An end to obesity

A new pipeline of safer weight loss drugs could spell the end of obesity, but are they too good to be true? Jasmin Fox-Skelly reports

Weight loss drugs to date have been plagued by side effects and product recalls. Quite rightly, doctors have been hesitant to prescribe these products – and companies have been nervous about investing in developing new ones. But this is set to change.

In June 2021, the US Food and Drug Administration approved a new weight-loss drug called semaglutide, or Wegovy. Marketed by pharmaceutical company Novo Nordisk, clinical trials of the drug show an average of 15% weight loss for participants, compared with about 2.5% weight loss in people given a placebo and counselling.¹

Some people in the treatment group lost much more. Nearly 35% of the 1059 people who completed the trial lost at least 20% of their body weight – a level no other weight-loss drug has achieved.

‘Not only does semaglutide produce that weight loss, but it also seems to improve a lot of the risk factors for heart disease – it lowers cholesterol, blood sugar and blood pressure,’ says John Wilding, who leads clinical research into obesity, diabetes and endocrinology at the University of Liverpool, UK. Wilding was involved in the Phase 3 trial of semaglutide.

The financial potential of a safe and effective weight-loss drug is staggering. About 42% of people in the US have a BMI over 30 and meet the CDC’s definition of obesity. This has major public health implications, as being overweight is linked to heart disease, stroke, diabetes, and certain types of cancer.

However so far efforts to produce such a weight loss drug have been beset by reports of dangerous side effects and even deaths. In the 1930s, one of the first diet pills to be developed, 2,4-dinitrophenol (DNP), was linked to uncontrolled increases in body temperature. DNP targets the mitochondria, the energy powerhouse within our cells which converts chemical energy from food into ATP, a kind of universal energy currency that our body uses to sustain itself. Any excess energy that isn’t needed is converted into fat. DNP interferes with this process, stopping the production of fat, but with no place to go, the energy is released as heat instead. Because of its deadly side effects, DNP has never been approved by regulatory authorities, but people can still buy it on the internet. Between 2001 and 2010, a dozen people died after taking it.

DNP isn’t the only harmful diet drug. In the 1960s, regulatory drug agencies like the US Food and Drug Administration (FDA) approved a few weight loss drugs based on derivatives of amphetamine, which suppresses the appetite. But this class of drugs can be addictive and cause dangerously high blood pressure.

In 1997, the FDA was forced to pull two weight loss drugs from the market – fenfluramine and dexfenfluramine – after reports of heart valve damage. Both drugs are part of a class of appetite suppressants called serotonergic anorectics which work by lowering the amount of serotonin in the brain.

Because of the way the brain tightly regulates appetite, if we try and disturb that homeostasis as an adult, for example, by going on a diet, what happens is the body tries to defend that previous weight by altering hormones like GLP-1.
John Wilding Institute of Life Course and Medical Sciences, University of Liverpool.

AOMs

So, what makes this new drug, semaglutide, any different? Well, over the last decade scientists have begun to understand much more about the molecular mechanisms that control appetite. This has led to a surge in research into anti-obesity medications (AOMs).

‘What the science is telling us is that just like other physiological mechanisms like heart rate, blood pressure or how fast you breathe, weight is really tightly regulated by the brain and central nervous system,’ says Wilding. ‘We now know that there are several hormones in the gut that tell us when we are full after a meal, and they all feed into the brain which then integrates this information.’

Semaglutide is a synthetic mimic of one of these hormones, glucagon-like peptide 1 (GLP-1). GLP-1 is naturally released by endocrine cells in the intestine after a meal. Once there, it encourages the release of insulin, which decreases blood glucose levels. It also slows the rate of gastric emptying – the time it takes for food to leave the stomach.

As they decrease blood sugar levels, GLP-1 agonists were initially used as drugs for Type 2 diabetes, however, when results from clinical trials showed their ability to induce weight loss, pharmaceutical companies were quick to investigate further. As a result, we now know that as well as regulating insulin, GLP-1 has a key role in suppressing appetite. People on GLP-1 analogue drugs are essentially tricking their brains into feeling less hungry, making them satisfied with smaller amounts of food.

‘If you think about how the brain regulates appetite there is an automatic responsive system, which works subconsciously in the background and is largely driven by the hypothalamus and brainstem,’ says Wilding. ‘However, there’s also the hedonic part which thinks, “ooh, that chocolate cake looks great, I’ll have two pieces of that today!” We think from rodent studies that GLP-1 works on both these systems.’

The first GLP-1 agonist, liraglutide (Saxenda), was approved for weight loss treatment in 2014. However, liraglutide only reduces body weight by 5–6%, compared with a placebo,² much less than semaglutide’s 15%.

As well as semaglutide, there are several other GLP-1 agonists in development. Pfizer’s danuglipron recently completed a Phase 2 trial, which saw 151 participants with Type 2 diabetes or obesity receive either the drug or a placebo.³ Interim results show the highest dose led to an average 5.4kg of weight loss, and a reduction in glycosylated haemoglobin (HbA1c), a marker of diabetes.

Other firms are designing drugs that target more than one receptor. AstraZeneca is developing a dual-agonist drug for diabetes that also causes weight loss.⁴ Called cotadutide, the molecule works on both the glucagon and GLP-1 receptors.

Meanwhile, pharmaceutical company Lilly is developing GLP-1 agonist tirzepatide for both Type 2 diabetes and weight loss. As well as GLP-1, tirzepatide contains a synthetic mimic of GIP (glucose-dependent insulinotropic polypeptide), another hormone released by the gut, which makes us feel full.

In a recent Phase 3 trial, researchers gave 2539 adults with a body-mass index of 27 or more once-weekly injections of tirzepatide (5mg, 10mg, or 15mg) or placebo.⁵ After 72 weeks, participants on the lowest dose of the drug lost an average of 15.0% of their body weight, with those on the highest dose losing an incredible 22.5% of their body mass. In contrast, those in the placebo group lost an average of 2.4% of their body weight.

Richard DiMarchi, a chemist from Indiana University Bloomington, US, is also developing a weight loss drug that activates both the GLP-1 and GIP receptors. In 2013 mouse trials, the new dual agonist lowered the blood sugar levels of rodents while simultaneously decreasing their body weight by nearly 21%.⁶ In comparison, a drug based on GLP-1 alone decreased the rodents’ body weight by an average of 15%. People with Type 2 diabetes who were given the new drug also showed improved blood sugar levels, an important step in managing the disease. They also experienced modest weight loss across the six-week span of the trial. In 2017, the drug also reduced patients’ blood glucose, body weight and total cholesterol in a 12-week Phase 2 study of people with Type 2 diabetes.⁷

The exact mechanisms of these dual-acting drugs are unclear, however, it’s possible that GIP may turbo-charge the well-known ability of GLP-1 to suppress appetite and lower body weight.

‘Energy balance is regulated by a complex system and targeting multiple components of the system has been shown to be more effective than targeting a single pathway,’ says Nadia Ahmad, Senior Medical Director for Lilly’s tirzepatide obesity development programme.

‘By using one single molecule to activate the body’s receptors for both GIP and GLP-1, tirzepatide is able to activate two of the body’s natural hormones that are involved in energy balance,’ she adds.

‘The results from tirzepatide and other dual agonist trials look really promising, although we need to see a bit more data before we can be sure,’ says Wilding. ‘It certainly looks like it is more potent than single agonist drugs, although we don’t fully understand why because while GIP is an important hormone for insulin secretion, when we give it on its own it doesn’t seem to do much to body weight.’

While a lot of attention has been paid to appetite suppressants, there are other drugs in preclinical development that work on different pathways. To try to understand what happens at the molecular level after exercise, researchers in the US at Baylor College of Medicine in Texas and Stanford University School of Medicine in California analysed the blood plasma of mice after they had completed intense treadmill runs.⁸ They discovered significantly raised levels of Lac-Phe, a metabolite synthesised from lactate and phenylalanine.

The scientists then gave obese mice fed on a high-fat diet a high dose of Lac-Phe. Their food intake decreased by 50% over 12 hours, compared with control mice. Over 10 days this pattern continued – mice given Lac-Phe had a lower overall food intake, causing them to lose fat. They also had improved glucose tolerance. Interestingly, Lac-Phe only suppressed appetite after exercise, and obese mice that were sedentary did not lose weight. Mice that lacked CNDP2 – an enzyme involved in the production of Lac-Phe – also didn’t lose as much weight compared with a control group on the same workout plan.

Mice given the metabolite Lac-Phe had a lower overall food intake, causing them to lose fat. They also had improved glucose tolerance. Lac-Phe only suppressed appetite after exercise, and obese mice that were sedentary did not lose weight.

‘We don’t know exactly how Lac-Phe regulates food intake, but we are working on this question,’ says Long. ‘In unpublished work, we can show that Lac-Phe activates certain neurons located in regions of the brain that regulate feeding, including the brain stem and the hypothalamus. We are currently trying to identify the brain Lac-Phe receptor, which currently remains unknown.’

Intriguingly, Long believes that Lac-Phe operates independently of other hunger hormones such as GLP-1 and GIP, and that Lac-Phe may be its own distinct anti-hunger hormone. 

However, despite the promise of all these new anti-obesity medications, there are downsides. Critics are quick to point out that once patients stop taking their medication, they begin to put the weight back on. A follow-on study tracking patients who lost weight using semaglutide showed that the majority had regained about two thirds of the weight they had lost a year later.⁹

‘Because of the way the brain tightly regulates appetite, if we try and disturb that homeostasis as an adult, for example, by going on a diet, what happens is the body tries to defend that previous weight by altering hormones like GLP-1,’ says Wilding.

‘So, the hormones that make us feel full will drop off, making us hungrier, while the hormones that make us feel hungry will increase. That’s why most people who have tried to diet will know that it’s comparatively easy to lose weight - the really hard part is keeping that weight off in the long term.’

Patients will therefore have to keep on taking the drugs if they want to maintain their weight loss. However, the good news is that apart from a minority of people who report sickness, most tolerate semaglutide fairly well.

‘The way I view it is If you take statins to lower your cholesterol you wouldn’t expect your cholesterol to stay down when you stop taking the medicine,’ says Wilding. ‘If you take a medicine for blood pressure, you don’t expect it to continue to work when you stop taking it. It will take time, but you will gradually regain weight if you come off the drug because your appetite control system kicks back in again and you will subconsciously start eating just a little bit more.’

References
1 The New England Journal of Medicine, doi: 10.1056/NEJMoa2032183
2 The International Journal of Obesity, doi: 10.1038/ijo.2013.120
3 Pfizer Q4 2021 Earnings Call, 2022, accessed online at https://fool.com/earnings/call-transcripts/2022/02/08/pfizer-pfe-q4-2021-earnings-call-transcript/
4 Diabetes Care, doi: 10.2337/dc20-2151.
5 Lilly News Release, 2022, accessed online at https://investor.lilly.com/news-releases/news-release-details/lillys-tirzepatide-delivered-225-weight-loss-adults-obesity-or
6 Science Translational Medicine, doi: 10.1126/scitranslmed.3007218.
7 Cell Metabolism, doi: 10.1016/j.cmet.2017.07.011.
8 Nature, doi: 10.1038/s41586-022-04828-5
9 Diabetes Obes. Metab., doi:10.1111/dom.14725