Diabetes Care

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Bo Ahr´en,1 Susan L. Johnson,2 Murray Stewart,3 Deborah T. Cirkel,4 Fred Yang,5 Caroline Perry,5 and Mark N. Feinglos,6 for the HARMONY 3 Study Group

DOI: 10.2337/dc14-0024

OBJECTIVE

To compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo. RESEARCH DESIGN AND METHODS

Patients with type 2 diabetes receiving metformin were randomized to albiglutide (30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined hyperglycemia criteria. The primary end point was change in HbA1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue. RESULTS

Baseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA1c was 8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104, albiglutide significantly reduced HbA1c compared with placebo (20.9% [29.8 mmol/mol]; P < 0.0001), sitagliptin (20.4% [24.4 mmol/mol]; P = 0.0001), and glimepiride (20.3% [23.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA1c were similar. Weight change from baseline for each were as follows: albiglutide 21.21 kg (95% CI 21.68 to 20.74), placebo 21.00 kg (95% CI 21.81 to 20.20), sitagliptin 20.86 kg (95% CI 21.32 to 20.39), glimepiride 1.17 kg (95% CI 0.70–1.63). The difference between albiglutide and glimepiride was statistically significant (P < 0.0001). Hyperglycemic rescue rate at week 104 was 25.8% for albiglutide compared with 59.2% (P < 0.0001), 36.4% (P = 0.0118), and 32.7% (P = 0.1504) for placebo, sitagliptin, and glimepiride, respectively. Rates of serious adverse events in the albiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%, other groups 8.6–10.9%) and nausea (albiglutide 10.3%, other groups 6.2–10.9%) were generally the most frequently reported gastrointestinal events. CONCLUSION

Added to metformin, albiglutide was well-tolerated; produced superior reductions in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.

1 Department of Clinical Sciences, Lund University, Lund, Sweden 2 Metabolic Pathways and Cardiovascular Unit, GlaxoSmithKline, Research Triangle Park, NC 3 Metabolic Pathways and Cardiovascular Unit, GlaxoSmithKline, Upper Merion, PA 4 RD Projects Clinical Platforms & Sciences, GlaxoSmithKline, Stevenage, Herts, U.K. 5 Alternate Development Program, GlaxoSmithKline, Upper Merion, PA 6 Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC

Corresponding author: Mark N. Feinglos, mark. [email protected]. Received 4 January 2014 and accepted 11 April 2014. Clinical trial reg. no. NCT00838903, clinicaltrials .gov. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc14-0024/-/DC1. © 2014 by the American Diabetes Association. See http://creativecommons.org/licenses/bync-nd/3.0/ for details.

Diabetes Care Publish Ahead of Print, published online June 4, 2014

CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL

HARMONY 3: 104-Week Randomized, Double-Blind, Placebo- and Active-Controlled Trial Assessing the Efficacy and Safety of Albiglutide Compared With Placebo, Sitagliptin, and Glimepiride in Patients With Type 2 Diabetes Taking Metformin

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HARMONY 3: 2-Year Albiglutide Efficacy/Safety

The management of type 2 diabetes has become an increasingly complex practice given the number of treatments available (1). Despite the availability of new therapeutic agents, many patients with type 2 diabetes continue to have uncontrolled glycemia (2–4), and treatment adherence varies but remains relatively poor (5–9). Among patients taking metformin but who do not have adequately controlled diabetes, data are limited regarding next-step concomitant treatment (10). As a result, extended head-to-head comparisons of type 2 diabetes medications mirroring treatment algorithms (i.e., combinations with metformin) are needed to aid clinicians in making treatment decisions (11,12). Recent treatment guidelines have positioned incretin-based therapies, such as GLP-1 receptor agonists (GLP-1RAs), as alternative first-line therapies in certain clinical settings and as second-line therapies following metformin because of their substantial effectiveness in improving glycemic control as well as other positive effects, such as weight loss and low hypoglycemia rates (10,13,14). Albiglutide is a novel, once-weekly, long-acting GLP-1RA composed of a dipeptidyl peptidase-4 (DPP-4)2resistant GLP-1 dimer fused to recombinant human albumin. This structure affords an extended half-life of ;5 days and, as a consequence, once-weekly dosing (15,16). In a multinational phase 2b study of type 2 diabetes, albiglutide 30 mg once-weekly reduced HbA1c by 20.87% (29.5 mmol/mol) and also reduced fasting plasma glucose (FPG) and weight, with a low incidence of gastrointestinal (GI) adverse events (AEs) (16). The HARMONY program for albiglutide includes eight pivotal phase 3 studies designed to evaluate the efficacy and safety of albiglutide compared with placebo, oral antidiabetic medications, insulin glargine, and another GLP-1RA in a typical type 2 diabetes population (17,18). Here, we present 2-year primary end point data for HARMONY 3, which is a 3-year phase 3 study comparing the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo in patients with diabetes receiving metformin but not adequately controlled by the medication.

Diabetes Care

RESEARCH DESIGN AND METHODS Study Design

This was a phase 3, randomized, doubleblind, placebo- and active-controlled parallel-group study that occurred between 17 February 2009 and 21 March 2013; the study comprised 4 study periods: screening, run-in/stabilization (4 weeks), treatment (156 weeks; 104week data are reported here), and posttreatment follow-up (8 weeks) (Fig. 1A); the trial is registered as NCT00838903 at clinicaltrials.gov. Eligible patients were stratified by HbA 1c level (,8.0% [,63.9 mmol/mol] vs. $8.0% [$63.9 mmol/mol]), history of myocardial infarction (MI), and age (,65 vs. $65 years) and were randomly assigned (3:3:3:1) to receive, in addition to their background metformin, 1 of 4 treatments at baseline: albiglutide 30 mg, sitagliptin 100 mg,

glimepiride 2 mg, or placebo. Matching placebos for albiglutide, sitagliptin, and glimepiride were used to maintain blinding to treatment. After randomization, patients with persistent hyperglycemia qualified to undergo dose titration and/or hyperglycemia rescue. Blinded up-titration of albiglutide from 30 to 50 mg once weekly or glimepiride from 2 to 4 mg once daily occurred if patients exceeded predefined FPG or HbA1c thresholds. The final titration threshold, from week 12 until week 143, was HbA1c 7.5% (58.5 mmol/mol); there was no titration from week 143 to week 156. In general, 4 weeks after up-titration, patients meeting criteria including predefined FPG or HbA1c thresholds could receive hyperglycemic rescue therapy, in addition to study medication, and remain in the trial. Rescue thresholds early in the trial were based

Figure 1—A: HARMONY 3 study design. QD, once daily; QW, once weekly. B: CONSORT flow diagram of the HARMONY 3 trial through week 104. DC, discontinue; FU, follow-up; ITT, intent to treat.

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on FPG ($280 mg/dL [15.6 mmol/L] from week 2 to week 4; $250 mg/dL [13.9 mmol/L] from week 4 to week 12) and, later, on HbA1c ($8.5% [69.4 mmol/mol] and a #0.5% reduction from baseline from week 12 to week 24; $8.5% [69.4 mmol/mol] from week 24 to week 104). Patients Inclusion Criteria

Patients were $18 years of age, had type 2 diabetes, and were experiencing inadequate glycemic control while taking background metformin ($1500 mg or maximum tolerated dose) $3 months before screening. They also had a baseline HbA1c of 7.0% (53.0 mmol/mol) to 10.0% (85.8 mmol/mol), inclusive; BMI 20 to 45 kg/m2; creatinine clearance .60 mL/min (determined using the Cockcroft-Gault formula); and normal thyroid-stimulating hormone concentration or were clinically euthyroid. Exclusion Criteria

Major exclusion criteria were current ongoing symptomatic biliary disease or history of pancreatitis, recent clinically significant cardiovascular and/or cerebrovascular disease (#2 months before screening), treated gastroparesis, history of GI surgery thought to significantly affect upper GI function, history of most cancers not in remission for at least 3 years, personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, resting systolic blood pressure (SBP) .160 mmHg and/or diastolic blood pressure (DBP) .100 mmHg, lipase above the upper limit of normal (ULN), hemoglobinopathy that could affect HbA 1c , and alanine aminotransferase or aspartate aminotransferase more than two and a half times the ULN. Withdrawal Criteria

Patients withdrew or were removed from the study drug because of loss to followup, protocol violation, noncompliance, withdrawal of consent, or an AE or laboratory result requiring withdrawal, including QTc prolongation, elevation of liver function test results, severe potential allergic reactions, confirmed pancreatitis, severe or repeated hypoglycemia, and calcitonin .100 pg/mL. Primary and Secondary End Points

The primary end point was the change in model-adjusted HbA1c from baseline to

week 104 between albiglutide and the comparators. Secondary end points included changes in HbA 1c , FPG, and weight from baseline over time; the proportion of patients who achieved HbA1c treatment goals (i.e., ,6.5% [,47.5 mmol/mol], ,7.0% [,53.0 mmol/mol], and ,7.5% [,58.5 mmol/mol]); and time to hyperglycemic rescue. Safety and tolerability were assessed, including AEs and serious AEs (SAEs); safety events of special interest (i.e., GI or hypoglycemic events, injection-site reactions, pancreatitis, thyroid tumors, potential systemic allergic reactions [SARs], and CV events); clinical laboratory evaluations; physical examinations; 12-lead electrocardiograms; vital sign measurements; and immunogenicity. All major CV AEs occurring postrandomization were adjudicated by a clinical end point committee and are part of an ongoing meta-analysis (results will be reported separately). An independent, blinded pancreatitis adjudication committee (PAC) comprising three GI specialists adjudicated AEs suggesting pancreatitis and all laboratory elevations of lipase and/or amylase more than or equal to three times the ULN. The PAC adjudicated both the probability of events being pancreatitis (definite, probable, possible, not likely) and the likelihood of a relationship to the study drug (definite, probable, possible, unlikely alternate etiology). To assess any association of study medication with potential SARs, investigators flagged AEs that were considered SARs. Additional evaluation of the AE data for SARs was conducted using standardized Medical Dictionary for Regulatory Activities queries for angioedema, anaphylaxis, and severe cutaneous reaction. Hypoglycemia was defined and assessed using American Diabetes Association criteria (19) and evaluated before hyperglycemic rescue. Statistical Methods

The planned sample size provided .90% power to demonstrate superiority versus placebo and noninferiority versus sitagliptin and glimepiride (noninferiority margin = 0.3%). Superiority of albiglutide versus sitagliptin and glimepiride was tested if noninferiority was established. The primary efficacy end point (intent-to-treat population/last observation carried forward algorithm)

was analyzed using an ANCOVA model to compare treatment effects adjusting for region, history of previous MI, age category, and baseline HbA1c. Patients rescued from hyperglycemia before week 104 had their latest HbA1c value before rescue carried forward for primary analyses. Those patients who achieved treatment goals were evaluated by nonparametric ANCOVA. Time to rescue was evaluated by KaplanMeier curves and log-rank tests. For primary end point analysis, log-rank tests for the duration up to the primary end point were added post hoc. A multiple comparisons adjustment strategy was implemented for various inferential tests among the primary and key secondary objectives; AEs were analyzed by incidence proportion and incidence density rate overall and before rescue (with additional type 2 diabetes medication); in this article, overall incidence/rate is used for all events except hypoglycemia. Study Conduct

This study was conducted in accordance with good clinical practice standards, all applicable privacy requirements, and the guiding principles of the Declaration of Helsinki. Written informed consent was obtained from each patient before participation. RESULTS

This study was conducted at 289 centers in 10 countries. Demographics and baseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) treatment groups (Supplementary Table 1).The mean age for the groups ranged from 54.3 to 56.1 years (84.3% were ,65 years old); approximately half of patients were men and the majority were white (63.4–74.5%). Approximately 67.0% of the total population were moderately to severely obese (BMI $30 kg/m2); mean weight in all treatment groups ranged from 89.6 to 91.8 kg, and mean duration of diabetes ranged from 5.8 to 6.7 years. In all treatment groups at baseline, HbA1c levels were similar (8.1–8.2% [65.0–66.1 mmol/mol]), as were FPG concentrations (9.0–9.3 mmol/L [162.8–167.4 mg/dL]). Overall, 67.4% of patients completed active treatment through week 104;

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HARMONY 3: 2-Year Albiglutide Efficacy/Safety

Diabetes Care

rates of completion were similar among the active treatment groups (sitagliptin 67.7%, glimepiride 68.8%, and albiglutide 68.3%) and lower for the placebo group (59.6%). The main reasons for discontinuing active treatment were withdrawal of consent (placebo 14.4%, sitagliptin 13.1%, glimepiride 13.2%, albiglutide 12.1%) and AEs (placebo 4.8%, sitagliptin 3.2%, glimepiride 4.1%, albiglutide 6.3%). Patient flow is presented in Fig. 1B. Although all treatment groups went through a blinded up-titration procedure, only the albiglutide and glimepiride groups actually up-titrated to 50 and 4 mg, respectively. By week 104, a higher proportion of patients went through the blinded up-titration process in the placebo (;69%) and sitagliptin (;59%) groups compared with the glimepiride (;54%) and albiglutide (;53%) groups. Mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. Primary Outcome: HbA1c

HbA1c reductions from baseline to week 104 were 20.63% (26.9 mmol/mol) for albiglutide, 20.28% (23.1 mmol/mol) for sitagliptin, 20.36% (23.9 mmol/mol) for glimepiride, and +0.27% (3.0 mmol/mol) for placebo. The model-adjusted mean difference (albiglutide vs. comparator treatment) demonstrated that albiglutide, when added to metformin, was clinically and statistically superior to placebo (20.9% [29.8 mmol/mol]; 95% CI 21.2 to 20.7; P , 0.0001), sitagliptin (20.4% [24.4 mmol/mol]; 95% CI 20.5 to 20.2; P = 0.0001), and glimepiride (20.3% [23.3 mmol/mol]; 95% CI 20.5 to 20.1; P = 0.0033) (Fig. 2A). Albiglutide had the most durable effect, with a mean HbA 1c of 7.5% (58.5 mmol/mol) at week 104 compared with sitagliptin (7.8% [61.7 mmol/mol]), glimepiride (7.8% [61.7 mmol/mol]), and placebo (8.4% [68.3 mmol/mol]) (Fig. 2B). More albiglutide-treated patients reached HbA1c treatment thresholds at each level (,6.5% [,47.5 mmol/mol], ,7.0% [,53.0 mmol/mol], ,7.5% [,58.5 mmol/mol]) compared with placebo, sitagliptin, and glimepiride at week 104 (Supplementary Fig. 1). The difference between albiglutide and the comparators was statistically significant for placebo at all threshold levels (P # 0.02) and was comparable with only

Figure 2—Change in HbA1c from baseline (A), mean HbA1c (B), FPG (C), and weight (D) over time through week 104. Intent-to-treat population data were determined using the last observation carried forward method. Data in Fig. 2A denote difference (95% CI). *P , 0.0001 vs. placebo; †P , 0.0001, noninferiority of albiglutide vs. sitagliptin or glimepiride; ‡P = 0.0033, superiority of albiglutide vs. glimepiride; §P = 0.0001, superiority of albiglutide vs. sitagliptin. BL, baseline.

sitagliptin and glimepiride at the ,7.5% (,58.5 mmol/mol; P # 0.04) level. For the albiglutide group, these treatment thresholds were met by 17.1%, 38.6%, and 58.7% of patients,

respectively. Subgroup analyses for age, race, ethnicity, sex, baseline BMI, and baseline HbA1c were all consistent with the primary end point (Supplementary Fig. 2).

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Secondary Outcomes FPG

Changes in FPG from baseline at week 104 were consistent with the primary end point (Fig. 2C). The treatment group difference (albiglutide – comparator treatment) for a model-adjusted least squares mean decrease from baseline to week 104 demonstrated that, when added to metformin, albiglutide was statistically superior to placebo (21.5 mmol/L [228 mg/dL]; P , 0.0001), sitagliptin (20.9 mmol/L [216 mg/dL]; P = 0.0002), and glimepiride (20.6 mmol/L [210 mg/dL]; P = 0.0133). Weight

At week 104, weight loss occurred among patients taking albiglutide (21.21 kg), placebo (21.0 kg), and sitagliptin (20.86 kg), whereas weight gain occurred in glimepiride patients (+1.17 kg). The treatment difference between albiglutide and glimepiride was statistically significant (P , 0.0001) (Fig. 2D).

Figure 3—Kaplan-Meier plot of time to hyperglycemic rescue (intent-to-treat population). Time to rescue was evaluated by log-rank tests and Kaplan-Meier curves.

Time to Hyperglycemic Rescue

The albiglutide group had the most durable glycemic control. Per KaplanMeier estimates, fewer patients received hyperglycemic rescue in the albiglutide group (25.8%) compared with the placebo (59.2%), sitagliptin (36.4%), and glimepiride groups (32.7%). The difference between baseline and time to rescue with albiglutide was statistically significantly longer compared with sitagliptin (P = 0.0118) and placebo (P , 0.00001) (Fig. 3).

patient-years for placebo). Fewer patients experienced SAEs in the albiglutide group (12.9%) than in the placebo group (15.8%) but were comparable with those who experienced SAEs in the sitagliptin and glimepiride groups (9.9% and 11.7%, respectively). Overall, eight fatal SAEs occurred through week 104 (three each for albiglutide and glimepiride and one each for sitagliptin and placebo); none were considered by the investigators to be related to study medication.

General Safety and Tolerability

Events of Special Interest (Through Week 104)

For overall safety, the proportion of patients experiencing AEs, SAEs, and AEs leading to withdrawal while receiving therapy was relatively balanced among treatment groups (Table 1). Most AEs were mild or moderate in intensity in all treatment groups. The most frequent AEs (occurring in .7% of patients taking albiglutide) were upper respiratory tract infection, diarrhea, nausea, injection-site reaction, hypertension, nasopharyngitis, and cough. The type of AEs overall and those occurring before rescue (i.e., before the addition of hyperglycemic rescue medication) were similar, and the majority of AEs occurred before rescue (Supplementary Table 2). The rate of AEs was higher with albiglutide and generally due to the higher rate of injection-site reactions (45 of 100 patient-years for albiglutide vs. 1 of 100

GI Events

GI AEs were experienced by a similar proportion of patients in the albiglutide (n = 110; 36.4%) and placebo groups (n = 38; 37.6%) and fewer in the sitagliptin (n = 75; 24.8%) and glimepiride groups (n = 85; 27.7%). Few GI events were severe in intensity (1.0%, 1.3%, 1.3%, and 4.0% for placebo, sitagliptin, glimepiride, and albiglutide, respectively) or led to withdrawal of the study drug (1.0%, 1.0%, 0.7%, and 2.0%, respectively). The most common GI event was diarrhea in the sitagliptin, glimepiride, and albiglutide groups and constipation in the placebo group. At week 104, nausea event rates were comparable between treatment groups (7.9, 5.3, 3.7, and 9.3 events per 100 patient-years for placebo,

sitagliptin, glimepiride, and albiglutide, respectively), even though the incidence was highest in the placebo group (10.9%) compared with sitagliptin (6.6%), glimepiride (6.2%), and albiglutide (10.3%). The incidence and event rate of vomiting over the 104 weeks was (5.6%, 4.4 events per 100 patientyears) in the albiglutide group compared with placebo (1.0%, 0.6 events per 100 patient-years), sitagliptin (4.3%, 3.2 events per 100 patientyears), and glimepiride (3.6%, 2.1 events per 100 patient-years). The per-visit prevalence of nausea/vomiting among patients receiving albiglutide was ,5% at each time point (Supplementary Fig. 3). Hypoglycemia

Documented symptomatic hypoglycemia (#3.9 mmol/L [#70 mg/dL]) before rescue with albiglutide was low (3.0%) and was similar to placebo (4.0%) and sitagliptin (1.7%) compared with glimepiride (17.9%) (Table 1). No severe hypoglycemic events were reported before rescue. Injection-Site Reactions

Events classified by investigators as injection-site reactions occurred more frequently with albiglutide (17.2%; n = 52) compared with glimepiride (7.8%; n = 24), sitagliptin (6.3%; n = 19), and placebo (5%; n = 5). Injection-site reactions for albiglutide were mostly mild to

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Diabetes Care

Table 1—AEs while receiving therapy, to week 104 Placebo + metformin Sitagliptin + metformin Glimepiride + metformin Albiglutide + metformin (n = 101) (n = 302) (n = 307) (n = 302) Overall safety to week 104 Any AEs SAEs Related AEs AEs leading to withdrawal Most common AEs (.7% with albiglutide) Upper respiratory tract infection Diarrhea Nausea Injection-site reaction Hypertension Nasopharyngitis Cough Hypoglycemia before rescue* Severe Documented symptomatic Asymptomatic

79.2/283.0 12.9/10.7 20.8/24.4 5.0/3.1

79.1/250.2 8.9/5.6 17.9/30.6 3.6/2.1

83.1/261.1 9.4/6.5 17.6/19.4 4.6/2.6

83.8/350.7 11.9/10.1 31.1/101.4 6.6/3.8

9.9/7.3 10.9/7.3 10.9/7.9 2.0/1.2 5.0/3.1 7.9/4.9 5.9/4.3

9.3/7.0 8.6/6.1 6.6/5.3 1.7/1.0 8.6/5.3 9.3/7.6 6.3/4.6

8.5/6.5 9.1/6.5 6.2/3.7 2.6/1.7 6.5/4.3 9.1/6.5 7.5/4.9

16.2/12.4 12.6/9.1 10.3/9.3 9.6/48.1 7.9/4.6 7.6/7.0 7.3/4.6

0 4 (4.0)/3.6 1 (1.0)/1.8

0 5 (1.7)/2.8 4 (1.3)/1.4

0 55 (17.9)/60.7 3 (1.0)/0.7

0 9 (3.0)/2.6 4 (1.3)/1.3

Data are incidence (percentage of patients with event) and event rate (events per 100 person-years). The order of AEs is based on albiglutide proportion in the overall data. *Patients with more than one hypoglycemic event were counted in all severity categories reported. Percentages are based on the number of patients in each treatment group for the study being summarized. Severity was derived using the American Diabetes Association guidelines for categorization of hypoglycemic events, as follows: severe = required assistance of another person; documented symptomatic = typical symptoms accompanied by a plasma glucose concentration of #3.9 mmol/L; and asymptomatic = no symptoms but plasma glucose concentration #3.9 mmol/L.

moderate in intensity (98.1%), were not progressive, and most patients (n = 32/ 52; 61.5%) experiencing injection-site reactions had 1 or 2 events that lasted #1 week (median duration). These reactions led to the withdrawal of 4 of 302 patients (1.3%) at 2 years. Most patients (41 of 52; 79.0%) treated with albiglutide who experienced injection-site reactions were negative for antialbiglutide antibodies. Pancreatitis

Six patients (albiglutide, n = 4; glimepiride, n = 2) were evaluated by a blinded, independent PAC because of a reported AE or a lipase/amylase concentration more than or equal to three times the ULN. Adjudication determined that neither patient from the glimepiride group had pancreatitis. Among the four patients receiving albiglutide, adjudication determined that one event was unlikely to reflect pancreatitis, one event was considered to reflect possible pancreatitis (laboratory elevations alone) unlikely related to the study drug, and two events were probable pancreatitis (laboratory elevations and suggestive symptoms), and both were considered possibly related to the study drug. Thyroid Cancer

One patient treated with albiglutide developed follicular cancer on day 243.

Two patients receiving sitagliptin developed thyroid cancer: one experienced follicular papillary carcinoma on day 48 and the other papillary thyroid cancer on day 549. In these three patients, thyroid cancer diagnoses were considered by the investigator to be not related to the study drug, and calcitonin concentrations were not abnormal. Potential SARs

A search of the standardized Medical Dictionary for Regulatory Activities queries identified two patients (placebo, n = 1; glimepiride, n = 1) who experienced angioedema as an SAE. The investigator considered neither to be related to the study drug but instead related to ACE inhibitor therapy. Both patients remained in the study after discontinuing ACE inhibitor therapy. Neither patient had positive antialbiglutide antibodies, and no other cases of angioedema, anaphylaxis, pharyngeal edema, or laryngeal edema occurred. The investigators did not flag any additional events of interest. Immunogenicity

Antialbiglutide antibody incidence among albiglutide-treated subjects was 7.0% (21 of 302 subjects), and included 1 subject (0.4%) with preexisting antibodies (positive at baseline). Antibodies were nonneutralizing and showed

reactivity with GLP-1 in 16 of the 21 antibody-positive subjects and with albumin in 5 antibody-positive subjects. No samples tested positive for antialbiglutide IgE antibodies, and no SARs were reported for antibody-positive subjects. Cardiovascular Parameters

At baseline, lipids and blood pressure were well controlled and mean values were similar across the four treatment groups (Supplementary Table 3). There were no clinically meaningful mean changes to lipids throughout the study. Minor changes in SBP and DBP, respectively, from baseline occurred in all treatment groups at week 104: placebo (2.2 and 0 mmHg), sitagliptin (0.2 and 0.2 mmHg), glimepiride (1.5 and 1.0 mmHg), albiglutide (21.0 and 20.7 mmHg). Treatment differences in SBP and DBP at week 104 between albiglutide and the three comparators were not statistically significant. Similarly, there were no meaningful changes from baseline at week 104 in mean heart rate: placebo, 2.3 bpm; sitagliptin, 0.8 bpm; glimepiride, 20.5 bpm; albiglutide, 1.3 bpm. CONCLUSIONS

When added to metformin, albiglutide produced clinically and statistically superior and more sustained reduction in HbA 1c at week 104 compared with

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placebo, sitagliptin, and glimepiride. The sustained treatment effect of albiglutide also is supported by the time to hyperglycemic rescue, which showed that fewer subjects taking albiglutide required rescue by week 104 compared with patients treated with placebo, sitagliptin, and glimepiride; the difference was statistically significant for albiglutide versus placebo and sitagliptin. Interestingly, the reduction in HbA1c was similar during the early treatment period (;4 weeks). This might not have been anticipated given the longer time to a steady state for the once-weekly albiglutide and the quick mechanism of action of sulfonylureas. Similar clinically and statistically superior results with albiglutide compared with all other treatment arms were observed for change in FPG from baseline and the proportion of patients meeting clinically relevant HbA1c treatment goals. In addition, patients receiving albiglutide, sitagliptin, and placebo lost weight through week 104, whereas patients treated with glimepiride gained weight; the difference between albiglutide and glimepiride was statistically significant (P , 0.0001). The sustained effect of diabetes therapy is a critical clinical issue. Previous type 2 diabetes comparator trials have demonstrated the superiority or noninferiority of GLP-1RAs with or without metformin but have been shorter 26week trials (20–22). The Diabetes Therapy Utilization: Researching Change in A1C, Weight, and Other Factors Through Intervention with Exenatide OnceWeekly (DURATION)-2 and Liraglutide Effect Action in Diabetes (LEAD)-2 trials, which included metformin in all treatment arms, demonstrated the superiority of exenatide over sitagliptin and pioglitazone and of liraglutide over placebo, respectively, with regard to HbA1c reductions (20–22). In another 26-week study (HARMONY 8), once-weekly albiglutide provided superior glycemic improvement, similar tolerability, and better patient compliance compared with sitagliptin therapy in patients with type 2 diabetes and renal impairment (21). Understanding the long-term effects on type 2 diabetes of different combination therapies has led to the 5-year Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study. This trial is comparing the efficacy and durability of four

classes of medications (DPP-4, sulfonylureas, GLP-1RAs, and long-acting insulin) in patients with type 2 diabetes who are receiving metformin (11). The results reported here may give a window to the eventual results of that trial. Albiglutide was generally well tolerated; the albiglutide group showed rates of SAEs and AEs leading to withdrawal similar to those of the comparator groups. The percentage of patients reporting AEs while receiving therapy was similar for albiglutide, sitagliptin, and glimepiride and slightly lower for placebo. The types of AEs noted for albiglutide are generally consistent with the type 2 diabetic population and the known profile of GLP-1RAs (23,24). The 104-week incidence of nausea/ vomiting with albiglutide (10.6%/5.6%) was lower than values observed in previous studies using other GLP-1RAs, particularly in the early weeks of therapy. In clinical practice, GI AEs occurring early in the course of treatment with GLP-1RAs may contribute to the discontinuation rates seen with this class, and agents with reduced GI effects may improve patient adherence. With respect to hypoglycemia, albiglutide had rates similar to sitagliptin and placebo and lower rates compared with glimepiride. Injection-site reactions were more common in the albiglutide-treated subjects, although a few (1.3%) withdrew because of reactions during the 104-week period. The proportion of patients developing antialbiglutide antibodies was low, and none were nonneutralizing. HARMONY 3 is a long-term, 3-year trial with unique design features that must be considered when interpreting results. First, up-titration was based on glucose thresholds established by protocol: the time point of titration was not prescribed or standardized, reflecting up-titration methods in clinical practice; thus, the efficacy and safety data reflect a mixture of 30- and 50-mg albiglutide doses and 2- and 4-mg glimepiride doses. In addition, there was no increased dose for placebo and sitagliptin despite patients who underwent the blinded up-titration procedure. Because of this design feature, many patients randomized to glimepiride and albiglutide were not receiving the maximum dose, as evidenced by the mean doses of each drug. Therefore, the maximum effect in these arms may not have been

achieved, depending on the dose curve for each agent, and there is a possibility that the relationship between the arms may have shifted at higher doses. Second, rescue medications were used in the program to permit patients to remain in the studies while receiving a blinded investigational product or control through 3 years. This represents a more “real-life” situation, where additional medications are added to regimens that are not meeting treatment goals. While the primary efficacy assessment was based on end points before rescue, the main safety assessment included data after rescue. These design features, however, may have complicated the interpretation of some results. Finally, interpretation of the proportion of patients reaching the treatment goal was complex; up-titration occurred at 7.5% and not 7.0%, and the full benefit of 50 mg may not be seen since the end point contains a mix of patients taking 30- and 50-mg albiglutide. In conclusion, when added to metformin, albiglutide produced clinically and statistically significant reductions in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride. Patients receiving albiglutide, sitagliptin, and placebo lost body weight through week 104, whereas patients taking glimepiride gained weight; the difference between albiglutide and glimepiride was statistically significant. Albiglutide was generally well tolerated, and rates of SAEs were similar across treatment groups. The most frequent AEs for albiglutide were largely consistent with the known profile for GLP-1RAs.

Acknowledgments. The authors thank Douglas L. Wicks, MPH, CMPP, of GlaxoSmithKline, for managing manuscript development. Editorial support was provided by Leonard Lionnet, PhD, of PharmaWrite, LLC (assistance with the production of a draft outline and the first draft of the manuscript, assembling tables and figures, and collating author comments); Diana Talag, ELS, of PharmaWrite, LLC (assistance with copyediting and fact-checking); and Shana Cambareri of PharmaWrite, LLC (art direction). Duality of Interest. B.A. received honoraria for lecturing and holds advisory board membership for Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Novo Nordisk, Merck, and Sanofi, which all are companies producing GLP-1RAs or DPP-4 inhibitors. S.L.J., M.S., D.T.C., F.Y., and C.P. are employed by and shareholders of GlaxoSmithKline. M.N.F. has received research support and has served either as an investigator

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HARMONY 3: 2-Year Albiglutide Efficacy/Safety

or principal investigator for Amylin, AstraZeneca, Eli Lilly and Company, GlaxoSmithKline, Merck & Co., Inc., Medtronic Inc., Novo Nordisk, Proctor & Gamble Co., Prodigy Diabetes Care, Sanofi, and Tethys, some of which are companies producing GLP-1RAs or DPP-4 inhibitors. M.N.F. also has served as a consultant for GlaxoSmithKline, Pfizer, and Proctor & Gamble Co. No other potential conflicts of interest relevant to this article were reported. The sponsor of the study participated in the study design, data collection, data review, data analysis, and writing of the report. All authors had full access to all the data in the study. The corresponding author reviewed the trial report (signatory investigator), had full access to all data in the study, and had final responsibility for the decision to submit for publication. Author Contributions. B.A. and M.N.F. provided study patients. S.L.J., M.S., D.T.C., F.Y., and C.P. analyzed and interpreted data. B.A., S.L.J., D.T.C., F.Y., and M.N.F. wrote and revised the manuscript. F.Y. performed the statistical analysis. All authors revised the manuscript, reviewed the final manuscript, and approved the manuscript for submission. M.N.F. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Data from this article were presented at the 73rd Scientific Sessions of the American Diabetes Association, Chicago, IL, 21– 25 June 2013, and published in Diabetes 2013;62(Suppl 1A):LB14 (Abstract 52-LB). Data also were presented via oral presentation at the 49th Annual Meeting of the European Association for the Study of Diabetes, Barcelona, Spain, 23–27 September 2013, and published in Diabetologia 2013;56(Suppl 1):S8.

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