglutide. Endocrine Society Meeting, Denver, CO, rannini E, Holman RR, Sherwin R, Zin- No other potential conflicts of interest relevant 2001. Chevy Chase, MD, The Endocrine man B. Management of hyperglycemia in to this article were reported. Society type 2 diabetes: a consensus algorithm for Parts of this study were presented in ab- 8. Wargent E, Nolan AL, Shen Y, Dong J, the initiation and adjustment of therapy: stract form at the 68th Scientific Sessions of Taylor JE, Culler M, Morgan B, Woon update regarding : a the American Diabetes Association, San Fran- CW, Cawthorne MA. Insulin secreta- consensus statement from the American cisco, California, 6–10 June 2008 (Abstract gogue activity in vitro and in perfused Diabetes Association and the European 108-OR) and at the 44th Annual Meeting of pancreas of dipeptidase IV resistant Association for the Study of Diabetes. Di- the European Association for Study of Diabe- GLP-1 analogs (Abstract). Diabetologia abetes Care 2008;51:173–175 tes, Rome, Italy, 8–11 September 2008 (Dia- 2000;44 (Suppl. 1):A532 18. Nijpels G, Popp-Snijders C, Kostense PJ, betologia 51 [Suppl. 1]: Abstract 871). 9. Culler MD, Carlile L, Sullivan T, Taylor Bouter LM, Heine RJ. Fasting proinsulin We thank the Taspoglutide BC20688 Clin- JA, Sennitt M, Nolan A, Stocker C, Caw- and 2-h post-load glucose levels predict ical Study Group (a complete list of the mem- thorne MA, Dong J, Shen Y, Jackson S, the conversion to NIDDM in subjects with bers can be found in an online appendix, Woon C. BIM-51077, a novel glucagon- impaired glucose tolerance: the Hoorn available at http://care.diabetesjournals.org/ like peptide-1 (GLP-1) analog with en- Study. Diabetologia 1996;39:113–118

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19. Tura A, Pacini G, Kautzky-Willer A, Lud- controlled with metformin alone. Diabe- Pyo¨ra¨la¨ K, Laakso M. Mortality from vik B, Prager R, Thomaseth K. Basal and tes Care 2006;29:2638–2643 coronary heart disease in subjects with dynamic proinsulin-insulin relationship 21. Gerstein HC, Miller ME, Byington RP, type 2 diabetes and in nondiabetic sub- to assess ␤-cell function during OGTT in Goff DC Jr, Bigger JT, Buse JB, Cushman jects with and without prior myocardial metabolic disorders. Am J Physiol Endo- WC, Genuth S, Ismail-Beigi F, Grimm RH infarction. N Engl J Med 1998;339: crinol Metab 2003;285:E155–E162 Jr, Probstfield JL, Simons-Morton DG, 229–234 20. Charbonnel B, Karasik A, Liu J, Wu M, Friedewald WT, Action to Control Car- 23. Fineman MS, Shen LZ, Taylor K, Kim DD, Meininger G, Study 020 diovascular Risk in Diabetes Study Baron AD. Effectiveness of progressive Group: Efficacy and safety of the dipepti- Group. Effects of intensive glucose lower- dose-escalation of exenatide (exendin-4) dyl peptidase-4 inhibitor sitagliptin ing in type 2 diabetes. N Engl J Med 2008; in reducing dose-limiting side effects in added to ongoing metformin therapy in 358:2545–2559 patients with type 2 diabetes. Diabetes patients with type 2 diabetes inadequately 22. Haffner SM, Lehto S, Ro¨nnemaa T, Metab Res Rev 2004;20:411–417

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