Part Four | Obesity, Type 2 diabetes and cardiovascular disease: Finding the magic bullet

The final part in our series looking at cardiovascular disease, type 2 diabetes, and obesity brings us to look at GLP-agonists and some of the novel therapies in development. Could these in time offer the magic bullet treatment that impacts positively on patient outcome and the advances in all three areas?

The rise of GLP-1 agonists

With the number of people with Type 2 diabetes reaching more than 300 million worldwide and rising, new treatments such as glucagon-like peptide-1 (GLP-1) agonists are under intense scrutiny in the pharma industry. These drugs exert beneficial effects on glucose homeostasis by regulating islet hormone function (promoting insulin secretion and inhibiting glucagon release), modifying nutrient delivery, and impacting food intake. They offer advantages over older Type 2 diabetes drugs through enhanced efficacy, along with potential for weight loss and cardiovascular benefits. There is also a lower risk of hypoglycaemia because they only act when glucose levels are high or rising and “switch off” when glucose returns to normal levels.

Following on from Saxenda and Ozempic, there are other glucagon-like peptide 1 (GLP-1) agonists currently approved for type 2 diabetes that not only improve blood sugar control but may also lead to weight loss and could become anti-obesity therapies in their own right, or in combination. This includes Trulicity (dulaglutide) and Bydureon (exenatide extended release), both of which are taken weekly. A 2012 study showed short term treatment with Bydureon resulted in “modest weight loss” in obese non diabetic women. A subset fared better. The COMBAT-JUDO study funded by the European Commission is ongoing since 2016. Other GLP-I agonists are daily drugs Adlyxin (lixisenatide) and Byetta (exenatide). The down side of GLP-1 agonist drugs is that they need to be taken by injection.

Potential hurdles facing GLP-1 agonists

GLP-1 agonists are not risk free and have been associated with both tolerability and safety concerns. Gastrointestinal side effects such as nausea, vomiting and diarrhoea are common in the first few weeks of treatment but tend to disappear with time. These side effects may be less common with longer acting agents.

Clearly GLP-1 agonists will continue to face stiff competition from other drugs with different mechanisms of action, particularly those that are orally medicated, which may be considerably cheaper or offer additional health benefits.

Novel therapies

There is also long term interest in anti-sense drugs and hormone/drug conjugation as a novel strategy for obesity and hyperlipidemia treatment, as well as the use of antibody-based therapies, such as bimagrumab, also known as BYM 338, a novel myostatin blocker from Novartis which is in Phase II trials to treat obesity but the drug failed in 2016 a trial for sporadic inclusion body myositis. All such studies are at early stages.

What is clear is that anti-obesity drugs will remain a growing focus for the pharma industry: a Milken Institute report published in October 2018 found that the cost of excess weight to the US economy alone has reached $1.7 trillion, or 9.3% of the nation’s gross domestic product! That includes $480 billion in direct healthcare costs and $1.24 trillion in lost productivity [Ref 1].

In this four-part series, we highlight that obesity, diabetes and cardiovascular disease are heavily intertwined and poses a major threat to the global economy. The obesity epidemic in Western countries have highlighted the need to address obesity at the outset. Indeed, obesity is on the rise globally, in an ever-younger demographic and independently of resource setting. The race is therefore on to find the magic bullet treatment that impacts positively on patient outcome for all three diseases, a key pharmaceutical industry aim that demands a great sense of urgency, with the prospect of great reward. The development of improved targeted drugs based on mechanistic insight, combined with more rigorous clinical trial design would save time and help toward this aim.

See part 1 here: The effects of obesity and the links to diabetes and cardiovascular disease – now and in the future.
See part 2 here: New hopes for treatment in the global obesity epidemic.
See part 3 here: Next generation obesity therapies.

Ref 1. America's Obesity Crisis: The Health and Economic Costs of Excess Weight Hugh Waters and Marlon Graf Milken Institute, October 2018 https://www.milkeninstitute.org/publications/view/944.