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02-08-2022 | Exenatide | At a glance | Article

A quick guide to the DURATION trials

Author: Eleanor McDermid

medwireNews: Exenatide was the first long-acting injectable glucagon-like peptide (GLP)-1 receptor agonist to be approved for the treatment of people with type 2 diabetes, at a dose of 2.0 mg/week.

Here we round up the efficacy findings from the DURATION phase 3 clinical trial series, which tested weekly exenatide against the older twice-daily version and against other antihyperglycemic medications available at the time. We also include several more recent trials launched by the sponsor (AstraZeneca) to provide data for specific markets and versus newer medications.

As with the other GLP-1 receptor agonists, gastrointestinal issues were the predominant adverse events in all these trials.

The EXSCEL trial tested the cardioprotective ability of weekly exenatide, and is covered in our Round-up of the GLP-1 receptor agonist CV outcome trials.

See also:

Trials of the original weekly formulation

In its original form, microspheres of exenatide required reconstitution in an aqueous diluent before injection.

DURATION-1: Published

Trial population: People with type 2 diabetes on oral diabetes medications or drug naïve

Comparator treatment: Exenatide, twice-daily formulation


This open-label randomized trial, published in The Lancet in 2008, tested the weekly formulation of exenatide, at a dose of 2 mg, against the pre-existing twice-daily 10 µg version in 295 participants.

Both the weekly and daily treatments produced significant reductions from baseline in glycated hemoglobin (HbA1c), by an average of 1.9% and 1.5%, respectively, at week 30, but the reduction was significantly larger with the weekly formulation. Changes in bodyweight, at corresponding averages of 3.7 and 3.6 kg, were significant versus baseline but not between the two treatment groups.

As expected for the medication class, gastrointestinal issues were the most common adverse events, but these were less frequent in people taking the weekly than daily formulation. Nausea, for example, was reported by 26.4% versus 34.5%.

DURATION-2: Published

Trial population: People with type 2 diabetes taking metformin

Comparator treatments: Sitagliptin, pioglitazone


The DURATION-2 trial showed that weekly exenatide was a more efficacious second-line treatment for people already taking metformin than either the dipeptidyl peptidase-4 inhibitor sitagliptin or the thiazolidinedione pioglitazone.

During 26 weeks of double-blind treatment in 491 trial participants, exenatide produced a significantly larger average HbA1c reduction than the comparator treatments, at 1.5%, 0.9%, and 1.2%, respectively.

As reported in The Lancet, exenatide treatment resulted in an average 2.3 kg weight loss, which was significant relative to the 0.8 kg reduction with sitagliptin and the 2.8 kg weight gain with pioglitazone.

DURATION-3: Published

Trial population: People with type 2 diabetes taking metformin with/without a sulfonylurea

Comparator treatment: Insulin glargine


The DURATION-3 trial, also reported in The Lancet, established weekly exenatide as a viable alternative to insulin glargine in people whose blood glucose was poorly controlled with oral antidiabetic medications, with the added benefit of weight loss.

The 456 trial participants received treatment for 26 weeks, at the end of which those taking exenatide had a slightly but significantly larger average HbA1c reduction than those taking glargine, at 1.5% versus 1.3%. In addition, exenatide was associated with an average 2.6 kg decrease in bodyweight, compared with a 1.4 kg increase with glargine.

DURATION-4: Published

Trial population: Medication-naïve people with type 2 diabetes

Comparator treatments: Metformin, sitagliptin, pioglitazone


DURATION-4 sought to position weekly exenatide as a first-line diabetes therapy for people unable to tolerate metformin by testing it against metformin, sitagliptin, and pioglitazone monotherapy in 820 people treated only with lifestyle modifications.

The findings reported in Diabetes Care showed it to be noninferior to metformin across 26 weeks of treatment, with the two reducing HbA1c by respective averages of 1.53% and 1.48%. Exenatide did not achieve noninferiority versus pioglitazone but was significantly better than sitagliptin; these medications reduced HbA1c by 1.63% and 1.15%, respectively.

The average weight change with exenatide was a 2.0 kg decrease, which was significantly superior to the average 1.5 kg increase with pioglitazone and the 0.8 kg reduction with sitagliptin.

DURATION-5: Published

Trial population: People with type 2 diabetes on oral diabetes medications or drug naïve

Comparator treatment: Exenatide, twice-daily formulation


This trial was essentially the same design as DURATION-1, but the primary endpoint was HbA1c changes over 24 weeks, rather than 30 weeks, in 252 participants.

Again, the weekly formulation gave better results than the twice-daily version. HbA1c reductions averaged 1.6% versus 0.9%, and bodyweight reductions averaged 2.3 versus 1.4 kg.

DURATION 5 is published in The Journal of Clinical Endocrinology & Metabolism.

DURATION-6: Published

Trial population: People with type 2 diabetes taking one or more oral antihyperglycemic medications

Comparator treatment: Liraglutide


The DURATION-6 trial, published in The Lancet, failed to demonstrate the noninferiority of weekly exenatide to the daily injectable liraglutide in 911 trial participants over 26 weeks of treatment.

The average HbA1c reductions were 1.28% and 1.48% with exenatide and liraglutide, respectively, and bodyweight reductions were also in favor of liraglutide, averaging a corresponding 2.68 and 3.57 kg.

DURATION-7: Published

Trial population: People with insulin-treated type 2 diabetes

Comparator treatment: Placebo


This trial, conducted over 28 weeks in 461 participants, showed weekly exenatide to be a valid option for people with poor glucose control despite basal insulin treatment, who would otherwise need to add multiple injections of a prandial insulin.

Exenatide reduced HbA1c by an average of 0.73% relative to placebo, and 32.5% of exenatide-treated participants achieved HbA1c lower than 7.0%, compared with 7.4% of those taking placebo. Bodyweight fell by an average of 1.5 kg with exenatide versus placebo.

The trial was published in Diabetes, Obesity and Metabolism.

Trials of the ready-to-use formulation

To simplify delivery of weekly exenatide, the manufacturer produced a revised version that came ready to use, with the microspheres suspended in a mixture of medium-chain triglycerides in an autoinjector.

DURATION-NEO-1: Published

Trial population: People with type 2 diabetes taking oral diabetes medications or drug naïve

Comparator treatment: Twice-daily exenatide


During 28 weeks of treatment of 375 trial participants, HbA1c decreased by an average of 1.39% with the revised weekly exenatide formulation, which was significantly more than the 1.02% reduction with the twice-daily version. Weight loss averaged 1.49 and 1.89 kg, respectively, with no significant difference between the two treatments.

The findings were published in Diabetes, Obesity and Metabolism.

DURATION-NEO-2: Published

Trial population: People with type 2 diabetes on metformin monotherapy

Comparator treatments: Sitagliptin, placebo


In this trial, also published in Diabetes, Obesity and Metabolism, the revised weekly exenatide formulation provided significantly better glycemic control than sitagliptin or placebo over 28 weeks in 364 participants.

The average HbA1c reductions were 1.13%, 0.75%, and 0.40%, respectively. Bodyweight decreased with both exenatide and sitagliptin, at an average of 1.12 and 1.19 kg, respectively, and increased by 0.15 kg in the placebo group.

Other industry-sponsored phase 3 trials

Exenatide versus long-acting insulin: Published

Trial population: People with type 2 diabetes on metformin with/without a sulfonylurea

Comparator treatment: insulin detemir


This trial published in Diabetes Care tested exenatide against insulin detemir, which the investigators noted is the “most weight-neutral” of the long-acting insulins currently available.

During 26 weeks of treatment, 44.1% of the 111 people given exenatide achieved the primary outcome of HbA1c of 7.0% (53 mmol/mol) or below plus at least 1.0 kg of weight loss. By contrast, just 11.4% of the 105 participants allocated to detemir achieved this outcome.

Exenatide in Asian people: Published

Trial population: Asian people with type 2 diabetes taking oral antidiabetes medications

Comparator treatment: Twice-daily exenatide


This trial published in the Journal of Diabetes Investigation demonstrated the glucose- and weight-lowering ability of weekly exenatide in people from China, India, Japan, South Korea, and Taiwan.

In the 678 study participants comprising the intention-to-treat population, the average HbA1c reductions over 26 weeks were 1.43% and 1.12% with weekly and twice-daily exenatide, respectively – a significant difference favoring the weekly formulation. The corresponding weight loss reductions were 1.63 and 2.45 kg, which was a significant difference in this case favoring the twice-daily formulation.

Exenatide versus insulin in Japanese people: Published

Trial population: Japanese people with type 2 diabetes taking oral antidiabetes medications

Comparator treatment: Insulin glargine


This trial randomly assigned 427 Japanese participants to take weekly exenatide or insulin glargine for 26 weeks. At this point, the corresponding average HbA1c reductions were 1.11% and 0.68%, making exenatide statistically superior to glargine in this population. The average weight changes were a 1.67 kg reduction with exenatide and a 0.34 kg increase with glargine.

The findings are published in Clinical Therapeutics.

Exenatide in adolescents: Complete, not yet published

Trial population: Adolescents with type 2 diabetes taking metformin and/or sulfonylurea, with or without insulin

Comparator treatment: Placebo


This trial tested exenatide as an adjunct to existing treatment in 84 adolescents with type 2 diabetes over 24 weeks.

The primary findings have not yet been published, but the investigators reported positive results at the 2021 ADA Scientific Sessions, and exenatide subsequently received FDA approval for its use in this age group.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

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