“Look and you Will Find it—What is Unsought Will go Undetected.” Sophocles

Abstract

This special issue of Journal of Veterinary Pharmacology and Therapeutics was precipitated by the launch of SGLT2-inhibitors onto the veterinary market for the treatment of diabetes mellitus in cats. It is hard to overstate the significance of a novel oral mode of treatment for diabetes given that a practitioner survey found that 1 in 10 owners will euthanise their pet because of not wanting to inject insulin (Niessen et al. 2017). As Drs Cook and Berend comprehensively discuss in this issue of JVPT, cats are well suited to treatment with SGLT-inhibitors because unlike dogs many have some residual β-cell function (Cook and Behrend 2025). These drugs may also be valuable in the management of insulin dysregulation that is a central feature of equine metabolic syndrome and the associated problem, equine laminitis, for which there are currently no licensed treatments (Menzies-Gow and Knowles 2025).

Now that SGLT2-inhibitors have been brought to the veterinary market it seems opportune to consider the potential of their wider use in treatment of renal and cardiovascular disease in veterinary patients (Elliott and Oyama 2025). The interest in their use for these indications stems from the evidence from human medicine that treatment with this class of drugs (and it does seem to be a class effect rather than being associated with any individual drug) reduces the risk of major cardiac adverse events and slows the rate of progression of diabetic kidney disease. Following these discoveries the clinical indications for these drugs have been expanded to include management of various forms of non-diabetic kidney and cardiac diseases, stemming in part from the observation that SGLT2-inhibitors actual benefits were greater in diabetic patients than would be anticipated just from the relatively mild weight loss and decrease in blood pressure.

Given the explosion in potential indications for these drugs, and the excitement surrounding their potential benefit for humans especially considering the current obesity epidemic with all its serious medical sequelae, it is easy to overlook the fact that these positive health effects were not anticipated. In fact, the huge trials that were performed with SGLT2-inhibitors were FDA-mandated studies required following the launch of any new glucose-lowering treatment due to concern that their use might be associated with ADVERSE cardiac outcomes (Udell et al. 2015). Indeed, the finding that SGLT2-inhibitors were not detrimental, but actually improved outcomes, was really quite unexpected (Zinman et al. 2015).

As a veterinary clinical researcher, it is possible to get quite despondent when looking at these clinical trials in humans, with the feeling that nothing on a comparable scale will ever be possible in veterinary patients. For example, a recent meta-analysis of the risk of reaching a composite end-point of End Stage Kidney Disease (ESKD), renal death or a doubling of serum creatinine concentration included over 15,000 participants treated with SGLT2-inhibitors and still recorded ≤ 500 events (Sridhar et al. 2023). It is hard to imagine that a metanalysis study of this size could ever be recapitulated on veterinary patients, large scale clinical trials are prohibitively expensive. However, there are still lessons to be learned from their experiences. These human studies show the value of detailed and rigorous studying drugs even once they are in widespread clinical use, such as occurs with EMA and FDA mandated post-authorisation pharmacovigilance studies. It is estimated that about 90% of adverse drug reactions are unreported, particularly if these are recognised and anticipated side-effects, so implementing systems that require veterinary surgeons to take additional steps to record events are unlikely to be the answer (Davies et al. 2024). Or such recording systems may only work if there is an incentive provided, or at least the process is facilitated by systems that allow direct access from the patient's clinical notes to record an event occurring. Data mining of information that is already being collected may prove more fruitful in this regard, and there are now several ways that have been developed for searching patient management databases. These include systems that are used within individual corporate practices (e.g., Banfield PetWare) or that compile data from numerous participating practices; independent and/or corporate (e.g., VetCompass, SAVSNET, CAVSNET), as well as various pet insurance databases, particularly from countries where subscription to these systems is high and concentrated within a small number of providers (e.g., Sweden). Of course, these data mining systems will only ever be as good as the data that are entered into them, and one must accept that there will be limitations. For example, a VetCompass study of cats diagnosed with Chronic Kidney Disease (CKD) found that in 10% of cases this diagnosis was made solely on the basis of physical examination, without any supporting bloodwork or urinalysis (Conroy et al. 2019). These more inclusive criteria can have both advantages and disadvantages; on the one hand not all of the cats that appear to have CKD will be confirmed with further testing, but on the other the less stringent inclusion criteria may be more representative of the general population at risk of the disease and the ways that they are being treated in first-opinion practices. Ultimately some events, such as death, or discontinuation of a drug, are incontrovertible and these data will be relatively easily extracted from medical records and could be very informative if large enough populations can be compared that have/haven't been treated with a certain drug or exposed to a particular event. This approach has recently been utilised to emulate clinical trials using veterinary clinical records to study the development of urinary incontinence and cruciate disease (Pegram et al. 2024a, 2024b).

An additional observation from the studies of SGLT2-inhibitors in humans is how they have disrupted the typical sequence of knowledge acquisition about a disease and its treatment. Although this may be overly simplistic one tends to consider the flow of information regarding a new class of drug as starting with the study of basic physiology, pharmacology and pathology before, if results are promising, progressing to different phases of clinical trials, probably with some animal research along the way. Unexpected highly beneficial results in clinical patients, however, triggers the reverse approach. A previous example of this is the explosion of interest in the basic anti-fibrotic mechanisms of mineralocorticoid antagonists that was triggered by the remarkable and unexpected survival benefits that followed the addition of low dose spironolactone to conventional heart failure treatment in the seminal RALES study (Pitt et al. 1999). The clinical trials of SGLT2-inhibitors have likewise shown such promise that this is now similarly fuelling an explosion of basic science using cell culture systems and in vitro models to study the impact of these drugs on endothelial dysfunction, apoptosis, fibrosis, oxidative stress and other common pathophysiological mechanisms and this in turn may support further clinical trials for other diseases such as pulmonary hypertension and hepatic cirrhosis (Zhang et al. 2025; Pradhan et al. 2025). Somehow veterinary clinicians need to try to get in on the act and show how use of these drugs in our patients, with their shorter lifespan and faster disease progression rates, can provide meaningful translational data—and in doing so further the ‘One Medicine’ approach.

Harriet M. Syme and Jonathan Elliott.

JE receives research grant funding from Boehringer Ingelheim and Elanco Animal Health and has acted as a consultant for both companies. These are relevant because both companies have SGLT2 inhibitors.