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08-09-2022 | Liraglutide (T2DM) | At a glance | Article

A quick guide to the LEAD trials

medwireNews: Liraglutide was the first daily (as opposed to twice daily) injectable glucagon-like peptide (GLP)-1 receptor agonist to be approved for use in people with type 2 diabetes.

Here we provide an overview of the LEAD trial series, which tested liraglutide against the diabetes medications most commonly used at the time; the first of these trials to publish did so in 2008. We also include several more recent trials launched by the sponsor (Novo Nordisk) to provide data for specific markets and populations, and versus newer medications.

The LEADER trial tested the cardiovascular safety profile of liraglutide, and is covered in our Round-up of the GLP-1 receptor agonist CV outcome trials.

See also:

The LEAD series

LEAD-1: Published

Trial population: People with type 2 diabetes on oral antidiabetic medications, all taking glimepiride

Comparator treatments: Rosiglitazone, placebo

NCT00318422

During 26 weeks of treatment, the average glycated hemoglobin (HbA1c) reduction was 1.1% with the highest dose of liraglutide used, of 1.8 mg/day. This was significantly greater than the 0.4% reduction achieved with rosiglitazone and the 0.2% increase seen in the placebo group.

Bodyweight fell by an average of 0.2 kg with liraglutide 1.8 mg and 0.1 kg with placebo, but increased with rosiglitazone.

The results are published in Diabetic Medicine.
 

LEAD-2: Published

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

Comparator treatments: Glimepiride, placebo

NCT00318461

In this trial, published in Diabetes Care, people taking the highest liraglutide dose of 1.8 mg achieved an average 1.0% reduction in HbA1 during 26 weeks of treatment, as did those taking glimepiride. Both changes were significant compared with the average 0.1% increase observed in the placebo group.

Liraglutide treatment was the best intervention for weight loss, however, producing an average reduction of 2.8 kg, which was significant relative to the 1.0 kg increase in the glimepiride group and the 1.5 kg reduction in the placebo group.


LEAD-3: Published

Trial population: People with type 2 diabetes treated with diet and exercise only or with a single oral antidiabetic medication at no more than half maximal dose

Comparator treatment: Glimepiride

NCT00294723

This 52-week trial, published in The Lancet, established the potential for liraglutide to be used as a monotherapy in type 2 diabetes, enrolling participants who were drug-naïve or taking low doses of a single medication, which was discontinued before starting the study interventions.

HbA1c decreased by an average of 0.84% and 1.14% with liraglutide 1.2 and 1.8 mg, respectively; both of these reductions were significantly larger than the 0.51% achieved in the glimepiride group.

And liraglutide treatment resulted in weight loss of approximately 2 kg, which was sustained for the duration of the study, whereas people taking glimepiride gained about 1 kg, on average.


LEAD-4: Published

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

Comparator treatment: Placebo

NCT00333151

As detailed in Diabetes Care, all participants in LEAD-4 were started on metformin or rosiglitazone (any other medications were discontinued), to which was added liraglutide or placebo.

During the following 26 weeks, those allocated to liraglutide 1.2 or 1.8 mg achieved an average HbA1c reduction of 1.5%, compared with 0.5% for people taking placebo, which was a significant difference.

There was also a significant difference in weight change, at an average 1.0 and 2.0 kg reduction with liraglutide 1.2 and 1.8 mg, respectively, compared with a 0.6 kg increase in the placebo group.


LEAD-5: Published

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

Comparator treatments: Insulin glargine, placebo

NCT00331851

The LEAD-5 investigators studied liraglutide as an alternative treatment for people who were candidates to receive insulin glargine and found it to provide better glycemic control and weight outcomes.

By week 26, HbA1c had decreased by an average of 1.33% with liraglutide 1.8 mg (the only dose studied in this trial), which was significantly more than the 1.09% achieved with glargine and the 0.24% with placebo.

As reported in Diabetologia, weight reduced by 1.80 kg, on average, in the liraglutide group, compared with 0.42 kg in the placebo group and a 1.60 kg increase in the glargine group.


LEAD-6: Published

Trial population: People with type 2 diabetes taking metformin, a sulfonylurea, or both

Comparator treatment: Exenatide twice daily

NCT00518882

The results of this trial showed that a single daily injection of liraglutide resulted in significantly better glycemic control than two daily injections of exenatide, while promoting similar amounts of weight loss.

As reported in The Lancet, the average HbA1c reductions at week 26 were 1.12% and 0.79% with liraglutide and exenatide, respectively, and average weight loss was 3.24 and 2.87 kg.


Other industry-sponsored phase 3 trials

Liraglutide versus a DPP-4 inhibitor: Published

Trial population: People with type 2 diabetes taking metformin

Comparator treatment: Sitagliptin

NCT00700817

This trial, published in The Lancet, compared liraglutide against sitagliptin, the first DPP-4 (dipeptidyl peptidase-4) inhibitor to be approved.

Both liraglutide doses used gave significantly better HbA1c lowering, at 1.24% and 1.50% for the 1.2 and 1.8 mg doses, respectively, versus 0.90% with sitagliptin. Bodyweight decreased by corresponding averages of 2.86 and 3.38 kg versus 0.96 kg during the 26-week study period.


Liraglutide added to an SGLT2 inhibitor: Published

Trial population: People with type 2 diabetes taking an SGLT2 inhibitor alone or with metformin

Comparator treatment: Placebo

NCT02964247

Adding liraglutide 1.8 mg to existing SGLT (sodium-glucose cotransporter)2 inhibitor treatment in this trial resulted in an average 0.98% reduction in HbA1c level between baseline and week 26. This was significantly greater than the average 0.30% decrease in the placebo group.

Liraglutide did not significantly enhance weight loss, although people assigned to the treatment lost numerically more weight than those given placebo, at respective averages of 2.81 and 1.99 kg.

The results are published in Diabetes, Obesity and Metabolism.


Liraglutide in insulin-treated diabetes: Published

Trial population: People with type 2 diabetes on basal insulin with/without metformin

Comparator treatment: Placebo

NCT01617434

This trial looked at liraglutide as an add-on to an insulin analog (glargine or detemir), rather than as an alternative as in LEAD-5.

As reported in Diabetes, Obesity and Metabolism, people taking liraglutide 1.8 mg experienced an average 1.3% reduction in HbA1c over 26 weeks of treatment, compared with just 0.1% in those taking placebo. Likewise, bodyweight decreased by an average of 3.5 versus 0.4 kg.


LIRA-PRIME: Published

Trial population: People with type 2 diabetes taking metformin

Comparator treatment: Investigator’s choice of oral antidiabetic agent

NCT02730377

In this trial, the median time to inadequate glycemic control was 109 weeks in people given liraglutide versus 65 weeks for those given physician’s choice of oral treatment, which was most commonly an SGLT2 inhibitor (47.9%), a DPP-4 inhibitor (39.7%), or a sulfonylurea (10.8%).

The trial is published in Diabetes, Obesity and Metabolism.

Related news story: Liraglutide add-on may offer better control than OADs in type 2 diabetes


LIRA-RENAL: Published

Trial population: People with type 2 diabetes and moderate renal impairment taking metformin, sulfonylurea, pioglitazone, or insulin, alone or in combination

Comparator treatment: Placebo

NCT01620489

Liraglutide 1.8 mg treatment resulted in the expected glycemic and weight benefits for people who also had moderate kidney impairment, in this trial published in Diabetes Care.

During the 26-week trial, HbA1c declined by an average of 1.05% with liraglutide compared with 0.38% with placebo, which was a significant difference, and the corresponding weight reductions were 2.41 and 1.09 kg.


The SCALE series: Published

Trial population: People with diabetes and obesity taking up to three oral antidiabetic agents (SCALE Diabetes) or up to two plus insulin (SCALE Insulin)

Comparator treatment: Placebo

NCT01272232 (SCALE Diabetes); NCT02963922 (SCALE Insulin)

The SCALE trial series investigated a higher dose of liraglutide (3.0 mg) as a treatment for people with obesity, in addition to intensive diet and exercise therapy.

Two of these trials exclusively enrolled people with type 2 diabetes: SCALE Diabetes, published in JAMA, and SCALE Insulin, published in Diabetes Care.

In SCALE Diabetes, participants lost an average of 6.0% of their bodyweight (6.4 kg) with liraglutide versus 2.0% (2.2 kg) with placebo. The corresponding values in SCALE Insulin were 5.8% and 1.5%.

Related news story: Liraglutide 3.0 mg boosts weight loss in insulin-dependent type 2 diabetes


Ellipse (Liraglutide in children): Published

Trial population: Children aged 10 to <17 years with type 2 diabetes treated with diet and exercise, metformin and/or insulin

Comparator treatment: Placebo

NCT01541215

Liraglutide was the first GLP-1 receptor agonist to be approved for use in a pediatric population, based on the results of the Ellipse trial, published in The New England Journal of Medicine.

The dose was titrated based on efficacy and side effects, with 55.6% of participants in the liraglutide group reaching the maximum adult dose of 1.8 mg. During 26 weeks of treatment, children taking liraglutide achieved an average 0.64% reduction in HbA1c, compared with a 0.42% increase in the placebo group, and this difference persisted at week 52.

Bodyweight decreased by an average of 2.3 kg in the liraglutide group versus 0.99 kg in the placebo group and the liraglutide group maintained this improvement at week 52, whereas placebo-treated participants gained weight.

Also relevant is another NEJM publication showing efficacy of liraglutide 3.0 mg versus placebo in adolescents with obesity (NCT02918279).

Related news stories:
Ellipse trial: Liraglutide expands treatment options for pediatric type 2 diabetes
Liraglutide for weight loss successful in obese adolescents


Published trials in Japanese/Asian populations

Participants of the above trials were predominantly of European descent, but there are also a number of published trials in Asian populations, largely Japanese, listed below. Most trials used liraglutide at a daily dose of 0.9 mg – lower than that used in other trials – but still found that it gave significantly better glycemic control than the comparator treatments.

One trial compared 0.9 and 1.8 mg doses and found the latter to produce a significantly larger HbA1c reduction, and the only Asian trial based outside of Japan tested the 1.8 mg dose.

Trial population

Comparator treatment

Links

Japanese populations given lower doses

Uncontrolled with lifestyle therapy and oral antidiabetic medication monotherapy

Glibenclamide

NCT00393718 
Journal publication

Uncontrolled with lifestyle therapy and oral antidiabetic medication monotherapy

Investigator’s choice of oral antidiabetic medication

NCT01512108
Journal publication

Uncontrolled on sulfonylurea monotherapy

Placebo

NCT00395746
Journal publication

Uncontrolled on insulin (basal/premixed/basal–bolus)

Placebo

NCT01572740 
Journal publication

Japanese populations given higher dose

Uncontrolled with lifestyle therapy and oral antidiabetic medication monotherapy

Liraglutide 0.9 mg

NCT02505334 

Chinese/Indian/Korean population given higher dose

Uncontrolled on one or more antidiabetic medications

Glimepiride

NCT00614120
Journal publication


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