Insulin choice in feline diabetes mellitus

a Knowledge Summary by

Yaiza Gómez Mejías LdaVet MANZCVS (Medicine of Cats) ISFM Adv Cert Feline Behaviour MRCVS ^1*

¹La Gatera Medicina Felina, Lomo del Capón 74, 35017 Tafira Alta, Las Palmas de Gran Canaria, Canary Islands, Spain
^*Corresponding Author (yaizagomezmejias@yahoo.co.uk)

Clinical scenario

A recently diagnosed diabetic cat shows a poor glycaemic and clinical response to protamine zinc insulin (PZI). You wonder whether there is sufficient evidence of superiority of efficacy of glargine over PZI to justify use of this insulin for avoiding hypoglycaemia whilst controlling the clinical signs.

The evidence

Only one peer-reviewed study was found where the effects of glargine were directly compared to those of PZI in diabetic cats. This study is a non-randomised trial and provides weak evidence about the superiority of glargine at reducing episodes of hypoglycaemia, lowering fructosamine levels and achieving higher rates of remission.

For completeness purposes the references were scrutinised and a relevant systematic review was found. This systematic review provides a strong level of evidence of the lack of existing evidence regarding a significant correlation between the type of insulin and diabetic remission. However, episodes of hypoglycaemia were not considered in this review.

Summary of the evidence

Appraisal, application and reflection

Long acting insulin (PZI, glargine or detemir) and high-protein/low-carbohydrate diets are recommended for the management of diabetic cats (Behrend et al. 2018; and Sparkes et al. 2015). Diabetes mellitus is a common disorder that affects a cat’s quality of life and survival. An appropriate management is key to positively contribute to their welfare and the cat-human bond.

The UK veterinary prescription cascade precludes the use of human insulin (e.g.: glargine, detemir) as first line treatment. ProZinc® (Boehringer Ingelheim Vetmedica), a human PZI produced by recombinant DNA technology (PZIR), is the only long acting insulin licensed for use in cats in the UK. However, a large part of the literature about diabetic management and remission in cats involves glargine trials (Gostelow et al. 2014).

A shift regarding feline diabetic remission is taking place and seems to be considered a main goal by many experts (Marshall et al. 2009; and Gostelow et al. 2014). However, the tight glycaemic control (Nack & DeClue, 2014) needed to achieve that period of time in which symptoms of diabetes are absent, is potentially concerning, as it may result in episodes of hypoglycaemia which may affect the cat’s quality of life. Whereas in 2015 the ISFM guidelines (Sparkes et al., 2015) highlighted the convenience of ‘avoiding hypoglycaemia at the expense of allowing periods of hyperglycaemia’, in 2018 Behrend et al. stated that ‘In cats, diabetic remission is a reasonable goal’.

However, limiting the cat’s clinical signs, using a treatment that fits into the owner’s daily life and preventing clinically significant hypoglycaemia and other complications are clear goals in both current guidelines of management of feline diabetes (Sparkes et al., 2015; and Behrend et al., 2018).

Most long-term effects on health, quality of life and cost effectiveness of a near-euglycaemic management and remission paradigm is unknown (Nack & DeClue, 2014). On the other hand, more comorbidities are included in the diagnostic work up nowadays. Over the last few decades new feline pathologies influencing the onset and management of diabetes have been identified and technical instruments are more readily available making it possible to diagnose these diseases. A close monitoring of the glycaemic levels and the work up of these comorbidities result in additional expenses and difficulties to achieving stabilisation of the feline diabetic patient (Gostelow et al., 2014).

Hence, when cost and effectiveness are outweighed, remission may be considered a goal but most veterinarians priorities may still be reducing clinical signs and likelihood of hypoglycaemic episodes. To avoid controversy, ‘remission’ has not been included as a keyword in the search but remission related evidence was not excluded from the search results and was taken into account.

At the time of writing, the study of Marshall et al. (2009) is the only peer-reviewed publication where PZI and glargine are directly compared. The evidence provided by this non-randomised trial regarding the superiority of glargine compared to PZI at reducing clinical signs in diabetic cats is weak.

With respect to the clinical signs, daily water intake in glargine treated cats was not different in the first 28 days of therapy, despite being associated with lower mean 12 hour blood glucose concentrations than porcine lente insulin and PZI. An extended trial period would have been necessary to assess the medium to long-term effects, since fructosamine concentrations were reported to be significantly lower in glargine treated cats from day 56. There was no significant effect of insulin type on change in body weight from initial hospital discharge to trial end.

However, the trial provides stronger evidence about influence of insulin type on the development of hypoglycaemia. During the trial, two cats treated with porcine lente insulin and one cat treated with PZI had severe clinical signs associated with low blood glucose levels, whereas none of the glargine treated cats exhibited signs of hypoglycaemia.

To ensure the completeness of the Knowledge Summary, references of selected search results were scrutinised. A relevant systematic review about feline diabetic remission (Gostelow et al., 2014) was found amongst them and included in the search table after applying the exclusion criteria.

The systematic review does not fully answer the PICO question because hypoglycaemia or other complications of treatment were not taken into account.

It was included in the Knowledge Summary because it analyses the evidence in the study published by Marshall et al. (2009). However, one of three confounding factors described in the review was unrelated to this PICO question as it was linked to the porcine lente insulin dosing protocol, which is not a type of insulin included in this Knowledge Summary. With respect to the confounding factor associated with the use of steroids, as explained by Marshall et al. (2009), the glargine group was disadvantaged with respect to the probability of remission compared to the other groups and that disadvantage could compensate the bias.

Regarding the overall conclusion, the systematic review shows a slightly lower existing evidence for remission in cats treated with PZI (3b) compared to glargine (3a), 1 being the highest and 4d the lowest grade of evidence (Table 1 in Gostelow et al., 2014).

Another potentially relevant study (Gostelow et al., 2017) was found during scrutinisation of the references. The results were included in the 2017 ACVIM Forum Research Abstract Forum, but were excluded from this summary as were other non-peer-reviewed publications since a detailed description of the study was not available and an assessment of possible biases could not be made.

A limitation of this Knowledge Summary could be the omission of the keyword ‘remission’. However, a similar search including this keyword was made and the results were not significantly different and did not include the systematic review published by Gostelow et al. (2014) either.

Another limitation could be that the PZI used in the trial published by Marshall et al. (2009) is a mixture of 90% beef and 10% pork insulin (PZI-Vet, Idexx® Pharmaceuticals USA, Westbrook, Maine USA) and not the PZIR (Boehringer Ingelheim). However, there is some evidence about similar results of PZI-Vet and PZIR (Nelson et al., 2009).

An observation made whilst reviewing these papers was a low level of satisfaction of owners with their veterinarian’s knowledge of diabetes ‘which may reflect owner access to the rapidly changing body of knowledge on the Internet’ (Aptekmann et al., 2014). There is also a possible bias in the veterinary literature, where the importance of temporary remission seems overestimated compared to that of limitation of clinical signs and hypoglycaemia.

Complete studies with large samples are difficult to perform due to the lack of adequate cases and it is possible that investigating other treatments and formulations such as incretins and glargine 300 U/mL (Gilor et al., 2016; and Saini et al., 2020) may be more appealing to researchers now. Multiple factors affect the prognosis of diabetes in cats that deserve some attention too and may be understandably leading the way in research.

There is more literature about glargine than about any other insulin type in cats and its use has been demonstrated to be safe and effective. There is weak evidence about glargine helping to achieve lower fructosamine levels as well as possibly reducing the likelihood of hypoglycaemia when it is directly compared to PZI. However, the results are mainly based on newly diagnosed diabetes, what may not reflect the situation of the majority of the population.

Methodology Section

Search Strategy
Databases searched and dates covered:	CAB Abstracts on OVID Platform 1973 – Week 07 2021] VetMed 1973 – February 2021 Pubmed 1973 – February 2021
Search strategy:	CAB Abstracts and VetMed: (cat OR cats OR feline OR felines OR queen OR tom) AND (diabetes mellitus OR diab*)) and (PZI OR protamine zinc insulin OR human recombinant protamine zinc insulin OR ProZinc) and (improvement OR glycaemic control OR glycemic control OR hyperglycaemia OR hyperglycemia OR hypoglycaemia OR hypoglycaemia OR blood glucose OR weight OR body condition score OR clinical signs OR polyuria OR polydipsia) (cat OR cats OR feline OR felines OR queen OR tom) AND (diabetes mellitus OR diab*)) and (PZI OR protamine zinc insulin OR human recombinant protamine zinc insulin OR ProZinc) and (Glargine OR Lantus OR iGlar)   PubMed: (cat OR cats OR feline OR felines OR queen OR tom) AND (diabetes mellitus OR diab*))(PZI OR protamine zinc insulin OR human recombinant protamine zinc insulin OR ProZinc) AND (Glargine OR Lantus OR iGlar) AND (improvement OR glycaemic control OR glycemic control OR hyperglycaemia OR hyperglycemia OR hypoglycaemia OR hypoglycaemia OR blood glucose OR weight OR body condition score OR clinical signs OR polyuria OR polydipsia)
Dates searches performed:	22 Feb 2021

Exclusion / Inclusion Criteria
Exclusion:	Excel was initially used to find duplicates. Duplicates that this initial approach failed to find were removed along the exclusion process. Studies that did not involve domestic cats were excluded. Studies that only included either iGlar or PZI were not included. Case reports, clinical reviews, guidelines, congress abstracts only were excluded to achieve a certain level of scientific evidence. Studies where the PICO question was not addressed were excluded.
Inclusion:	Studies that involved both PZI and iGlar in domestic cats with diabetes mellitus were included. A thorough scrutinisation of the references was made and relevant studies offering a strong level of evidence were included.

Search Outcome
Database	Number of results	Excluded – Duplicates	Excluded – Non feline, non PZI or iGlar related	Excluded – Non-English, case reports, clinical reviews, guidelines, congress abstracts	Excluded – Did not address the PICO question	Total relevant papers
CAB Abstracts	62	28	10	7	17	0
VetMed	195	106	45	12	31	1
PubMed	387	46	312	23	6	0
Total relevant papers when duplicates removed						1

The author declares no conflicts of interest.

I would like to thank Clare Boulton for her help during the search process.

1. Aptekmann, K. P., Armstrong, J., Coradini, M. & Rand, J. (2014). Owner Experiences in Treating Dogs and Cats Diagnosed with Diabetes Mellitus in the United States. Journal of the American Animal Hospital Association. 50(4), 247–253. DOI: https://doi.org/10.5326/JAAHA-MS-6101
2. Behrend, E., Holford, A., Lathan, P., Rucinsky, R. & Schulman, R. (2018). 2018 AAHA Diabetes Management Guidelines for Dogs and Cats. Journal of the American Animal Hospital Association. 54(1), 1–21. DOI: https://doi.org/10.5326/JAAHA-MS-6822
3. CEBM. (2011). The Oxford 2011 Levels of Evidence. Available at: http://www.cebm.net/index.aspx?o=5653 [Accessed 10 August 2014].
4. Gilor, C, Rudinsky, A. J. & Hall, M. J. (2016). New Approaches to Feline Diabetes Mellitus: Glucagon-like peptide-1 analogs. Journal of Feline Medicine and Surgery. 18(9), 733–743. DOI: https://doi.org/10.1177%2F1098612X16660441
5. Gostelow, R., Forcada, Y., Graves, T., Church, D. & Niessen, S. (2014). Systematic review of feline diabetic remission: Separating fact from opinion. Veterinary Journal. 202(2), 208–221. DOI: https://doi.org/10.1016/j.tvjl.2014.08.014
6. Gostelow, R., Scudder, C., Hazuchova, K., Forcada, Y., Church D. & Niessen, S. (2017). 2017 ACVIM Forum Research Abstract Program Index of Abstracts ORAL PRESENTATIONS – Thursday , June 8. 1273.
7. Marshall, R. D., Rand, J. S. & Morton, J. M. (2009). Treatment of Newly Diagnosed Diabetic Cats with Glargine Insulin Improves Glycaemic Control and Results in Higher Probability of Remission than Protamine Zinc and Lente Insulins. Journal of Feline Medicine and Surgery. 11(8), 683–691. DOI: https://doi.org/10.1016/j.jfms.2009.05.016
8. Nack, R. & DeClue, A. E. (2014). In cats with newly diagnosed diabetes mellitus, use of a near-euglycemic management paradigm improves remission rate over a traditional paradigm. Veterinary Quarterly. 34(3), 132–136. DOI: https://doi.org/10.1080/01652176.2014.924057
9. Nelson, R. W., Henley, K., Cole, C. & PZIR Clinical Study Group. (2009). Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. Journal of Veterinary Internal Medicine. 23(4), 787–793. DOI: https://doi.org/10.1111/j.1939-1676.2009.0342.x
10. Saini, N. K., Wasik, B., Pires, J., Leale, D. M., Quach, N., Culp, W. T. N., Samms, R. J., Johnson, A. E., Owens, J. G. & Gilor, C. (2020). Comparison of pharmacodynamics between insulin glargine 100 U/mL and insulin glargine 300 U/mL in healthy cats. Domestic Animal Endocrinology. 75. DOI: https://doi.org/10.1016/j.domaniend.2020.106595
11. Sparkes, A. H., Cannon, M., Church, D., Fleeman, L., Harvey, A., Hoenig, M., Peterson, M. E., Reusch, C. E., Taylor, S. & Rosenberg, D. (2015). ISFM Consensus Guidelines on the Practical Management of Diabetes Mellitus in Cats. Journal of Feline Medicine and Surgery. 17(3), 235–250. DOI: https://doi.org/10.1177%2F1098612X15571880