Canine diabetes mellitus – what’s new?

Introduction

Diabetes mellitus (DM) remains one of the most prevalent endocrine disorders in dogs, presenting ongoing challenges for both veterinarians and pet owners (1,2). In the past, despite often being diagnosed at a relatively young age, and being a treatable disease, DM negatively affected both the survival time of dogs and their quality of life, as well as the quality of life of their caregivers (1-3). This can largely be attributed to the complexities associated with treatment and monitoring, the presence of comorbidities, and care-giver fatigue (1,2). With new treatment options, however, these challenges are now substantially diminished. This article provides a review of recent developments in canine DM and their practical implications; the goal is to equip veterinarians with new tools that will make the management and monitoring of DM easier, increasing the chance of long-term treatment success. 

Historical DM Treatment 

For several decades, insulin therapy has constituted the primary approach to DM management, with the use of intermediate-acting insulin suspensions, such as porcine lente insulin, protamine-zinc insulin (PZI), and neutral protamine Hagedorn insulin (NPH). However, these suspensions are associated with three major limitations: 

1. Substantial day-to-day variability in insulin action, stemming from dose inaccuracies (related to the inconsistent resuspension process and the use of insulin syringes) and inconsistent absorption from the subcutaneous depot; 
2. A need to feed at the time of injection in order to avoid hypoglycemia; 
3. A need to administer insulin q12h. (4). 

 

The combination of these limitations leads to rigid, intense, and sometimes overwhelming treatment and monitoring protocols: veterinarians instruct owners to keep a consistent schedule, which includes insulin administration (exactly every 12 hours), immediately after feeding (with the same type and amount of food), while mostly avoiding treats. While short-term compliance with these requirements might be feasible, it presents an impossible long-term challenge, especially considering that many dogs would occasionally refuse to consume a full meal at exactly the time owners would like to feed them. In addition, these treatment protocols are associated with frequent rechecks, and often require months of dose adjustments until clinical control is achieved (Figure 1). 

New developments 

In recent years, DM management in dogs has undergone a significant transformation. Drawing upon advancements in human medicine, veterinary endocrinology is increasingly adopting innovative pharmacological and monitoring strategies that have the potential to enhance both the prognosis and quality of life for dogs diagnosed with DM. Notable innovations in this field include basal insulin analogues (which obviate the need to feed at the time of injection, and require only once-daily administration at a relatively flexible time interval), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and adjunctive therapies, such as fenofibrate (5-9). Each of these offer a unique approach to addressing the intricate pathophysiology of DM, as they focus on various aspects – such as optimizing insulin delivery, reducing renal glucose reabsorption, modulating appetite and satiety, and repairing intestinal barrier dysfunction – that may contribute to systemic inflammation (5-9). While insulin continues to be a crucial component of treatment, the integration of SGLT2i’s and fenofibrate into the therapeutic framework – augmented by continuous glucose monitoring (CGM) – reflects a shift toward a multimodal, physiology-based approach to care. 

Continuous glucose monitoring

The advancements in therapy are being significantly supported by the increased utilization of CGM devices (Figure 2) (10). These provide real-time insights into glycemic variability, effectively revealing patterns that traditional glucose curves cannot capture, and as such, optimization of therapy can be achieved much faster and more safely than before. A comprehensive understanding of glucose dynamics within the home environment is critical for evaluating novel therapies, individualizing treatment approaches, and assuring the patient’s safety (10). A full discussion of CGM is beyond the scope of this review, but throughout the article mention will be made of its integration as a basic monitoring modality. It is important to emphasize that when used correctly (including correct application, remote daily monitoring, etc.), CGM leads to an overall cost reduction for the client, fewer trips to the veterinary clinic, and improved quality of life. 

Basal insulin formulations

Recombinant basal insulin formulations are designed to deliver consistent insulin action over a minimum of a 24-hour period (i.e., a peakless time-action profile) with low day-to-day variability. Recent studies have begun to evaluate the application of these formulations in dogs and are demonstrating promising results (7,8). Because of their low day-to-day variability, when monitored using CGM, dose titration can be achieved rapidly, while targeting a relatively low nadir (as low as 50-60 mg/dL, or 2.8-3.3 mmol/L). In most dogs, and using CGM, adequate glycemic control is achieved with once-daily administration in less than 3 weeks and with no in-person rechecks (Figure 3). After establishing the appropriate daily dose, the exact time of injection can be flexible, with a window of about ± 2-3 hours around the usual time (e.g., if usually administered at 8:00 pm, it is acceptable to administer the insulin any time between 6:00-10:00 pm). 

These formulations can be administered independently of the amount, type, and time of feeding. Glucose nadirs are typically observed immediately before feeding, with substantial post-prandial hyperglycemia. In less than 5% of patients, because of excessive post-prandial hyperglycemia, adequate control is only achieved with either: 

1. Addition of an insulin bolus during a meal, or
2. Reduction of digestible carbohydrates in the diet or 
3. Addition of an SGLT2i (see below). 

 

However, in our experience, in this small minority of cases, switching from dry to canned food (of the same diet) is sufficient to achieve adequate glycemic control.

By decoupling insulin administration from strict feeding schedules, basal insulins alleviate the burden on pet owners and facilitate more customized treatment regimens. Owners may provide smaller or more frequent meals without significantly increasing the risk of hypoglycemia; in certain instances, meal omission may also be tolerated. Such flexibility addresses critical factors that contribute to owner fatigue and the possible premature euthanasia of diabetic dogs.

Because of their long duration of action, and because treatment success depends on the ability to assess the effect of post-prandial hyperglycemia, we recommend starting dogs on basal insulin formulations only if they are monitored with CGM. Once glycemic control is reached, we recommend using CGM intermittently: every few months or when there is a change in clinical signs or in daily routine (e.g., alteration in diet, exercise, etc.).

There are currently two formulations we use as basal insulins in dogs, with similar protocols and similar clinical outcomes: insulin degludec and insulin glargine 300 U/mL. Detailed dose titration protocols for both formulations are available online (open access) (7,8). Both formulations are supplied as clear solutions that do not need to be mixed or resuspended prior to drawing a dose, increasing dosing accuracy compared to suspension insulin formulations. Research conducted in purpose-bred beagles has demonstrated that both formulations exhibit lower day-to-day variability as compared to porcine lente insulin, thereby offering significant safety advantages and a lesser need for monitoring (11).

We recommend starting either product at 0.5 U/kg q24h in diabetic dogs that are naïve to treatment. Dogs previously treated with insulin suspensions q12h can be transitioned to q24h glargine U-300 or degludec at a starting dose that is higher by 30% (for example, a dog treated with 10 U q12h of NPH would be transitioned to 13 U q24h of degludec), with the expectation of eventually reaching similar total daily doses.

Insulin degludec is a recombinant human insulin analog in which B30 is replaced by a fatty acid (hexadecanedioic acid) that is bound to B29 via a glutamic spacer. After injection into the subcutaneous tissue, it forms multi-hexamers that gradually dissociate in a consistent manner (unlike insulin crystals in suspension insulins). After it dissociates, insulin degludec binds reversibly to albumin, which protects it from degradation, buffers its serum concentrations, and further increases its half-life and consistency (12,13). In dogs, insulin degludec has a duration of action > 20 hours, accompanied by a flat time-action profile (14). 

In a recent clinical trial, insulin degludec was safe and effective as a once-daily injection for around 80% of diabetic dogs, with a final median dose of 1.3 U/kg (range 0.4-2.2 U/kg) achieved in a median of 14 days (range 3-32). These promising results were achieved despite having a high percentage (79%) of comorbidities in the study population (8). Currently, the product is priced in the USA at about $0.13/unit, making it one of the most affordable insulin formulations (Table 1). Combined with excellent clinical outcomes, it is currently our first choice for most diabetic dogs.

 

Table 1. Current insulin prices in the USA as of September 2025. Bold text denotes basal insulin formulations (in dogs).

Insulin	Concentration	Vial/ pen size	Number of units	$	$/unit
Glargine U-100	U-100	5 x 3 mL	1500	35	0.02
NPH/Reg 70/30	U-100	10 mL	1000	60	0.06
Degludec	U-100 or U-200	3 mL	1000	130	0.06
Vetsulin	U-40	10 mL	400	70	0.18
Prozinc	U-40	10 mL	400	110	0.28
Glargine U-300	U-300	3 x 1.5 mL	1350	495	0.36
Note: Detemir is being discontinued globally and is no longer available in many countries

 

 

Insulin glargine 300 U/mL is identical in structure to insulin glargine 100 U/mL, but because it is three times more concentrated, the unit volume and, therefore, the droplet surface area is smaller, leading to slower absorption from the subcutaneous depot. This leads to an extended duration of action, and a flatter pharmacokinetic profile compared to glargine 100 U/mL. Glargine U-300 is also less potent than other formulations, which might be an advantage in small patients.

In a multi-institutional clinical trial involving 95 client-owned dogs, good or excellent glycemic control was achieved in most cases treated with glargine 300 U/mL as monotherapy; however, only about 60% of cases were controlled with once-daily dosing. The final median dose of 1.9 U/kg (range 0.2-5.2 U/kg) was achieved in a median of 16 days (range 3-99 days) with 72% of dogs controlled in < 30 days. These results were achieved despite having a high percentage (60%) of comorbidities in the study population, with a third of all dogs having concurrent hypercortisolism (7).

Currently, glargine 300 U/mL is priced in the USA at about $0.36/unit, making it one of the more expensive insulin formulations (Table 1). In small dogs, where low doses are required, glargine 300 U/mL might be an excellent choice because of its low potency. In people, insulin glargine 100 U/mL has a relatively prolonged and “peakless” pharmacodynamic profile and reduced day-to-day variability compared to traditional intermediate-acting suspension insulins, although it is clearly inferior to insulin glargine 300 U/mL. It is unknown if this is the case in dogs. While this formulation has been used in dogs as a q12h injection (15,16) its utility as a basal insulin has not been studied in dogs.

SGLT2 inhibitors in canine DM

Sodium-glucose cotransporter-2 inhibitors have revolutionized the management of type 2 DM in people and cats, providing insulin-independent glucose lowering by promoting urinary glucose excretion. The advantages of these inhibitors extend beyond mere glycemic control; they have also demonstrated cardioprotective and renoprotective effects in non-diabetic people. Consequently, there is increasing interest in exploring whether similar benefits may apply to canine patients with naturally occurring DM (5). In contrast to most cats and people, diabetic dogs are permanently incapable of producing insulin and, therefore, are not expected to be treated with SGLT2i’s as monotherapy. Rather, SGLT2i’s might be useful in dogs in combination with insulin injections. As such, the most important complication of SGLT2i in people (17) and cats, euglycemic diabetic ketoacidosis (eDKA), is less likely to be a major concern in dogs. However, SGLT2i’s might increase the risk of insulin-induced hypoglycemia (5,18). 

There are to date two peer-reviewed reports of SGLT2i administration in canine DM, one on canagliflozin (which is commercially available in some countries) and one on DWP16001, a novel SGLT2i. Both studies evaluated SGLT2i’s as a once-daily add-on therapy to intermediate-acting insulin, and in both studies administration of SGLT2i resulted in reductions in glucose levels, a need to decrease insulin dose, and no instances of eDKA (5,19). When CGM was used for monitoring, SGLT2i reduced glucose variability but increased the frequency of low interstitial glucose (although no clinical hypoglycemia was reported) (19). When administered over months, SGLT2i resulted in weight loss (5). Although studies are yet to be published at the time of writing this article, velagliflozin and bexagliflozin (both of which are available as veterinary-approved formulations in some countries), as well as dapagliflozin seem to be effective in dogs with similar results to the above. Depending on the dose, these drugs might cause an increase in polyuria and polydipsia. 

Overall, based on these studies and our clinical experience, we consider using SGLT2i’s in diabetic dogs that are difficult to control on insulin alone, especially when insulin resistance leads to extremely high insulin requirement (and thus potentially lowering the overall cost of treatment), or in dogs that are not well controlled on a basal insulin because of excessive post-prandial hyperglycemia. 

In people, in addition to eDKA and hypoglycemia, SGLT2i’s also increase the risk of mycotic urinary tract infections and volume depletion (18). While these adverse effects have not been observed in the canine studies conducted so far, the small sample sizes and short follow-up periods limit the conclusions that can be drawn. Therefore, careful monitoring, along with larger and longer-term trials in client-owned populations, is essential before these agents can be widely recommended. Their use will likely require integration with CGM and blood ketone monitoring to identify both benefits and risks* early in treatment.

* https://academy.royalcanin.com/en/veterinary/canine-diabetic-ketoacidosis

Fenofibrate and the intestinal barrier 

In multiple models of DM (including people, rodents, dogs and cats), hyperglycemia leads to intestinal barrier dysfunction and alterations in the gut microbiome, which then contribute to intestinal and systemic inflammation and metabolic instability (6,20-23). Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is widely used to treat hyperlipidemia. It has recently attracted attention in veterinary endocrinology for its potential effects beyond lipid control, specifically in the context of improving gut barrier function in DM. In diabetic dogs, fenofibrate may aid in restoring intestinal barrier function and enhancing overall management of DM (6,23). At 10 mg/kg PO q24h, a micronized nanocrystal formulation of fenofibrate enhances the integrity of the intestinal epithelial barrier by increasing the expression of tight junction proteins, decreasing permeability to bacterial components, decreasing intestinal epithelial lymphocytic infiltration, and reducing systemic inflammation (6,23). Generic fenofibrate formulations might require increasing this dose by about 50% (Figure 4). 

We routinely use fenofibrate to treat hyperlipidemia in both non-diabetic and diabetic dogs at a dose range of 2-20 mg/kg with no apparent adverse effects. Whether the improvements in gut barrier function in diabetic dogs translate into tangible clinical benefits (such as improved glycemic control, reduced insulin requirements, or enhanced survival) remains to be demonstrated in long-term clinical trials. However, clinical experience currently suggests a reduction in the overall frequency of gastrointestinal signs in diabetic dogs. 

Conclusion

The combination of basal insulin analogues and CGM constitutes a quantum leap forward in the management of canine DM, making it simpler for the veterinarian and substantially less stressful, less time demanding, and usually less expensive for the owner. Basal insulin products demonstrate more predictable pharmacodynamic profiles and more prolonged action than traditional insulin formulations, reducing between-day glucose variability, and facilitating simplified dosing regimens. When utilized in conjunction with CGM monitoring and, in select instances, adjunctive prandial insulin, these formulations help improve glycemic control, enhance quality of life, and extending the long-term survival of diabetic dogs. SGLT2i’s also hold promise for future multimodal management of canine DM, especially when integrated with basal insulin analogues and guided titration using CGM. Similarly, fenofibrate may help alleviate complications of DM, and future research should prioritize larger, controlled trials that assess these insulin adjuncts and their effect on clinical outcomes.

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