Liraglutide Approval in the US and EU
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Liraglutide Approval in the US and EU

Liraglutide, a long-lasting analogue of a natural weight-control protein, has recently been made legal for marketing in America and Europe, under the name Saxenda.

What is Liraglutide and How Does it Work?

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Liraglutide is a protein which is chemically very similar to a protein produced in the body called Glucagon-like peptide-1 (GLP-1). GLP-1 is released by the body to moderate digestion of food and blood glucose levels, and has many physiological effects, including increased release of insulin (the hormone which encourages uptake of glucose from the blood into the body’s tissues), decreased release of glucagon (the hormone with the opposite effect to insulin), and promotes proliferation of, and helps protect, the ß-cells in the pancreas which manufacture insulin. Crucially, GLP-1 has also been shown to decrease gastric motility- the speed at which food passes through the digestive system- and appetite.

Studies have shown that these properties make GLP-1 fundamental in weight management. GLP-1 is typically released during periods of high blood sugar, towards the end of a meal for example, to prevent the organism from overeating and allow the digestive system to make the most of food. However, GLP-1’s activity is very short-lived, with an average half-life (the time for half of the original active GLP-1 molecules to be removed) of less than two minutes; this is because the body releases another protein, dipeptidyl peptidase (DPP-4), very shortly after GLP-1 is released, thus limiting its ability to spread.

Liraglutide demonstrates most of the same functions as GLP-1, but acts for a much longer period of time. There are two reasons for this. Firstly, liraglutide has additional fatty-acid and amino-acid groups which prevent it from clumping together with other liraglutide molecules (which GLP-1 is prone to do); this prevents net absorption of liraglutide back into the gut walls. Secondly, the fatty-acid groups promote binding by the protein albumin; since albumin is large, this changes the shape of the liraglutide significantly and makes it more resistant to degradation by DPP-4. As a result, liraglutide is more suitable for inducing weight loss when given as a supplement than GLP-1; and thus liraglutide acts as an effective anti-diabetic and weight-loss agent for severely overweight individuals.

Liraglutide is an effective weight loss agent because it acts through multiple mechanisms, though these are not entirely understood yet. GLP-1 is known to act on both the peripheral and central nervous systems, causing reduction of ‘hunger’ hormones like grehlin and production of satisfaction agents like serotonin and dopamine; it also acts to decrease the diameter of the intestines, preventing food from moving quickly, and to increase the transit of food through the colon, making room for the additional waste. Liraglutide is believed to replicate this activity.

What mechanisms have been suggested for its activity?

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Liraglutide’s analogue, GLP-1, has been suggested to act both directly upon its environment and via both the parasympathetic and central nervous systems. A paper from 2013 reviewed current studies conducted on GLP-1 activity and developed a model of how it acts; firstly, L-cells, found in the intestine, secrete GLP-1 in response to nutrients entering the stomach or proximal intestine, both through nerves in the stomach and through direct contact with the cells. GLP-1 is therefore released in stages corresponding to ‘progress through a meal’.

However, GLP-1 is also released from neurons that feed directly into, and from, different areas of the brain, demonstrating the neural properties of this protein. This release is believed to be triggered by the activity of hormones including leptin and oxytocin, as well as nutrients like lipopolysaccharides, suggesting GLP-1 is a messenger to alert the body that food intake should be slowed.

GLP-1’s receptor is present at all areas where GLP-1 is released, and also in the adipose tissue, pancreas and further along the intestine, since GLP-1 travels to act on multiple areas of the body. It is not clear whether GLP-1 released in the digestive organs is able to exert brain activity, but it is known to enter the bloodstream via the capillaries and act on other areas of the body. When GLP-1 enters the capillaries, however, it is rapidly destroyed by the DPP-4 present, and so its ability to exert whole body effects has been attributed to stimulation of the nerves in the intestines; it’s also possible that it can saturate the available DPP-4 and move through the blood to the brain, where it crosses the blood-brain barrier. This is likely to happen when food intake has been very high, meaning huge appetite reduction is required.

The nervous system action is not well understood, but it is believed that the multiple receptors present have different outcomes; those closest to the brain activate neurons which use anorexigenic (satiety-inducing) pathways and limit the mRNA transcription of glucagon, whereas others can activate the production of the adrenaline-producing-system, which is known to reduce appetite.

Overall, the nervous mechanisms employed have not been defined yet; however, the activity of GLP-1 on the intestinal motor control is known to be caused by increased activity of the ileal brake, an inhibitory feedback mechanism that functions to optimise nutrient digestion and absorption. Again, this is mediated neuronally, but GLP-1 receptors in intestinal walls directly link to the contractions of the circular muscle around the intestines, but moderating the effectiveness of nerve junctions. The circular muscle determines how fast food can move through the intestines, and GLP-1 is believed to cause ‘clamping down’ on food through this mechanism.

Liraglutide is known to demonstrate all of these activities; additionally, a study from 2015 demonstrated that liraglutide also exhibits protective effects on pancreatic beta cells. Cells from the pancreas were treated with high fatty-acid concentrated solution, which normally leads to cell death owing to the high concentration of energy entering the cells. Additionally, mice were fed a high-fat diet for 8 weeks and had their pancreatic function measured; some of the mice were also given injections of liraglutide.

It was determined that in both the in vitro and mice studies, the presence of liraglutide led to lower apoptosis of pancreatic beta cells, and also led to reduced body weight and fasting blood glucose levels in the mice. This was associated with greater activity of autophages, cells which consume dangerous chemicals to the beta cells including the fatty acids (and also consume ‘bad’ or dangerous beta cells); so liraglutide was believed to enhance the activity of the autophages, as demonstrated by reduced liraglutide activity when autophage inhibitors were introduced.

Clinical studies of Liraglutide

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The main study which has led to the approval of Liraglutide in the EU and US was a 56 week randomised trial of over 3000 obese individuals in over 27 countries, which saw once-daily injection of Liraglutide or a placebo along with reduced calorie diets and regular exercise. Both diabetic and prediabetic (patients on the borderline of diabetes) patients were considered, with a micro-study on the link between liraglutide and delayed onset of diabetes.

Diabetic patients were not able to take part in the main study, along with any individuals taking any medication that could interfere with the results, or individuals with histories of mental illness. All individuals received the same support and advice regarding diet and exercise. The study examined weight change (including average weight loss), the number of patients losing a specific percentage of bodyweight, and indicators of cardiovascular and general health, along with subjective quality of life. Additionally, the study recorded side-effects experienced by the individuals, and the study analysed whether prediabetes could affect the outcome.

The results, with about 40% of the patients completing the trial (and more in the liraglutide group leaving due to adverse side-effects), demonstrated an average weight loss of 8% in the Liraglutide group compared to 2.6% in the placebo group. Prediabetes was discovered not the affect the outcome of the study. More than 335 of the Liraglutide patients lost more than 10% of their bodyweight, and over 90% lost weight. However, Liraglutide proved to be less effective in severely obese individuals than in middle-line candidates. Liraglutide also demonstrated reduction in glycated hemoglobin, fasting glucose, and fasting insulin levels, and overall lower blood glucose levels than placebo; beta-cell function was also shown to be improved, supporting the studies which suggest Liraglutide has protective effects on beta-cells.

Higher levels of adiponectin, the hormone which mobilises fat from adipose tissue for metabolism, were detected in the Liraglutide group, along with lower blood pressure and greater cardiovascular health. Finally, significantly greater quality of life, both mentally and physically, was achieved in the liraglutide group than with placebo. Overall, the researchers concluded that Liraglutide was an effective weight loss agent in overweight individuals.

However, it is important to recognise that while Liraglutide was proven to be effective for weight loss, the other benefits are not necessarily the direct result of Liraglutide consumption. Improved glucose control, cardiovascular function and blood pressure are consistent with weight loss in overweight individuals, and so Liraglutide may not have been responsible for these benefits. This is important as the researchers did not conclude that Liraglutide was suitable as medication for individuals suffering from issues specifically in these areas, and not simply through being overweight.

Additionally, adverse effects noted in Liraglutide users include nausea and other gastrointestinal issues, gallbladder issues (though these were noticed in both groups and significance was not established), pancreatis, cardiac arrhythmia, spontaneous hypoglycaemia, and neurological incidences. However, though each was noticed to a greater extent in Liraglutide users than in the placebo group, the number of individuals experiencing these events never exceeded 5% of all users; in most cases, these events were reasoned to be due to health.

Recent decision to approve use in the US and EU

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The European medicine agencies released a report in 2015 describing the drug ‘Saxenda’, the marketable form of Liraglutide. The report highlights the issue of obesity and describes the release of Liraglutide in Europe, describing the clinical studies that support the effectiveness of Liraglutide and the pharmacology which it employs, along with side-effects of Saxenda.

Though some groups have not been tested with Liraglutide- older individuals in particular- the report argues that the lack of side-effects makes Saxenda safe for use in overweight individuals. It also compares modern results to the results of a 2009 trial of Liraglutide, marketed under the name ‘Victoza’, pointing out that side-effects observed in this study were likely due to other causes. The report ultimately recommends Saxenda for individuals with a BMI over 30kg/m2 (obese) and over 27 kg/m2 if a weight-related issue, such as diabetes, has been identified.

The manufacturer of Saxenda, Novo Norodisk, reported that on the 23rd of March 2015, Saxenda became legal in all European states, and that it would be launched in multiple markets in 2015. This primarily followed the 56 week study previously described. The article also mentions that Saxenda was approved in the United States in December 2014, and Canada in February 2015. The FDA have stated that three clinical studies were considered to prove the safety and efficacy of Saxenda, including the 56 week trial, and also a study of Saxenda in diabetic patients, which gave positive results.

Where to get and how to use Liraglutide

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Saxenda is currently only available on prescription due to limited range of suitability. It does not appear to be currently available through the NHS. Victoza is still available, but is only prescribed to treat diabetes. Novo Norodisk have yet to announce when Saxenda will be released. Saxenda is taken via injection, and is carried around in a similar manner to an insulin pen; the exact dosages required depend on the advice of the doctor.

Conclusion

Based on the studies of liraglutide, it appears to be an effective weight-loss agent for overweight individuals. It is also associated with health benefits including greater beta cell functioning, cardiovascular and digestive health, and better response to high blood sugar levels; few side-effects have been noted and the mechanisms by which Liraglutide operates, though numerous, are mostly traceable. However, Liraglutide is only available via prescription and is not currently marketed in the UK. Moreoever, individuals below a certain BMI are not eligible for prescription. Thus Liraglutide is not a dieting solution for most individuals, but is suitable in more severe cases.

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