GLP-1: Opportunity for humanity, risk for big pharma

That the world’s leading cause of death so rarely hits the headlines, compared with other diseases and disasters, suggests a measure of complacency. Has society simply accepted that nothing can be done? Perhaps that was once defensible, but growing awareness of new indications for a range of existing medications is challenging the status quo and could revolutionise healthcare.

The killer is cardiovascular disease (CVD), responsible for an estimated 17.9m deaths per year.¹ The majority of these are preventable. Readily available options include behavioural adjustments, appropriate management, and clinical interventions that target risk factors.

Obesity is at the heart of all three options. Approximately 43% of adults are overweight and more than 1bn people in the world are now living with obesity, with the incidence of obesity among adults having more than doubled since 1990 – and quadrupled among children and adolescents.²

Global prevalence of obesity among adults

Historically, the consensus was a poor diet and lifestyle were associated with CVD. It has since become clearer that there is a more direct link between being overweight and heart conditions. Diet and diabetes still remain risk factors, but we now understand that the relationship between obesity and CVD is more direct than previously thought.

Traditional compounds for losing weight struggle with variable efficacy levels and are hindered by risks over their safety; indeed, the historical consensus did not consider obesity a disease that could be treated pharmacologically, so recognising it as such is an important development. The US and Latin America approve phentermine in combination with topiramate to manage weight, for instance, but patients on this course must monitor their heart rate and levels of creatinine.

The dawn of GLP-1

Fortunately, a class of drugs originally used for managing blood sugar is emerging as a potent force for weight loss too. These are based on glucagon-like peptide 1 (GLP-1) agonists. In essence, these help the body to absorb glucose after eating, and so they were first examined and approved for diabetes patients. At the time GLP-1 agonists were approved for diabetes, experts knew that one by-product of this therapy was that it slowed down gastric emptying, allowing the food to remain in the stomach for longer, so suppressing appetite.

Although the first such GLP-1 medication was approved by the US FDA in 2005, they really entered the mainstream only in 2021 thanks to positive results in clinical trials in overweight or obese patients. Initially, semaglutide produced a mean change in body weight over a 68-week once-weekly course of -14.9% versus -2.4% for a placebo group.³ In August 2023, a five-year long clinical trial found that semaglutide induced a 20% reduction in major adverse cardiovascular events such as stroke, heart attacks and death in adults with heart disease, who were either overweight or obese.⁴

This was the first study to show that such an approach could protect against serious CVD episodes in people without type 2 diabetes.

More recently, survodutide has shown positive results in being able to treat a liver condition called MASH or metabolic dysfunction-associated teatohepatitis. In this disease, excessive fat build-up in the liver potentially leads to liver insufficiency or liver cancer.

The impact of GLP-1 agonists does not extend only to CVD and metabolism; some scientists in fact demonstrated that these drugs can have an impact for treating brain disorders characterised by inflammation such as Alzheimer’s disease and Parkinson’s disease. Since 2021, the maker of semaglutide has been experimenting in clinical trials involving more that 1,800 patients.

Today, the only three approved GLP-1 drugs are liraglutide, semaglutide and tirzepatide. Looking at their widespread impact, investors are naturally excited. Semaglutide’s maker has become Europe’s largest listed company, its share price having appreciated by almost 60% over the past year. This is wonderful and well earned for an innovative healthcare business that can ease the suffering of millions worldwide. Moreover, a wave of competitors is pushing the market to outdo the current therapies, striving for fewer side-effects and more effective weight loss.

Broader implications

But what about the rest of the healthcare industry? Drugs for heart disease have been the lifeblood of many pharmaceutical giants. Lipitor, which lowers cholesterol, once earned more than $12 billion a year for its manufacturer.⁵ Even after losing US patent protection in 2011, the former blockbuster statin still generated billions in international sales. Major groups are reported to be counting on new products of their own to reinvigorate the $48 billion market for heart medications.⁶

This is just one area of the second-order effects of reducing the incidence of CVD. Another is that what’s negative for drugmakers could be positive for buyers of healthcare.

Naturally, this is not likely to happen quickly given the high current prices of GLP-1 drugs (although the cost of allowing the obesity and CVD public health emergency to grow should be borne in mind too). Over the long term, however, we would expect cheaper versions of these treatments to become available, not least once they become generic.

Equally, we should not take any of these potential benefits as guaranteed. It’s essential to consider the challenges:

1. Efficacy and sustainability of chronic treatment: Consistent efficacy in promoting sustainable weight loss is still a challenge as results vary widely among individuals. Even if weight-loss drugs initially help individuals shed weight, many people eventually regain the lost weight.
   
2. Supply constraints: Weight-loss drugs’ present expense in some markets limits their widespread accessibility, so affordable access is crucial. Where the treatments are more affordable, such as in the EU, current production capacity is still a limit.
   
3. Lifestyle factors: Reducing obesity, CVD and liver diseases also depends on individuals’ lifestyle choices, including diet and exercise. Medications like semaglutide are typically most effective when combined with lifestyle modifications.
   
4. Healthcare systems: The effectiveness of weight-loss drugs may vary depending on the healthcare infrastructure, patient adherence, and healthcare policies.
   
5. Long-term data: The long-term effects of semaglutide on reducing obesity and CVD in the general population are still being studied, and the preservation of muscle mass on these treatments is a critical factor for health.
   

Yet these notes of caution should not diminish optimism among patients, doctors, policymakers and investors. The GLP-1 discoveries highlight both the incredible scope for innovation and positive change, and the risks to incumbents. Healthcare has always been prone to disruption. We will continue to favour supporting and investing in the disruptors.