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Efficacy and safety of exenatide once weekly: an overview of the DURATION trials Expert Rev. Endocrinol. Metab. 7(6), 611–623 (2012)

Christophe EM De Block* and Luc F Van Gaal Department of Diabetology– Endocrinology and Metabolism, Faculty of Medicine, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium *Address for correspondence: Tel.: +32 3 821 32 78 Fax: +32 3 825 49 80 [email protected]

Diabetes management involves controlling glycemia and cardiometabolic risk factors. In the DURATION trials, the efficacy and safety of exenatide (EX) once weekly (q.w.), a new longacting glucagon-like-peptide-1 receptor agonist, was studied as monotherapy or as add-on to metformin with or without sulfonylurea, and compared with oral (metformin, pioglitazone or sitagliptin) and injectable antidiabetic drugs (EX twice daily [EX b.i.d.], liraglutide and insulin glargine). EX q.w. reduced HbA1c by 1.3–1.9% and showed better overall glycemic control compared with EX b.i.d., sitagliptin, pioglitazone and insulin glargine, but not liraglutide. Fasting plasma glucose was reduced more by EX q.w. than by EX b.i.d. or sitagliptin, whereas postprandial glycemia was better controlled by EX b.i.d. Weight loss was achieved by EX q.w. and EX b.i.d., in contrast to pioglitazone and insulin glargine. EX q.w. improved systolic blood pressure, lipids and cardiovascular risk markers. EX q.w. was well tolerated without safety issues. The most common adverse events were nausea, vomiting and constipation. Injection-site reactions were present in 5–13%. The risk of hypoglycemia of EX q.w. was similar to EX b.i.d., sitagliptin and pioglitazone. Hypoglycemia risk was not increased when EX q.w. was not combined with sulfonylurea. Keywords: diabetes • DURATION trial • exenatide • GLP-1 • incretin

The incidence of Type 2 diabetes mellitus (T2DM) is increasing worldwide. Over 80% of all T2DM patients are overweight and 50% are obese. Obesity exacerbates metabolic and ­cardiovascular risk factors such as dyslipidemia and ­hypertension in this population. Therefore, management of diabetes has evolved from a glucocentric approach towards strategies that include targeting pathophysiological and cardiometabolic problems. Optimal treatments should address both fasting and postprandial glucose (PPG) control, limit the risk of hypoglycemia, preserve functional b-cell mass, reduce bodyweight and blood pressure, improve dyslipidemia and be convenient and safe. In recent years, glucagon-like peptide-1 ­(GLP-1) receptor agonists such as exenatide (EX) and liraglutide have proven their usefulness in the treatment of T2DM [1–3] . They improve glycemic control through glucosedependent stimulation of insulin secretion, suppression of glucagon secretion, slowing gastric emptying and reduced appetite. Randomized, www.expert-reviews.com

10.1586/EEM.12.51

controlled studies have shown a similar reduction in HbA1c compared with insulin glargine once a day (q.d.) or premixed insulin aspart (30/70) twice a day, but with the a­ dvantages of less hypoglycemia and weight loss [4–7] . Adherence to treatment is also crucial for effective glucose management. The complexity of a treatment regimen and the number of injections may influence outcome. The development of a long-acting release formulation of EX might hold the promise of a once-weekly (q.w.) injectable that improves cardiometabolic risk factors, compliance and treatment satisfaction. However, caution is needed as with any newly developed drug. Long-term efficacy data for glucose control, capacity to reduce chronic complications, tolerance and safety profile, ease of use, and costs are still unclear. This article presents an update on currently available randomized, controlled trials (‘DURATION’ trials) evaluating the efficacy and safety of EX q.w. (Bydureon®, Amylin Pharmaceutical, Eli Lilly and Alkermes Inc.,

© 2012 Expert Reviews Ltd

ISSN 1744-6651

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MA, USA). DUR ATION is the acronym of ‘Diabetes therapy utilization: researching changes in A1C, weight and other factors through intervention with exenatide once weekly’. DURATION trials included more than 3200 T2DM subjects in more than 30 countries in America, Europe, Australia and Asia. It was designed to study EX q.w. as a monotherapy or as add-on to metformin with or without sulfonylurea (SU), and to compare it with other antidiabetic drugs, both oral (metformin, pioglitazone or sitagliptin) and injectable (EX twice daily [EX b.i.d.], insulin glargine and liraglutide). As such, it investigated the use of EX q.w. across the continuum of care of T2DM. EX q.w. (Bydureon)

EX q.w. is a long-acting release form of EX, consisting of injectable biodegradable polymeric microspheres that entrap EX [8,9] . EX is incorporated into a matrix of poly(d,l-lactide-co-glycolide) that allows gradual drug delivery at a controlled rate [10] . Once released, EX is eliminated via the kidneys. A stable plasma concentration of EX is obtained 5–10 weeks after subcutaneous injection of 2 mg of EX q.w. This level is ­comparable with the peak c­ oncentrations obtained by EX b.i.d.

In the 26-week double-blind DURATION-4 study, patients were randomized to EX q.w. 2 mg subcutaneous plus oral placebo (n = 248) versus metformin 2000 mg/day plus subcutaneous placebo (n = 246) versus pioglitazone 45 mg/day plus subcutaneous placebo (n = 163) versus sitagliptin 100 mg/day plus subcutaneous placebo (n = 163) [17] . Patients had a shorter mean diabetes duration compared with the other DURATION trials (3 years) and HbA1c averaged 8.5% at start. The DURATION-5, like the DURATION-1 trial, compared EX q.w. versus EX b.i.d. during a 26-week open-label study in 252 T2DM subjects [18] . The duration of diabetes averaged 7 years and HbA1c 8%. This study included more Hispanic subjects than in the DURATION-1 trial. In the 26-week open-label DURATION-6 study, EX q.w. was compared with liraglutide 1.8 mg q.d. in 912 patients [19] . HbA1c averaged 8.5% at start. Ethnicity, mean age, BMI at baseline and other factors that illustrate the setting of the different studies are shown in Table 1. They are important to be taken into account when interpreting the results. Glycemic control parameters

Study design, background and setting of the DURATION trials

In the open-label DURATION-1 trial, the efficacy and safety of 2 mg of EX q.w. was compared with that of 10 µg of EX b.i.d. in 295 T2DM subjects over a 30-week period [11] . Patients were drug naive or were treated with metformin, sulphonyl­ ureum, thiazolidine­d ione or any combination of two of these agents. They had a mean diabetes duration of 6.5 years and a mean HbA1c of 8.3% (Table 1) . After 30 weeks in the core study, patients treated with EX q.w. continued treatment, while those randomized to EX b.i.d. shifted to EX q.w. in an open-label extension study for initially another 22 weeks [12] , and finally up to 2 years [13] . Of the 295 intent-to-treat patients who entered the trial, 73% (n = 216) completed 2 years of treatment. DURATION-2 compared EX q.w. with pioglitazone and with sitagliptin as an add-on to metformin [14] . In this 26-week randomized, double-blind, double-dummy trial, 170 T2DM subjects were assigned to receive 2 mg of EX q.w. plus oral placebo q.d., 172 to receive 45 mg of pioglitazone q.d. plus injected placebo q.w. and 172 to receive 100 mg of sitagliptin q.d. plus injected placebo q.w. The mean duration of diabetes was 6 years and HbA1c averaged 8.5% at baseline. A 26-week open-label extension phase of this trial assessed the efficacy and safety of continued EX q.w. treatment and that of switching patients initially randomized to pioglitazone or sitagliptin to EX q.w. Of the 364 patients who ­continued into the open-label study, 319 (88%) completed 52 weeks [15] . The DURATION-3 trial was a 26-week open-label study comparing EX q.w. (2 mg) with q.d. insulin glargine in 456 T2DM subjects [16] . A total of 70% of patients were treated with metformin and 30% with metformin plus sulphonylureum. The mean duration of diabetes was 8 years and HbA1c was 8.3%.

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HbA1c

At baseline, mean HbA1c varied between 8.3 and 8.5% across the six studies. As shown in Table 2 & Figure 1, EX q.w. improved glycemic control across the DURATION trials. In drug-naive T2DM patients previously inadequately controlled with diet and exercise, EX q.w. reduced HbA1c by 1.4% (DURATION-4). Further down the continuum of care, in subjects treated with metformin, EX q.w. lowered HbA1c by 1.5% (DURATION-2). At more advanced stages in the disease process, HbA1c was reduced by 1.3–1.9% by EX q.w. Most of the patients treated with EX q.w. reached an HbA1c ≤7%, varying between 58 and 77%. An HbA1c ≤6.5% could be reached in the range of 35–49% of the subjects. Treatment with EX q.w. reduced HbA1c significantly more than with EX b.i.d., sitagliptin and insulin glargine. In the DURATION-4 study, the reduction in HbA1c was greater with EX q.w. than with sitagliptin, but was as equally effective as metformin and pioglitazone. The only comparator that improved HbA1c to a greater extent than EX q.w. was liraglutide (DURATION-6). The reduction in HbA1c was sustained throughout the study periods and beyond, as the open-label extension studies show. After the 30-week DURATION-1 core study and the 22-week open-label extension study, subjects continuing EX q.w. proved to maintain their HbA1c improvement (-2%) [12] . Patients switching from EX b.i.d. to EX q.w. showed further improvements in HbA1c and both groups reached the same reduction and mean HbA1c (6.6%) at 52 weeks. In patients with a baseline HbA1c >9%, the reduction in HbA1c varied between 2.6 and 2.8%. In the completer population (n = 216), improvements in HbA1c (-1.7%) were maintained at 2 years [13] . Patients in the open-label extension phase of the DURATION-2 trial who were treated only with EX q.w. showed a 1.6% improvement in HbA1c at 52 weeks [15] . Those who were switched from sitagliptin to EX q.w. demonstrated an incremental amelioration Expert Rev. Endocrinol. Metab. 7(6), (2012)

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Efficacy & safety of exenatide once weekly: the DURATION trials

Table 1. Baseline characteristics and study design across the DURATION trials. Parameter

DURATION-1

DURATION-2

DURATION-3

DURATION-4

DURATION-5

DURATION-6

Comparator

Exenatide b.i.d.

Sitagliptin or pioglitazone

Insulin glargine

Metformin, sitagliptin or pioglitazone

Exenatide b.i.d.

Liraglutide 1.8 mg

Type of study

Open-label

Double-blind

Open-label

Double-blind

Open-label

Open-label

Population

Drug naive or ≥1 oral antidiabetic drug

Metformin failure

Metformin ± sulfonylurea failure

Drug naive

Drug naive or ≥ 1 oral antidiabetic drug

≥1 oral antidiabetic drug

Study duration

30 weeks + open-label extension

26 weeks + open-label extension

26 weeks + 2.5-year open-label extension

26 weeks + 10-week safety follow-up

24 weeks

26 weeks + 10-week safety follow-up

Number of patients

295 ITT

491 ITT

456 ITT

820 ITT

252 ITT

912 ITT

Age (years)

55 ± 10

52 ± 10

58 ± 10

54 ± 11

56 ± 11

57 ± 10

Duration of DM (years)

6.5 ± 5.5

6 ± 5

8 ± 6

2.7 ± 3.6

7 ± 5

NR

Gender (male/female; %)

53/47

52/48

53/47

59/41

58/42

NR

Ethnicity (%) – Caucasian – Black – Asian – Native American – Hispanic – Other

78 9 0.3 0 12 0

34 11 24 0.6 29 1

83 0.6 6 0 10 0

67 3 21 NR 8 1

59 6 4 0 31 0

NR NR NR NR NR NR NR

Weight (kg)

102 ± 20

88 ± 20

91 ± 17

87 ± 19

96 ± 20

NR

BMI (kg/m )

35 ± 5

32 ± 5

32 ± 5

31 ± 5

33 ± 5

32 ± 6

HbA1c (%)

8.3 ± 1

8.5 ± 1.2

8.3 ± 1

8.5 ± 1.2

8.4 ± 1.2

8.5 ± 1

FPG (mmol/l)

9.4 ± 2.3

9.1 ± 2.6

9.8 ± 2.6

9.9 ± 3

9.5 ± 2.6

9.7

2

b.i.d.: Twice daily; DM: Diabetes mellitus; FPG: Fasting plasma glucose; ITT: Intent-to-treat; NR: Not reported.

in HbA1c of 0.3 %, resulting in a 52-week reduction in HbA1c of 1.4%. Those who were shifted from pioglitazone to EX q.w. maintained HbA1c improvement (at week 52: -1.6%). Fasting plasma glucose & PPG

At the start of the studies, the average fasting plasma glucose (FPG) level varied between 9.1 and 9.9 mmol/l. FPG reductions from baseline ranged between 1.8 and 2.3 mmol/l. EX q.w., both as monotherapy and as part of a combination regimen, has been shown to reduce FPG. Reductions in FPG were significantly greater with EX q.w. than with EX b.i.d. and with sitagliptin, but similar to pioglitazone. Insulin glargine was more effective in lowering FPG than EX q.w. Doses for insulin glargine increased from baseline 10 to 31 IU/day, targeting a FPG of 4–5.5 mmol/l following a prespecified titration algorithm. In the open-label extension of the DUR ATION-1 trial, patients receiving 2 years of EX q.w. treatment showed a 2.2 ± 0.2 mmol/l of decrease in FPG [13] . In the open-label extension of the DURATION-2 trial, patients who received only EX q.w. demonstrated a significant 52-week improvement in FPG www.expert-reviews.com

(-1.8 ± 0.3 mmol/l) [15] . Patients who were shifted from sitagliptin to EX q.w. incrementally improved their FPG (-0.7 ± 0.2 mmol/l) and those who were switched from pioglitazone to EX q.w. ­maintained their FPG improvement (-1.7 ± 0.3 mmol/l). PPG was better controlled with EX b.i.d. than with EX q.w. (-6.9 vs -5.3 mmol/l). By contrast, EX q.w. caused greater reductions in PPG than did insulin glargine after morning and evening meals. No data on PPG control were reported in the DURATION-2 and -4 trials. Cardiovascular risk factors Bodyweight

GLP-1 receptor agonist-based therapies have the potential to produce weight loss, in contrast to many alternative therapeutic options. EX q.w. has consistently shown a significant weight loss throughout all DURATION trials (Figure 2) . Baseline weight varied between 87 kg in the DURATION-4 study and 102 kg in the DURATION-1 study. Mean BMI ranged between 31 and 35 kg/m2. After 24–30 weeks, patients randomized to EX q.w. lost weight in the range of 2–3.7 kg. 613

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Table 2. Changes in HbA1C , fasting plasma glucose and weight across the DURATION trials. Parameter

DURATION-1

DURATION-2

DURATION-3

DURATION-4

DURATION-5

DURATION-6

Number of patients

295

491

456

820

252

912

At entry

8.3 ± 1

8.5 ± 1.2

8.3 ± 1

8.5 ± 1.2

8.4 ± 1.2

8.5 ± 1.0

At end – EX q.w. – EX b.i.d. – Metformin – Sitagliptin – Pioglitazone – Glargine – Liraglutide

-1.9 ± 0.1 -1.5 ± 0.1 NR NR NR NR NR

-1.5 ± 0.1 NR NR -0.9 ± 0.1 -1.2 ± 0.1 NR NR

-1.5 ± 0.05 NR NR NR NR -1.3 ± 0.06 NR

-1.53 ± 0.07 NR -1.48 ± 0.07 -1.15 ± 0.08 -1.63 ± 0.08 NR NR

-1.6 ± 0.1 -0.9 ± 0.1 NR NR NR NR NR

-1.28 NR NR NR NR NR -1.48

HbA1c 4 kg) [12] . Patients in the EX q.w.-only group lost 4.1 kg and those switching from EX b.i.d. to EX q.w. lost 4.5 kg of bodyweight. Both groups displayed a similar weight evolution. Approximately 78% of patients achieved a reduction in HbA1c and weight. After 2 years of treatment, in the completer population, significant improvements were maintained in bodyweight (-2.6 kg) compared with baseline [13] . Furthermore, 61% achieved reductions in A1C and bodyweight at 2 years of treatment. In the DURATION-2 open-label extension trial, patients who received EX q.w.-only demonstrated a significant improvement 614

in weight (-1.8 kg) at 52 weeks [15] . Patients who switched from sitagliptin to EX q.w. demonstrated significant incremental improvements in weight (-1.1 kg), and those who switched from ­pioglitazone to EX q.w. showed a significant weight reduction (-3 kg). Blood pressure

Clinically significant improvements in systolic blood pressure (SBP) were observed in patients treated with EX q.w. throughout all DURATION trials Figure 3. Baseline SBP varied between 126 and 135 mmHg and was reduced by 1.3–4.7 mmHg. Diastolic blood pressure ranged between 78 and 81 mmHg at the start, but was not significantly lowered by EX q.w. In patients with abnormal baseline SBP (≥130 mmHg), treatment with EX q.w. improved SBP by 6.3–11.1 mmHg. In the open-label extension of the DURATION-1 trial, 50% of patients continuing EX q.w. and 46% patients switching from EX b.i.d. to EX q.w. with elevated SBP (≥130 mmHg) at baseline achieved normal SBP at week 52 [12] . The majority of Expert Rev. Endocrinol. Metab. 7(6), (2012)

Efficacy & safety of exenatide once weekly: the DURATION trials

patients (84%) did not change concomitant antihypertensive treatment. A 3-mmHg benefit in SBP was maintained through 2 years of treatment [13] . In the open-label extension phase of the DURATION-2 trial, patients with a baseline abnormal SBP (≥130 mmHg) treated with EX q.w. for 52 weeks (n = 42) exhibited a 12.2-mmHg improvement in SBP [15] . Patients with an abnormal SBP at week 26 after treatment with sitagliptin (n = 46) or pioglitazone (n = 34), and then switched to EX q.w. demonstrated a SBP reduction of 11.3 and 9.4 mmHg, respectively. Changes in concomitant antihypertensive medications were only allowed if deemed necessary by the investigator. Of the 186 patients who used an antihypertensive agent at the start of the open-label assessment period, 172 patients (99, 87 and 93% of patients originally randomized to EX q.w., sitagliptin and pioglitazone, respectively) did not change dose. Lipid levels

Lipid levels were marginally ameliorated with EX q.w. treatment in most studies (Figure 4) . In the DURATION-1 trial, total and LDL cholesterol (LDL-C) were slightly improved, while triglyceride (TG) levels decreased by 15% (baseline TG level: 1.88 mmol/l). In the DURATION-2 trial, statistically significant improvements in HDL cholesterol (HDL-C) were recorded in all treatment groups, but were greatest for pioglitazone. The DURATION-3 trial did not show differences in lipid levels between the two treatment groups. No clinically significant changes in fasting serum lipids were observed during the treatment period in the DURATION-4 trial. In the DURATION-5 study, significant reductions in mean fasting total and LDL-C were observed with EX q.w. but not with EX b.i.d. Few subjects (