Liraglutide Subcutaneous Injection for Weight Loss
In a prior editorial in the International Journal of Clinical Practice, three oral medications approved for chronic weight management were compared. Since then, a new agent has also been approved for this purpose: liraglutide, an injectable solution for subcutaneous use, commercialised with the brand name of Saxenda. Is liraglutide effective? Is it safe? How does liraglutide compare with lorcaserin, phentermine topiramate combination and naltrexone bupropion combination? To answer these questions, information was abstracted from the US product label for liraglutide as approved by the US Food and Drug Administration (FDA) and comparisons made with data previously presented.
Liraglutide has the same indication for use as lorcaserin, phentermine topiramate combination and naltrexone bupropion combination, namely as adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m or greater (obese), or 27 kg/m or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g. hypertension, type 2 diabetes mellitus or dyslipidaemia). Obesity and overweight are worldwide epidemics and are risk factors for increased mortality from cardiovascular disease, diabetes, stroke and other diseases. When diet and lifestyle modifications fail, chronic weight management becomes a challenge for physicians across specialties. With the plethora of weight-loss agents in the market, from prescription to over the counter, it can be challenging for a clinician to distinguish which drug is most effective and best tolerated.
Liraglutide differs from the oral alternatives in route of administration, mechanism of action, efficacy, tolerability, and safety monitoring. As an injectable agent liraglutide is administered subcutaneously in the abdomen, thigh, or upper arm, and dosed once a day at any time without regard to the timing of meals. The recommended dose is 3 mg/day, initiated at 0.6 mg/day for 1 week and titrated weekly over 5 weeks until a dose of 3 mg/day is reached. If an increased dose is not tolerated during titration, the product label recommends delaying dose escalation for approximately one additional week. The product label also recommends that if a patient cannot tolerate the 3 mg/day dose, liraglutide should be discontinued as efficacy has not been established at lower doses; however, the potential dose response, or the lack thereof, of liraglutide and weight loss remains to be fully discerned. Liraglutide is available in a prefilled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg or 3 mg (6 mg/ml, 3 ml). Although liraglutide is also approved as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus under the brand name Victoza, the maximum recommended dose for that indication is 1.8 mg/day. Specific limitations of use for Saxenda-branded liraglutide include that this product is not indicated for the treatment of type 2 diabetes, should not be used in combination with any other GLP-1 receptor agonist or with insulin, the effects on cardiovascular morbidity and mortality have not been established, the safety and efficacy of co-administration with other products for weight loss have not been established, and the product has not been studied in patients with a history of pancreatitis. Contraindications include a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2, hypersensitivity to liraglutide or any product components, and pregnancy. Warnings and precautions include thyroid C-cell tumours, acute pancreatitis, acute gallbladder disease, serious hypoglycaemia, heart rate increase, renal impairment, hypersensitivity reactions and suicidal behaviour and ideation. Drug interactions can occur as liraglutide delays gastric emptying and may impact absorption of concomitantly administered oral medications.
Efficacy information regarding the achievement of a ≥ 5% or 10% reduction from baseline body weight was extracted from the product label and number needed to treat (NNT) vs. placebo was calculated ( Table 1 ). The pooled NNT vs. placebo was 4 for the outcome of losing ≥ 5% body weight, and 6 for losing ≥ 10% body weight.
The most common adverse events, reported in ≥ 5% of participants in the clinical trials, were nausea, hypoglycaemia, diarrhoea, constipation, vomiting, headache, decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain and increased lipase. Number needed to harm (NNH) vs. placebo was calculated ( Table 2 ). The 2 adverse events with a NNH vs. placebo of < 10 were nausea (NNH 4) and vomiting (NNH 9). Most episodes of gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy. In the clinical trials, 9.8% of patients treated with liraglutide and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse events, resulting in a NNH vs. placebo of 19 (95% CI: 15–25). Discontinuation rates caused by any gastrointestinal adverse events were observed in 6.2% for patients receiving liraglutide vs. 0.8% with placebo, for a NNH of 19 (95% CI: 16–23). The most common adverse events leading to discontinuation were nausea (2.9% vs. 0.2% for liraglutide and placebo, respectively; NNH 37 (95% CI: 31–48)), vomiting (1.7% vs. < 0.1%; NNH 63 (95% CI: 49–88)) and diarrhoea (1.4% vs. 0%; NNH 72 (95% CI 56–100)).
Injection site reactions including erythema, pruritus, and rash were reported in approximately 13.9% of liraglutide-treated patients vs. 10.5% for placebo, yielding a NNH of 30 (95% CI: 20–63). However, rates of discontinuation because of injection site reactions were low: 0.6% for liraglutide vs. 0.5% for placebo, yielding a non-statistically significant NNH of 1000.
Trade-offs between efficacy and tolerability can be quantified by examining the likelihood to be helped or harmed (LHH), provided that one selects a relevant harm to contrast with the anticipated benefit. LHH is calculated by dividing the NNH of interest by the relevant NNT; higher LHH values are considered more desirable. With a NNT of 4 for ≥ 5% weight loss and a NNH of 19 for discontinuation because of an adverse event, liraglutide is almost five times more likely to result in ≥ 5% weight loss than a discontinuation because of an adverse event (i.e. LHH is 5). However, liraglutide is equally likely to be associated with nausea as with a ≥ 5% weight loss (LHH 1); this does not necessarily eliminate liraglutide from further consideration if the nausea is mild, temporary, and easily managed.
Liraglutide differs in many ways from lorcaserin, phentermine topiramate combination and naltrexone bupropion combination. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist; GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. Liraglutide lowers body weight through decreased calorie intake and does not increase 24-h energy expenditure. Liraglutide stimulates insulin secretion and reduces glucagon secretion, potentially leading to a reduction in blood glucose.
Other differences regarding dosing and titration are that liraglutide is taken once daily (such as the case with phentermine topiramate combination, but unlike lorcaserin and naltrexone bupropion combination which are taken twice daily), and that liraglutide requires titration to its therapeutic dose (such as the case with phentermine topiramate combination and naltrexone bupropion combination, but unlike lorcaserin where the starting dose is the target therapeutic dose).
Liraglutide's NNT vs. placebo for the outcome of ≥ 5% reduction from baseline body weight (NNT 4) is more robust than what was observed for lorcaserin and naltrexone bupropion combination (NNT 5), but falls short of what was observed for phentermine topiramate combination (NNT 2). The NNH vs. placebo for discontinuing because of an adverse event for liraglutide was 19, making this agent potentially better tolerated than phentermine topiramate combination (NNH 12) or naltrexone bupropion combination (NNH 9), but not as well tolerated as lorcaserin (NNH 53). LHH for losing ≥ 5% body weight vs. discontinuing because of an adverse event was almost 5 for liraglutide, almost matching the corresponding LHH for phentermine topiramate combination (LHH 6), superior to that observed for naltrexone bupropion combination (LHH almost 2), but inferior to that observed for lorcaserin (LHH almost 11).
Liraglutide has a black box warning regarding the risk of thyroid C-cell tumours and a warning about acute pancreatitis, resulting in a mandated risk evaluation and mitigation strategy (REMS) (see http://www.saxendarems.com/). The FDA can require a REMS for certain prescription drugs that they determine need safety measures beyond the product label to ensure benefits outweigh the risks. Among the medications discussed here, both liraglutide and phentermine topiramate combination are subject to a REMS, in contrast to lorcaserin and naltrexone bupropion combination which do not have a REMS requirement. Other regulatory differences include action by the US Drug Enforcement Agency where lorcaserin and phentermine topiramate combination are classified as Category IV because of a potential of abuse; however, this is not the case for liraglutide or naltrexone bupropion combination.
The data presented here are from carefully conducted registration trials that enrolled motivated subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ in important ways from persons encountered in routine clinical practice. It is not known if subcutaneous injection will be a generally acceptable choice for a weight-loss intervention, given the availability of several oral alternatives. Required are pragmatic clinical trials that can be more generalisable to help place these weight-loss agents into clinical perspective for their use in the 'real world.'