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Reviewing the evidence: Feline diabetic remission
The Veterinary Journal 203 (2015) 268–269
Contents lists available at ScienceDirect
The Veterinary Journal j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l
Guest Editorial
Reviewing the evidence: Feline diabetic remission
The systematic review of feline diabetic remission by Dr. Ruth Gostelow and co-authors from the Royal Veterinary College, London, published in a recent issue of The Veterinary Journal (Gostelow et al., 2014), highlights important concerns in the current understanding of optimal treatment of diabetic cats and, most importantly, reveals the need for adequately powered, controlled trials to enable us to make firm conclusions regarding factors affecting diabetic remission. The authors systematically review published literature following the Cochrane Collaboration guidelines to answer the following research questions: (1) What are the factors affecting the rate of diabetic remission in cats? (2) Which factors could be used to predict diabetic remission in cats? The review demonstrates that there are only a small number of relevant studies published and that these vary widely in study design. All of these studies identify common sources of bias, such as lack of randomisation and inadequate blinding, as well as small sample sizes; hence, most papers included in the review provided evidence graded as moderate to poor. The systematic review by Gostelow et al. (2014) focuses on diabetic remission and not on general glycaemic control. Because of the high remission rates in recent reports, diabetic remission is a relevant goal of diabetes treatment in cats. Cats achieving remission are considered to be ‘cured’, at least temporarily, which saves cats from twice daily injections, possible hypoglycaemic crises, diabetic ketoacidosis or other diabetic complications. It can also save their owners considerable financial outlay. Veterinarians should advise owners of diabetic cats that the aim of treatment is to achieve adequate glycaemic control and to optimise the chance of remission, while minimising the risk of hypoglycaemia. These goals emphasise the relevance of the review by Gostelow et al. (2014) for the veterinary community. In cats, glargine and protamine zinc insulin (PZI) have a longer duration of action than porcine lente, potentially providing better glycaemic control for diabetic cats treated with these insulins (Marshall et al., 2008). However, the level of evidence for the effect of insulin type on diabetic remission rate is assessed as only moderate to poor. Gostelow et al. (2014) concluded that glargine, PZI and possibly detemir might be superior to porcine lente in achieving remission, but prospective randomised controlled trials are needed to confirm whether a difference exists. Evaluating the published data on dietary intervention, the authors identify major risks of bias in most studies, concluding that the effects of carbohydrate reduction, optimal level of carbohydrate reduction and fibre content also warrant further investigation. A major confounder identified when comparing the different studies was the stringency of glucose monitoring and insulin dosage adjustment used. It has been hypothesised that, if euglycaemia is achieved relatively quickly, the chance of remission is significantly http://dx.doi.org/10.1016/j.tvjl.2014.11.007 1090-0233/© 2014 Elsevier Ltd. All rights reserved.
increased because the glucotoxic effect on the remaining β cells is reduced; this has been observed in human diabetes mellitus (Ilkova et al., 1997; Hu et al., 2011). This requires further investigation, especially since the current American Animal Hospital Association (AAHA) guidelines recommend initiating treatment with a relatively low insulin dose (0.25 U/kg ideal bodyweight) twice daily, irrespective of blood glucose level, and the main focus of initial monitoring is avoiding hypoglycaemia (Rucinsky et al., 2010). Recently, our group at the University of Copenhagen published a retrospective study of detemir treatment of diabetic cats, following a protocol based on the current AAHA guidelines (Hoelmkjaer et al., 2015). A remission rate of 21% was achieved in that feline population and, although not all cats were fed low carbohydrate diets, this could have confounded the study. Additionally, less rigid glucose monitoring and a slower return to euglycaemia might have contributed to our relatively low remission rate compared with earlier studies using detemir and similar long acting insulins. The review by Gostelow et al. (2014) identified considerable heterogeneity between studies, partly explained by the lack of common criteria for diagnosis and the evaluation of outcome measures such as diabetic remission. The proposed definition of feline diabetic remission, (normoglycaemia without antihyperglycaemic treatment for a minimum of 4 weeks), seems like a good place for future research to start. Ideally, systematic reviews assessing the effect of an intervention should be based on adequately powered, randomised controlled trials. However, in fields where published research is limited, in number and/or in quality, the inclusion of studies with a lower level of evidence could be justified (Reeves et al., 2008; Jessen et al., 2015). This is exemplified in the review by Gostelow et al. (2014), where most studies are non-controlled and retrospective. Thus, based on the available evidence, the review was unable to definitively recommend which diabetic treatment optimises the chances of feline diabetic remission. So what is the value of systematic reviews in areas of limited research? The absence of answers to relevant questions per se constitutes an important finding, and systematic reviews are extremely valuable, since they can identify and characterise important gaps in published evidence and help to direct future research in the field. When based on studies with a high level of evidence, systematic reviews represent excellent evidence and form a solid base for decision-making and the creation of guidelines. To reach their full potential, data from studies can be combined in meta-analyses to produce more accurate conclusions. For that to happen, however, such studies must be sufficiently comparable to allow for their results to be combined in a meaningful way. Therefore, it is important to recognise the value of similar studies, despite their lack of novelty.
Guest Editorial/The Veterinary Journal 203 (2015) 268–269
Furthermore, studies reporting negative results contribute important data for meta-analyses and strengthen the conclusions of systematic reviews. We hope that these comments are considered by editors and reviewers when they decide which studies are suitable for publication. Charlotte Reinhard Bjornvad Lisbeth Rem Jessen Department of Veterinary Clinical and Animal Sciences University of Copenhagen Dyrlaegevej 16, 1870 Frb. C, Denmark, E-mail address: [email protected] References Gostelow, R., Forcada, Y., Graves, T., Church, D., Niessen, S., 2014. Systematic review of feline diabetic remission: Separating fact from opinion. The Veterinary Journal 202, 208–211.
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Hoelmkjaer, K.M., Spodsberg, E.H., Bjornvad, C.R., 2015. Insulin detemir treatment in diabetic cats in a practice setting. Journal of Feline Medicine and Surgery 17, 144–151. Hu, Y., Li, L., Xu, Y., Yu, T., Tong, G., Huang, H., Bi, Y., Weng, J., Zhu, D., 2011. Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and beta-cell function in subjects with long-term remission. Diabetes Care 34, 1848–1853. Ilkova, H., Glaser, B., Tunckale, A., Bagriacik, N., Cerasi, E., 1997. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 20, 1353–1356. Jessen, L.R., Sørensen, T.M., Bjornvad, C.R., Nielsen, S.S., Guardabassi, L., 2015. Effect of antibiotic treatment in canine and feline urinary tract infections: A systematic review. The Veterinary Journal. The Veterinary Journal 203, 270–277. Marshall, R.D., Rand, J.S., Morton, J.M., 2008. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. Journal of Veterinary Pharmacology and Therapeutics 31, 205–212. Reeves, B.C., Deeks, J.J., Higgins, J.P.T., Wells, G.A., 2008. Including non-randomized studies. In: Cochrane Handbook for Systematic Reviews of Interventions. (Chapter 13) (accessed 11 January 2015). Rucinsky, R., Cook, A., Haley, S., Nelson, R., Zoran, D.L., Poundstone, M., 2010. AAHA diabetes management guidelines for dogs and cats. Journal of the American Animal Hospital Association 46, 215–224.
Contents lists available at ScienceDirect
The Veterinary Journal j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t v j l
Guest Editorial
Reviewing the evidence: Feline diabetic remission
The systematic review of feline diabetic remission by Dr. Ruth Gostelow and co-authors from the Royal Veterinary College, London, published in a recent issue of The Veterinary Journal (Gostelow et al., 2014), highlights important concerns in the current understanding of optimal treatment of diabetic cats and, most importantly, reveals the need for adequately powered, controlled trials to enable us to make firm conclusions regarding factors affecting diabetic remission. The authors systematically review published literature following the Cochrane Collaboration guidelines to answer the following research questions: (1) What are the factors affecting the rate of diabetic remission in cats? (2) Which factors could be used to predict diabetic remission in cats? The review demonstrates that there are only a small number of relevant studies published and that these vary widely in study design. All of these studies identify common sources of bias, such as lack of randomisation and inadequate blinding, as well as small sample sizes; hence, most papers included in the review provided evidence graded as moderate to poor. The systematic review by Gostelow et al. (2014) focuses on diabetic remission and not on general glycaemic control. Because of the high remission rates in recent reports, diabetic remission is a relevant goal of diabetes treatment in cats. Cats achieving remission are considered to be ‘cured’, at least temporarily, which saves cats from twice daily injections, possible hypoglycaemic crises, diabetic ketoacidosis or other diabetic complications. It can also save their owners considerable financial outlay. Veterinarians should advise owners of diabetic cats that the aim of treatment is to achieve adequate glycaemic control and to optimise the chance of remission, while minimising the risk of hypoglycaemia. These goals emphasise the relevance of the review by Gostelow et al. (2014) for the veterinary community. In cats, glargine and protamine zinc insulin (PZI) have a longer duration of action than porcine lente, potentially providing better glycaemic control for diabetic cats treated with these insulins (Marshall et al., 2008). However, the level of evidence for the effect of insulin type on diabetic remission rate is assessed as only moderate to poor. Gostelow et al. (2014) concluded that glargine, PZI and possibly detemir might be superior to porcine lente in achieving remission, but prospective randomised controlled trials are needed to confirm whether a difference exists. Evaluating the published data on dietary intervention, the authors identify major risks of bias in most studies, concluding that the effects of carbohydrate reduction, optimal level of carbohydrate reduction and fibre content also warrant further investigation. A major confounder identified when comparing the different studies was the stringency of glucose monitoring and insulin dosage adjustment used. It has been hypothesised that, if euglycaemia is achieved relatively quickly, the chance of remission is significantly http://dx.doi.org/10.1016/j.tvjl.2014.11.007 1090-0233/© 2014 Elsevier Ltd. All rights reserved.
increased because the glucotoxic effect on the remaining β cells is reduced; this has been observed in human diabetes mellitus (Ilkova et al., 1997; Hu et al., 2011). This requires further investigation, especially since the current American Animal Hospital Association (AAHA) guidelines recommend initiating treatment with a relatively low insulin dose (0.25 U/kg ideal bodyweight) twice daily, irrespective of blood glucose level, and the main focus of initial monitoring is avoiding hypoglycaemia (Rucinsky et al., 2010). Recently, our group at the University of Copenhagen published a retrospective study of detemir treatment of diabetic cats, following a protocol based on the current AAHA guidelines (Hoelmkjaer et al., 2015). A remission rate of 21% was achieved in that feline population and, although not all cats were fed low carbohydrate diets, this could have confounded the study. Additionally, less rigid glucose monitoring and a slower return to euglycaemia might have contributed to our relatively low remission rate compared with earlier studies using detemir and similar long acting insulins. The review by Gostelow et al. (2014) identified considerable heterogeneity between studies, partly explained by the lack of common criteria for diagnosis and the evaluation of outcome measures such as diabetic remission. The proposed definition of feline diabetic remission, (normoglycaemia without antihyperglycaemic treatment for a minimum of 4 weeks), seems like a good place for future research to start. Ideally, systematic reviews assessing the effect of an intervention should be based on adequately powered, randomised controlled trials. However, in fields where published research is limited, in number and/or in quality, the inclusion of studies with a lower level of evidence could be justified (Reeves et al., 2008; Jessen et al., 2015). This is exemplified in the review by Gostelow et al. (2014), where most studies are non-controlled and retrospective. Thus, based on the available evidence, the review was unable to definitively recommend which diabetic treatment optimises the chances of feline diabetic remission. So what is the value of systematic reviews in areas of limited research? The absence of answers to relevant questions per se constitutes an important finding, and systematic reviews are extremely valuable, since they can identify and characterise important gaps in published evidence and help to direct future research in the field. When based on studies with a high level of evidence, systematic reviews represent excellent evidence and form a solid base for decision-making and the creation of guidelines. To reach their full potential, data from studies can be combined in meta-analyses to produce more accurate conclusions. For that to happen, however, such studies must be sufficiently comparable to allow for their results to be combined in a meaningful way. Therefore, it is important to recognise the value of similar studies, despite their lack of novelty.
Guest Editorial/The Veterinary Journal 203 (2015) 268–269
Furthermore, studies reporting negative results contribute important data for meta-analyses and strengthen the conclusions of systematic reviews. We hope that these comments are considered by editors and reviewers when they decide which studies are suitable for publication. Charlotte Reinhard Bjornvad Lisbeth Rem Jessen Department of Veterinary Clinical and Animal Sciences University of Copenhagen Dyrlaegevej 16, 1870 Frb. C, Denmark, E-mail address: [email protected] References Gostelow, R., Forcada, Y., Graves, T., Church, D., Niessen, S., 2014. Systematic review of feline diabetic remission: Separating fact from opinion. The Veterinary Journal 202, 208–211.
269
Hoelmkjaer, K.M., Spodsberg, E.H., Bjornvad, C.R., 2015. Insulin detemir treatment in diabetic cats in a practice setting. Journal of Feline Medicine and Surgery 17, 144–151. Hu, Y., Li, L., Xu, Y., Yu, T., Tong, G., Huang, H., Bi, Y., Weng, J., Zhu, D., 2011. Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and beta-cell function in subjects with long-term remission. Diabetes Care 34, 1848–1853. Ilkova, H., Glaser, B., Tunckale, A., Bagriacik, N., Cerasi, E., 1997. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 20, 1353–1356. Jessen, L.R., Sørensen, T.M., Bjornvad, C.R., Nielsen, S.S., Guardabassi, L., 2015. Effect of antibiotic treatment in canine and feline urinary tract infections: A systematic review. The Veterinary Journal. The Veterinary Journal 203, 270–277. Marshall, R.D., Rand, J.S., Morton, J.M., 2008. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. Journal of Veterinary Pharmacology and Therapeutics 31, 205–212. Reeves, B.C., Deeks, J.J., Higgins, J.P.T., Wells, G.A., 2008. Including non-randomized studies. In: Cochrane Handbook for Systematic Reviews of Interventions. (Chapter 13)