Drug Evaluation
Liraglutide in the treatment of obesity Sarah Yoon Ai Ng & John P H Wilding† 1.
Introduction
2.
Overview of the market: unmet needs of current
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therapies 3.
Introduction to the compound
4.
Safety and tolerability
5.
Regulatory status
6.
Conclusion
7.
Expert opinion
University of Liverpool, Aintree University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Department of Diabetes and Endocrinology, Liverpool, UK
Introduction: Obesity is a global epidemic with important healthcare and financial implications. Most current antiobesity pharmacological therapies are unsatisfactory due to undesirable side effects. Many drugs have been withdrawn due to safety concerns. Maintaining weight loss remains the Achilles’ heel of antiobesity therapy. Areas covered: This is an overview of the use of liraglutide for obesity treatment. Clinical efficacy on weight, cardiovascular parameters, as well as safety and tolerability issues are discussed. Expert opinion: Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist, which has a protracted pharmacokinetic profile compared to native GLP-1 while maintaining its biological activity. It induces weight loss by reducing appetite and energy intake. It stimulates insulin release and decreases glucagon secretion in response to hyperglycaemia. Treatment with liraglutide, in addition with diet and exercise, induces sustained mean weight loss of 7.6 kg at 2 years (weight loss induced by orlistat = 5.7 kg, phentermine/ topiramate controlled release 15/92 = 10.9 kg). It reduces blood pressure and improves glycaemic control, which has clinically relevant significance on reducing obesity-related morbidity and mortality. Liraglutide is reasonably well tolerated with gastrointestinal side effects being most commonly encountered. Novo Nordisk filed for regulatory approval of liraglutide 3.0 mg for obesity treatment in December 2013. Keywords: glucagon-like peptide 1 receptor agonist, liraglutide, obesity, overweight Expert Opin. Biol. Ther. [Early Online]
1.
Introduction
Obesity is a global epidemic, with a projected increase of 65 million more obese adults in the USA and 11 million in the UK by 2030, leading to an additional 6 -- 8.5 million cases of diabetes, 5.7 -- 7.3 million cases of cardiovascular disease, 492,000 -- 669,000 additional cases of cancer and 26 -- 55 million quality-adjusted life years forgone for the USA and UK combined [1,2]. It is predicted that by 2030, obesity and its associated co-morbidities could cost the National Health Service £2 billion per year [2]. 2.
Overview of the market: unmet needs of current therapies
Treatment modalities that are currently available for inducing weight loss in obese individual are unsatisfactory. Drug therapy for obesity remains challenging as several have been discontinued or have had their use restricted due to safety and efficacy concerns [3]. Although existing agents allow modest weight loss with improvement in cardiovascular risk factors and glycaemia in impaired glucose tolerance and diabetes, none have been shown to reduce cardiovascular events. Sustaining weight loss is often the Achilles’ heel of obesity therapy.
10.1517/14712598.2014.925870 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
1
S. Y. A. Ng & J. P. H. Wilding
Box 1. Drug summary. Drug name Phase Indication Mechanism of action Route of administration Chemical structure
Liraglutide Submitted to FDA and European Medicines Evaluation Agency for regulatory approval on 20 December 2013 Obesity and overweight Glucagon-like peptide 1 (GLP-1) receptor agonist Subcutaneous H
His
Ala
Glu
Gly
Thr
Phe
Thr
Ser
H3C
Asp
Val
Glu
OH
Ser
O
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Ser
Ile
Pivotal trial(s) (Completed)
Tyr Ala
Leu
Trp
Glu
Leu
Gly Val
Gln
Arg
Ala
Gly
Ala
Arg
Lys
Gly
Glu
Phe
OH
Phase I: Effects of the once-daily GLP-1 analogue liraglutide on gastric emptying, glycaemic parameters, appetite and energy metabolism in obese, non-diabetic adults (NN8022-3630) Phase II: Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study (NN8022-1807) Phase II: Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analogue, liraglutide. (NN8022-1807) Phase III: Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomised study (NN8022-1923)
Table 1. Currently approved antiobesity pharmacotherapy in the market (US and/or EU approvals). Name or code Lorcaserin (ADP 359) Phentermine Diethylpropion Phendimetrazine Benzphetamine Phentermine/ topiramate Orlistat
Type of agent or combination
Current status
5-HT2C receptor agonist Noradrenergic sympathomimetic amine
FDA approved 2012, following re-file FDA approved in 1959 for short-term use (< 12 weeks)
Noradrenergic sympathomimetic amine/sulfamate-substituted monosaccharide derivative Lipase inhibitor
FDA approved 2012, following re-file
FDA and EMEA approved in 1998
EMEA: European Medicines Evaluation Agency.
At present, the only medical therapy approved in the European Union (EU) is the lipase inhibitor orlistat. Orlistat was approved by the FDA and the European Medicines Evaluation Agency (EMEA) for the treatment of obesity in 1998. Orlistat inhibits pancreatic lipases and reduces fat absorption from the gut by 30%, resulting in energy loss of 300 kcal/day [4]. The effects on weight loss is modest (6 -- 9 kg) [5] but is enough to have beneficial effects on cardiovascular risk factors. Treatment with orlistat leads to a decrease in low-density lipoprotein (LDL) cholesterol, blood pressure and improves glycaemic control [6,7]. However, gastrointestinal side effects limit its tolerability [8]. Sibutramine was approved in the EU in 1999 and rimonabant in 2009 but both have subsequently been withdrawn due to safety concerns and adverse effects that outweigh the modest benefits of treatment. Lorcaserin was approved by the FDA in June 2012 for the treatment of obesity in patients with body mass index (BMI) 2
of ‡ 30 or ‡ 27 kg/m2 with at least one weight-related comorbidity. Binding of lorcaserin to the 5-HT2C receptors in pro-opiomelanocortin neurons promotes satiety [9]. Its causes a mean weight loss of 5.8 kg compared to 2.2 kg for placebo over 12 months [10]. Concerns remain regarding breast tumours in preclinical studies and higher rates of new cardiac valvulopathy, leading to withdrawal of the EU marketing application in 2013 (Table 1). Phentermine-topiramate (Phen-Top) was approved by the FDA for the treatment of obesity in patients with BMI of ‡ 30 or ‡ 27 kg/m2 with at least one weight-related comorbidity in July 2012. Phentermine reduces food intake by enhancing norepinephrine release and blocking norepinephrine reuptake [11]. The weight loss effects of topiramate is largely unexplained but believed to be due to reduced energy intake and increased energy expenditure. There is a 10.9 kg observed weight loss for high-dose Phen-Top compared with
Expert Opin. Biol. Ther. (2014) 14(8)
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Liraglutide
2.1 kg for placebo [12]. Frequently reported side effects were paraesthesia, dry mouth and constipation and have significant teratogenic risks. The EMEA has chosen not to license PhenTop, as the benefits were not thought to outweigh the risks. Contrave is a combination agent consisting of naltrexone and bupropion, which is under evaluation. The combination is effective because naltrexone blocks inhibitory influences of opioid receptors activated by the b-endorphin that stimulates feeding. It also allows the activity of a-melanocyte-stimulating hormone, which inhibits food intake. The FDA has requested for a premarketing study of the drug with assessment of cardiovascular outcomes in view of increases in pulse and blood pressure in Phase III studies [13]. Bariatric surgery produces effective weight loss, reduces the incidence of diabetes in obese individuals with impaired glucose tolerance and is associated with remission of diabetes in a proportion of patients [14]. However, it is invasive and has risks and potential complications. Non-pharmacological weight loss programmes frequently fail due to nonadherence. Therefore, there is a need and strong incentive to develop an effective drug therapy for the treatment of obesity. 3.
Introduction to the compound
Glucagon-like peptide 1 Glucagon-like peptide-1 (GLP-1) is an incretin hormone which has a glucose-dependent stimulatory effect on insulin production and secretion and an inhibitory effect on glucagon secretion from the pancreatic islets in response to hyperglycaemia [15]. This leads to a reduction in blood glucose in insulindeprived states by increasing glucose deposition in peripheral tissues, and reducing hepatic glucose output [15]. GLP-1 also binds to receptors in the brainstem, hypothalamus and amygdala, where it is thought to promote satiety, leading to decreased energy intake [16-19]. GLP-1 receptor agonists also increase the expression of IL-6 and IL-1b in the hypothalamus and hindbrain, and this could contribute to GLP-1-induced weight loss [20]. 3.1
Liraglutide Liraglutide (Box 1) is a long-acting GLP-1 agonist, developed by Novo Nordisk, that is 97% homologous to native human GLP-1 [21]. Liraglutide has a protracted pharmacokinetic profile, while maintaining its biologic activity [22]. Liraglutide was approved by the EMEA for the treatment of type 2 diabetes in June 2009. 3.2
Pharmacological properties of liraglutide Liraglutide binds and activates GLP-1 receptors, leading to potentiation of glucose-dependent insulin secretion from pancreatic b cells. It stimulates insulin release and inhibits glucagon secretion, but only in response to hyperglycaemia [23,24], lowering blood-glucose without causing hypoglycaemia. Liraglutide has a protein-binding capability of > 98% [25]. 3.3
The use of native GLP-1 is limited by the very short elimination half-life of < 1.5 min due to rapid degradation by ubiquitous dipeptidyl peptidase-4 [26]. The structural modifications in liraglutide result in a compound with a slower absorption rate and a longer half-life of 11 -- 13 h, rendering it suitable for a once-daily injection (Figure 1) [22]. Maximum plasma concentrations of liraglutide are achieved 10 -- 14 h after a subcutaneous dose was given [22,27]. Steady state is reached after about three dose administrations. Only low levels of metabolites are found in plasma, urine and faeces [28]. Liraglutide is fully degraded in the body with no single organ as a major route of elimination. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia-2 and in patients with type 1 diabetes and a history of pancreatitis. The delayed gastric emptying caused by liraglutide may also influence the absorption of concomitantly administered oral medications [29,30]. Clinical efficacy We searched www.clinicaltrials.gov using the keywords ‘liraglutide’ and ‘obesity’ to identify ongoing and completed clinical trials for the use of liraglutide in the treatment of obesity. We also searched PubMed and the Cochrane database using the keywords ‘liraglutide’, ‘obesity’ and ‘GLP-1 agonists’ to identify relevant papers Tables 2 and 3. Treatment with liraglutide 2.4/3.0 mg as an adjunct to a low-calorie diet and exercise programme produces a clinically relevant, dose-dependent effect on weight loss that is greater than placebo and orlistat [31]. Astrup et al. demonstrated that after 20 weeks of treatment with liraglutide 3.0 mg, there is a 7.2 kg mean weight loss compared to 2.8 kg with placebo and 4.1 kg with orlistat. The mean weight loss with liraglutide 3.0 mg at 1 year was 7.8 kg (95% CI: 3.7 -- 8.0) (2.0 kg with placebo and 3.9 kg with orlistat) [32]. Participants randomised to liraglutide 3.0 mg for 1 year, and maintained on 2.4/3.0 mg for the second year were able to maintain a mean weight loss of 10.3 ± 7.1 kg from screening over 2 years. Mean weight loss at 2 years for obese individuals treated with liraglutide 2.4/3.0 mg was 7.8 kg from screening. At week 20, the proportion of individuals treated with liraglutide 3.0 mg who lost > 10% of baseline weight is greater than those treated with orlistat (28%, n = 26 vs 2%, n = 2; p < 0.0001, odds ratio [OR] 3.0) [31]. The SEQUEL study demonstrated that individuals who were treated with controlled release phentermine/topiramate 7.5/46 and 15/92 achieved mean changes from baseline body weight of -9.3 and -10.5%, respectively (-1.8% for placebo) [12]. Weight loss for individuals on liraglutide 2.4/3.0 mg for 2 years was significantly greater than with orlistat (-5.3 vs -2.3 kg, p < 0.001), with > 85% of those losing > 5% weight maintaining this at year 2 [32]. There was a decrease in waist circumference at year 2 of 6.2 cm with liraglutide 2.4/3.0 mg compared to 4.5 cm with orlistat. Mean change in systolic blood pressure at 20 weeks 3.4
Expert Opin. Biol. Ther. (2014) 14(8)
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S. Y. A. Ng & J. P. H. Wilding
• Controls appetite • Induces satiety
Brain
Adipocytes Liver
↓ Fatty acids release
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GLP-1 or GLP-1R agonists
• ↓ Glucagonmediated glycogenolysis • ↓ Glucagonmediated gluconeogenesis
Vagus effects Pancreas
• ↓ Sympathetic nervous system Blood pressure regulation
activity • ↑ Heart rate and stroke volume
• ↑ Inslin production
• Vasodilation
• ↓ Glucose levels • Promotes β cell growth • ↓ Inuslin resistance
• ↓ Catecholamine secretion from adrenal • ↑ Urine excretion and natriuresis
Figure 1. Effects of GLP-1 and GLP-1 receptor agonists.
in individuals treated with liraglutide was -- 13.3 mm Hg, (-7.8 mm Hg with placebo and -9.3 with orlistat) [31]. This effect in reduction in systolic BP was sustained at 2 years (-12.5 mm Hg) [32]. Liraglutide-treated individuals had a higher probability of having normal glucose tolerance at week 20 compared with those on placebo or orlistat (p < 0.01) [31]. Fasting blood glucose was reduced by 0.39 -- 0.44 mmol/l at week 20 with liraglutide-treated individuals, while there was no observed effect in those on placebo or orlistat. There is a dosedependent reduction in glycosylated haemoglobin with individuals treated with liraglutide, ranging from -0.14% with liraglutide 1.2 mg to -0.24% with 3.0 mg. Up to 62% of liraglutide-treated individuals with prediabetes at randomisation achieved normal glucose tolerance at year 2, compared with 26% on orlistat [32]. At year 2, those treated with liraglutide 2.4/3.0 mg had a significantly higher high-density lipoprotein cholesterol compared with those on orlistat (treatment difference 0.07 mmol/l, p = 0.03) and decreased LDL cholesterol and triglycerides (treatment difference -0.12 mmol/l for triglycerides, p = 0.053 vs orlistat) [32]. The proportion of individuals with metabolic syndrome at week 20 decreased by > 60% in those treated with liraglutide 2.4/3.0 mg, compared to 38 and 13% reduction in the placebo and orlistat groups [31]. Individuals reported improved scores for physical function, self-esteem and quality of life in those treated with liraglutide 3.0 mg compared to orlistat, in addition to diet and exercise. 4
The SCALE Maintenance study is a 56-week randomised, double-blind, placebo-controlled, parallel group, multi-centre trial that investigated the use of liraglutide on weight loss maintenance induced by a 12-week low-calorie diet in obese subjects. The liraglutide group achieved greater mean absolute weight loss of 6.0 versus 0.1 kg than the placebo group. This data of a weight loss difference of 6.0 kg for liraglutide 3.0 mg versus 0.1 kg for placebo (estimated treatment difference of -5.9 kg) at week 56 is consistent with what was reported by Astrup et al. [32]. The number of participants who maintained the ‡ 5% weight loss in the initial run-in period in the liraglutide group was significantly higher compared to the placebo group (81.4 vs 48.9%, p < 0.00001). The number of participants who lost ‡ 5% of randomisation weight was also significantly higher compared to the placebo group (50.5 vs 21.8%; p < 0.00001). Liraglutide-treated participants also achieved greater decreases in waist circumference and glycaemic parameters at week 56 [33]. 4.
Safety and tolerability
Gastrointestinal side effects were most commonly encountered with liraglutide, with up to 14% of individuals reporting vomiting as a side effect [31]. These were mostly mild to moderate in severity and transient and became more frequent with increasing doses. However, the transient nausea and vomiting caused by liraglutide is associated with greater weight loss [34]. Fifteen to thirty per cent of individuals on orlistat report
Expert Opin. Biol. Ther. (2014) 14(8)
Effect of liraglutide on body weight in overweight or obese subjects with type 2 diabetes -- SCALE Diabetes Comparison of liraglutide versus placebo in weight loss maintenance on obese subjects: SCALE -- Maintanence Effect if liraglutide in obese subjects with moderate or severe obstructive sleep apnoea -- SCALE Sleep Apnoea Liraglutide and a calorie-restricted diet augments weight loss and decreases risk of type 2 diabetes and cardiovascular disease
NCT01272232
Expert Opin. Biol. Ther. (2014) 14(8)
mg, mg, mg, mg,
69
359
422 (212 liraglutide 3.0 mg, 210 placebo)
846
564 (98 placebo, 95 liraglutide 1.2 90 liraglutide 1.8 93 liraglutide 2.4 93 liraglutide 3.0 95 orlistat) 46
49
Subjects (n)
None
18 -- 65
None
None
None
18 -- 65
40 -- 75
846
18 years and above (mean age = 46.2)
18 years and above
46
None
18 -- 75
18 -- 65 (mean age = 54.4)
Subjects with type 2 diabetes
Age (years)
Liraglutide 1.8 mg OD versus placebo
Liraglutide (up to 3.0 mg/day) versus placebo
Daily s.c. doses of 3.0 mg liraglutide or placebo
Daily s.c. doses of liraglutide 1.8, 3.0 mg or placebo
Liraglutide followed by placebo; placebo followed by glimepiride; glimepiride followed by liraglutide
Daily s.c. doses of 1.2, 1.8, 2.4, 3.0 mg liraglutide or placebo or orlistat 120 mg/day
Daily s.c. doses of 1.8 or 3.0 mg liraglutide or placebo
Trial treatment
14
32
56
56
8
20 followed by 84-week extension period
5
Duration (weeks)
Weight, systolic blood pressure, fasting glucose, triglyceride
Change in baseline body weight, fasting plasma glucose, fasting insulin, HbA1c, blood pressure, waist circumference Changes from baseline in apnoea-hypopnoea index
Change in weight, fat mass, weight circumference, spontaneous energy intake, appetite, HbA1c, energy expenditure, adverse events Change in baseline body weight, fasting plasma glucose, fasting insulin, HbA1c, blood pressure, waist circumference
Change in baseline body weight, fasting plasma glucose, fasting insulin, HbA1c, blood pressure, waist circumference
Gastric emptying, energy expenditure and appetite
Outcomes
Source: www.clinicaltrials.gov. BD: Twice a day; BMI: Body mass index; DHEAS: Dehydroepiandrosterone sulphate; FSH: Follicle-stimulating hormone; HbA1c: Glycosylated haemoglobin; LH: Luteinising hormone; OD: Once a day; SHBG: Sex hormonebinding globulin.
NCT01784965
NCT01557166
NCT00781937
Effect of liraglutide on weight and appetite in obese subjects with type 2 diabetes
A trial to assess the effect of liraglutide on gastric emptying in healthy obese volunteers The effect of liraglutide on body weight in obese subjects
Study
NCT01508949
NCT00422058
NCT00978393
Trial
Table 2. Summary of completed clinical trials investigating liraglutide for the treatment of obesity in diabetic and non-diabetic individuals.
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Liraglutide
5
6
Source: www.clinicaltrials.gov. BD: Twice a day; BMI: Body mass index; DHEAS: Dehydroepiandrosterone sulphate; FSH: Follicle-stimulating hormone; HbA1c: Glycosylated haemoglobin; LH: Luteinising hormone; OD: Once a day; SHBG: Sex hormonebinding globulin.
None PCOS and liraglutide as add-on therapy to metformin NCT01911468
36
18 -- 55
Metformin alone, liraglutide alone (up to 0.6 -- 1.2 mg/day) or metformin and liraglutide
12
Change in body weight, BMI, weight circumference, glucose, insulin, LH, FSH, testosterone, SHBG, androstenedione, DHEAS Change in body weight, BMI, weight circumference, glucose, insulin, LH, FSH, testosterone, SHBG, androstenedione, DHEAS 12 None Polycystic ovary syndrome (PCOS) and liraglutide NCT01899430
32
18 -- 55
Daily s.c. doses 0.6 -- 1.2 liraglutide or metformin up to 1 g BD
Outcomes Duration (weeks) Trial treatment Subjects with type 2 diabetes Age (years) Subjects (n) Study Trial
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Table 2. Summary of completed clinical trials investigating liraglutide for the treatment of obesity in diabetic and non-diabetic individuals (continued).
S. Y. A. Ng & J. P. H. Wilding
gastrointestinal side effects, but these side effects often subside as patients learn not to take fatty meals [13,35]. Injection-site symptoms (pain, haematoma, irritation of skin) were infrequently reported. There was an increase in pulse by 3.1 beats/min observed following 2 years of treatment with liraglutide 2.4/3.0 mg [32]. Previous studies suggested that an increased resting heart rate is associated with a reduced life expectancy and an increase in cardiovascular mortality [36-38]. The clinical relevance of the increased heart rate, in the context of a reduced systolic blood pressure, is unclear as there is no evidence to suggest that liraglutide use leads to increased cardiovascular event rates [39,40]. Studies of longer follow-up duration should be conducted. The LEADER is an ongoing multi-centre trial that will be prospectively evaluating the cardiovascular safety of liraglutide in patients with type 2 diabetes. The SCALE Obesity and pre-diabetes studies will evaluate the effects of liraglutide on progression to diabetes in at risk participants. There was one event of cholelithiasis occurring simultaneously with acute pancreatitis 299 days after treatment on liraglutide 3.0 mg [32]. Concerns regarding pancreatitis were raised in post-marketing adverse event reports and in clinical trials conducted with liraglutide for the treatment of type 2 diabetes. Twelve liraglutide randomised controlled trials reported acute pancreatitis as an outcome, with an estimated OR of liraglutide and pancreatitis being 0.97 (95% CI: 0.21 -- 4.39) [41]. The drug labelling for liraglutide was changed in 2011 to alert prescribers of the increased risk of pancreatitis [42]. However, type 2 diabetic patients have up to three times as high baseline rates of pancreatitis in patients with diabetes compared to those without diabetes [43]. Significant and rapid weight loss is associated with gallstone formation, which is a major cause of acute pancreatitis [44]. These reasons, in addition to the fact that there is limited data from post-marketing reporting, make it difficult to draw firm conclusions on whether or not the use of liraglutide is associated with an increased risk of pancreatitis. Data from longer term studies specifically designed to study the association between liraglutide and acute pancreatitis and post-marketing pharmacovigilance need to be evaluated in order to better determine if there is any causal effect. There is a dose-dependent and treatment-durationdependent effect of liraglutide on thyroid C-cell tumours observed at clinically relevant exposures in rodents. These effects are not observed in humans and are thought to be seen only in rodents due to a higher density of GLP-1R on rodent C-cells. Calcitonin is released from C-cells in rodents following GLP-1 receptor activation but this was not observed in human C-cells [30,45]. The incidence of liraglutide-induced medullary thyroid cancer did not affect the overall survival rate among rodents. The FDA concluded that this translates into a low risk for humans but has required additional studies in animals and the establishment of a cancer registry to monitor the annual incidence of medullary thyroid cancer over the next 15 years [29,30,46].
Expert Opin. Biol. Ther. (2014) 14(8)
Liraglutide
Table 3. Summary of ongoing clinical trials investigating liraglutide for the treatment of obesity in diabetic and non-diabetic individuals. Trial
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NCT01789086
NCT01363609
NCT01677104
NCT01562678
NCT01272219
NCT02043054
NCT01272219
NCT02055014
NCT01739049
NCT01761318
Study
A randomised, double-blind, placebocontrolled trial to assess safety, tolerability and pharmacokinetics of liraglutide in obese adolescent subjects aged 12 -- 17 years Effects of glucagon-like peptide-1 (GLP-1) and Liraglutide on Brain Satiety and Reward Circuits and Feeding Behaviour in Diabetes (LIBRA) The microvascular function of GLP-1 and its analogues Liraglutide in obesity and diabetes: Identification of the CNS targets using fMRI Effect of liraglutide on body weight in non-diabetic obese subjects or overweight morbidities: SCALE -Obesity and Pre-diabetes Effects of Liraglutide in Young Adults with Type 2 DIAbetes (LYDIA) Effect of liraglutide on body weight in non-diabetic obese subjects or overweight morbidities: SCALE -Obesity and Pre-diabetes
Randomisation to Endobarrier Alone Versus with Incretin Analogue in SustainEd Diabesity (REVISE- Diabesity) Influence of appetiterelated hormones in binge eating behaviour among the overweight and obese Effect of liraglutide on cardiovascular end points in diabetes mellitus type 2 patients (MAGNA VICTORIA)
Subjects (n)
Trial treatment
Duration (weeks)
Outcomes
21
Liraglutide (up to 3.0 mg/day) versus placebo
6
Number of treatment emergent adverse events
20
Liraglutide up to 1.8 mg/day or insulin glargine
12
Food-stimuli-related neuronal activity in reward and satiety circuits as represented by bold fMRI signal change from baseline (%)
63
GLP-1 (native GLP-1, liraglutide or exenatide) or placebo Liraglutide (up to 1.8 mg/day) or placebo
3h
Skin blood flow
8
Effects of liraglutide on brain activation in areas involved in cognitive control and reward during food visualization Change in baseline body weight, onset of type 2 diabetes, pre-diabetes status
24
3735 subjects enrolled and treated. 1000 subjects prediabetes stratified to 3-year treatment 90
Daily s.c. doses of 3.0 mg liraglutide or placebo
68 or 160
Liraglutide up to 1.8 mg/day versus sitagliptin Daily s.c. doses of 3.0 mg liraglutide or placebo
26
Changes in peak end diastolic strain rate, HBA1c
68 or 160
Change in baseline body weight, onset of type 2 diabetes, pre-diabetes status
Liraglutide 1.8 mg OD alone, endobarrier alone or endobarrier and liraglutide 1.2 mg OD
24
HbA1c, weight
60
Liraglutide (up to 1.8 mg OD) or lifestyle counselling, diet and exercise
12
Reduction in binge eating scale score, weight, hormone profile
50
Liraglutide (up to 1.8 mg/day) versus placebo
26
Cardiovascular endpoints
3735 subjects enrolled and treated. 1000 subjects prediabetes stratified to 3 years treatment 72
Some trials are not purely investigating efficacy of liraglutide for weight loss but have other end points (e.g., cardiovascular safety). HbA1c: Glycosylated haemoglobin, OD: Once a day
Expert Opin. Biol. Ther. (2014) 14(8)
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S. Y. A. Ng & J. P. H. Wilding
5.
Regulatory status
Novo Nordisk filed for regulatory approval of liraglutide 3 mg for the treatment of obesity on 20 December 2013. The company filed a New Drug Application with the US FDA and a Marketing Authorisation Application with the EMEA.
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6.
Conclusion
Results of the completed clinical trials published to date in overweight and obese subjects demonstrate that treatment with liraglutide 3.0 mg is effective in providing sustained weight loss over 2 years in overweight and obese individuals and leads to significant improvements in metabolic and cardiovascular risk factors. It is tolerable and has an acceptable side effects profile, but longer term safety outcome data are still needed. There is convincing evidence that treatment with liraglutide for obesity results in clinically relevant beneficial effects on body weight. Liraglutide’s effect on morbidity and mortality needs to be proven by longer term studies designed specifically to investigate cardiovascular outcomes. 7.
Expert opinion
The rising epidemic of obesity is concerning, especially in developed countries, as it has a significant impact on healthcare systems and is fast becoming unsustainable. Urgent advances in treatment are needed but drug development in obesity has been fraught with failures and withdrawals due to limited efficacy and side effects and a particularly challenging area. Pharmacological therapy could play an important role as an adjunct to lifestyle changes in obese patients. Orlistat has been shown to produce modest effects on weight loss for up to 4 years with slight improvements in cardiovascular risk factors and reduced progression to diabetes in those with impaired glucose tolerance; however, its side effects are intolerable to many, and long-term effects on obesity-related morbidity are unknown. Liraglutide 3.0 mg daily has been shown result in sustained weight loss, improved cardiovascular risk factors and improved glycaemic control in obese individuals. For the majority of patients who do not get persistent nausea, liraglutide has an acceptable adverse effect profile, although concerns about risk of pancreatitis remain and the clinical significance of the increase in heart rate is uncertain. It is thus of potential clinical value for the treatment of obesity. The downside is that liraglutide is delivered subcutaneously, which limits its use in needle-phobic people. The current drug costs for liraglutide 1.8 mg daily as reported by Novo Nordisk are £3.92 per day and £1432.26 per year [47]. Liraglutide is not available in generic form. The economic
8
considerations of this may limit liraglutide to only obese individuals with significant co-morbidities who are proven to not be controlled with conventional therapy. Liraglutide treatment for obesity seems promising with efficacy advantages over orlistat. This, coupled with diet and exercise could lead to weight loss that is sustainable. There needs to be further trials of sufficient size and vigorous design to look at tolerability issues and side effect profiles to objectively assess the long-term safety of liraglutide. The multi-national SCALE - Obesity and Pre-diabetes 3a trial was presented at the American Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific and Clinical Congree on May 16, 2014. Results from the trials showed that after 56 weeks of treatment, liraglutide 3 mg, in combination with diet and exercise, provided significantly greater weight loss of 8% from baseline compared to 2.6% with placebo (p < 0.0001). 64% of patients lost more than 5% of their body weight (27% for placebo, p < 0.0001). There was also reduction in waist circumference (-8.19cm vs 3.94 cm, p < 0.0001), improvement in lipid profile and blood pressure reduction of 2.82 mmHg (systolic) and 0.89 mmHg (diastolic) [48]. Childhood obesity is also becoming more prevalent [49]. This will have a huge medical and financial implication on the healthcare service. Results from an ongoing Phase I trial assessing the use of liraglutide in the adolescent obese population will provide information on the safety and tolerability of using this drug in this group. Many physicians are still reluctant to view obesity as a disease rather than a risk factor, which makes them more hesitant to prescribe antiobesity therapy, especially ones which are associated with significant risks and side effects. There needs to be more data studying the cost of liraglutide in comparison to obesity-related morbidity. Approval of liraglutide for the treatment of obesity will depend on the ongoing review by the regulatory authorities: if it is approved, use by physicians may depend on it being shown to be a costeffective intervention by organisations such as the National Institute for Health and Care Excellence (NICE) in the UK.
Declaration of interest J Wilding has been an investigator for clinical trials with liraglutide and other GLP-1-based treatments for type 2 diabetes and obesity. He has received lecture and consultancy fees from Novo Nordisk and other companies involved in the development and marketing of drugs for diabetes and obesity. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Biol. Ther. (2014) 14(8)
Liraglutide
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Affiliation
Sarah Yoon Ai Ng1 & John P H Wilding†2 † Author for correspondence 1 Academic Clinical Fellow, University of Liverpool, Aintree University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Department of Diabetes and Endocrinology, Longmoor Lane, Liverpool L9 7AL, UK 2 Professor of Medicine, University of Liverpool, Aintree University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Department of Diabetes and Endocrinology, Longmoor Lane, Liverpool L9 7AL, UK Tel: +44 151 529 5885; Fax: +44 151 529 5888; E-mail: [email protected]
Liraglutide in the treatment of obesity Sarah Yoon Ai Ng & John P H Wilding† 1.
Introduction
2.
Overview of the market: unmet needs of current
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therapies 3.
Introduction to the compound
4.
Safety and tolerability
5.
Regulatory status
6.
Conclusion
7.
Expert opinion
University of Liverpool, Aintree University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Department of Diabetes and Endocrinology, Liverpool, UK
Introduction: Obesity is a global epidemic with important healthcare and financial implications. Most current antiobesity pharmacological therapies are unsatisfactory due to undesirable side effects. Many drugs have been withdrawn due to safety concerns. Maintaining weight loss remains the Achilles’ heel of antiobesity therapy. Areas covered: This is an overview of the use of liraglutide for obesity treatment. Clinical efficacy on weight, cardiovascular parameters, as well as safety and tolerability issues are discussed. Expert opinion: Liraglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist, which has a protracted pharmacokinetic profile compared to native GLP-1 while maintaining its biological activity. It induces weight loss by reducing appetite and energy intake. It stimulates insulin release and decreases glucagon secretion in response to hyperglycaemia. Treatment with liraglutide, in addition with diet and exercise, induces sustained mean weight loss of 7.6 kg at 2 years (weight loss induced by orlistat = 5.7 kg, phentermine/ topiramate controlled release 15/92 = 10.9 kg). It reduces blood pressure and improves glycaemic control, which has clinically relevant significance on reducing obesity-related morbidity and mortality. Liraglutide is reasonably well tolerated with gastrointestinal side effects being most commonly encountered. Novo Nordisk filed for regulatory approval of liraglutide 3.0 mg for obesity treatment in December 2013. Keywords: glucagon-like peptide 1 receptor agonist, liraglutide, obesity, overweight Expert Opin. Biol. Ther. [Early Online]
1.
Introduction
Obesity is a global epidemic, with a projected increase of 65 million more obese adults in the USA and 11 million in the UK by 2030, leading to an additional 6 -- 8.5 million cases of diabetes, 5.7 -- 7.3 million cases of cardiovascular disease, 492,000 -- 669,000 additional cases of cancer and 26 -- 55 million quality-adjusted life years forgone for the USA and UK combined [1,2]. It is predicted that by 2030, obesity and its associated co-morbidities could cost the National Health Service £2 billion per year [2]. 2.
Overview of the market: unmet needs of current therapies
Treatment modalities that are currently available for inducing weight loss in obese individual are unsatisfactory. Drug therapy for obesity remains challenging as several have been discontinued or have had their use restricted due to safety and efficacy concerns [3]. Although existing agents allow modest weight loss with improvement in cardiovascular risk factors and glycaemia in impaired glucose tolerance and diabetes, none have been shown to reduce cardiovascular events. Sustaining weight loss is often the Achilles’ heel of obesity therapy.
10.1517/14712598.2014.925870 © 2014 Informa UK, Ltd. ISSN 1471-2598, e-ISSN 1744-7682 All rights reserved: reproduction in whole or in part not permitted
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S. Y. A. Ng & J. P. H. Wilding
Box 1. Drug summary. Drug name Phase Indication Mechanism of action Route of administration Chemical structure
Liraglutide Submitted to FDA and European Medicines Evaluation Agency for regulatory approval on 20 December 2013 Obesity and overweight Glucagon-like peptide 1 (GLP-1) receptor agonist Subcutaneous H
His
Ala
Glu
Gly
Thr
Phe
Thr
Ser
H3C
Asp
Val
Glu
OH
Ser
O
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Ser
Ile
Pivotal trial(s) (Completed)
Tyr Ala
Leu
Trp
Glu
Leu
Gly Val
Gln
Arg
Ala
Gly
Ala
Arg
Lys
Gly
Glu
Phe
OH
Phase I: Effects of the once-daily GLP-1 analogue liraglutide on gastric emptying, glycaemic parameters, appetite and energy metabolism in obese, non-diabetic adults (NN8022-3630) Phase II: Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study (NN8022-1807) Phase II: Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analogue, liraglutide. (NN8022-1807) Phase III: Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomised study (NN8022-1923)
Table 1. Currently approved antiobesity pharmacotherapy in the market (US and/or EU approvals). Name or code Lorcaserin (ADP 359) Phentermine Diethylpropion Phendimetrazine Benzphetamine Phentermine/ topiramate Orlistat
Type of agent or combination
Current status
5-HT2C receptor agonist Noradrenergic sympathomimetic amine
FDA approved 2012, following re-file FDA approved in 1959 for short-term use (< 12 weeks)
Noradrenergic sympathomimetic amine/sulfamate-substituted monosaccharide derivative Lipase inhibitor
FDA approved 2012, following re-file
FDA and EMEA approved in 1998
EMEA: European Medicines Evaluation Agency.
At present, the only medical therapy approved in the European Union (EU) is the lipase inhibitor orlistat. Orlistat was approved by the FDA and the European Medicines Evaluation Agency (EMEA) for the treatment of obesity in 1998. Orlistat inhibits pancreatic lipases and reduces fat absorption from the gut by 30%, resulting in energy loss of 300 kcal/day [4]. The effects on weight loss is modest (6 -- 9 kg) [5] but is enough to have beneficial effects on cardiovascular risk factors. Treatment with orlistat leads to a decrease in low-density lipoprotein (LDL) cholesterol, blood pressure and improves glycaemic control [6,7]. However, gastrointestinal side effects limit its tolerability [8]. Sibutramine was approved in the EU in 1999 and rimonabant in 2009 but both have subsequently been withdrawn due to safety concerns and adverse effects that outweigh the modest benefits of treatment. Lorcaserin was approved by the FDA in June 2012 for the treatment of obesity in patients with body mass index (BMI) 2
of ‡ 30 or ‡ 27 kg/m2 with at least one weight-related comorbidity. Binding of lorcaserin to the 5-HT2C receptors in pro-opiomelanocortin neurons promotes satiety [9]. Its causes a mean weight loss of 5.8 kg compared to 2.2 kg for placebo over 12 months [10]. Concerns remain regarding breast tumours in preclinical studies and higher rates of new cardiac valvulopathy, leading to withdrawal of the EU marketing application in 2013 (Table 1). Phentermine-topiramate (Phen-Top) was approved by the FDA for the treatment of obesity in patients with BMI of ‡ 30 or ‡ 27 kg/m2 with at least one weight-related comorbidity in July 2012. Phentermine reduces food intake by enhancing norepinephrine release and blocking norepinephrine reuptake [11]. The weight loss effects of topiramate is largely unexplained but believed to be due to reduced energy intake and increased energy expenditure. There is a 10.9 kg observed weight loss for high-dose Phen-Top compared with
Expert Opin. Biol. Ther. (2014) 14(8)
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Liraglutide
2.1 kg for placebo [12]. Frequently reported side effects were paraesthesia, dry mouth and constipation and have significant teratogenic risks. The EMEA has chosen not to license PhenTop, as the benefits were not thought to outweigh the risks. Contrave is a combination agent consisting of naltrexone and bupropion, which is under evaluation. The combination is effective because naltrexone blocks inhibitory influences of opioid receptors activated by the b-endorphin that stimulates feeding. It also allows the activity of a-melanocyte-stimulating hormone, which inhibits food intake. The FDA has requested for a premarketing study of the drug with assessment of cardiovascular outcomes in view of increases in pulse and blood pressure in Phase III studies [13]. Bariatric surgery produces effective weight loss, reduces the incidence of diabetes in obese individuals with impaired glucose tolerance and is associated with remission of diabetes in a proportion of patients [14]. However, it is invasive and has risks and potential complications. Non-pharmacological weight loss programmes frequently fail due to nonadherence. Therefore, there is a need and strong incentive to develop an effective drug therapy for the treatment of obesity. 3.
Introduction to the compound
Glucagon-like peptide 1 Glucagon-like peptide-1 (GLP-1) is an incretin hormone which has a glucose-dependent stimulatory effect on insulin production and secretion and an inhibitory effect on glucagon secretion from the pancreatic islets in response to hyperglycaemia [15]. This leads to a reduction in blood glucose in insulindeprived states by increasing glucose deposition in peripheral tissues, and reducing hepatic glucose output [15]. GLP-1 also binds to receptors in the brainstem, hypothalamus and amygdala, where it is thought to promote satiety, leading to decreased energy intake [16-19]. GLP-1 receptor agonists also increase the expression of IL-6 and IL-1b in the hypothalamus and hindbrain, and this could contribute to GLP-1-induced weight loss [20]. 3.1
Liraglutide Liraglutide (Box 1) is a long-acting GLP-1 agonist, developed by Novo Nordisk, that is 97% homologous to native human GLP-1 [21]. Liraglutide has a protracted pharmacokinetic profile, while maintaining its biologic activity [22]. Liraglutide was approved by the EMEA for the treatment of type 2 diabetes in June 2009. 3.2
Pharmacological properties of liraglutide Liraglutide binds and activates GLP-1 receptors, leading to potentiation of glucose-dependent insulin secretion from pancreatic b cells. It stimulates insulin release and inhibits glucagon secretion, but only in response to hyperglycaemia [23,24], lowering blood-glucose without causing hypoglycaemia. Liraglutide has a protein-binding capability of > 98% [25]. 3.3
The use of native GLP-1 is limited by the very short elimination half-life of < 1.5 min due to rapid degradation by ubiquitous dipeptidyl peptidase-4 [26]. The structural modifications in liraglutide result in a compound with a slower absorption rate and a longer half-life of 11 -- 13 h, rendering it suitable for a once-daily injection (Figure 1) [22]. Maximum plasma concentrations of liraglutide are achieved 10 -- 14 h after a subcutaneous dose was given [22,27]. Steady state is reached after about three dose administrations. Only low levels of metabolites are found in plasma, urine and faeces [28]. Liraglutide is fully degraded in the body with no single organ as a major route of elimination. Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia-2 and in patients with type 1 diabetes and a history of pancreatitis. The delayed gastric emptying caused by liraglutide may also influence the absorption of concomitantly administered oral medications [29,30]. Clinical efficacy We searched www.clinicaltrials.gov using the keywords ‘liraglutide’ and ‘obesity’ to identify ongoing and completed clinical trials for the use of liraglutide in the treatment of obesity. We also searched PubMed and the Cochrane database using the keywords ‘liraglutide’, ‘obesity’ and ‘GLP-1 agonists’ to identify relevant papers Tables 2 and 3. Treatment with liraglutide 2.4/3.0 mg as an adjunct to a low-calorie diet and exercise programme produces a clinically relevant, dose-dependent effect on weight loss that is greater than placebo and orlistat [31]. Astrup et al. demonstrated that after 20 weeks of treatment with liraglutide 3.0 mg, there is a 7.2 kg mean weight loss compared to 2.8 kg with placebo and 4.1 kg with orlistat. The mean weight loss with liraglutide 3.0 mg at 1 year was 7.8 kg (95% CI: 3.7 -- 8.0) (2.0 kg with placebo and 3.9 kg with orlistat) [32]. Participants randomised to liraglutide 3.0 mg for 1 year, and maintained on 2.4/3.0 mg for the second year were able to maintain a mean weight loss of 10.3 ± 7.1 kg from screening over 2 years. Mean weight loss at 2 years for obese individuals treated with liraglutide 2.4/3.0 mg was 7.8 kg from screening. At week 20, the proportion of individuals treated with liraglutide 3.0 mg who lost > 10% of baseline weight is greater than those treated with orlistat (28%, n = 26 vs 2%, n = 2; p < 0.0001, odds ratio [OR] 3.0) [31]. The SEQUEL study demonstrated that individuals who were treated with controlled release phentermine/topiramate 7.5/46 and 15/92 achieved mean changes from baseline body weight of -9.3 and -10.5%, respectively (-1.8% for placebo) [12]. Weight loss for individuals on liraglutide 2.4/3.0 mg for 2 years was significantly greater than with orlistat (-5.3 vs -2.3 kg, p < 0.001), with > 85% of those losing > 5% weight maintaining this at year 2 [32]. There was a decrease in waist circumference at year 2 of 6.2 cm with liraglutide 2.4/3.0 mg compared to 4.5 cm with orlistat. Mean change in systolic blood pressure at 20 weeks 3.4
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• Controls appetite • Induces satiety
Brain
Adipocytes Liver
↓ Fatty acids release
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GLP-1 or GLP-1R agonists
• ↓ Glucagonmediated glycogenolysis • ↓ Glucagonmediated gluconeogenesis
Vagus effects Pancreas
• ↓ Sympathetic nervous system Blood pressure regulation
activity • ↑ Heart rate and stroke volume
• ↑ Inslin production
• Vasodilation
• ↓ Glucose levels • Promotes β cell growth • ↓ Inuslin resistance
• ↓ Catecholamine secretion from adrenal • ↑ Urine excretion and natriuresis
Figure 1. Effects of GLP-1 and GLP-1 receptor agonists.
in individuals treated with liraglutide was -- 13.3 mm Hg, (-7.8 mm Hg with placebo and -9.3 with orlistat) [31]. This effect in reduction in systolic BP was sustained at 2 years (-12.5 mm Hg) [32]. Liraglutide-treated individuals had a higher probability of having normal glucose tolerance at week 20 compared with those on placebo or orlistat (p < 0.01) [31]. Fasting blood glucose was reduced by 0.39 -- 0.44 mmol/l at week 20 with liraglutide-treated individuals, while there was no observed effect in those on placebo or orlistat. There is a dosedependent reduction in glycosylated haemoglobin with individuals treated with liraglutide, ranging from -0.14% with liraglutide 1.2 mg to -0.24% with 3.0 mg. Up to 62% of liraglutide-treated individuals with prediabetes at randomisation achieved normal glucose tolerance at year 2, compared with 26% on orlistat [32]. At year 2, those treated with liraglutide 2.4/3.0 mg had a significantly higher high-density lipoprotein cholesterol compared with those on orlistat (treatment difference 0.07 mmol/l, p = 0.03) and decreased LDL cholesterol and triglycerides (treatment difference -0.12 mmol/l for triglycerides, p = 0.053 vs orlistat) [32]. The proportion of individuals with metabolic syndrome at week 20 decreased by > 60% in those treated with liraglutide 2.4/3.0 mg, compared to 38 and 13% reduction in the placebo and orlistat groups [31]. Individuals reported improved scores for physical function, self-esteem and quality of life in those treated with liraglutide 3.0 mg compared to orlistat, in addition to diet and exercise. 4
The SCALE Maintenance study is a 56-week randomised, double-blind, placebo-controlled, parallel group, multi-centre trial that investigated the use of liraglutide on weight loss maintenance induced by a 12-week low-calorie diet in obese subjects. The liraglutide group achieved greater mean absolute weight loss of 6.0 versus 0.1 kg than the placebo group. This data of a weight loss difference of 6.0 kg for liraglutide 3.0 mg versus 0.1 kg for placebo (estimated treatment difference of -5.9 kg) at week 56 is consistent with what was reported by Astrup et al. [32]. The number of participants who maintained the ‡ 5% weight loss in the initial run-in period in the liraglutide group was significantly higher compared to the placebo group (81.4 vs 48.9%, p < 0.00001). The number of participants who lost ‡ 5% of randomisation weight was also significantly higher compared to the placebo group (50.5 vs 21.8%; p < 0.00001). Liraglutide-treated participants also achieved greater decreases in waist circumference and glycaemic parameters at week 56 [33]. 4.
Safety and tolerability
Gastrointestinal side effects were most commonly encountered with liraglutide, with up to 14% of individuals reporting vomiting as a side effect [31]. These were mostly mild to moderate in severity and transient and became more frequent with increasing doses. However, the transient nausea and vomiting caused by liraglutide is associated with greater weight loss [34]. Fifteen to thirty per cent of individuals on orlistat report
Expert Opin. Biol. Ther. (2014) 14(8)
Effect of liraglutide on body weight in overweight or obese subjects with type 2 diabetes -- SCALE Diabetes Comparison of liraglutide versus placebo in weight loss maintenance on obese subjects: SCALE -- Maintanence Effect if liraglutide in obese subjects with moderate or severe obstructive sleep apnoea -- SCALE Sleep Apnoea Liraglutide and a calorie-restricted diet augments weight loss and decreases risk of type 2 diabetes and cardiovascular disease
NCT01272232
Expert Opin. Biol. Ther. (2014) 14(8)
mg, mg, mg, mg,
69
359
422 (212 liraglutide 3.0 mg, 210 placebo)
846
564 (98 placebo, 95 liraglutide 1.2 90 liraglutide 1.8 93 liraglutide 2.4 93 liraglutide 3.0 95 orlistat) 46
49
Subjects (n)
None
18 -- 65
None
None
None
18 -- 65
40 -- 75
846
18 years and above (mean age = 46.2)
18 years and above
46
None
18 -- 75
18 -- 65 (mean age = 54.4)
Subjects with type 2 diabetes
Age (years)
Liraglutide 1.8 mg OD versus placebo
Liraglutide (up to 3.0 mg/day) versus placebo
Daily s.c. doses of 3.0 mg liraglutide or placebo
Daily s.c. doses of liraglutide 1.8, 3.0 mg or placebo
Liraglutide followed by placebo; placebo followed by glimepiride; glimepiride followed by liraglutide
Daily s.c. doses of 1.2, 1.8, 2.4, 3.0 mg liraglutide or placebo or orlistat 120 mg/day
Daily s.c. doses of 1.8 or 3.0 mg liraglutide or placebo
Trial treatment
14
32
56
56
8
20 followed by 84-week extension period
5
Duration (weeks)
Weight, systolic blood pressure, fasting glucose, triglyceride
Change in baseline body weight, fasting plasma glucose, fasting insulin, HbA1c, blood pressure, waist circumference Changes from baseline in apnoea-hypopnoea index
Change in weight, fat mass, weight circumference, spontaneous energy intake, appetite, HbA1c, energy expenditure, adverse events Change in baseline body weight, fasting plasma glucose, fasting insulin, HbA1c, blood pressure, waist circumference
Change in baseline body weight, fasting plasma glucose, fasting insulin, HbA1c, blood pressure, waist circumference
Gastric emptying, energy expenditure and appetite
Outcomes
Source: www.clinicaltrials.gov. BD: Twice a day; BMI: Body mass index; DHEAS: Dehydroepiandrosterone sulphate; FSH: Follicle-stimulating hormone; HbA1c: Glycosylated haemoglobin; LH: Luteinising hormone; OD: Once a day; SHBG: Sex hormonebinding globulin.
NCT01784965
NCT01557166
NCT00781937
Effect of liraglutide on weight and appetite in obese subjects with type 2 diabetes
A trial to assess the effect of liraglutide on gastric emptying in healthy obese volunteers The effect of liraglutide on body weight in obese subjects
Study
NCT01508949
NCT00422058
NCT00978393
Trial
Table 2. Summary of completed clinical trials investigating liraglutide for the treatment of obesity in diabetic and non-diabetic individuals.
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Maastricht on 06/09/14 For personal use only.
Liraglutide
5
6
Source: www.clinicaltrials.gov. BD: Twice a day; BMI: Body mass index; DHEAS: Dehydroepiandrosterone sulphate; FSH: Follicle-stimulating hormone; HbA1c: Glycosylated haemoglobin; LH: Luteinising hormone; OD: Once a day; SHBG: Sex hormonebinding globulin.
None PCOS and liraglutide as add-on therapy to metformin NCT01911468
36
18 -- 55
Metformin alone, liraglutide alone (up to 0.6 -- 1.2 mg/day) or metformin and liraglutide
12
Change in body weight, BMI, weight circumference, glucose, insulin, LH, FSH, testosterone, SHBG, androstenedione, DHEAS Change in body weight, BMI, weight circumference, glucose, insulin, LH, FSH, testosterone, SHBG, androstenedione, DHEAS 12 None Polycystic ovary syndrome (PCOS) and liraglutide NCT01899430
32
18 -- 55
Daily s.c. doses 0.6 -- 1.2 liraglutide or metformin up to 1 g BD
Outcomes Duration (weeks) Trial treatment Subjects with type 2 diabetes Age (years) Subjects (n) Study Trial
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Maastricht on 06/09/14 For personal use only.
Table 2. Summary of completed clinical trials investigating liraglutide for the treatment of obesity in diabetic and non-diabetic individuals (continued).
S. Y. A. Ng & J. P. H. Wilding
gastrointestinal side effects, but these side effects often subside as patients learn not to take fatty meals [13,35]. Injection-site symptoms (pain, haematoma, irritation of skin) were infrequently reported. There was an increase in pulse by 3.1 beats/min observed following 2 years of treatment with liraglutide 2.4/3.0 mg [32]. Previous studies suggested that an increased resting heart rate is associated with a reduced life expectancy and an increase in cardiovascular mortality [36-38]. The clinical relevance of the increased heart rate, in the context of a reduced systolic blood pressure, is unclear as there is no evidence to suggest that liraglutide use leads to increased cardiovascular event rates [39,40]. Studies of longer follow-up duration should be conducted. The LEADER is an ongoing multi-centre trial that will be prospectively evaluating the cardiovascular safety of liraglutide in patients with type 2 diabetes. The SCALE Obesity and pre-diabetes studies will evaluate the effects of liraglutide on progression to diabetes in at risk participants. There was one event of cholelithiasis occurring simultaneously with acute pancreatitis 299 days after treatment on liraglutide 3.0 mg [32]. Concerns regarding pancreatitis were raised in post-marketing adverse event reports and in clinical trials conducted with liraglutide for the treatment of type 2 diabetes. Twelve liraglutide randomised controlled trials reported acute pancreatitis as an outcome, with an estimated OR of liraglutide and pancreatitis being 0.97 (95% CI: 0.21 -- 4.39) [41]. The drug labelling for liraglutide was changed in 2011 to alert prescribers of the increased risk of pancreatitis [42]. However, type 2 diabetic patients have up to three times as high baseline rates of pancreatitis in patients with diabetes compared to those without diabetes [43]. Significant and rapid weight loss is associated with gallstone formation, which is a major cause of acute pancreatitis [44]. These reasons, in addition to the fact that there is limited data from post-marketing reporting, make it difficult to draw firm conclusions on whether or not the use of liraglutide is associated with an increased risk of pancreatitis. Data from longer term studies specifically designed to study the association between liraglutide and acute pancreatitis and post-marketing pharmacovigilance need to be evaluated in order to better determine if there is any causal effect. There is a dose-dependent and treatment-durationdependent effect of liraglutide on thyroid C-cell tumours observed at clinically relevant exposures in rodents. These effects are not observed in humans and are thought to be seen only in rodents due to a higher density of GLP-1R on rodent C-cells. Calcitonin is released from C-cells in rodents following GLP-1 receptor activation but this was not observed in human C-cells [30,45]. The incidence of liraglutide-induced medullary thyroid cancer did not affect the overall survival rate among rodents. The FDA concluded that this translates into a low risk for humans but has required additional studies in animals and the establishment of a cancer registry to monitor the annual incidence of medullary thyroid cancer over the next 15 years [29,30,46].
Expert Opin. Biol. Ther. (2014) 14(8)
Liraglutide
Table 3. Summary of ongoing clinical trials investigating liraglutide for the treatment of obesity in diabetic and non-diabetic individuals. Trial
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Maastricht on 06/09/14 For personal use only.
NCT01789086
NCT01363609
NCT01677104
NCT01562678
NCT01272219
NCT02043054
NCT01272219
NCT02055014
NCT01739049
NCT01761318
Study
A randomised, double-blind, placebocontrolled trial to assess safety, tolerability and pharmacokinetics of liraglutide in obese adolescent subjects aged 12 -- 17 years Effects of glucagon-like peptide-1 (GLP-1) and Liraglutide on Brain Satiety and Reward Circuits and Feeding Behaviour in Diabetes (LIBRA) The microvascular function of GLP-1 and its analogues Liraglutide in obesity and diabetes: Identification of the CNS targets using fMRI Effect of liraglutide on body weight in non-diabetic obese subjects or overweight morbidities: SCALE -Obesity and Pre-diabetes Effects of Liraglutide in Young Adults with Type 2 DIAbetes (LYDIA) Effect of liraglutide on body weight in non-diabetic obese subjects or overweight morbidities: SCALE -Obesity and Pre-diabetes
Randomisation to Endobarrier Alone Versus with Incretin Analogue in SustainEd Diabesity (REVISE- Diabesity) Influence of appetiterelated hormones in binge eating behaviour among the overweight and obese Effect of liraglutide on cardiovascular end points in diabetes mellitus type 2 patients (MAGNA VICTORIA)
Subjects (n)
Trial treatment
Duration (weeks)
Outcomes
21
Liraglutide (up to 3.0 mg/day) versus placebo
6
Number of treatment emergent adverse events
20
Liraglutide up to 1.8 mg/day or insulin glargine
12
Food-stimuli-related neuronal activity in reward and satiety circuits as represented by bold fMRI signal change from baseline (%)
63
GLP-1 (native GLP-1, liraglutide or exenatide) or placebo Liraglutide (up to 1.8 mg/day) or placebo
3h
Skin blood flow
8
Effects of liraglutide on brain activation in areas involved in cognitive control and reward during food visualization Change in baseline body weight, onset of type 2 diabetes, pre-diabetes status
24
3735 subjects enrolled and treated. 1000 subjects prediabetes stratified to 3-year treatment 90
Daily s.c. doses of 3.0 mg liraglutide or placebo
68 or 160
Liraglutide up to 1.8 mg/day versus sitagliptin Daily s.c. doses of 3.0 mg liraglutide or placebo
26
Changes in peak end diastolic strain rate, HBA1c
68 or 160
Change in baseline body weight, onset of type 2 diabetes, pre-diabetes status
Liraglutide 1.8 mg OD alone, endobarrier alone or endobarrier and liraglutide 1.2 mg OD
24
HbA1c, weight
60
Liraglutide (up to 1.8 mg OD) or lifestyle counselling, diet and exercise
12
Reduction in binge eating scale score, weight, hormone profile
50
Liraglutide (up to 1.8 mg/day) versus placebo
26
Cardiovascular endpoints
3735 subjects enrolled and treated. 1000 subjects prediabetes stratified to 3 years treatment 72
Some trials are not purely investigating efficacy of liraglutide for weight loss but have other end points (e.g., cardiovascular safety). HbA1c: Glycosylated haemoglobin, OD: Once a day
Expert Opin. Biol. Ther. (2014) 14(8)
7
S. Y. A. Ng & J. P. H. Wilding
5.
Regulatory status
Novo Nordisk filed for regulatory approval of liraglutide 3 mg for the treatment of obesity on 20 December 2013. The company filed a New Drug Application with the US FDA and a Marketing Authorisation Application with the EMEA.
Expert Opin. Biol. Ther. Downloaded from informahealthcare.com by University of Maastricht on 06/09/14 For personal use only.
6.
Conclusion
Results of the completed clinical trials published to date in overweight and obese subjects demonstrate that treatment with liraglutide 3.0 mg is effective in providing sustained weight loss over 2 years in overweight and obese individuals and leads to significant improvements in metabolic and cardiovascular risk factors. It is tolerable and has an acceptable side effects profile, but longer term safety outcome data are still needed. There is convincing evidence that treatment with liraglutide for obesity results in clinically relevant beneficial effects on body weight. Liraglutide’s effect on morbidity and mortality needs to be proven by longer term studies designed specifically to investigate cardiovascular outcomes. 7.
Expert opinion
The rising epidemic of obesity is concerning, especially in developed countries, as it has a significant impact on healthcare systems and is fast becoming unsustainable. Urgent advances in treatment are needed but drug development in obesity has been fraught with failures and withdrawals due to limited efficacy and side effects and a particularly challenging area. Pharmacological therapy could play an important role as an adjunct to lifestyle changes in obese patients. Orlistat has been shown to produce modest effects on weight loss for up to 4 years with slight improvements in cardiovascular risk factors and reduced progression to diabetes in those with impaired glucose tolerance; however, its side effects are intolerable to many, and long-term effects on obesity-related morbidity are unknown. Liraglutide 3.0 mg daily has been shown result in sustained weight loss, improved cardiovascular risk factors and improved glycaemic control in obese individuals. For the majority of patients who do not get persistent nausea, liraglutide has an acceptable adverse effect profile, although concerns about risk of pancreatitis remain and the clinical significance of the increase in heart rate is uncertain. It is thus of potential clinical value for the treatment of obesity. The downside is that liraglutide is delivered subcutaneously, which limits its use in needle-phobic people. The current drug costs for liraglutide 1.8 mg daily as reported by Novo Nordisk are £3.92 per day and £1432.26 per year [47]. Liraglutide is not available in generic form. The economic
8
considerations of this may limit liraglutide to only obese individuals with significant co-morbidities who are proven to not be controlled with conventional therapy. Liraglutide treatment for obesity seems promising with efficacy advantages over orlistat. This, coupled with diet and exercise could lead to weight loss that is sustainable. There needs to be further trials of sufficient size and vigorous design to look at tolerability issues and side effect profiles to objectively assess the long-term safety of liraglutide. The multi-national SCALE - Obesity and Pre-diabetes 3a trial was presented at the American Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific and Clinical Congree on May 16, 2014. Results from the trials showed that after 56 weeks of treatment, liraglutide 3 mg, in combination with diet and exercise, provided significantly greater weight loss of 8% from baseline compared to 2.6% with placebo (p < 0.0001). 64% of patients lost more than 5% of their body weight (27% for placebo, p < 0.0001). There was also reduction in waist circumference (-8.19cm vs 3.94 cm, p < 0.0001), improvement in lipid profile and blood pressure reduction of 2.82 mmHg (systolic) and 0.89 mmHg (diastolic) [48]. Childhood obesity is also becoming more prevalent [49]. This will have a huge medical and financial implication on the healthcare service. Results from an ongoing Phase I trial assessing the use of liraglutide in the adolescent obese population will provide information on the safety and tolerability of using this drug in this group. Many physicians are still reluctant to view obesity as a disease rather than a risk factor, which makes them more hesitant to prescribe antiobesity therapy, especially ones which are associated with significant risks and side effects. There needs to be more data studying the cost of liraglutide in comparison to obesity-related morbidity. Approval of liraglutide for the treatment of obesity will depend on the ongoing review by the regulatory authorities: if it is approved, use by physicians may depend on it being shown to be a costeffective intervention by organisations such as the National Institute for Health and Care Excellence (NICE) in the UK.
Declaration of interest J Wilding has been an investigator for clinical trials with liraglutide and other GLP-1-based treatments for type 2 diabetes and obesity. He has received lecture and consultancy fees from Novo Nordisk and other companies involved in the development and marketing of drugs for diabetes and obesity. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Biol. Ther. (2014) 14(8)
Liraglutide
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Affiliation
Sarah Yoon Ai Ng1 & John P H Wilding†2 † Author for correspondence 1 Academic Clinical Fellow, University of Liverpool, Aintree University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Department of Diabetes and Endocrinology, Longmoor Lane, Liverpool L9 7AL, UK 2 Professor of Medicine, University of Liverpool, Aintree University Hospitals NHS Foundation Trust, Clinical Sciences Centre, Department of Diabetes and Endocrinology, Longmoor Lane, Liverpool L9 7AL, UK Tel: +44 151 529 5885; Fax: +44 151 529 5888; E-mail: [email protected]
