Introduction
Diabetes mellitus occurs in approximately 0.3% to 1.5% of dogs.1,2 From 2006 to 2015, the reported prevalence of diabetes mellitus in dogs increased from 13.1 cases/10,000 to 23.6 cases/10,000 (79.7%).3 Most commonly, it is due to immune-mediated destruction of beta cells (type 1) or other specific types of diseases such as pancreatitis, hyperadrenocorticism, acromegaly, or diestrus associated.4 Diabetic dogs usually require twice-daily insulin administration to achieve adequate glycemic control. Typically, dogs are treated with intermediate-acting insulins such as neutral protamine Hagedorn (NPH) or porcine lente.5 Reported average duration of action in diabetic dogs for NPH is 6 to 10 hours, with a time to peak action between 2 to 8 hours.6–9 Porcine lente has an average duration of action of 8 to 16 hours, with a time to peak action between 4 to 6 hours.7–9
In some dogs, achieving good glycemic control is difficult, and they continue to experience persistent hyperglycemia despite adequate insulin doses or have marked fluctuations in blood glucose concentrations, including hypoglycemia.5,8 In some of these dogs, the cause of poor glycemic control may not be clear, but others have poor control due to insulin resistance associated with comorbidities or they have inadequate duration of insulin action. Poor glycemic control as a result of insulin resistance may occur secondary to an increase in insulin antagonistic hormones associated with growth hormone excess in diestrus-associated diabetes, acromegaly, or excess exogenous progestogens; glucocorticoid excess in spontaneous hyperadrenocorticism or excess exogenous glucocorticoids; or inflammation.10–15 Poor glycemic control may occur in some diabetic dogs due to inadequate duration of action of insulin, especially when intermediate-acting insulin is used. In many diabetic dogs, NPH and lente insulin have adequate duration of action (≥ 12 hours), but in some dogs, duration is less than 8 to 10 hours, resulting in daily periods of hyperglycemia despite appropriate nadir glucose concentrations.5,8 Inadequate glycemic control causes persistent polydipsia, polyuria, polyphagia, weight loss, cataract formation leading to blindness, and lens-induced uveitis.16,17 It also increases the risk of euthanasia. In a study18 evaluating diabetic pets euthanized after being diagnosed with diabetes, 35% were euthanized due to inadequate glycemic control and persistence of diabetic signs.
In diabetic dogs poorly controlled by intermediate-acting insulin, especially when inadequate duration of action is suspected or documented, long-acting insulins are an alternative. These include protamine zinc insulin and glargine. Protamine zinc insulin was reported to provide adequate glycemic control in 82% (14/17) of diabetic dogs in 1 study.19 Glargine was evaluated in 2 studies involving newly diagnosed diabetic dogs and previously treated, poorly controlled diabetic dogs. Treatment resulted in good glycemic control in 58% of patients in 1 study,20 and 100% were well controlled by a mean of 38 days in a later study.21 Detemir is a basal synthetic long-acting insulin analog used in humans with diabetes. It reversibly binds to albumin, slowing absorption and providing a prolonged and consistent metabolic effect for up to 24 hours.22 In dogs, detemir is 4 times more potent than NPH and porcine lente.23,24 It also has a slow onset of action (2 to 11 hours), with peak effects occurring at 8 to 10 hours.23,24
The authors are only aware of 2 studies in which detemir was used involving 5 and 10 newly diagnosed diabetic dogs without concomitant disease that were treated for up to 6 months23 and 21 days,24 respectively. Twice-daily administration was used, and the authors reported that lower doses were required to maintain glycemic control and prevent hypoglycemia than with other insulins. To our knowledge, there are no studies reporting use of detemir in poorly controlled diabetic dogs with concurrent diseases, and therefore the purpose of our study was to report the use of detemir in this cohort of diabetic dogs that were poorly controlled with intermediate-acting insulins.
Materials and Methods
Inclusion criteria
Medical records from client-owned diabetic dogs with poor diabetic regulation were collected from VCA Emergency Animal Hospital and Referral Center in San Diego and Tatum Point Animal Hospital from 2005 to 2009 and from BluePearl Pet hospital in Scottsdale, Arizona from 2018 to 2019. For study inclusion, medical records were reviewed for patients with evidence of poor diabetic regulation (persistent hyperglycemia, polyuria, polydipsia, weight loss, polyphagia, anorexia, and/or vision loss) and documentation of a change to detemir. Dogs previously treated with glucocorticoids were also included, and 17 diabetic dogs met the inclusion criteria. Newly diagnosed diabetic dogs without previous insulin therapy (n = 3) were excluded from the study, as were patients that received regular insulin or intermediate-acting insulin concurrently with detemir (n = 4). Patients with insufficient data or poor owner compliance were also excluded (n = 3).
Glycemic control
Glycemic control was assessed as the proportion of days in each month that mean glucose concentration was in 1 of the 3 categories of glycemic control (good, < 13.9 mmol/L [< 250 mg/dL]; moderate, 13.9 to 19.4 mmol/L [250 to 350 mg/dL]; and poor, > 19.4 mmol/L [> 350 mg/dL]).
Insulin treatment
Treatment with detemir was started on the day of presentation at the referral clinic (day 1). The veterinarian determined the detemir dose after reviewing the patient history, including dose of current insulin, and results of the physical examination, body weight, and blood glucose concentrations measured on day 0. If blood glucose was between 6.7 to 11 mmol/L (120 to 199 mg/dL), the starting detemir dose was one-fourth the previous insulin dose of intermediate-acting insulin. Initial detemir dose was then adjusted using an insulin dosage chart depending on the blood glucose and the amount of food eaten (Appendix 1). In general, insulin was increased when preinsulin blood glucose was 11.1 mmol/L (200 mg/dL) or higher, with larger dose increases at higher blood glucose concentrations. If blood glucose was < 6.7 mmol/L (120 mg/dL), insulin was withheld and blood glucose measured 1 hour after feeding and insulin then dosed according to the chart. Insulin dose was halved if the dogs ate < 50% of their meal. An initial insulin dosing chart was provided to owners.
Diet
Diet at entry into the study was determined by the owner and veterinarian. There was no standardized diet for the patients in this study. However, all owners were encouraged to feed a prescription diet formulated for canine diabetes unless there was a concurrent disease for which a more appropriate diet was indicated. Diets fed to patients included the following: Hill’s i/d, Royal Canin Gastrointestinal low fat, Purina DCO (Société des Produits Nestlé SA), Hill’s r/d, Crave dog food (Mars), and a home-cooked low-carbohydrate diet. Owners were asked to divide the daily caloric intake in half and feed one-half each time detemir was administered.
Monitoring by owner
Blood glucose concentrations were measured by the owner at home using a handheld blood glucose meter calibrated for dogs (AlphaTRAK blood glucose monitoring system; Zoetis Services LLC) at approximately 12-hour intervals, immediately prior to insulin administration (preinsulin) and feeding, with additional measurements optional at midday and bedtime. Owners were provided with a diary to record daily blood glucose concentrations and dose of detemir administered and the respective times. Adverse events and health-related problems such as lethargy, weakness, inappetence, vomiting, and inappropriate urination were also recorded. Owners performed blood glucose measurements at home with 2 to 4 measurements/day for the first 6 to 8 weeks as dose was adjusted in the initial stabilization period, and twice daily thereafter. The blood glucose log was collected and reviewed at each visit and a new blood glucose log provided to the owner.
In-hospital monitoring
Dogs were evaluated by the veterinarian every 7 to 14 days for the first 30 days and every 90 days thereafter. The blood glucose and dosing log was reviewed, and a history was obtained, including the owner’s perception of changes (increased, decreased, or no change) in their dog’s frequency of urination, water consumption, and appetite compared to the previous visit, as well as any adverse events they had observed. At each visit, a complete physical examination was performed and abnormalities and body weight documented. Results of blood and urine analysis for hematology, serum biochemistry, serum fructosamine concentration, and urinalysis were reviewed.
In addition to the insulin dose adjustments based on the insulin dosing chart provided to the owners, adjustments in insulin dose were at the veterinarian’s discretion based on the owner’s perception of presence and severity of clinical signs of diabetes, the results of the physical examination, change in body weight, and home blood glucose measurements and previous response to insulin dose. Insulin dose was adjusted by the veterinarian (SLF) to maintain blood glucose concentration between 4.4 mmol/L (80 mg/dL) and 16.7 mmol/L (300 mg/dL) and the blood glucose nadir between 4.4 mmol/L (80 mg/dL) and 8.3 mmol/L (150 mg/dL).
Statistical analysis
All analyses were performed using SAS version 9.4 (SAS Institute Inc). A significance threshold of 0.05 was used.
Linear mixed models (LMMs) were used to compare daily mean, peak, nadir, and preinsulin morning (AM) and evening (PM) blood glucose concentrations obtained during the last month of treatment with the shorter-acting insulin(s) to those obtained during the first, third, and sixth months of treatment with detemir. The models included a single fixed factor for insulin per month. Similarly, LMMs were used to compare glucose concentrations obtained during the last month of treatment with the shorter-acting insulin(s) to the last month of treatment with detemir.
When detemir was withheld because preinsulin blood glucose concentration in the morning or evening was < 6.7 mmol/L (< 120 mg/dL), LMMs were also used to compare between preinsulin, 1-hour, and 12-hour (next preinsulin) blood glucose concentrations on days insulin was withheld for either 1 or 12 hours. Dogs with blood glucose concentrations for preinsulin and 12 hours (missing value for 1 hour) were only included in the analysis of preinsulin versus 12 hours. Similarly, dogs with a preinsulin, 1-hour, and missing 12-hour blood glucose concentration were only included in the analysis of preinsulin versus 1 hour. Glucose concentrations were averaged for each dog first and then over dogs to obtain the reported concentrations.
Generalized LMMs were used to compare odds of glucose being controlled or having a biochemical hypoglycemic event during the last month of the shorter-acting insulin to the first, third, sixth, and last month of detemir. For control, a multinomial distribution with a cumulative logit link function was assumed. For hypoglycemic event, a binomial distribution with a logit link function was assumed.
All LMMs and generalized LMMs had random intercepts for each dog to account for within dog correlation of glucose levels. Histograms and Q-Q plots of LMM conditional model residuals were examined to evaluate the assumption of normality. Plots of LMM conditional residuals versus predicted values of measurements were examined to evaluate the assumption of homogeneity of variances.
Data were averaged by insulin per month by dog for descriptive statistics and graphs. Histograms and Q-Q plots for each insulin per month were examined and confirmed the assumption of normality of daily mean, peak, nadir, and preinsulin AM and PM blood glucose values. Mean, median, SD, minimum, and maximum were reported.
Results
Study animals
Seven diabetic dogs (2 spayed females and 5 neutered males) met the inclusion criteria of a history of poor glycemic control with intermediate-acting insulins such as NPH and porcine lente insulin and were subsequently changed to detemir insulin. Dogs were determined to have poor glycemic control on the basis of the presence of polyuria, polydipsia, persistent hyperglycemia (peak blood glucose > 19.4 mmol/L [> 350 mg/dL] based on home monitoring), and glucosuria, with or without polyphagia or anorexia, despite insulin being administered for a minimum of 4 weeks at appropriate doses (0.5 U/kg, q 12 h, in 5/7 dogs and 0.36 U/kg, q 12 h in 2/7 dogs; Appendix 2). Dogs were a variety of breeds. Age ranged from 7.5 to 16 years (median, 10 years), and median body weight was 23 kg (range, 5.6 to 43.8 kg). All study dogs had concurrent diseases, which included the following: chronic pancreatitis (n = 3) diagnosed via ultrasound or canine pancreas-specific lipase, suspected inflammatory bowel disease (1), cholangiohepatopathy (2), hyperlipidemia (1), osteoarthritis (3), urinary tract infection (2) (chronic recurrent, 1; acute, 1), hypothyroidism (1), pituitary-dependent hyperadrenocorticism (1), neoplasia (1) (anal sac adenocarcinoma with metastasis), and chronic intervertebral disc disease (IVDD; 1). One patient was euthanized at 4 months after being started on detemir because of metastatic anal sac carcinoma and was the only dog that did not have 6 months of data. Age at diagnosis, signalment, duration and dose of initial insulin, persistent clinical signs, and concurrent diseases for the 7 dogs are shown (Appendix 2).
Insulin treatment
After initial diagnosis of diabetes, dogs were started on NPH (n = 6) and porcine lente insulin (1), and 1 dog was initially placed on NPH for 18 weeks but switched to porcine lente insulin. Two diabetic dogs were initially placed on porcine lente insulin and then changed to NPH. Data from both insulins were included in the evaluation for both dogs. Median dose immediately prior to the change to detemir was 0.69 U/kg (range, 0.37 to 1.2 U/kg) twice daily. Median duration of treatment with intermediate-acting insulin was 17 weeks (mean, 48 weeks; range, 4 to 154 weeks). Patient’s insulin therapy was changed to detemir because of an inadequate glucose lowering effect (n = 4) or short duration of action (3). At the time of change to detemir, clinical signs such as polyuria (n = 6), polydipsia (6), polyphagia (5), anorexia/weight loss (3), lethargy, weakness, inappetence, and vision loss were present despite previous insulin therapy (Appendix 2). The median initial detemir insulin dose was 0.2 U/kg (range, 0.09 to 0.74 U/kg) twice daily. Data were available for a median of 14 months (average, 17 months; range, 4 to 51 months) during treatment with detemir. Median insulin dose of detemir in the final month of treatment was 0.33 U/kg (range, 0.017 to 1.1 U/kg).
Mean, peak, nadir, and preinsulin glucose concentrations
Mean, peak, and nadir blood glucose concentrations were all significantly lower after dosing with detemir for 1, 3, or 6 months and during the last month of treatment for which data were available, compared with concentrations during the last month of dosing with an intermediate-acting insulin (P values from .021 to < .0001; Table 1; Figures 1 and 2). For example, mean blood glucose concentrations after 1, 3, and 6 months of treatment with detemir were 16.8, 16.3, and 16.9 mmol/L (302, 294, and 305 mg/dL) compared to the mean during intermediate-acting insulin treatment of 21.8 mmol/L (393 mg/dL; P values from .024 to < .001. However, there were no significant differences between the mean blood glucose concentrations with detemir between months 1, 3, or 6 (P > .3). Morning and evening preinsulin daily blood glucose concentrations were also significantly lower (P values from .006 to < .0001) after dosing with detemir for 1, 3, or 6 months (evening mean 16.7, 16.0, and 16.6 mmol/L [301, 288, and 299 mg/dL], respectively) than during dosing with an intermediate-acting insulin (evening 22.7 mmol/L [409 mg/dL]). Evening preinsulin daily blood glucose concentrations (P < .0001) were also significantly lower during the last month of detemir administration than during last month with an intermediate-acting insulin. Nadir blood glucose concentration for the intermediate-acting insulin (mean, 17.5 mmol/L [316 mg/dL]) was significantly higher than detemir at month 1, 3, or 6 or the last month (mean, 12.9, 12.0, 12.8, and 12.0 mmol/L [232, 216, 230, and 217 mg/dL]; P values from .0003 to .017), but there were no significant differences between months 1, 3, or 6 (P > .2).
Mean, median, SD, minimum, and maximum blood glucose concentrations for mean, peak, nadir, and morning and evening preinsulin in 7 diabetic dogs with comorbidities and poor glycemic control that were previously treated with intermediate-acting insulin and then switched to detemir. Data shown for last month on intermediate-acting insulin and for months 1, 3, 6 and last month on detemir.
| N | Mean | Median | SD | Minimum | Maximum | P value | |
|---|---|---|---|---|---|---|---|
| Mean glucose | |||||||
| Intermediate-acting insulin last month | 7 | 393a | 373 | 78 | 285 | 506 | |
| Detemir 1 month | 7 | 302b | 274 | 88 | 252 | 499 | .0001 |
| Detemir 3 month | 7 | 294b | 299 | 71 | 201 | 415 | .0001 |
| Detemir 6 month | 6 | 305b | 308 | 74 | 183 | 390 | .0001 |
| Detemir last month | 7 | 301b | 318 | 85 | 151 | 383 | .017 |
| Peak glucose | |||||||
| Intermediate-acting insulin last month | 7 | 476a | 434 | 396 | 582 | ||
| Detemir 1 month | 7 | 381b | 348 | 303 | 588 | .0006 | |
| Detemir 3 month | 7 | 379b | 387 | 284 | 516 | .0003 | |
| Detemir 6 month | 6 | 377b | 372 | 216 | 491 | .0001 | |
| Detemir last month | 7 | 385b | 414 | 198 | 485 | .14 | |
| Nadir glucose | |||||||
| Intermediate-acting insulin last month | 7 | 316a | 317 | 75.0 | 203 | 419 | |
| Detemir 1 month | 7 | 232b | 208 | 83 | 162 | 410 | .0001 |
| Detemir 3 month | 7 | 216b | 209 | 69 | 114 | 310 | .0001 |
| Detemir 6 month | 6 | 2311b | 228 | 53 | 152 | 290 | .0001 |
| Detemir last month | 7 | 217b | 223 | 74 | 102 | 323 | .0006 |
| Preinsulin glucose in AM | |||||||
| Intermediate-acting insulin last month | 7 | 381a | 370 | 60 | 308 | 464 | |
| Detemir 1 month | 7 | 285b | 263 | 63 | 249 | 425 | .0003 |
| Detemir 3 month | 7 | 280b | 319 | 65 | 187 | 344 | < .0001 |
| Detemir 6 month | 6 | 305b | 305 | 87 | 169 | 435 | .006 |
| Detemir last month | 7 | 312b | 318 | 94 | 163 | 423 | .7 |
| Preinsulin glucose in PM | |||||||
| Intermediate-acting insulin last month | 6 | 409a | 405 | 86 | 295 | 543 | |
| Detemir 1 month | 7 | 301b | 256 | 124 | 200 | 570 | .0001 |
| Detemir 3 month | 7 | 288b | 257 | 110 | 173 | 505 | .0001 |
| Detemir 6 month | 6 | 299b | 274 | 104 | 183 | 490 | .0001 |
| Detemir last month | 7 | 289b | 282 | 106 | 129 | 466 | .002 |
Blood glucose variables are for the last month of treatment with intermediate-acting insulin and 1, 3, and 6 months and the final month of treatment with detemir. Mean values that have different superscripts are significantly different. P values are for comparison with intermediate-acting insulin dose.
Mean blood glucose concentrations (+ SE) were significantly lower after dosing with detemir for 1, 3, or 6 months (P < .0001 for all) than during dosing with an intermediate-acting insulin. Mean daily blood glucose levels were also significantly lower during the last month of detemir administration than during dosing with an intermediate-acting insulin (P = .0003). There were no significant differences between mean glucose concentrations after dosing with detemir for 1, 3, or 6 months (P > .70 for all).
Citation: Journal of the American Veterinary Medical Association 261, 3; 10.2460/javma.22.09.0402
Nadir daily blood glucose levels (+ SE) were significantly lower after dosing with detemir for 1, 3, or 6 months (P < .0001 for all) and during the last month (P < .0001) than during dosing with an intermediate-acting insulin. There were no significant differences in nadir glucose concentrations after dosing with detemir for 1, 3, or 6 months (P > .30 for all).
Citation: Journal of the American Veterinary Medical Association 261, 3; 10.2460/javma.22.09.0402
Glycemic control
Intermediate-acting insulins resulted in significantly worse glycemic control than detemir based on the proportion of days that were in the 3 categories of control at month 1 (P < .0001), 3 (P < .0001), or 6 (P < .0001) or the last month (P = .024) of detemir treatment (Table 2). For example, based on the last month of data for intermediate-acting insulin, the proportion of days that mean glucose was in the good, moderate, and poor control categories was 11%, 23%, and 67% compared to the sixth month of detemir treatment when the corresponding proportions were 30%, 34%, and 36%. When glycemic control was assessed by the proportion of days in each month that the nadir glucose was in each category of glycemic control (hypoglycemia, < 3.3 mmol/L [< 60 mg/dL]; good, 3.3 to 8.3 mmol/L [60 to 150 mg/dL]; moderate, > 8.3 to 11.1 mmol/L [> 150 to 200 mg/dL]; and poor, > 11.1 mmol/L [> 200 mg/dL]), intermediate-acting insulins also had significantly worse control based on the nadir than detemir at month 1 (P = .006), 3 (P = .0003), or 6 (P = .017) or the last month (P = .0006; Table 2). For example, the proportion of nadir glucose concentrations in the respective categories in the last month of treatment with intermediate-acting insulin was 0.5%, 14%, 12%, and 74% of days compared to 1.6%, 27%, 17%, and 55% in the sixth month of detemir treatment. There were no significant differences between months 1, 3, or 6 of detemir treatment (P > .2).
Proportion of days in each month that mean and nadir glucose concentrations were in 1 of 3 categories of glycemic control.
| Insulin/mo | Control | Nadir control | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Good < 14 mmol/L (< 250 mg/dL) | Moderate 14-1.49 mmol/L (250–350 mg/dL) | Poor > 19.4 mmol/L (350 mg/dL) | Hypoglycemia < 3.3 mmol/L (60 mg/dL) | Good 3.3–8.3 mmol/L (60–150 mg/dL) | Moderate > 8.3–11 mmol/L (150–200 mg/dL) | Poor > 11 mmol/L (200 mg/dL) | ||||||||
| N | Mean | N | Mean | N | Mean | N | Mean | N | Mean | N | Mean | N | Mean | |
| Intermediate-acting insulin last mo | 7 | 11% | 7 | 23% | 7 | 67% | 7 | 0.5% | 7 | 14% | 7 | 12% | 7 | 74% |
| Detemir 1 mo | 7 | 39% | 7 | 33% | 7 | 28% | 7 | 5.7% | 7 | 24% | 7 | 15% | 7 | 56% |
| Detemir 3 mo | 7 | 36% | 7 | 34% | 7 | 30% | 7 | 2.3% | 7 | 35% | 7 | 12% | 7 | 51% |
| Detemir 6 mo | 6 | 30% | 6 | 34% | 6 | 36% | 6 | 1.6% | 6 | 27% | 6 | 17% | 6 | 55% |
| Detemir last mo | 7 | 33% | 7 | 30% | 7 | 37% | 7 | 4.8% | 7 | 30% | 7 | 17% | 7 | 49% |
Hypoglycemia
The odds of having a biochemical hypoglycemic measurement (< 3.3 mmol/L [< 60 mg/dL]) were not significantly different after month 1 (marginally significant, P = .052), 3 (P = .52), or 6 (P = .86) or the last month (P = .14) on detemir compared to the shorter-acting insulin. For example, in the last month of treatment with intermediate-acting insulin, the average number of biochemical hypoglycemic measurements (< 3.3 mmol/L [< 60 mg/dL]) was 0.1/mo compared with 0.3/mo at the sixth month of detemir treatment. There was no difference in odds of a biochemical hypoglycemic measurement with detemir treatment between 1, 3, and 6 months (P > .1). No episodes of clinical hypoglycemia were recorded following detemir treatment, and no patients had a documented history of clinical hypoglycemia when treated with intermediate-acting insulin. The average percentage of blood glucose measurements per month that were in the hypoglycemic range were higher with detemir versus intermediate-acting insulins except for the last month of detemir treatment. For example, the average percentage of biochemical hypoglycemic measurements with detemir for months 1, 3, and 6 were 2.9%, 0.9%, and 0.7%, respectively, compared to 0.1% with intermediate-acting insulins.
Effect of withholding insulin when preinsulin glucose concentration was < 6.7 mmol/L (< 120 mg/dL)
When insulin was withheld because of a low morning preinsulin blood glucose concentration (< 6.7 mmol/L [< 120 mg/dL]), dogs were fed and mean blood glucose concentrations were significantly higher 1 hour later (5.4 mmol/L [98 mg/dL] vs 13.6 mmol/L [244 mg/dL], respectively; P < .0001; Table 3). In nearly all dogs, mean blood glucose 1 hour after eating was at least double the initial blood glucose concentration (Figure 3). In addition, glucose concentrations were significantly higher 12 hours later, on days when insulin was withheld in the morning or evening for either 1 or 12 hours (P < .0001 for both). Glucose concentrations were significantly higher if insulin was withheld for 12 hours (mean, 24.5 mmol/L [442 mg/dL]) compared to 1 hour only (mean, 12.9 mmol/L [233 mg/dL]; P < .0001; Table 3) and were on average 4 times higher than initial blood glucose (Figure 4).
Mean blood glucose concentration preinsulin (morning or evening), 1 hour, and 12 hours after insulin was withheld because blood glucose concentration was < 6.7 mmol/L (< 120 mg/dL). Dogs were fed after insulin was withheld, and blood glucose measured 1 hour later. If 1 hour glucose was > 6.7 mmol/L (> 120 mg/dL), insulin was administered.
| Insulin within 12 h | Glucose concentrations preinsulin (0) and 1 hour (1) later after eating | Glucose 12 hours later when insulin was withheld at preinsulin (0) and 1 hour later (no insulin given for 12 hours), or was withheld preinsulin and given 1 hour later | ||||
|---|---|---|---|---|---|---|
| Mean glucose mmol/L (mg/dL) | Mean glucose mmol/L (mg/dL) | |||||
| N/A | N/A | Yes (insulin was given 1 h later) | No (insulin dose not given 1 h later) | |||
| Time (h) | 0 | 1 | 0 | 12 | 0 | 12 |
| N | 7 | 7 | 7 | 7 | 5 | 5 |
| Mean | 5.4 (98) | 13.5 (244) | 5.5 (99) | 12.9 (233) | 5.7 (102) | 24.5 (442) |
| Medium | 5.1 (91) | 13.1 (236) | 5.3 (95) | 11.6 (209 | 5.4 (98) | 26.3 (474) |
| SD | 0.8 (15) | 2.8 (51) | 0.8 (14) | 4 (72) | 1.4 (25) | 5.3 (96) |
| Minimum | 4.5 mmol/L (81 mg/dL) | 8.8 mmol/L (159 mg/dL) | 4.7 mmol/L (85 mg/dL) | 9.7 mmol/L (174 mg/dL) | 4.1 mmol/L (74 mg/dL) | 16.9 mmol/L (304 mg/dL) |
| Maximum | 6.7 mmol/L (120 mg/dL) | 18.2 mmol/L (328 mg/dL) | 6.5 mmol/L (118 mg/dL) | 21.3 mmol/L (384 mg/dL) | 7.8 mmol/L (140 mg/dL) | 30.5 mmol/L (550 mg/dL) |
Mean glucose concentrations when insulin was withheld in the morning because glucose concentration was < 6.7 mmol/L (< 120 mg/dL). Dogs were fed at the time insulin was withheld. Glucose concentration was significantly higher 1 hour later (P < .0001).
Citation: Journal of the American Veterinary Medical Association 261, 3; 10.2460/javma.22.09.0402
Mean glucose concentrations after 12 hours when insulin was withheld for 1 or 12 hours because preinsulin blood glucose was < 6.7 mmol/L (120 mg/dL). Glucose concentrations were significantly higher 12 hours later on days when insulin was withheld for either 1 or 12 hours (P < .0001 for both). Glucose concentrations were significantly higher if insulin was withheld 12 hours compared to for only 1 hour (P < .0001).
Citation: Journal of the American Veterinary Medical Association 261, 3; 10.2460/javma.22.09.0402
Discussion
Seven diabetic dogs with concurrent disease and poor glycemic control were evaluated after being changed from an intermediate-acting insulin to the long-acting insulin detemir. This is the first report of the use of detemir in dogs with poor diabetic regulation and concomitant disease. The most important findings were that administration of detemir improved glycemic control compared to treatment with intermediate-acting insulin and, at the doses used, did not increase the probability of hypoglycemia.
Our patients had multiple diseases that contributed to their poor glycemic control and were consistent with the reported causes of insulin resistance in diabetic dogs. For example, 1 study15 reported that hyperadrenocorticism, urinary tract infections, acute pancreatitis, neoplasia, and hypothyroidism were associated with insulin resistance. One dog in our study had chronic IVDD. Although no studies in veterinary medicine exist to demonstrate an association between IVDD and insulin resistance, in our clinical experience, IVDD is associated with a requirement for higher insulin doses to control glycemia, suggesting insulin resistance. However, there are reports that diabetes mellitus could potentially be a risk factor for IVDD disease in humans and rodents with type 2 diabetes. An experimental study in rodents showed a positive link between IVDD and type 2 diabetes mellitus.25 Also, humans with type 2 diabetes for > 10 years and who were poorly controlled were at risk for developing lumbar disc disease.26
Average dose of intermediate-acting insulin in well-controlled diabetic dogs is approximately 0.5 U/kg for porcine lente and 0.25 to 0.5 U/kg for NPH, but the dogs in our study had poor glycemic control despite a median dose of 0.7 U/kg prior to being changed to detemir.27 Although 2 dogs were on 0.4 U/kg for their final doses of intermediate-acting insulin, both dogs had poor glycemic control and were polydipsic or polyuric at that dose. Detemir is reported to be 4 times more potent on a unit basis than other insulins in dogs, and the recommended starting dose is 0.1 to 0.2 U/kg for newly diagnosed diabetics.23,24 When changing from intermediate-acting insulin to insulin detemir, the dose advised is one-fourth the dose of intermediate insulin and dosed twice daily compared to 0.25 to 0.5 U/kg twice daily for most other insulins. Dogs in our study were started on a median dose of 0.2 U/kg on the basis of their previous doses on intermediate-acting insulin, and none had clinical evidence of hypoglycemia associated with this dose.
Overall, all patients had an improvement in the mean, peak, and nadir blood glucose concentrations after being changed to detemir at 1, 3, and 6 months of treatment, compared to treatment with a previous intermediate insulin. However, no further improvement in any measure of glycemic control was observed after the first month. At the time the first 5 dogs in our study were started on detemir, there were no reports in the literature of detemir being used in diabetic dogs. Conservative dose increases were made by the clinician (SLF) because detemir is approximately 4-fold more potent in dogs than other insulins on a unit basis. In initial trials with detemir, the molar potency in humans was approximately one-fourth that of human insulin, but in dogs, detemir was found to be equipotent on a molar basis to human insulin. To maintain a similar glucose lowering effect in humans per unit of detemir compared to other human insulins, 1 unit was manufactured with 24 nmol of detemir, whereas 1 unit of human insulin consists of 6 nmol of insulin. The lower molar potency of detemir compared to human insulin is attributed to the addition of the fatty acid myristic acid, which is covalently bound to lysine and postulated to interfere with receptor binding, as well as possible differences between species in detemir’s binding to albumin, which influences its duration of action.28
Given that no clinical hypoglycemia was observed in the dogs in our study, it is recommended that, in the future, cautious dosage increments are continued to be made in dogs, as with other insulins, with the aim of all blood glucose measurements being < 13.9 mmol/L (250 mg/dL) and > 4 mmol/dL (72 mg/dL). It is likely that with a less conservative dosing regimen, further improvements in glycemic control over the treatment period would have been noted. It is recommended that home blood glucose measurements be made at a minimum twice daily before each insulin dose and feeding (preinsulin and preprandial) on a daily basis to inform dose adjustments, particularly in dogs with concomitant disease and poor glycemic control or requiring higher than normal insulin doses, suggesting insulin resistance.
Intermediate-acting insulins resulted in significantly worse glycemic control than detemir. This is likely due to faster release of insulin into the blood after injection, leading to a rapid peak and shorter duration of action for porcine lente and NPH.29 In our study, no significant difference was noticed in the odds of biochemical hypoglycemia or the average number of biochemical hypoglycemic measurements per month compared to intermediate-acting insulin throughout the course of treatment. However, detemir had a slightly higher percentage of blood glucose measurements that were in the hypoglycemic range. This could be attributed to owners taking more glucose measurements around the time of a low blood glucose measurement because they were doing home monitoring. Owners were instructed to recheck the blood glucose concentration to verify the measurement if the blood glucose was low. If the concentration was persistently low, owners were instructed to feed their pet and recheck the blood glucose concentration in 1 hour (Appendix 1). No clinical hypoglycemia was reported in our study dogs.
Our study showed that withholding insulin if preinsulin blood glucose was < 6.7 mmol/L (120 mg/dL) either in the morning or evening resulted in a mean glucose concentration of 13.5 mmol/L (244 mg/dL) 1 hour later and, when withheld both initially and 1 hour later, a concentration of 24.5 mmol/L (442 mg/dL) 12 hours later. Therefore, the results of our study suggest glycemic control would be improved if insulin is not withheld in diabetic patients with preinsulin glucose concentrations above the upper limit of the normal range (6.5 mmol/L [117 mg/dL]). This is consistent with our subsequent clinical experience with detemir. If blood glucose is in the normal range (3 to < 6.5 mmol/dL [54 to < 117 mg/dL]), it is recommended that insulin be withheld and the response in the individual dog to eating be evaluated. If blood glucose increases above the normal range within 1 hour after feeding, it is recommended that in subsequent situations when preinsulin glucose is in the normal range that insulin and food be administered and the glycemic response evaluated to ensure that hypoglycemia does not occur.
For the dogs in our study, no diet changes were implemented throughout the course of the study. Detemir reversibly binds to albumin via its fatty chain, resulting in a slower and more gradual release of insulin and a longer duration of action compared to intermediate-acting insulins. The insulin peak is more pronounced in NPH, and it is recommended that the timing of feeding and injection of NPH be coordinated so the postprandial glucose peak corresponds with the insulin peak to minimize the postprandial hyperglycemia.25 Glargine has a similarly long duration of action as detemir in cats, and low-carbohydrate diets (≤ 3.7 g/100 kcal) have been developed for diabetic cats and reduce the postprandial glucose peak, but low-carbohydrate diets are not generally available for diabetic dogs.30
Our study had several limitations. The primary limitation was that it was a retrospective pilot study, and complete data were not collected for each patient. In addition, an a priori power analysis was not performed. This study was a retrospective study and as such was practically limited to the number of patients available that met the inclusion criteria for the study. Since there were clinically significant differences in glucose concentrations (the primary end point of the study) that were also found to be statistically significant in this study, despite the small sample size, there was adequate power. The number of dogs was small (7 dogs), and they were not a homogenous cohort, with differing comorbidities, likely contributing different levels of poor glycemic control. This decreased the power to demonstrate a difference in glycemic variables if one was present. Another limitation was that the insulin-dosing protocol was likely too conservative to achieve further improvements in glycemic control after the first month, limiting evaluation of detemir’s effectiveness over time. Lastly, one of our major limitations was that not every patient had sufficient blood glucose measurements to appropriately assess insulin dose.
In conclusion, detemir was a useful and safe insulin for treatment in diabetic dogs with various comorbidities and improved glycemic control in dogs that had poor control when treated with intermediate-acting insulin. In dogs fed diets similar to those of our cohort, it is not recommended to withhold insulin if preinsulin glucose is above the upper limit of the reference range (> 6.5 mmol/L [> 117 mg/dL]), because it will lead to worsening glycemia. Further prospective studies are needed to develop insulin-dosing protocols for detemir that achieve excellent glycemic control in otherwise healthy diabetic dogs, and dogs with poor glycemic control with other insulins, other comorbidities, and insulin resistance. It is recommended that low-carbohydrate diets be developed for diabetic dogs, as they have for cats, for use in conjunction with long-acting insulins.
Acknowledgments
The authors declare that there were no conflicts of interest relative to this work.
Comprehensive statistical analysis was provided by Deborah A. Keys, PhD, with Kaleidoscope Statistics.
References
- 1.↑
Mattin M, O’Neill D, Church D, McGreevy PD, Thomson PC, Brodbelt D. An epidemiological study of diabetes mellitus in dogs attending first opinion practice in the UK. Vet Rec. 2014;174(14):349. doi:10.1136/vr.101950
- 2.↑
Davison LJ, Herrtage ME, Catchpole B. Study of 253 dogs in the United Kingdom with diabetes mellitus. Vet Rec. 2005;156(15):467–471. doi:10.1136/vr.156.15.467
- 3.↑
Verdon DR. Banfield releases major veterinary study showing spike in diabetes, dental disease, and otitis externa. dvm360. Accessed October 22, 2019. https://www.veterinarynews.dvm360.com/banfield-releases-major-veterinary-study-showing-spike-diabetes-dental-disease-and-otitis-externa?rel=canonical
- 4.↑
Hoenig M. Comparative aspects of diabetes mellitus in dogs and cats. Mol Cell Endocrinol. 2002;197(1-2):221–229. doi:10.1016/s0303-7207(02)00264-2
- 5.↑
Ettinger S, Feldman E. Diabetes mellitus. In: Textbook of Veterinary Internal Medicine. 6th ed. Elsevier Saunders; 2005:1563–1591.
- 6.↑
Palm CA, Boston RC, Refsal KR, Hess RS. An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. J Vet Intern Med. 2009;23(1):50–55. doi:10.1111/j.1939-1676.2008.0249.x
- 7.↑
Lathan P, Fleeman L. Comparing lente insulin and NPH insulin for treating diabetic dogs. Vet Rec. 2018;183(8):260–261. doi:10.1136/vr.k3636
- 8.↑
Nelson RW. Disorders of the endocrine pancreas. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine. 5th ed. Elsevier Saunders; 2014:777–798.
- 9.↑
Fracassi F, Linari G, Del Baldo F, et al. Comparison of lente insulin and NPH insulin therapy for the treatment of newly diagnosed diabetic dogs: a randomised study. Vet Rec. 2018;183(8):262. doi:10.1136/vr.104818
- 10.↑
Eigenmann JE, Eigenmann RY, Rijnberk A, van der Gaag I, Zapf J, Froesch ER. Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly. Acta Endocrinol (Copenh). 1983;104(2):167–176. doi:10.1530/acta.0.1040167
- 11.
Fall T, Johansson Kreuger S, Juberget A, Bergström A, Hedhammar A. Gestational diabetes mellitus in 13 dogs. J Vet Intern Med. 2008;22(6):1296–1300. doi:10.1111/j.1939-1676.2008.0199.x
- 12.
Fleeman LM, Rand JS. Management of canine diabetes. Vet Clin North Am Small Anim Pract. 2001;31(5):855–880, vi. doi:10.1016/S0195-5616(01)50003-0
- 13.
Miceli DD, Pignataro OP, Castillo VA. Concurrent hyperadrenocorticism and diabetes mellitus in dogs. Res Vet Sci. 2017;115:425–431. doi:10.1016/j.rvsc.2017.07.026
- 14.
Catchpole B, Ristic JM, Fleeman LM, Davison LJ. Canine diabetes mellitus: can old dogs teach us new tricks? Diabetologia. 2005;48(10):1948–1956. doi:10.1007/s00125-005-1921-1
- 15.↑
Hess RS. Insulin resistance in dogs. Vet Clin North Am Small Anim Pract. 2010;40(2):309–316. doi:10.1016/j.cvsm.2009.12.001
- 16.↑
Richter M, Guscetti F, Spiess B. Aldose reductase activity and glucose-related opacities in incubated lenses from dogs and cats. Am J Vet Res. 2002;63(11):1591–1597. doi:10.2460/ajvr.2002.63.1591
- 17.↑
Beam S, Correa MT, Davidson MG. A retrospective-cohort study on the development of cataracts in dogs with diabetes mellitus: 200 cases. Vet Ophthalmol. 1999;2(3):169–172. doi:10.1046/j.1463-5224.1999.00073.x
- 18.↑
Niessen SJM, Hazuchova K, Powney SL, et al. The Big Pet Diabetes Survey: perceived frequency and triggers for euthanasia. Vet Sci. 2017;4(2):27. doi:10.3390/vetsci4020027
- 19.↑
Maggiore AD, Nelson RW, Dennis J, Johnson E, Kass PH. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med. 2012;26(1):109–115. doi:10.1111/j.1939-1676.2011.00861.x
- 20.↑
Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, Reusch CE. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec. 2012;170(2):52. doi:10.1136/vr.100070
- 22.↑
Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs. 2004;64(22):2577–2595. doi:10.2165/00003495-200464220-00008
- 23.↑
Fracassi F, Corradini S, Hafner M, Boretti FS, Sieber-Ruckstuhl NS, Reusch CE. Detemir insulin for the treatment of diabetes mellitus in dogs. J Am Vet Med Assoc. 2015;247(1):73–78. doi:10.2460/javma.247.1.73
- 24.↑
Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci. 2011;90(3):396–403. doi:10.1016/j.rvsc.2010.07.001
- 25.↑
Mahmoud M, Kokozidou M, Auffarth A, Schulze-Tanzil G. The relationship between diabetes mellitus type II and intervertebral disc degeneration in diabetic rodent models: a systematic and comprehensive review. Cells. 2020;9(10):2208. doi:10.3390/cells9102208
- 26.↑
Liu X, Pan F, Ba Z, Wang S, Wu D. The potential effect of type 2 diabetes mellitus on lumbar disc degeneration: a retrospective single-center study. J Orthop Surg Res. 2018;13(1):52. doi:10.1186/s13018-018-0755-8
- 27.↑
Thompson A, Lathan P, Fleeman L. Update on insulin treatment for dogs and cats: insulin dosing pens and more. Vet Med (Auckl). 2015;6:129–142. doi:10.2147/VMRR.S39984
- 28.↑
Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg. 2012;14(8):566–572. doi:10.1177/1098612X12446211
- 29.↑
Donner T, Sarkar S. Insulin – pharmacology, therapeutic regimens, and principles of intensive insulin therapy. In: Feingold KR, Anawalt B, Boyce A, eds. Endotext. MDText.com Inc; 2019:2000.
- 30.↑
Coradini M, Rand JS, Morton JM, Rawlings JM. Effects of two commercially available feline diets on glucose and insulin concentrations, insulin sensitivity and energetic efficiency of weight gain. Br J Nutr. 2011;106(suppl 1):S64–S77. doi:10.1017/S0007114511005046
Appendix 1
Sample insulin dosing chart provided to owners for insulin adjustments at home. Charts were adjusted during recheck appointments on the basis of blood glucose concentrations. If the blood glucose was in the “normal” or “good” range, the initial dose was calculated on the basis of the previous insulin dose of intermediate-acting insulin and divided by 4. The dose was halved if the animals ate < 50% of their meal.
| Blood glucose | Eats > 50% food | Eats < 50% food | |
|---|---|---|---|
| Too high | > 750 “HI” | 3.0 units | 1.5 units |
| 676–750 | 3.0 units | 1.5 units | |
| 601–675 | 3.0 units | 1.5 units | |
| 526–600 | 2.5 units | 1.0 units | |
| 450–525 | 2.5 units | 1.0 units | |
| 375–449 | 2.5 units | 1.0 units | |
| 300–374 | 2.0 units | 1.0 units | |
| Okay | 250–299 | 2.0 units | 1.0 units |
| 200–249 | 2.0 units | 1.0 units | |
| Good | 150–199 | 1.5 units | 0.5 units |
| Normal | 120–149 | 1.5 units | 0.5 units |
If blood glucose is < 120 mg/dL, withhold insulin and recheck blood glucose 1 hour after feeding and dose according to chart |
|||
| Too low | 60–119 | 0 units | 0 units |
| < 60 | * | * | |
*(1) Recheck immediately to verify. (2) If alert, feed and recheck in 30 minutes. (3) If weak, give 5 mL Karo syrup by mouth and call hospital. (4) Recheck glucose in 30 minutes.
Appendix 2
Signalment, insulin type and dose, and characteristics of 7 dogs with concurrent disease transitioned to detemir due to poorly controlled clinical signs with intermediate acting insulins.
| Patient | Age at diagnosis (y) | Breed | Sex | Weight (kg) | Duration of initial insulin treatment (wks) | Initial insulin | Last dose (units/kg/12 h) of initial insulin before change to detemir | Persistent clinical signs | Concurrent diseases |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 7.5 | Miniature Pinscher | FS | 6.4 | 154 | NPH | 0.69 | PU/PD, polyphagia | Relapsing pancreatitis, suspected IBD |
| 2 | 9 | Shepherd mix | MN | 43.8 | 14 | NPH | 0.57 | Weight loss | Chronic IVDD, OA, UTI, hypothyroid, pancreatitis |
| 3 | 14 | Heeler mix | MN | 23 | 10 | NPH | 0.75 | Weight loss, PU/PD, polyphagia | Anal sac adenocarcinoma with region metastasis to sublumbar lymph nodes, PDH |
| 4 | 16 | Labrador Retriever | FS | 26.7 | 95 | PL | 0.93 | PU/PD, polyphagia | Chronic recurrent UTI, OA |
| 5 | 10 | Labrador Retriever | MN | 32.9 | 4 | NPH | 0.37 | Lethargy, weakness, inappetence, PU/PD | Cholangiohepatopathy |
| 6 | 9 | Yorkie | MN | 5.6 | 17 | NPH/PL | 0.53/0.36 | PU/PD,/PP vision loss, weight loss | Cholangiohepatopathy |
| 7 | 10 | Miniature Schnauzer | MN | 10.5 | 44 | NPH/PL | 1.2/1 | PU/PD, polyphagia | Familial hyperlipidemia, chronic pancreatitis, OA |
FS = Female spayed. IBD = Inflammatory bowel disease. IVDD = Intervertebral disc disease. MN = Male neutered. NPH = Neutral protamine Hagedorn. OA = Osteoarthritis. PD = Pituitary dependent hyperadrenocorticism. PL = Porcine lente. PP = Polyphagia. PU/PD = Polyuria/polydipsia. UTI = Urinary tract infection.
