In 1903, the Wright brothers changed the world with their successful flight over Kitty Hawk. They expected that aviation would mainly become a sporting activity with no practical applications. Anybody who’s been on a budget holiday or sent a greetings card halfway across the world is reminded of just how much they underestimated their own invention, and the immense possibilities that it unlocked. Alexander Fleming's chance encounter with penicillin in 1928 propelled him to worldwide fame and some academics sought to diminish this as a fluke from not cleaning his lab equipment rather than being the intended result of a properly conducted experiment.

Yet, such is the nature of progress. Serendipity often plays a huge role in shaping history and even the most visionary pioneers can be surprised by the far-reaching consequences of their discoveries. The events we’ve witnessed with the new diabetes drugs serves as a prime example of this.
 

A paradigm shift

Safety concerns about the drug rosiglitazone arose when Dr. Nissen’s meta-analysis linked it to major adverse cardiovascular events (MACEs) back in 2007. The resulting slew of market withdrawals and lawsuits prompted regulators like the FDA to mandate that future antidiabetic agents undergo cardiovascular outcome trials (CVOTs). In a very happy accident, a CVOT for a new drug called empagliflozin showed that it significantly reduced MACEs. I cannot emphasise just how unprecedented this discovery was – a new drug with the primary aim of lowering blood glucose had to undergo a CVOT, purely as a safeguard against repeating the rosiglitazone debacle – nobody was expecting it to unearth additional benefits. This has led to a paradigm shift in the management of type 2 diabetes and chronic disease management has never been the same since. The table below shows the newer classes of antidiabetic agents and their UK licensed indications in 2015:

 

SGLT-2 inhibitors were then found to have positive renal outcomes too - a welcomed surprise for nephrologists, who lacked new kidney-preserving drugs since the advent of ACE inhibitors and ARBs in the 1980s. We have also learned that GLP-1 agonists are multifunctional. Here is what those drugs are licensed for in the UK today:

 

The drugs demand it of us

There’s a pervasive notion that SGLT-2 inhibitors and GLP-1 agonists have been ingeniously repurposed, as if their new applications are a direct result of human agency, but the truth is that they haven’t changed at all. Rather, it has taken time for us to recognise and exploit their inherent pharmacological properties beyond their initial purpose of reducing blood sugar.

Our interventions have not magically transformed these medicines into cardioprotective and kidney-preserving agents, instead it is the intrinsic properties of the drugs themselves have compelled us to shift our focus of type 2 diabetes from being a condition that affects glucose levels to an all-encompassing cardiovascular-renal-metabolic disease process that intersects with many other chronic disorders. It’s as if the drugs themselves have demanded that we change our practice. We have now transitioned to an era where we have unifying terms like cardiovascular-renal-metabolic health and this year's Diabetes Professional Care event will be the first to incorporate Cardiovascular Professional Care into its agenda.

The eminent Dr Kevin Fernando, at his GP surgery in North Berwick, allocates 30–40 minute appointment slots for his patients to undergo comprehensive multi-morbidity reviews. This allows him and his team the time to address the patient’s entire cardiovascular-renal-metabolic health in one sitting, rather than providing fragmented reviews for each condition. Many healthcare professionals are now adopting this method. For advice on how to introduce these changes to your own practice, I highly recommend reading his and Dr Eimear Darcy’s Cardiovascular Renal Metabolic Review Checklist.
 

The gifts that keep on giving

This is such an exciting time to be involved in chronic disease management. Despite the meaningful progress witnessed in recent years, the journey is far from over.  We continue to uncover the remarkable versatility of these new diabetes drugs. The premature halt of the FLOW trial due to the remarkably positive renal outcomes associated with semaglutide underscores the vast capabilities of GLP-1 agonists and why they are so often called the gifts that keep on giving. Moreover, these agents are being investigated for liver disease, Alzheimer’s, sleep apnoea and autoimmune conditions.

GLP-1 belongs to the incretin family of hormones that are secreted by the gut in response to food intake to augment insulin secretion. The ongoing development of compounds that target various incretin receptor sites has yielded some very promising results. Tirzepatide is a licensed example of this approach, being a single compound with selectivity for both GLP-1 and GIP activity, showing superior effects on weight loss compared to GLP-1 agonists alone in several studies.

In March this year, Novo Nordisk unveiled phase I trial results for amycretin, a treatment that can be given orally to target both GLP-1 and amylin receptors. The data showed that subjects lost 13.1% of their bodyweight in 12 weeks. This is overshadowed by the drug retatrutide, known as a ‘triple G’ agonist because of its affinity for three hormone receptors: GLP-1, GIP and glucagon. Lilly reported phase II outcomes last year, with participants achieving a weight reduction exceeding 24% in 48 weeks. The weight loss outcomes with these newer classes of drugs are comparable to those typically observed after bariatric surgery.

(Sidenote: Please be aware that despite the important roles of amylin and glucagon in glycaemic regulation, they are not formally categorised as incretins because they are secreted by the pancreas, not the gut and don’t directly enhance insulin secretion.)

While it's essential not to draw any definitive conclusions from these trials, they do offer valuable insight into the untapped potential for exploiting these hormone receptor sites to develop treatments for a multitude of diseases.


Embrace the happy accidents

History shows us that pivotal breakthroughs often come out of blue rather than through deliberate scientific enquiry. Do not be disheartened by this. The intention of this article is not to deter you from pursuing scientific progress.

As clinicians, our opportunity to excel lies in the effective implementation of these discoveries or happy accidents. Reflecting on my own practice, my best achievements have not come from conceiving some ingenious thought but rather from recognising a good idea when I see it, taking it very seriously and putting in the hard work to make sure patients actually benefit from it. We play a key role in bridging the gap between innovation and patient care, facilitating the transfer of useful ideas to those who need them most.

 

By Jack Smith

Jack Smith has held various professional roles within healthcare, most recently working as a clinical Pharmacist for West Knowsley PCN. He is passionate about addressing diabetes through improved patient education, behaviour change and the upskilling of clinicians.

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