Diabetes mellitus is one of the most commonly encountered endocrine diseases in cats, with a prevalence of 1 in 230 in an insured population.1 Predisposing factors, such as male sex, obesity, indoor confinement, and physical inactivity, contribute to the development of the disease.1,2 Pathophysiologic features of diabetes and treatment options for affected cats have been reported frequently, but only few studies3–5 address life expectancy and prognostic factors of the disease.
On the basis of currently available literature, median survival time after diagnosis seems to vary widely in cats. In a recent study,3 median survival time of diabetic cats was 13 months, whereas it was 20 and 29 months in 2 previous investigations.4,5 Mortality rate was high soon after diagnosis, with 11% and 12% of cats dying within 3 weeks after diagnosis or not surviving to discharge from first hospitalization, respectively.4,5 Among prognostic factors, older age was negatively associated with survival time,4 whereas body weight, sex, ketonuria, and glycemic control were not.4,5 Furthermore, presence of pancreatitis and a greater amount of amyloid deposition in the islets, determined on the basis of postmortem histologic diagnosis, were not associated with shorter survival times.5 In previous reports,4,5 however, comprehensive analysis of medical records, including data for signalment, history, hematologic and serum biochemical findings, information pertaining to presence of concurrent diseases or ketoacidosis (ie, metabolic acidosis and ketonuria), clinical remission of diabetes, and type of insulin administered, were often missing. All these factors may affect survival times of diabetic cats.
Detailed data about outcome and prognostic factors of diabetes mellitus in cats would help a veterinarian to better characterize the disease and, possibly, increase owners' willingness to accept treatment for their cat and maintain compliance. Hence, the purpose of the study reported here was to assess survival time and prognostic factors in a large population of cats with newly diagnosed diabetes mellitus.
Materials and Methods
Selection of cases—Medical records of all diabetic cats admitted to the Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich (Switzerland), between January 2000 and July 2009 were reviewed. Cats were included in the study if they had newly diagnosed diabetes mellitus, had not been treated for diabetes, and had follow-up examinations at the same institution until death or until the last reevaluation for which records were available. Cats were excluded if, at diagnosis, the owners denied a comprehensive diagnostic evaluation and hospitalization or if the cats were referred and previously treated by private practitioners.
Medical records review—From all records, information obtained at the time of diagnosis was retrieved pertaining to history (including administration of corticosteroids and progestogens in the previous 6 months), signalment, physical examination findings, and hematologic results. Ketoacidosis and any concurrent disease diagnosed at initial evaluation were recorded. The type of insulin administered after discharge was also recorded.
Also retrieved from records for each cat's follow-up period were the number of diabetic cats that achieved clinical remission (ie, insulin was no longer required to maintain normoglycemia) and the duration of clinical remission. Similar to previous studies, only cats that did not need insulin for at least 4 consecutive weeks were considered to be in remission.6,7 As a standard procedure at our institution, all diabetic cats had been reassessed at 1, 2 to 3, 4 to 6, and 8 to 12 weeks and at 6 months following discharge and had been reassessed every 3 to 6 months thereafter, regardless of remission. Additional evaluations had been planned according to individual needs.
Statistical analysis—The Kaplan-Meier product-limit method was used to estimate the median survival time of diabetic cats. The following variables were investigated to determine their association with overall survival time, which was defined as time from diagnosis to death: previous administration of corticosteroids and progestogens, age, sex (male or female), breed (purebred or crossbred), body weight, Hct, WBC count, serum concentrations of glucose, fructosamine, albumin, total protein, creatinine, urea, potassium, cholesterol, and bilirubin, serum activity of lipase, and the presence of ketoacidosis or concurrent diseases. The type of insulin administered, either porcine insulin zinc suspensiona or insulin glargine,b was also included in the analysis. The association of these variables with diabetes was preliminarily assessed by use of univariate Cox proportional hazard models, assuming linearity between the variable and the hazard for continuous variables. Variables that yielded values of P < 0.20 via univariate analysis or that were arbitrarily considered of clinical importance (ie, body weight, Hct, serum glucose concentration, and serum fructosamine concentration) or that could act as a confounder (ie, age) were entered in the multivariable Cox proportional hazard model. The selection of a parsimonious model that described the relevant prognostic factor was based on the stepwise deletion of variables from this full model, guided by the Akaike information criterion.8 In the model-building process, the selection of variables that were strongly collinear (eg, creatinine and urea concentrations) was also considered. A complete casewise deletion of observations with missing values was performed (ie, 4 observations for the final model). Linearity was assumed for the continuous predictors, and the study of the martingale residuals did not contradict this assumption. The assumption of proportional hazards was tested by use of the graphical and weighted residual method of Grambsch and Therneau.9 Additivity was also assumed, and the interaction among variables was not considered. Hazard ratios and 95% CIs were calculated. Cats had censored survival time if alive by the end of the study or lost to follow-up. Statistical analysis was conducted with software packages.c,d For final comparisons, a value of P < 0.05 was considered significant.
Results
Cats—Of the 275 diabetic cats admitted during the study period, 149 were excluded because the diagnosis had been made previously and they had been treated by private practitioners, and 12 were excluded because owners denied permission for a comprehensive diagnostic evaluation and hospitalization. One hundred fourteen diabetic cats met the inclusion criteria and were used in the analysis; characteristics of the cat population were summarized (Table 1). Seventy-seven of the 114 (67.5%) cats were neutered males, and 37 (32.5%) were spayed females. Seventy-seven of 106 (72.6%) cats for which information was available were crossbred domestic shorthairs or domestic longhairs, and 29 (27.4%) were purebred, including 5 each of Maine Coon, Persian, and Siamese; 3 each of Burmese and Chartreux; 2 Birman; and 1 each of Abyssinian, Havana Brown, Norwegian Forest, Oriental shorthair, Ragdoll, and Russian Blue. Breed was not recorded in 8 cats. Median age at diagnosis was 11 years (range, 2 to 18 years). Median body weight was 5.0 kg (11.0 lb); body weight was not available in 1 cat. Corticosteroids or progestogens had been administered to 11 cats and up to 4 months prior to admission.
Descriptive statistics of continuous variables in 114 cats with newly diagnosed diabetes mellitus.
| Variable | Mean | Median (range) | Interquartile range | Reference range |
|---|---|---|---|---|
| Age (y) | 10.6 | 11 (2–18) | 9–13 | — |
| Body weight (kg) | 5.4 | 5.0 (2.5–11.3) | 4.1–6.2 | — |
| Hct (%) | 36.1 | 36.0 (23.0–54.0) | 31.5–39.5 | 33–45 |
| WBC count (WBCs/ul) | 15,193 | 12,450 (3,700–54,500) | 8,725–17,775 | 4,600–12,800 |
| Glucose (mg/dL) | 445 | 427 (243–1,260) | 363–498 | 90–180 |
| Fructosamine (μmol/L) | 608 | 612(371–984) | 526–688 | 200–340 |
| Albumin (g/L) | 34 | 35 (19–44) | 32–38 | 30–40 |
| Total protein (g/L) | 74 | 74 (47–95) | 69–79 | 64–80 |
| Creatinine (mg/dL) | 1.5 | 1.2 (0.4–9.6) | 1.0–1.6 | 1.1–1.7 |
| Urea (mg/dL) | 36 | 28 (12–151) | 20–40 | 21–35 |
| Potassium (mEq/L) | 4.6 | 4.8 (2.0–6.6) | 4.0–5.2 | 3.8–5.4 |
| Cholesterol (mg/dL) | 278 | 258 (89–640) | 200–328 | 100–263 |
| Bilirubin (mg/dL) | 1.6 | 0.2 (0.0–24.1) | 0.1–0.8 | < 0.2 |
| Lipase activity (U/L) | 64 | 36 (1–569) | 21–61 | 8–26 |
— = Not reported.
At the time of diagnosis, median serum glucose concentration was 427 mg/dL and median fructosamine concentration was 612 μmol/L. Ketoacidosis was diagnosed in 39 (34.2%) cats. Concurrent diseases were documented in 51 (44.7%) cats, including 6 each with cholangitis or lung disease; 5 with suspected pancreatitis; 4 each with cystitis or renal failure; 3 each with hypertrophic cardiomyopathy, skin disease, or stomatitis; 2 each with FIV, inflammatory bowel disease, or lymphoma; and 1 each with acromegaly, bone fracture, epilepsy, histiocytosis, hyperthyroidism, idiopathic hypercalcemia, idiopathic myopathy, megacolon, polyneuropathy, dermatophytic pseudomycetoma, or pure RBC aplasia.
Of the 114 diabetic cats, 95 (83.3%) survived to discharge and 19 (16.7%) died during hospitalization. With regard to treatment, in the former group, 39 (41.9%) cats received insulin glargine and 54 (58.1%) received porcine insulin zinc suspension; in 2 cats, the type of insulin was unknown. In the latter group, 12 cats received regular insulin because of ketoacidosis. Seven additional cats (without ketoacidosis) died before discharge; 2 of them received insulin glargine or lente insulin, and 5 died before insulin treatment. Additional treatment was administered to treat concurrent diseases.
During follow-up, ketoacidosis developed in 6 (6.3%) of the cats that were discharged; ketoacidosis had also been diagnosed in 3 of these cats at initial examination, and this was the first episode in the other 3. One cat, in which this was the first episode, survived, whereas the remaining 5 cats died or were euthanized after 1 to 8 days.
Survival analysis—Of the 114 diabetic cats, by the end of the study, 59 (51.8%) had died, and the remaining 55 (48.2%) were alive or lost to follow-up (censored survival time). In the former group, necropsy results were available from 31 cats. Regarding histopathologic diagnoses, 7 cats had hepatic lipidosis; 5 had nephritis; 2 each had cholangitis, gastric ulcers, hypertrophic cardiomyopathy, or pancreatitis; and 1 each had acromegaly, bronchitis, bronchial carcinoma, duodenal carcinoma, encephalitis, inflammatory bowel disease, lymphoma, meningioma, pituitary-dependent hyperadrenocorticism, pancreatic carcinoma, or squamous cell carcinoma. With regard to the pancreatic islets, 20 of the 31 (64.5%) cats had amyloid deposits, and 25 (80.6%) had a decreased number of islet cells. Median survival time (from time of diagnosis) of the 114 diabetic cats was 516 days (range, 1 to 3,468 days); 70% lived > 3 months, 64% > 6 months, 59% > 1 year, and 46% > 2 years (Figure 1). Several factors recorded at the time of diagnosis were associated with decreased survival time via univariate analysis, including serum concentrations of creatinine, urea, and bilirubin; serum activity of lipase; and presence of concurrent disease (Table 2). According to the multivariable Cox proportional hazard model that was selected, the expected adjusted hazard of dying (P < 0.001) was approximately 5% greater for each increase of 10 μg/dL in serum creatinine concentration (HR, 1.005; 95% CI, 1.003 to 1.007; Figure 2); of the 112 cats with available data for creatinine concentration at diagnosis, 19 (17.0%) had increased serum creatinine concentrations. In addition, cats with concurrent diseases were expected to have a mortality rate approximately 70% greater than those without concurrent diseases (HR, 1.67; 95% CI, 0.98 to 2.92), although significance (P = 0.058) was not reached. Factors such as sex; breed; body weight; previous administration of corticosteroids or progestogens; Hct; WBC count; serum concentrations of glucose, fructosamine, albumin, total protein, urea, potassium, cholesterol, and bilirubin; serum activity of lipase; type of insulin; and presence of ketoacidosis were not associated with survival time. Of note, 32% of cats with ketoacidosis survived > 3 years.
Kaplan-Meier analysis of overall median (solid line) and range (dashed lines) survival time of 114 cats with newly diagnosed diabetes mellitus.
Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.91
Kaplan-Meier analysis of overall median (solid line) and range (dashed lines) survival time of 114 cats with newly diagnosed diabetes mellitus.
Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.91
Kaplan-Meier analysis of overall median (solid line) and range (dashed lines) survival time of 114 cats with newly diagnosed diabetes mellitus.
Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.91
Results of univariate analysis of factors potentially associated with survival time (days) in cats with newly diagnosed diabetes mellitus.
| Variable | Median survival time (d) | HR (95% CI) | P value* |
|---|---|---|---|
| Age | — | 0.95 (0.88–1.04) | 0.266 |
| Sex (female vs male) | 516 vs 1,430 | 0.98 (0.55–1.76) | 0.950 |
| Breed (crossbred vs purebred) | 913 vs 1,643 | 0.78 (0.40–1.51) | 0.463 |
| Body weight | — | 0.94 (0.78–1.13) | 0.495 |
| Previous administration of corticosteroids or | 516 vs NA | 1.36 (0.54–3.44) | 0.520 |
| progestogens (administered vs not administered) | |||
| Hct | — | 0.97 (0.93–1.02) | 0.225 |
| WBC count | — | 1.00 (1.00–1.00) | 0.912 |
| Glucose | — | 1.01 (0.98–1.04) | 0.478 |
| Fructosamine | — | 1.00 (1.00–1.00) | 0.419 |
| Albumin | — | 0.99 (0.93–1.05) | 0.710 |
| Total protein | — | 1.00 (0.97–1.03) | 0.836 |
| Creatinine | — | 1.004 (1.002–1.007) | 0.000 |
| Urea | — | 1.05 (1.02–1.07) | 0.000 |
| Potassium | — | 0.92 (0.67–1.25) | 0.577 |
| Cholesterol | — | 1.03 (0.94–1.13) | 0.561 |
| Bilirubin | — | 1.01 (1.00–1.01) | 0.001 |
| Lipase activity | — | 1.00 (1.00–1.00) | 0.020 |
| Ketoacidosis (presence vs absence) | 516 vs 1,170 | 1.02 (0.59–1.78) | 0.932 |
| Concurrent disease (absence vs presence) | 913 vs 173 | 1.87 (1.11–3.14) | 0.017 |
| Insulin type (insulin zinc vs insulin glargine) | 1,140 vs 1,005 | 1.26 (0.58–2.74) | 0.561 |
Wald test.
— = Not applicable. HR = Hazard ratio. NA = Not available.
Expected survival times associated with various calculated serum creatinine concentrations (mmol/L) in cats with diabetes mellitus, as determined with a Cox proportional hazard model. Survival time has been truncated at 1,750 days.
Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.91
Expected survival times associated with various calculated serum creatinine concentrations (mmol/L) in cats with diabetes mellitus, as determined with a Cox proportional hazard model. Survival time has been truncated at 1,750 days.
Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.91
Expected survival times associated with various calculated serum creatinine concentrations (mmol/L) in cats with diabetes mellitus, as determined with a Cox proportional hazard model. Survival time has been truncated at 1,750 days.
Citation: Journal of the American Veterinary Medical Association 243, 1; 10.2460/javma.243.1.91
Diabetic cats with clinical remission—Forty-five of the 114 (39.5%) diabetic cats achieved clinical remission. By the end of the study, median remission duration was 114 days (range, 30 to 3,370 days) in cats that had follow-up until death (n = 15) and 151 days (range, 28 to 1,180 days) in cats that were still alive or lost to follow-up (30).
Considering the 59 diabetic cats that had follow-up until death, median survival time of those with clinical remission (n = 15) was 913 days (range, 35 to 3,468 days), and median survival time of those that did not achieve clinical remission (44) was 25 days (range, 1 to 1,470 days). In the remaining 55 diabetic cats that were still alive or lost to follow-up, median survival time of those with clinical remission (n = 30) was 244 days (range, 67 to 1,370 days), and median survival time of those that did not achieve clinical remission (25) was 118 days (range, 30 to 1,811 days).
Discussion
Results of the present study indicated that diabetic cats had a fairly good prognosis. Survival time was shorter with each incremental increase in serum creatinine concentration. In particular, in the present series, mortality rate of diabetic cats during the first 10 days from diagnosis was 16.7%. This frequency was moderately high but similar to 2 previous investigations in which case fatality rate was 11% in the first 3 weeks4 and 12% during the first hospitalization period.5
Overall median survival time in the group of diabetic cats analyzed here was 516 days, with 59% living > 1 year and 46% > 2 years. Kraus et al4 reported a longer median survival time of 870 days. The discrepancy between studies may be attributable to the fact that, in the study by Kraus et al,4 second-opinion cases that had been treated before starting calculation of survival time were also included; thus, the estimated survival time may have been biased toward longer survival time by the exclusion of cats that died soon after diagnosis. Goossens et al5 calculated median survival time as the time after the first period of hospitalization, yielding 780 days. Cats that died during the first period of hospitalization might have been excluded, making it difficult to compare that investigation with the present study.
With regard to prognostic factors, an interesting finding was that greater creatinine concentration at diagnosis was significantly associated with shorter survival time, with a hazard of dying approximately 5% greater for each increase of 10 μg/dL in serum concentration. This finding may be explained by the fact that greater azotemia is associated with faster progression of renal dysfunction in cats, in turn leading to decreased survival time.10,11 Of note, 17.0% of diabetic cats had increased serum creatinine concentrations, and in most cases, the concentrations were only mildly increased. However, it is possible that polyuria and reduced muscle mass caused by diabetes decreased the serum creatinine concentration so that renal dysfunction was not apparent in some cats.
The presence of concurrent illness was associated with decreased survival time in univariate analysis but not in multivariate analysis, although the P value approached significance (P = 0.058). This possible association might be attributed to increased insulin resistance induced by the concurrent disease, the direct association between the concurrent disease and an unfavorable outcome, and decreased willingness of owners to pursue treatment. No study has been performed to systematically assess whether concurrent diseases affect survival time. In a large group of diabetic cats, Goossens et al5 found that the presence of pancreatic disease was not a negative prognostic factor, but the observation was based on necropsy results and not on results obtained at the time of diagnosis.5
Ketoacidosis is a severe complication of diabetes and was present in 34.2% of cats at the time of diagnosis, which was in agreement with a recent investigation12 that found a rate of approximately 40%. The metabolic derangements associated with this complication and its difficult management often lead practitioners to consider ketoacidosis as being associated with an unfavorable outcome. However, on the basis of the present results, ketoacidosis should not necessarily be considered a negative outcome predictor. Importantly, 32% of cats that had ketoacidosis survived > 3 years. Thus, treatment of diabetic cats with ketoacidosis should always be pursued. In support of the favorable outcome of cats with ketoacidosis, recent reports7,13 indicate that clinical remission of diabetes is possible in 50% of cases, irrespective of the complication.
In the present study, cats that achieved clinical remission of diabetes mellitus had longer median survival time than cats that were persistently diabetic. One reason for this finding might be that a diabetic cat that does not need insulin to control blood glucose concentration (ie, in remission) is expected to have a better quality of life and fewer complications (eg, hepatic lipidosis, urinary tract infection, or neuropathy) than cats without remission. It is also likely that owners of diabetic cats, if clinical remission has occurred, are more likely to closely monitor their pets and continue with investigations and treatments if additional disorders develop.
This study did have some limitations. Because of its retrospective nature, incomplete records were occasionally present. For instance, in some cases, it was unclear whether the owner chose euthanasia or the cat died spontaneously. This ambiguity may have partly biased the analysis. Furthermore, information on diet was not always provided, and many cats were fed different commercial or homemade foods. Therefore, this variable could not be included in the survival calculation.
Cats with newly diagnosed diabetes mellitus had a fairly good prognosis. At diagnosis, greater serum creatinine concentration was associated with decreased survival time, and the presence of concurrent diseases might also be associated with decreased survival time. Ketoacidosis may not represent a negative prognostic factor. Diabetic cats in remission had greater survival time, compared with cats in which remission was not achieved.
ABBREVIATIONS
| CI | Confidence interval |
Caninsulin, Intervet International BV, Boxmeer, The Netherlands.
Lantus, Sanofi Aventis (Suisse) SA, Meyrin, Switzerland.
A package for survival analysis in S, R package, version 2. 36-14, Terry Therneau, Rochester, Minn. Available at: cran.r-project.org/web/packages/survival/index.html. Accessed Sep 4, 2012.
R, version 2.15.1, R Foundation for Statistical Computing, Vienna, Austria. Available at: www.R-project.org/. Accessed Sep 4, 2012.
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