Are we underutilising pharmacotherapies when it comes to managing obesity?
It is well known that obesity is becoming a global epidemic. The prevalence of obesity has tripled over the past four decades. Worldwide, WHO data from 2016 suggests that 39% of adults are overweight and 13% are obese.1
In Australia, the prevalence of overweight and obese adults has also increased significantly, from 56.3% in 1995 to 62.8% in 2012.2 Obesity is associated with increased morbidity and premature mortality due to hypertension, dyslipidemia, type 2 diabetes, cardiovascular disease, obstructive sleep apnoea and stroke.3
It has been shown that losing 5 to 10% of total body weight can improve adverse metabolic outcomes significantly.3
While lifestyle changes such as diet and exercise are fundamental to losing weight, lifestyle change alone has been shown to be challenging due to metabolic, hormonal and neuronal adaptive mechanisms that prevent weight loss.4
Hence, pharmacotherapies and/or bariatric surgery to counteract these mechanisms have been advised to be used in conjunction with lifestyle modifications, in order to achieve long-term weight management.5
According to an Australian study, only 17.2% of obese or overweight patients sought weight-loss advice from GPs. In addition, research showed GPs underestimated 30% of obese patients as overweight and 3% of overweight patients as having normal weight.6 And while 65% and 58% of these patients were given dietary and exercise advice, respectively, only 6% were managed with pharmacotherapy and less than 1% were referred for bariatric surgery.6 This data suggests effective pharmacotherapies for use in obesity management may be underutilised.
Current TGA approved pharmacotherapies for weight loss in Australia include orlistat (Xenical®), phentermine (Duromine®) and liraglutide (Saxenda®).7
Other agents, such as sibutramine and rimonabant, have been withdrawn from the market due to safety concerns, despite their effectiveness and favourable effect on cardiovascular surrogates.8
Bariatric surgical procedures are the most effective weight-loss options, although their widespread availability is limited as they remain largely unfunded in the public domain.3
This article will focus on the use of liraglutide in weight loss management in adults with obesity.
Liraglutide is a synthetic form of a protein that is 97% homologous to native GLP-1, a gut-derived incretin hormone.9 It was initially approved for use as 0.6mg weekly injections for management of type 2 diabetes with the maximal recommended dose being 1.8 mg weekly.9
In animal studies, GLP-1 was shown to suppress appetite and reduce weight.9 The mechanisms behind the weight loss are thought to be due to effects on both the gastrointestinal tract and the brain.9
Their action is deemed to be due to the activation of GLP-1 receptors on melanocortin 4 receptor neurons, resulting in an activation cascade that ultimately reduces food intake.10
In a double blind, open label placebo-controlled trial of liraglutide versus orlistat 120 mg in addition to a 500 kcal per day energy-deficit diet and increased physical activity, liraglutide was shown to induce a more significant weight loss at the end of 20 weeks, with 76% losing more than 5% of body weight by 20 weeks compared with placebo (30%) or orlistat (44%).9
The subsequent trial at the two-year mark highlighted that a greater proportion of participants on liraglutide 2.4/3.0?mg, than on orlistat, lost >5 and >10% weight.
At year two, 52% of patients on Liraglutide lost >5% of weight compared to 29% on orlistat (p value <0.001). 26% of patients on liraglutide lost >10% of screening weight compared with 16% on orlistat at two years (p value 0.04).
This long-term weight maintenance effect of liraglutide was further confirmed by the SCALE trial, a phase three randomised double blinded placebo-controlled trial conducted over 160 weeks in pre-diabetic patients.12
At week 160 49.6% of participants on liraglutide lost >5% of weight compared to 23.7% on placebo. This was true for >10% of body weight loss (24.8% on liraglutide versus 9.9% on placebo) as well as for 15% body weight loss (11% on liraglutide versus 3.1% on placebo).
Liraglutide use is associated with a reduction in diabetes risk in obese patients and improved glycaemic parameters and cardiovascular risk factors.11-13 More than 50% of obese patients with pre-diabetes achieved normal glucose tolerance after treatment with liraglutide for two years.11
In the SCALE trial, the proportion of pre-diabetic patients diagnosed with diabetes was reduced compared with placebo. By week 160, 2% of the 1472 individuals in the liraglutide group were diagnosed with diabetes while on treatment, compared with 6% of the 738 in the placebo group.12 The cumulative probability of a diagnosis of diabetes taking censoring into account was: 3% of individuals in the liraglutide group were diagnosed with diabetes by week 160, compared with 11% in the placebo group.12
There was a significant reduction in glycated haemoglobin (HbA1c) and mean fasting plasma glucose level, with a non-significant reduction in low-density lipoprotein (LDL) cholesterol and triglycerides but a significant increase in high-density lipoprotein (HDL) cholesterol.12 Liraglutide use was also associated with a reduction in systolic blood pressure compared to orlistat and placebo.10,13
However, the effect of liraglutide on diastolic blood pressure was variable.10,13 Evidence to date has been reassuring with regards to the cardiovascular safety of liraglutide. In a 56-week randomised double-blinded placebo-controlled trial in type 2 diabetes patients with high cardiovascular risk (LEADER), death due to cardiovascular events was lower in patients treated with liraglutide 1.8mg daily.13
This study showed that liraglutide is non-inferior to placebo with regards to primary outcomes of death from cardiovascular causes. The same study though, showed that death from any cause was lower with liraglutide.13
Common side-effects of liraglutide are nausea and/or vomiting.10-13 This is dose-dependent, occurring in up to 30-50% of patients using liraglutide 3mg weekly.9,10 These side-effects are usually transient and occur between week one to six.10,11
There were concerns regarding benign and malignant C-cell thyroid tumours in rodent studies with liraglutide therapy,10,13 but studies in humans have not revealed any association with C-cell thyroid tumours.10-13
Serum calcitonin level remained below upper normal limit even with long-term liraglutide therapy.12
This is likely due to the fact that humans have fewer C-cells than rodents.12 Data on association of liraglutide use with acute pancreatitis has been controversial.13-15 In one study, acute pancreatitis occurred in less than 1% of obese individuals treated with liraglutide over 56 weeks. All individuals recovered without any sequeale.12
However, another population-based study involving type 2 diabetes patients reported that use of GLP-1 based therapy (sitaplitin and exenetide) was associated with increased risk of hospital admission for acute pancreatitis.14 Systematic reviews and meta-analyses have showed that the incidence of acute pancreatitis is low with GLP-1 agonist use and a causal relationship has not established.15,16
Currently however, liraglutide is not recommended in patients with a history of pancreatitis. If a patient develops acute abdominal pain while on liraglutide, the possibility of acute pancreatitis should be explored.
Treatment should not be recommenced after the pancreatitis episode. There is no need for dose adjustment of liraglutide for renal impairment, as the presence of mild or moderate renal impairment has been shown not to impair the efficacy of the GLP-1 agonist.17
However, there is limited data on the use of liraglutide in patients with end-stage renal disease.17
While liraglutide can be administered subcutaneously in the abdomen, thigh and upper arm,10-13 the fear of injection may deter the use of liraglutide in some patients. Also, the cost of treatment needs to be taken into consideration as neither liraglutide nor phentermine are PBS approved for obesity management in Australia.
When discussing liraglutide with patients, it is important to highlight that this therapy does not replace lifestyle modification. While the research shows liraglutide is an effective therapy for the management of obesity, all studies were undertaken in conjunction with a low-calorie diet and increased physical activity.10-13
Dietary modification and physical activity should still be the backbone of weight management even though the need for medication (or bariatric surgery) is consistent with what is known about the genetics of obesity and the long-term success rates of lifestyle change alone.18
In summary, liraglutide-use in obese, non-diabetic individuals can lead to clinically-significant weight loss and improvements in cardiovascular risk factors and metabolic outcomes. Whether this improvement is sustainable and translatable to a reduction in cardiovascular events is yet to be determined.
Thaw D Htet, Lesley V Campbell and Jerry R Greenfield work for the Endocrinology Department, St Vincent’s Hospital, and the Diabetes Department, Garvan Institute of Medical Research, Darlinghurst, Sydney.
References:
1. Obesity and overweight fact sheet. World Health Organisation. (cited March 2018). Available from http://www.who.int/mediacentre/factsheets/fs311/en/.
2. Profiles of Health, Australia (2011-2013). Australia Bureau of Statistics. (cited March 2018). Available from http://www.abs.gov.au/ausstats/abs@.nsf/Lookup/by%20 Subject/4338. 0~2011-13~Main%20Features~Overweight%20and%20obesity~10007
3. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults. Circulation. 2014;129(25 suppl 2):S102-S38.
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7. The Australian Obesity Management Algorithm 2016. (cited March 2018). Available from https://diabetessociety.com.au/documents/ObesityManagementAlgorithm18.10.2016FINAL.pdf
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12. le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, 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. The Lancet. 2017;389(10077):1399-409.
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14. Singh S, Chang H, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus A Population-Based Matched Case-Control Study. JAMA Intern Med. 2013;173(7):534–539. doi:10.1001/jamainternmed.2013.2720
15. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Glucagon-like peptide-1 receptor agonists and pancreatitis: A meta-analysis of randomized clinical trials. Diabetes Research and Clinical Practice.103(2):269-75.
16. Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. The BMJ. 2014;348:g2366. doi:10.1136/bmj.g2366.
17. Leiter LA, Carr MC, Stewart M, Jones-Leone A, Scott R, Yang F, et al. Efficacy and Safety of the Once-Weekly GLP-1 Receptor Agonist Albiglutide Versus Sitagliptin in Patients With Type 2 Diabetes and Renal Impairment: A Randomized Phase III Study. Diabetes Care. 2014;37(10):2723.
18. Campbell LV. Genetics of Obesity Australian Family Physician 2017: Vol 46; no 7; p456-459.
