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Saxenda® (liraglutide injection 3mg) efficacy

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The clinical efficacy of Saxenda® has been assessed in a number of clinical trials.

 

SCALE Obesity and Prediabetes (56 weeks)1-3

Objectives

  • To evaluate the efficacy and safety of Saxenda® (liraglutide 3.0 mg) as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adults with overweight or obesity, without diabetes.

Study design

  • A 56-week, randomised, placebo-controlled, double-blind trial at 191 research sites in 27 countries (N=3,731).

Inclusion criteria

  • Adults with a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 in the presence of treated or untreated comorbidities such as dyslipidaemia and/or hypertension, without diabetes, and with a stable body weight.

Treatment period

  • Participants were randomly assigned, in a 2:1 ratio, to receive Saxenda® or placebo once daily.
  • Participants were stratified by prediabetes status at screening, and by BMI (≥30 or <30 kg/m2).
  • After 56 weeks, participants on Saxenda® without prediabetes at screening were again randomly assigned, in a 1:1 ratio, to continue receiving Saxenda®, or to switch to placebo treatment for an additional 12 weeks to assess the effects of treatment discontinuation on efficacy and safety. Participants in the placebo group continued to receive placebo (Figure 1.1).
  • All participants received counselling on lifestyle modification that included a 500 kcal deficit/day diet and 150 min/week physical activity.

SCALE Obesity and Prediabetes study design, comparing weight loss with Saxenda® vs placebo (56-week trial)

Figure 1.1 SCALE Obesity and Prediabetes study design. EOT, end of treatment; FU, follow-up.

Endpoints

  • Co-primary:
    • Weight change from baseline.
    • Proportion of participants who lost ≥5% of their baseline body weight.
    • Proportion of participants who lost ≥10% of their baseline body weight.
  • Secondary:
    • Change from baseline in: BMI, waist circumference, cardiometabolic biomarkers, glycaemic control parameters and health-related quality-of-life parameters.
  • Re-randomisation period:
    • Change from baseline in fasting body weight from week 56 to week 68.

Results

  • A total of 1789 patients (71.9%) in the liraglutide group, as compared with 801 patients (64.4%) in the placebo group, completed 56 weeks of treatment.
  • At week 56, participants in the Saxenda® group had lost a mean of 8.0% of their body weight compared with participants in the placebo group who lost 2.6% (Figure 1.2).
  • Weight loss with Saxenda® was maintained over the 56 weeks, and was not dependent on prediabetes status.
  • 63.2% of participants lost ≥5% of their body weight from baseline in the Saxenda® group versus 27.1% in the placebo group (P<0.001).
  • 33.1% of participants lost >10% of their body weight from baseline in the Saxenda® group versus 10.6% in the placebo group (P<0.001).
  • Saxenda® led to a greater reduction than placebo in waist circumference and BMI. Glycaemic control was also improved with Saxenda®, along with a greater decrease in systolic and diastolic blood pressure (Table 1.1).
  • Saxenda® was also associated with higher patient-reported quality-of-life scores.

Line graph depicting change in body weight from baseline comparing use of Saxenda® and placebo

Figure 1.2 Mean percentage change in body weight from baseline to week 56. Data are observed means (±SE). Statistical analysis is ANCOVA. ANCOVA, analysis of covariance; LOCF, last observation carried forward; SE, standard error.

able comparing improvements seen in cardiometabolic risk factors between baseline and week 56 of Saxenda® use

Table 1.1 Change in cardiometabolic risk factors from baseline to week 56. BMI, body mass index; CI, confidence interval; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

 

Tolerability

  • The most common adverse events (AEs) in the Saxenda® group were gastrointestinal disorders (nausea, diarrhoea, vomiting, and constipation); most were of mild or moderate severity. Nausea and vomiting was transient and occurred primarily within the first 4–8 weeks after initiation of liraglutide treatment.
  • Gallbladder-related events were more frequent with Saxenda® than placebo; greater weight loss was observed in those individuals who developed these events compared with the mean weight loss in the total population.
  • The incidence of pancreatitis events was low; however, it was more common with Saxenda® than with placebo. Six of the 11 total cases were diagnosed as gallstone-related pancreatitis.
  • Resting pulse was increased with Saxenda® at end of trial, with a placebo-subtracted difference of 2.4 beats per minute.
  • There were no cases of medullary thyroid carcinoma or C-cell hyperplasia, and liraglutide did not increase serum calcitonin concentrations.
  • The proportion of participants with spontaneous hypoglycaemia was similar for the Saxenda® group (1.3%) and the placebo group (1.0%); no events were serious or required third-party assistance.

SCALE Obesity and Prediabetes (3 year)1,4,5

Objectives

  • To evaluate the effect of Saxenda® (liraglutide 3.0 mg), as an adjunct to a reduced calorie diet and exercise, in delaying time of onset of type 2 diabetes in individuals with prediabetes, as well as on weight loss, and to evaluate safety and tolerability of Saxenda® over 3 years.

Study design

  • A 3-year, double blind, randomised, placebo-controlled trial at 191 sites in 27 countries (N=2254).

Inclusion criteria

  • Participants with prediabetes and a BMI of at least 30 kg/m², or at least 27 kg/m² with treated or untreated dyslipidaemia, or hypertension, or both.

Treatment period

  • Participants were randomised to receive once-daily Saxenda® (n=1505) or placebo (n=749), in conjunction with a lifestyle modification programme that included increased physical activity and a 500 kcal deficit/day diet.
  • After a 4-week dose-escalation period, participants received a stable dose for a further 156 weeks, followed by a 12 week off-drug follow-up (Figure 2.1).

SCALE Obesity and Prediabetes study design, comparing diabetes onset and weight loss with Saxenda® vs placebo (3-year trial)

Figure 2.1 SCALE Obesity and Prediabetes 3-year study design. FU, follow-up.

 

Endpoints

  • Co-primary:
    • Proportion of participants with type 2 diabetes at 3 years, evaluated as time to onset of diabetes.
    • Mean weight loss assessed at 56 weeks.
    • Proportion of participants who lost >5% of their baseline body weight assessed at 56 weeks.
    • Proportion of participants who lost >10% of their baseline body weight assessed at 56 weeks.
  • Secondary:
    • Change from baseline in: glycaemic control parameters, mean and categorical body weight, BMI, mean waist circumference, cardiometabolic biomarkers and health-related quality-of-life at 3 years.

Results

  • A total of 791 patients (52.6%) in the liraglutide group, as compared with 337 patients (45.0%) in the placebo group, completed 160 weeks of treatment.
  • 3% of participants treated with Saxenda® developed type 2 diabetes at 3 years versus 11% of participants on placebo (P<0.0001).
  • Time to onset of type 2 diabetes over 3 years while on treatment was 2.7 times longer with Saxenda® than with placebo (95% confidence interval [CI], 1.9 to 3.9, P<0.0001). This corresponded to a risk reduction of approximately 80% for development of type 2 diabetes for Saxenda® relative to placebo (hazard ratio [HR] 0.21, 95% CI 0.13 to 0.34, P<0.0001).
  • Mean weight loss for participants treated with Saxenda® and completing the trial was 6.1% versus 1.9% for participants on placebo (95% CI –4·9 to –3·7, P<0.0001).
  • 50% of participants on Saxenda® lost ≥5% of baseline body weight at 3 years versus 24% of participants on placebo (P<0.0001).
  • 25% of participants on Saxenda® lost >10% of baseline body weight at 3 years versus 10% of participants on placebo (P<0.0001).
  • Saxenda® was associated with superior glycaemic control, a greater decrease in waist circumference and systolic blood pressure, and higher mean scores on patient-reported quality-of-life assessments (Table 2.1).

Sustained weight loss

  • Participants receiving Saxenda® experienced sustained weight loss over the 3 years compared with participants receiving placebo (estimated treatment different at 160 months –4.3% [–4.9; –3.7] P<0.0001) (Figure 2.2).

Line graph depicting change in body weight from baseline comparing use of Saxenda® and placebo

Figure 2.2 Change in weight with Saxenda® from baseline to 160 weeks.LOCF, last observation carried forward.

Table comparing additional improvements seen in risk factors between baseline and week 160 of Saxenda® use

Table 2.1 Additional improvements seen in risk factors from baseline to week 160. BMI, body mass index; LOCF, last observation carried forward.

 

Tolerability

  • Saxenda® was generally well tolerated and no new safety signals were observed as compared with the previous evaluation after 1 year of treatment.
  • The most common AEs in the Saxenda® group were gastrointestinal disorders; 93% of which were of mild or moderate severity.
  • Gastrointestinal disorders were also the most common cause of withdrawal (118 of 1501 participants [8%] in the Saxenda® group versus 11 of 747 [2%] in the placebo group).
  • Gallbladder-related events were more frequent with Saxenda® (74 of 1501 [5%]) than placebo (13 of 747 [2%]) and occurred at relative constant rates in the Saxenda® group over the 3 year period.
  • The incidence of pancreatitis was low but more common with Saxenda® than with placebo. Of the 12 total cases, 5 were diagnosed as gallstone-related pancreatitis.
  • Resting heart rate increased by about 2 beats per minute with Saxenda®, as observed with other glucagon-like peptide-1 receptor agonists.
  • The incidence of adjudicated and confirmed neoplasms was similar in both the Saxenda® group and the placebo group (2.2 events per 100 person-years of observation for liraglutide versus 2.4 for placebo).

SCALE Maintenance1,6,7

Objectives

  • To assess the efficacy of Saxenda® (liraglutide 3.0 mg) in maintaining clinically meaningful weight loss achieved with a low-calorie diet (LCD) in individuals with overweight or obesity, without type 2 diabetes.

Study design

  • A 56-week, randomised, double-blind, placebo-controlled trial at 36 research sites in 2 countries (United States and Canada) (N=422).

Inclusion criteria

  • Men and women aged ≥18 years with BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with comorbidities of treated or untreated dyslipidaemia and/or treated or untreated hypertension.

Prior to randomisation

  • Participants had to lose ≥5% of initial body weight during a variable-length (4 to 12 weeks) low calorie diet (1200–1400 kcal/day) run-in period.
  • Participants were provided with diet and exercise counselling throughout the trial.

Treatment period

  • Participants were randomised 1:1 after run-in period to receive once-daily Saxenda® (n=212) or placebo (n=210) for 56 weeks (Figure 3.1).
  • Participants were provided with diet and exercise counselling throughout the trial.

Following medication discontinuation at week 56, participants completed a 12-week follow-up assessment, which included monthly visits.

SCALE Maintenance trial design, comparing weight loss with Saxenda® vs placebo

Figure 3.1 SCALE Maintenance trial design. BW, body weight; EOT, end of treatment; FU, follow-up; LCD, low-calorie diet.

 

Endpoints

  • Co-primary:
    • Mean percent change in fasting body weight from randomisation.
    • Proportion of participants maintaining the ≥5% reduction in fasting body weight achieved during low-calorie diet run-in.
    • Proportion of participants who lost ≥5% of their fasting body weight after randomisation.
  • Secondary:
    • Weight change (kg) from randomisation to week 56 and fasting weight change from randomisation to week 68.
    • Proportion of participants who lost >10% of their fasting randomisation weight.
    • Proportion of participants maintaining >50% and >75% of fasting weight loss during run-in.
  • Additional:
    • Cardiovascular disease risk factors.
    • Glycaemic control parameters.

Results

  • A total of 159 patients (75.0%) in the liraglutide group, as compared with 146 patients (69.5%) in the placebo group, completed 56 weeks of treatment.
  • Saxenda® was superior to placebo on all three co-primary endpoints.
  • Participants who lost ≥5% of body weight during run-in and received treatment with Saxenda® lost an additional 6.2% of body weight after 56 weeks versus 0.2% for the placebo group (Figure 3.2).
  • Significantly more participants in the Saxenda® group maintained the ≥5% weight loss achieved in the run-in versus participants in the placebo group (81.4% versus 48.9%; P<0.0001) (Table 3.1).
  • Additionally, significantly more participants in the Saxenda® group lost ≥5% of their randomisation body weight when compared with the placebo group (50.5% versus 21.8%; P<0.0001) (Table 3.1).
  • At follow-up (week 68), the Saxenda® group maintained a 4.1% reduction compared with a gain of 0.3% for the placebo group (P<0.0001).
  • Saxenda® was also superior in the percentage of participants who lost >10% of their body weight compared with placebo (26.1% versus 6.3%, respectively; P<0.0001).
  • Saxenda® was associated with superior decreases in BMI and waist circumference, as well as greater reduction in glycaemic and cardiometabolic parameters (Table 3.2).

Graph comparing change in body weight from start of run-in period to end of 56-week trial of Saxenda®

Figure 3.2 Change in body weight from start of run-in period to end of 56-week trial. Full analysis set, LOCF at week 56. LOCF, last observation carried forward.

 

Table comparing change in body weight measures from randomisation to week 56 of Saxenda use®

Table 3.1 Change in body weight measures from randomisation to week 56. SD, standard deviation.

 

Changes in metabolic and CVD risk factors from randomisation to week 56 in the Saxenda® and placebo treatment groups

Table 3.2 Changes in metabolic and CVD risk factors from randomisation to week 56. Data are observed means. Statistical analysis is ANCOVA with LOCF. ANCOVA, analysis of covariance; BMI, body mass index; CVD, cardiovascular disease; hsCRP, high-sensitivity C-reactive protein; LCD, low-calorie diet; LOCF, last observation carried forward; SD, standard deviation.

 

Tolerability

  • 11 out of 16 participants who exhibited symptomatic hypoglycaemia were receiving Saxenda®; none of the events were classified as severe.
  • The overall rate of cardiac disorders in participants on Saxenda® was low and less than in participants on placebo.
  • A similar percentage of participants in the groups treated with Saxenda® and placebo reported experiencing an AE during the study (91.5% and 88.6%, respectively).
  • Gastrointestinal disorders were the most common side effects in the Saxenda® group, occurring at a higher incidence than placebo. Participants treated with Saxenda® reported transient nausea that coincided with dose escalation.
  • There were no cases of acute pancreatitis, and all neoplasms (malignant or benign) were considered unlikely to be related to treatment.
  • Psychiatric disorders occurred in 24 participants treated with Saxenda® and 26 placebo-treated participants (11.3% versus 12.4%, respectively).

SCALE Diabetes1,8,9

Objectives

  • To assess the efficacy and safety of Saxenda® (liraglutide 3.0 mg) for weight management in adults with overweight or obesity and type 2 diabetes.

Study design

  • A 56-week, randomised, double-blind, placebo-controlled, parallel-group trial at 126 research sites in 9 countries with a 12-week observational off-drug follow-up (N=846).

Inclusion criteria

  • Adults with overweight or obesity (BMI ≥27 kg/m2) and a stable body weight with type 2 diabetes previously treated with diet and exercise alone or with 1–3 oral hypoglycaemic agents.

Treatment period

  • Participants were randomised 2:1 to receive once-daily Saxenda® (n=423), or placebo (n=212) for 56 weeks.
  • Participants were encouraged to follow a 500 kcal/day deficient diet.
  • Following medication discontinuation at week 56, participants completed a 12-week follow-up assessment, where body weight was measured (Figure 4.1).

SCALE Diabetes trial design, comparing weight loss with Saxenda® vs placebo

Figure 4.1 SCALE Diabetes trial design. EOT, end of treatment; FU, follow-up.

 

Endpoints

  • Co-primary:
    • Relative change in body weight at week 56.
    • Proportion of participants losing ≥5% of their baseline body weight at week 56.
    • Proportion of participants who lost >10% of their baseline body weight at week 56.
  • Secondary:
    • Change from baseline to week 56 in: waist circumference, BMI, HbA1c, glycaemic control parameters, cardiovascular biomarkers and patient-reported outcomes.

Results

  • A total of 324 patients (76.6%) in the liraglutide group, as compared with 140 patients (66.0%) in the placebo group, completed 56 weeks of treatment.
  • Participants in the Saxenda® group lost significantly more weight than participants in the placebo group (–6.0%, –2.0%, respectively; Figure 4.2). The estimated treatment difference versus placebo at week 56 was –4.00 (P<0.001).

A significantly higher proportion of participants lost ≥5% and >10% of their baseline body weight in the Saxenda® group than in the placebo group (estimated treatment differences versus placebo at week 56 were 32.9 [P<0.001] and 18.5 [P<0.001], respectively).

Line graph indicating time course of body weight loss from baseline to week 56 for Saxenda® and placebo.

Figure 4.2 Time course of body weight loss from baseline to week 56 for Saxenda® and placebo. Full analysis set, fasting visit data only. Observed mean weight loss at fasting visits.

 

Secondary endpoints

  • Saxenda® was superior to placebo in reducing mean waist circumference and BMI (Table 4.1).
  • Treatment with Saxenda® led to superior glycaemic control, including improved HbA1c, when compared with placebo (Table 4.1).
  • Saxenda® significantly improved patient quality-of-life versus placebo (Impact of Weight on Quality of Life-Lite [IWQoL-Lite] mean total score 11.68 versus 7.58, estimated treatment difference at 56 weeks: 2.75 [P=0.01]) (Table 4.1).

Table indicating changes in secondary endpoints from randomisation to week 56 in the Saxenda® and placebo treatment groups

Table 4.1 Changes in secondary endpoints from randomisation to week 56. Full analysis set. Data are raw means. ***P<0.001 vs placebo; **P<0.01 vs placebo; *P<0.05 vs placebo. BMI, body mass index; FPG, fasting plasma glucose; IWQoL-Lite, Impact of Weight on Quality of Life-Lite; PPG, postprandial plasma glucose; SBP, systolic blood pressure; SD, standard deviation.

 

Tolerability

  • A higher proportion of participants in the Saxenda® group withdrew from the study due to treatment-emergent AEs compared with the placebo group (9.2% vs 3.3%).
  • The most common AEs experienced were gastrointestinal, most notably nausea, which was reported in 32.7% of participants in the Saxenda® group and 13.7% of participants in the placebo group.
  • Hypoglycaemic episodes were reported more frequently with Saxenda® than with placebo for those with and without background sulphonylurea therapy.

While most AEs were mild, the rate of serious AEs was 8.8% with Saxenda® and 6.1% with placebo.

SCALE Sleep Apnoea1,10

Objective

  • To assess the efficacy of Saxenda® in reducing obstructive sleep apnea (OSA) using the primary endpoint of change in apnea–hypopnea index (AHI) after 32 weeks.

Study design

  • A 32-week, randomised, double-blind, placebo-controlled, parallel-group trial at 40 research sites in 2 countries (USA and Canada) (N=359).

Inclusion criteria

  • Adults with obesity (BMI ≥30 kg/m2), without diabetes, aged 18–64 years with a stable body weight and with moderate or severe OSA who were unable or unwilling to use continuous positive airway pressure (CPAP) therapy.

Treatment period

  • Participants were randomised 1:1 to receive once-daily Saxenda® (n=180), or placebo (n=179) for 32 weeks (Figure 5.1).
  • Participants received counselling on diet and exercise throughout the treatment period, and were prescribed a 500 kcal/day deficient diet.

SCALE Sleep Apnoea trial design, comparing reduction of obstructive sleep apnoea (OSA) with Saxenda® vs placebo

Figure 5.1 SCALE Sleep Apnoea trial design. EOT, end of treatment; FU, follow-up.

 

Endpoints

  • The primary endpoint was the change in AHI from baseline to week 32.
  • Key secondary efficacy endpoints included:
    • Changes from baseline to week 32 in OSA severity category.
    • Blood oxygen saturation parameters.
    • Weight-related parameters.
    • Glycaemic parameters.
    • Cardiovascular biomarkers.
    • Self-reported quality-of-life assessments.

Results

  • A total of 134 patients (74.0%) in the liraglutide group, as compared with 142 patients (79.0%) in the placebo group, completed 32 weeks of treatment.
  • At week 32, Saxenda® caused a significantly greater reduction in AHI events compared with placebo (–12.2 versus –6.1 events/h; estimated treatment difference: –6.1 events/h, P=0.015) (Figure 5.2).
  • The reduction of AHI in the Saxenda® group was not dependent on the participants’ gender, baseline BMI or OSA severity category.
  • Participants in the Saxenda® group experienced a significantly greater reduction in mean body weight compared with the placebo group (–5.7% versus –1.6%; estimated treatment difference: –4.2%, P<0.0001).
  • Saxenda® produced significantly greater reductions in HbA1c and fasting plasma glucose and resulted in greater improvements in patient-reported quality-of-life assessments than placebo, at week 32.

Line graph indicating change in AHI (events/h) in the Saxenda® and placebo treatment groups over 32 weeks.

Figure 5.2 Change in AHI (events/h) in the Saxenda® and placebo treatment groups over 32 weeks. FAS. Line graphs are means (±SE). Circles are observed means LOCF. Statistical analysis is ANCOVA. AHI, apnoea-hypopnoea index; ANCOVA, analysis of covariance; events/h, events per hour of sleep; FAS, full analysis set; LOCF, last observation carried forward; SE, standard error.

 

Tolerability

  • A higher proportion of participants in the Saxenda® group (80.1%) experienced AEs than in the placebo group (69.3%).
  • The most common AEs experienced were gastrointestinal. Nausea, experienced by 26.7% and 6.7% of participants in the Saxenda® and placebo groups, respectively, was mild and transient, occurring mainly within the initial 8 weeks of treatment.
  • Most AEs reported were mild in severity, and no deaths occurred during the treatment period. An identical proportion of participants in both groups (3.4%) reported serious AEs.

References

  1. Saxenda® Summary of Product Characteristics.
  2. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015;373:11–22.
  3. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015;373:11–22, supplementary appendix.
  4. Le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 2017;389:1399–409.
  5. Le Roux CW, Astrup A, Fujioka K, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 2017;389:1399–409, supplementary appendix.
  6. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-dietinduced weight loss: the SCALE maintenance randomized study. Int J Obes (Lond) 2013;37:1443–51.
  7. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-dietinduced weight loss: the SCALE maintenance randomized study. Int J Obes (Lond) 2013;37:1443–51, supplementary appendix.
  8. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA 2015;314:687–99.
  9. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA 2015;314:687–99, supplementary appendix.
  10. Blackman A, Foster GD, Zammit G, et al. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE sleep apnea randomized clinical trial. Int J Obes (Lond) 2016;40:1310–9.
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