Part two | New hopes for treatment in the global obesity epidemic
Part two of this series brings us to look recent developments in treatments for obesity, In parallel with conventional therapies for obesity – diet, exercise, and in extreme cases, surgery – the pharma industry has long sought a magic bullet that could tackle the problem in a single treatment.
What's coming next? Skip to part 3: Next generation in obesity therapies.
We'll take a look at a series of drug options and their effectiveness as treatments for obesity, as well as their ability to tackle diabetes and cardiovascular disease.
Since 2012, there have been a number of new therapeutics for obesity which have been approved. The first of these was Belviq (lorcaserin), from Arena Pharmaceuticals and collaborator, Eisai. First approved in the US in 2012, its European marketing application was subsequently withdrawn and since then the drug has struggled to maintain market share, partly due to limited efficacy: typical body weight loss is between 3-4% (see image).
Yet there is some evidence that this drug can help tackle diabetes.
Belviq (lorcaserin) as a treatment for type 2 diabetes
According to data from the CAMELLIA-TIMI 61 cardiovascular outcomes trial, treatment with lorcaserin reduced the risk of incident diabetes by 19% versus placebo. It also slightly increased the rate of remission of hyperglycemia in diabetic patients [Ref 1].
Data on cardiovascular risk is less clear. At study completion, major adverse cardiovascular events (MACE) occurred in 6.1 % of those taking lorcaserin versus 6.2% on placebo. The trial did not meet its superiority endpoint for the composite of MACE plus hospitalisation for unstable angina, heart failure, or any coronary revascularization (11.8% in lorcaserin group versus 12.1% for placebo).
Qsymia/Qsiva (phentermine plus topiramate)
Weight-loss drug Qsymia/Qsiva (phentermine plus topiramate), from Vivus, was also FDA approved in 2012, but again, the EU refused to approve. Trials showed that Qsymia appeared to have better efficacy than Belviq, producing weight loss of around 8% typically (see image).
Glycemic control in obese/overweight patients with type 2 diabetes
Studies have shown that Qsymia plus lifestyle modification can offer a small improvement in glycemic control in obese/overweight patients with type 2 diabetes, and analysis of patients in the SEQUEL trial with pre-diabetes or metabolic syndrome showed a reduction of 78.7% in the annualized incidence rate of developing diabetes [Ref 2].
However, data on inflammatory markers was inconclusive, and so far, there has been no large-scale detailed study into the effect of the drug on cardiovascular outcomes (a 2018 study reported that “MACE risk trended lower”, but it admitted sample size was small).
Figure below showing obesity treatments average-adjusted % weight loss:
A further competitor arrived on the market in 2014: namely Contrave/Mysimba, from Takeda and Orexigen Therapeutics, which combines bupropion and naltrexone. This was US approved in 2014 with EU approval the following year. In the phase III COR trials, Contrave demonstrated placebo-adjusted weight losses at 56 weeks, ranging between 2.5% and 5.2% of initial body weight (see image).
Limited cardiovascular benefits
Contrave ran into problems when Orexigen prematurely disclosed portions of an interim analysis of the LIGHT study which suggested a 41% reduction in death, stroke, and heart attack. This disclosure was deemed inappropriate by the FDA, and any cardiovascular benefits evaporated as further data accumulated [Ref 2].
Analysts also proved overly optimistic, suggesting that Contrave would raise $634 million in sales by 2020 but the obesity market is much smaller than expected and is dominated by low-cost generic amphetamines. Despite the fact that Contrave had become one of the most widely-prescribed weight-loss drugs in the US, Takeda abandoned the partnership in 2016.
The second weight-loss drug approved in the US in 2014 was Saxenda (liraglutide), an injectable glucagon-like peptide (GLP)-1 receptor agonist from Novo Nordisk.
Based on a successful diabetes drug Victoza, Saxenda lowers blood glucose by stimulating the release of insulin and lowering glucagon secretion when blood sugar levels are high. It also slows gastric emptying and reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake.
Subsequently EU approved in 2015, some analysts estimated the new obesity indication could bring another $1 billion annually to liraglutide's sales. However, weight loss data from Phase III trials has been similar to Qsymia: in data from a real-world trial reported in 2018, people treated with Saxenda as an adjunct to diet and exercise achieved 7.1% weight loss from baseline after six months (see image).
Reductions in glycosylated haemoglobin
The beneficial effects of liraglutide on blood sugar have been documented, and the phase III LEADER studies showed its efficacy in treating type 2 diabetes with reductions in glycosylated haemoglobin (HbA1c) ranging from 0.33% to 1.85%. Clinical evidence also shows a nonsignificant trend toward a decrease in cardiovascular events.
Reducing the risk of cardiovascular death
In 2017 European regulators recommended updating the label of Saxenda to include information about the drug’s ability to reduce cardiovascular risk. Although Saxenda had not been investigated specifically, the diabetes drug Victoza contains the liraglutide at a lower dose and has been shown to reduce the risk of cardiovascular death, non-fatal heart attack, and non-fatal stroke by 13% versus placebo. Results of the LEADER trial showed a significant 22% reduction in cardiovascular death and non-significant reductions in heart attacks and strokes. In October 2018, the FDA approved an update to the Saxenda labelling to include cardiovascular data from the LEADER trial.
Saxenda has not been without concerns over side-effects, including thyroid tumours and pancreatitis. Moreover, not all patients welcome injections, even weekly ones, and prefer tablets.
In part 3 we will look at the next generation of drugs that aim to help combat the worldwide obesity epidemic, including another GLP-1 antagonist currently in trial and combination drug treatments.
See part 3 here: Next generation in obesity therapies.
Ref 1. Weight-Loss Therapy in Type 2 Diabetes: Effects of Phentermine and Topiramate Extended Release. W. Timothy Garvey et al.Diabetes Care 2014 Dec; 37(12): 3309-3316. https://doi.org/10.2337/dc14-0930.
Ref 2. Cardiovascular Effects of the New Weight Loss Agents. Matthew H. Vorsanger et al. Journal of the American College of Cardiology vol. 68, no. 8, 2016. http://dx.doi.org/10.1016/j.jacc.2016.06.007.