Evidence tables

Evidence tables

Table 4 Pi-Sunyer et al. 2015

Study references

Pi‑Sunyer X, Astrup A, Fujioka K et al. (2015) A randomized, controlled trial of 3.0 mg of liraglutide in weight management −New England Journal of Medicine 373 (1), 11–22

Unique identifier

NCT01272219

Study type

RCT

Aim of the study

To evaluate the safety and efficacy of liraglutide as an adjunct to a reduced calorie diet and increased physical activity, for weight management in overweight or obese adults who did not have diabetes at baseline

Study dates

June 2011 to March 2013

Setting

191 sites in 27 countries in Europe, North America, South America, Asia, Africa and Australia

Number of participants

n=3,731

Population

Adults aged 18 years and over with a stable body weight and either a BMI of 30 kg/m² or above or 27 kg/m² or above in addition to dyslipidaemia or hypertension. The mean age of participants was 45 years, the mean BMI was 38 kg/m², 78% of participants were female and 85% were white. All participants received lifestyle interventions for weight loss based on advice to increase physical activity to 150 minutes per week and reduce daily energy intake by 500 kcal below their individualised energy requirements.

Inclusion criteria

Adults with a BMI of 30 kg/m² or above or 27 kg/m² or above in addition to treated or untreated dyslipidaemia or hypertension. Participants had a stable body weight, defined as less than 5 kg self-reported change during the previous 3 months and had a previous failed dietary effort at weight loss.

Exclusion criteria

Exclusion criteria included adults with type 1 or type 2 diabetes, use of any medicines that can cause clinically significant weight changes, previous bariatric surgery, a history of pancreatitis, a history of major depression or another severe psychiatric disorder, a family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma and previous treatment with a GLP-1 receptor agonist within the last 3 months. People who had taken part in an organised weight loss programme or taken any other medicines for weight management in the previous 3 months were also excluded from the study.

Intervention(s)

Liraglutide (n=2,487) injected subcutaneously, starting at a dose of 0.6 mg once daily increased to 3.0 mg once daily at 0.6 mg weekly incrementsa

Comparator(s)

Placebo (n=1,244) injected subcutaneouslya

Length of follow-up

70 weeksb

Outcomes

Co-primary outcomes (all assessed at week 56):

  • weight change from baseline

  • proportion of participants who lost at least 5% of their baseline bodyweight

  • proportion of participants who lost more than 10% of their baseline bodyweight

A fourth co-primary outcome on time to onset of type 2 diabetes over 160 weeks of treatment in the subgroup of people with prediabetes at baseline was assessed in le Roux et al. 2017

Secondary outcomes:

  • secondary outcomes include change from baseline in waist circumference, BMI, blood pressure, total lipid level concentrations and health-related quality of life scores

Safety outcomes:

  • Adverse events that occurred during the main 56 week trial period were reported that had an onset on or after the first day of treatment and no later than 14 days after the last day of treatment. Specific attention was given to types of adverse events that have an increased incidence in people with obesity or that are relevant to the GLP-1 agonist drug class.

Source of funding

Novo Nordisk

Overall risk of bias/quality assessment ( CASP RCT checklist )

Did the trial address a clearly focused issue?

Yes

Was the assignment of participants to treatments randomised?

Yesa,c

Were participants, health workers and study personnel blinded?

Yes

Were the groups similar at the start of the trial?

Yes

Aside from the experimental intervention, were the groups treated equally?

Yesd

Were all of the participants who entered the trial properly accounted for at its conclusion?

Yese

How large was the treatment effect?

See table 8

How precise was the estimate of the treatment effect?

See table 8

Can the results be applied in your context? (or to the local population)

Yes

Were all clinically important outcomes considered?

Yes

Are the benefits worth the harms and costs?

See overview

Study limitations

  • Study compares liraglutide to placebo and not active treatment.

  • The primary outcomes on weight loss are assessed after 56 weeks' treatment in all participants. Assessment of weight outcomes after 56 weeks is not reflective of the treatment indication in the summary of product characteristics (SPC: Saxenda), which recommends that treatment should be discontinued after 12 weeks on the 3.0 mg daily dose (recommended maintenance dose) if patients have not lost at least 5% of their initial body weight.

  • There was a high drop-out rate in the study; 28.1% in the liraglutide group and 35.6% in the placebo group.

  • No correction for multiple testing was made for the secondary outcomes. Therefore any statistical analysis provided for these outcomes should be interpreted with caution.

Comments

a Randomisation to treatment was stratified according to prediabetes status at screening and according to BMI (less than 30 kg/m² and 30 kg/m² or more). Prediabetes was defined as either an HbA1c measurement from 39 to 46 mmol/mol or a fasting plasma glucose measurement from 5.6 to 6.9 mmol per litre or a 2 hour oral glucose tolerance test of 7.8 to 11.0 mmol per litre.

b Participants were evaluated every 2 weeks until week 8, then every 4 weeks until week 44 and then again at weeks 50, 56, 60, 64, 68 and 70. The 3 co-primary outcomes and secondary outcomes were assessed at 56 weeks.

c The method of randomisation suggests allocation was concealed. Participants were randomised to each treatment group (2:1) via a telephone or web based system provided by the manufacturers.

d After 56 weeks, participants in the liraglutide group who did not have prediabetes at screening were randomly assigned in a 1:1 ratio to continue receiving liraglutide or to switch to placebo for 12 weeks to assess whether efficacy was maintained after discontinuation of liraglutide treatment and whether there were safety issues related to discontinuation. Participants in the placebo group continued to receive placebo.

e There was a high dropout rate in the study. Missing values were imputed with the use of the last observation carried forward method for measurements made after baseline.

Abbreviations: GLP-1, glucagon-like peptide-1; HDL, high density lipoprotein; LDL, low density lipoprotein

Table 5 le Roux et al. 2017

Study references

le Roux , Carel W, Astrup A et al. (2017) 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial The Lancet DOI.org/10.1016/S0140–67361(17) 30069–7

Unique identifier

NCT01272219

Study type

RCT

Aim of the study

To evaluate the effect of liraglutide 3.0 mg daily on the time to onset of type 2 diabetes and its effect on weight loss and safety over 3 years in a population of people with prediabetes

Study dates

June 2011 to March 2015

Setting

191 sites in 27 countries in Europe, North America, South America, Asia, Africa and Australia

Number of participants

n=2,254

Population

Adults aged 18 years and over with prediabetes, a stable body weight and either a BMI of 30 kg/m² or above or 27 kg/m² or above in addition to dyslipidaemia or hypertension. The mean age of participants was 47 years, the mean BMI was 39 kg/m2 and the mean HbA1c was 40 mmol/mol in the liraglutide group and 39 mmol/mol in the placebo group. All participants received lifestyle interventions for weight loss based on advice to increase physical activity to 150 minutes per week and reduce daily energy intake by 500 kcal below their individualised energy requirements.

Inclusion criteria

Participants who had prediabetesa at baseline in Pi-Sunyer et al. 2015 and completed 56 weeks of treatment were enrolled onto this extension phase of the study.

Exclusion criteria

Exclusion criteria included adults with type 1 or type 2 diabetes, use of any medication that can cause clinically significant weight changes, previous bariatric surgery, a history of pancreatitis, a history of major depression or another severe psychiatric disorder, a family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma and previous treatment with a GLP-1 receptor agonist within the last 3 months.

Intervention(s)

Liraglutide (n=1,505) injected subcutaneously, 3.0 mg once daily

Comparator(s)

Placebo (n=749) injected subcutaneously

Length of follow-up

172 weeksb

Outcomes

Primary outcome: time to onset of type 2 diabetesa

Secondary outcomes:

  • secondary outcomes included change from baseline in bodyweight

Safety outcomes:

  • adverse events that occurred during the main 160 week trial period were reported that had an onset on or after the first day of treatment and no later than 14 days after the last day of treatment

Source of funding

Novo Nordisk

Overall risk of bias/quality assessment ( CASP RCT checklist )

Did the trial address a clearly focused issue?

Yes

Was the assignment of participants to treatments randomised?

Yesc

Were participants, health workers and study personnel blinded?

Uncleard

Were the groups similar at the start of the trial?

Yes

Aside from the experimental intervention, were the groups treated equally?

Yes

Were all of the participants who entered the trial properly accounted for at its conclusion?

Yese

How large was the treatment effect?

See table 9

How precise was the estimate of the treatment effect?

See table 9

Can the results be applied in your context? (or to the local population)

Yes

Were all clinically important outcomes considered?

Yes

Are the benefits worth the harms and costs?

See overview

Study limitations

  • Study compares liraglutide to placebo and not active treatment.

  • There was a high drop-out rate in the study; 47% in the liraglutide group and 55% in the placebo group.

  • The manufacturers were unmasked to treatment allocation at 56 weeks.

  • No corrections for multiple testing was made for the secondary outcomes. Therefore any statistical analysis provided for these outcomes should be interpreted with caution.

Comments

a Prediabetes was defined as either an HbA1c measurement from 39 to 46 mmol/mol or a fasting plasma glucose measurement from 5.6 to 6.9 mmol per litre or a 2-hour oral glucose tolerance test of 7.8 to 11.0 mmol per litre. A diagnosis of type 2 diabetes was made following 2 consecutive measurements of: an HbA1c of 48 mmol/mol and above, or a fasting plasma glucose concentration of 7.0 mmol per litre and above, or a 2 hour oral glucose tolerance test of 11.1 mmol per litre and above.

b Participants had up to 160 weeks of treatment in total followed by a 12-week off-treatment follow up period. The primary and secondary outcomes were assessed at 160 weeks.

c The method of randomisation suggests allocation was concealed. Participants were randomised to each treatment group (2:1) via a telephone or web based system provided by the manufacturers.

d Participants and investigators were masked to treatment allocation during the entire trial (160 weeks plus the 12-week off treatment follow-up period). However, the manufacturers were unmasked to treatment allocation at week 56.

e There was a high dropout rate from the study. Missing values were imputed with the use of the last observation carried forward method for measurements made after baseline.

Abbreviations: GLP-1, glucagon-like peptide-1

Table 6 Davies et al. (2015)

Study reference

Davies M J, Bergenstal R, Bode B et al. (2015) Efficacy of liraglutide for weight loss among patients with type 2 diabetes. (The SCALE diabetes randomised clinical trial) Journal of American Medical Association 314 (7), 687–699

Unique identifier

NCT01272232

Study type

RCT

Aim of the study

To evaluate the safety and efficacy of liraglutide 3.0 mg daily as an adjunct to a reduced calorie diet and increased physical activity, for weight management in overweight or obese adults with type 2 diabetes

Study dates

June 2011 to January 2013

Setting

126 sites in 9 countries; France, Germany, Israel, South Africa, Spain, Sweden, Turkey and the UK (England and Scotland only)

Number of participants

n=846

Population

Adults aged 18 years and over with type 2 diabetes (mean duration of diabetes ranged from 6.7 to 7.5 years across the 3 groups in the study), a stable body weight and a BMI of 27 kg/m² or above. The mean age of participants was 55 years, the mean BMI was 37 kg/m², 50% of participants were female and 83% were white. All participants received lifestyle interventions for weight loss based on 150 minutes or more per week of brisk walking and a reduction in daily energy intake by 500 kcal below their individualised energy requirements.

Inclusion criteria

Adults with a BMI of 27 kg/m² and above and type 2 diabetes (HbA1c 53 to 86 mmol/mol), treated with diet and exercise alone or in combination with 1 to 3 oral hypoglycaemic agents. Around 11% of the group were being treated with diet and exercise only for type 2 diabetes and around 56% of the group were treated with metformin alone. Participants taking a sulfonylurea had their dose reduced by 50%. Participants had a stable body weight, defined as less than 5 kg change in weight during the previous 3 months.

Exclusion criteria

Exclusion criteria included treatment with GLP-1 agonists, insulin or any hypoglycaemic agents other than metformin, sulfonylurea or glitazones within the last 3 months, recurrent major hypoglycaemia, use of any medication that can cause clinically significant weight changes, previous surgical treatment for obesity, untreated or uncontrolled hypothyroidism or hyperthyroidism, known proliferative retinopathy or maculopathy requiring acute treatment, history of pancreatitis, a history of major depression or other severe psychiatric disorder, and a family or personal history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. People who had taken part in an organised weight loss programme or taken any other medicines for weight management in the previous 3 months were also excluded from the study.

Intervention(s)

Liraglutide injected subcutaneously at a dose of either 3.0 mg (n=423) or 1.8 mg (n=211) once daily. Liraglutide was started at a dose of 0.6 mg once daily and increased at weekly increments of 0.6 mg until the treatment dose of 1.8 mg or 3.0 mg was reacheda,b

Comparator(s)

Placebo (n=212) injected subcutaneouslya

Length of follow-up

68 weeksc

Outcomes

Co-primary outcomes (all assessed at week 56 and based on fasting body weight):

  • relative change in body weight

  • proportion of participants who lost at least 5% of their baseline bodyweight

  • proportion of participants who lost more than 10% of their baseline bodyweight

Secondary outcomes:

  • secondary outcomes included change from baseline in glycaemic control measures

Safety outcomes:

  • safety and tolerability assessments included adverse events, standard laboratory tests, physical examinations, mental health questionnaires and ECGs

Source of funding

Novo Nordisk

Overall risk of bias/quality assessment ( CASP RCT checklist )

Did the trial address a clearly focused issue?

Yes

Was the assignment of participants to treatments randomised?

Yesa,d

Were participants, health workers and study personnel blinded?

Yes

Were the groups similar at the start of the trial?

Yes

Aside from the experimental intervention, were the groups treated equally?

Yes

Were all of the participants who entered the trial properly accounted for at its conclusion?

Yese

How large was the treatment effect?

See table 10

How precise was the estimate of the treatment effect?

See table 10

Can the results be applied in your context? (or to the local population)

Yes

Were all clinically important outcomes considered?

Yes

Are the benefits worth the harms and costs?

See overview

Study limitations

  • Study compares liraglutide to placebo and not active treatment.

  • The primary outcomes on weight loss are assessed after 56 weeks' treatment. Assessment of weight outcomes after 56 weeks is not reflective of the treatment indication in the summary of product characteristics (SPC: Saxenda) which recommends that treatment should be discontinued after 12 weeks on the 3.0 mg daily dose (recommended maintenance dose) if patients have not lost at least 5% of their initial body weight.

  • There was a high drop-out rate in the study; 23.4% in the liraglutide 3.0 mg group, 22.3% in the liraglutide 1.8 mg group and 34.0% in the placebo group.

  • Secondary endpoints are to be considered exploratory because no controls were applied for multiple comparisons for the secondary outcomes.

Comments

a Randomisation to treatment was stratified according to the participants' baseline treatment for type 2 diabetes and baseline HbA1c level.

b The results for the liraglutide 1.8 mg once daily group are not discussed in this evidence summary because this is not a licensed dose for this indication.

c The 56-week study was followed by an observational 12-week off-drug follow up period to assess treatment cessation effects.

d The method of randomisation suggests allocation was concealed. Participants were randomised to each treatment group (2:1:1) via an interactive voice or web based system.

e There was a high dropout rate from the study. Missing values were imputed using a multiple imputation method for the 3 co-primary outcomes. Missing values for the secondary outcomes were imputed with the use of the last observation carried forward method for measurements made after baseline.

Abbreviations: ECG, electrocardiogram; GLP-1, glucagon-like peptide-1

Table 7 Blackman et al. (2016)

Study reference

Blackman A, Foster GD, Zammit G et al (2016) Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnoea: the SCALE Sleep Apnoea randomized clinical trial International Journal of obesity 40 (8),1310–19

Unique identifier

NCT01557166

Study type

RCT

Aim of the study

To evaluate whether liraglutide 3.0 mg daily would reduce the severity of OSA compared with placebo in people with obesity and moderate or severe OSA who were unwilling or unable to use CPAP therapy.

Study dates

June 2012 to June 2013

Setting

40 sites in the US and Canada

Number of participants

n=359

Population

Adults with a stable body weight and a BMI of 30 kg/m² or above and moderate or severe OSA who were unwilling or unable to use CPAP therapy. The mean age of participants was 48 years, 72% of participants were male and 74% were white. All participants received lifestyle interventions for weight loss based on advice to increase physical activity to at least 150 minutes per week and reduce daily energy intake by 500 kcal below their individualised energy requirements.

Inclusion criteria

Adults aged 18 to 64 years with a BMI of 30 kg/m² and above, stable body weight (defined as less than 5% change in weight during the previous 3 months) and a diagnosis of moderate or severe OSA unwilling or unable to use CPAP or other positive airway pressure treatment. Moderate OSA was defined as an AHI of 15.0 to 29.9 apnoea or hypopnea events per hour of sleep; severe OSA was defined as an AHI of 30 or more events per hour of sleep.

Exclusion criteria

Exclusion criteria included adults with type 1 or type 2 diabetes, significant craniofacial abnormalities that may be causing OSA, relevant respiratory and neuromuscular disorders, use of any medication that can cause clinically significant weight changes, previous surgical treatment for obesity, history of pancreatitis and a history of major depression or other severe psychiatric disorder. People who had taken part in an organised weight loss programme or taken any other medicines for weight management in the previous 3 months were also excluded from the study.

Intervention(s)

Liraglutide (n=180) injected subcutaneously, starting at a dose of 0.6 mg once daily increased to 3.0 mg once daily at 0.6 mg weekly increments

Comparator(s)

Placebo (n=179) injected subcutaneously

Length of follow-up

34 weeksa

Outcomes

Primary outcome: change in AHI from baselineb

Secondary outcomes:

  • secondary outcomes included change from baseline in weight related outcomes

Safety outcomes:

  • safety and tolerability assessments included adverse events, standard laboratory tests, physical examinations, mental health questionnaires and ECGs

Source of funding

Novo Nordisk

Overall risk of bias/quality assessment ( CASP RCT checklist )

Did the trial address a clearly focused issue?

Yes

Was the assignment of participants to treatments randomised?

Yesc

Were participants, health workers and study personnel blinded?

Yes

Were the groups similar at the start of the trial?

Yes

Aside from the experimental intervention, were the groups treated equally?

Yes

Were all of the participants who entered the trial properly accounted for at its conclusion?

Yesd

How large was the treatment effect?

See table 11

How precise was the estimate of the treatment effect?

See table 11

Can the results be applied in your context? (or to the local population)

Uncleare

Were all clinically important outcomes considered?

Uncleare

Are the benefits worth the harms and costs?

See overview

Study limitations

  • Study compares liraglutide to placebo and not active treatment.

  • There was a high drop-out rate in the study; 26% in the liraglutide group and 21% in the placebo group.

  • There is no established minimal clinical important difference for AHI, making interpretation of this outcome difficult.

  • No adjustments were made for multiple testing for the secondary analyses. Therefore any statistical analysis provided for these outcomes should be interpreted with caution.

Comments

a Treatment was for 32 weeks followed by a 2-week follow-up period. The primary outcome was assessed at week 32.

b Change in AHI based on the American Academy of Sleep Medicine's 2007 definition with hypopnea requiring 30% or more reduction in nasal pressure signal excursions from baseline and 4% or more desaturation from pre-event baseline. AHI was assessed during overnight clinic stays at screening, week 12 and week 32.

c The method of randomisation suggests allocation was concealed. Participants were randomised to each treatment group (1:1) via a telephone or web based system provided by the manufacturers.

d There was a high dropout rate from the study. Missing values were imputed with the use of the last observation carried forward method for measurements made after baseline.

e The relevance of the primary outcome to clinical practice is unclear. The outcome was assessed during an overnight clinic stay and there is no established minimal clinically importance difference.

Abbreviations: AHI, apnoea-hypopnea index; CPAP, continuous positive airways pressure; OSA, obstructive sleep apnoea