Detemir improves diabetic regulation

in poorly controlled diabetic dogs with concurrent diseases

Antoinette R. Harris-Samson, DVM1*; Jacquie Rand, BVSc, DVSc, DACVIM2,3; Sara L. Ford, DVM, DACVIM1

1BluePearl Pet Hospital, Scottsdale, AZ

2School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia
3Australian Pet Welfare Foundation, Kenmore, QLD, Australia

*Corresponding author: Dr. Harris-Samson (antoinette.harris@bluepearlvet.com)

doi.org/10.2460/javma.22.09.0402

OBJECTIVE
This study evaluated the use of detemir for treating diabetic dogs with comorbidities that were poorly controlled
with intermediate-acting insulins.
ANIMALS
7 insulin-treated diabetic dogs.
PROCEDURES
Retrospective pilot study. Dogs were treated with detemir for at least 3 months, and glycemia was assessed by the
owners at home initially 2 to 4 times daily for 6 to 8 weeks and twice daily thereafter. Clinical evaluations occurred
on days 7 to 14, day 30, and then every 60 to 90 days, and dosage adjustments of detemir occurred as needed to
control glycemia.
RESULTS
The mean, peak, nadir, morning, and evening preinsulin daily blood glucose concentrations were significantly lower
after dosing with detemir for 1, 3, or 6 months and during the last month of treatment compared to the final month
of treatment with intermediate-acting insulin. Intermediate-acting insulins resulted in significantly worse glycemic
control than detemir in all 3 categories of control. The odds of a biochemical hypoglycemic measurement with de-
temir were not significantly different compared to intermediate-acting insulins. Clinical hypoglycemia did not occur
following detemir treatment. When insulin was withheld because of low morning preinsulin blood glucose concen-
tration < 6.7 mmol/L (≤ 120 mg/dL) and dogs were fed, mean blood glucose concentration was significantly higher
1 hour later. Glucose concentrations were also significantly higher 12 hours later on days when insulin was withheld
in the morning or evening for either 1 or 12 hours.
CLINICAL RELEVANCE
Detemir is useful in diabetic dogs with other comorbidities and can be considered an alternative treatment in poorly
controlled diabetic dogs.

D iabetes 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
In some dogs, achieving good glycemic control
is difficult, and they continue to experience persis-
tent hyperglycemia despite adequate insulin doses
13.1 cases/10,000 to 23.6 cases/10,000 (79.7%).3 or have marked fluctuations in blood glucose con-
Most commonly, it is due to immune-mediated de- centrations, including hypoglycemia.5,8 In some of
struction of beta cells (type 1) or other specific types these dogs, the cause of poor glycemic control may
of diseases such as pancreatitis, hyperadrenocorti- not be clear, but others have poor control due to
cism, acromegaly, or diestrus associated.4 Diabetic insulin resistance associated with comorbidities or
dogs usually require twice-daily insulin administration they have inadequate duration of insulin action. Poor
to achieve adequate glycemic control. Typically, dogs glycemic control as a result of insulin resistance may
are treated with intermediate-acting insulins such as occur secondary to an increase in insulin antagonistic
neutral protamine Hagedorn (NPH) or porcine lente.5 hormones associated with growth hormone excess in
Reported average duration of action in diabetic dogs diestrus-associated diabetes, acromegaly, or excess
for NPH is 6 to 10 hours, with a time to peak action exogenous progestogens; glucocorticoid excess in
between 2 to 8 hours.6–9 Porcine lente has an average spontaneous hyperadrenocorticism or excess exog-
duration of action of 8 to 16 hours, with a time to peak enous glucocorticoids; or inflammation.10–15 Poor
action between 4 to 6 hours.7–9 glycemic control may occur in some diabetic dogs

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due to inadequate duration of action of insulin, es- treated with glucocorticoids were also included, and
pecially when intermediate-acting insulin is used. In 17 diabetic dogs met the inclusion criteria. Newly
many diabetic dogs, NPH and lente insulin have ad- diagnosed diabetic dogs without previous insulin
equate duration of action (≥ 12 hours), but in some therapy (n = 3) were excluded from the study, as
dogs, duration is less than 8 to 10 hours, resulting were patients that received regular insulin or inter-
in daily periods of hyperglycemia despite appropri- mediate-acting insulin concurrently with detemir (n
ate nadir glucose concentrations.5,8 Inadequate gly- = 4). Patients with insufficient data or poor owner
cemic control causes persistent polydipsia, polyuria, compliance were also excluded (n = 3).
polyphagia, weight loss, cataract formation leading
to blindness, and lens-induced uveitis.16,17 It also in- Glycemic control
creases the risk of euthanasia. In a study18 evaluating Glycemic control was assessed as the proportion
diabetic pets euthanized after being diagnosed with of days in each month that mean glucose concentra-
diabetes, 35% were euthanized due to inadequate tion was in 1 of the 3 categories of glycemic control
glycemic control and persistence of diabetic signs. (good, < 13.9 mmol/L [< 250 mg/dL]; moderate,
In diabetic dogs poorly controlled by interme- 13.9 to 19.4 mmol/L [250 to 350 mg/dL]; and poor,
diate-acting insulin, especially when inadequate > 19.4 mmol/L [> 350 mg/dL]).
duration of action is suspected or documented,
long-acting insulins are an alternative. These include Insulin treatment
protamine zinc insulin and glargine. Protamine zinc Treatment with detemir was started on the day of
insulin was reported to provide adequate glycemic presentation at the referral clinic (day 1). The veteri-
control in 82% (14/17) of diabetic dogs in 1 study.19 narian determined the detemir dose after reviewing
Glargine was evaluated in 2 studies involving new- the patient history, including dose of current insulin,
ly diagnosed diabetic dogs and previously treated, and results of the physical examination, body weight,
poorly controlled diabetic dogs. Treatment result- and blood glucose concentrations measured on day
ed in good glycemic control in 58% of patients in 1 0. If blood glucose was between 6.7 to 11 mmol/L
study,20 and 100% were well controlled by a mean of (120 to 199 mg/dL), the starting detemir dose was
38 days in a later study.21 Detemir is a basal synthetic one-fourth the previous insulin dose of intermediate-
long-acting insulin analog used in humans with dia- acting insulin. Initial detemir dose was then adjust-
betes. It reversibly binds to albumin, slowing absorp- ed using an insulin dosage chart depending on the
tion and providing a prolonged and consistent meta- blood glucose and the amount of food eaten (Ap-
bolic effect for up to 24 hours.22 In dogs, detemir is 4 pendix 1). In general, insulin was increased when
times more potent than NPH and porcine lente.23,24 It preinsulin blood glucose was 11.1 mmol/L (200 mg/
also has a slow onset of action (2 to 11 hours), with dL) or higher, with larger dose increases at higher
peak effects occurring at 8 to 10 hours.23,24 blood glucose concentrations. If blood glucose was
The authors are only aware of 2 studies in which < 6.7 mmol/L (120 mg/dL), insulin was withheld and
detemir was used involving 5 and 10 newly diagnosed blood glucose measured 1 hour after feeding and in-
diabetic dogs without concomitant disease that were sulin then dosed according to the chart. Insulin dose
treated for up to 6 months23 and 21 days,24 respec- was halved if the dogs ate < 50% of their meal. An
tively. Twice-daily administration was used, and the initial insulin dosing chart was provided to owners.
authors reported that lower doses were required to
maintain glycemic control and prevent hypoglycemia Diet
than with other insulins. To our knowledge, there are Diet at entry into the study was determined by
no studies reporting use of detemir in poorly controlled the owner and veterinarian. There was no standard-
diabetic dogs with concurrent diseases, and therefore ized diet for the patients in this study. However, all
the purpose of our study was to report the use of de- owners were encouraged to feed a prescription diet
temir in this cohort of diabetic dogs that were poorly formulated for canine diabetes unless there was a
controlled with intermediate-acting insulins. 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
Materials and Methods fat, Purina DCO (Société des Produits Nestlé SA),
Hill’s r/d, Crave dog food (Mars), and a home-cooked
Inclusion criteria low-carbohydrate diet. Owners were asked to divide
Medical records from client-owned diabetic the daily caloric intake in half and feed one-half each
dogs with poor diabetic regulation were collected time detemir was administered.
from VCA Emergency Animal Hospital and Referral
Center in San Diego and Tatum Point Animal Hospital Monitoring by owner
from 2005 to 2009 and from BluePearl Pet hospital in Blood glucose concentrations were measured
Scottsdale, Arizona from 2018 to 2019. For study in- by the owner at home using a handheld blood glu-
clusion, medical records were reviewed for patients cose meter calibrated for dogs (AlphaTRAK blood
with evidence of poor diabetic regulation (persistent glucose monitoring system; Zoetis Services LLC) at
hyperglycemia, polyuria, polydipsia, weight loss, approximately 12-hour intervals, immediately prior
polyphagia, anorexia, and/or vision loss) and docu- to insulin administration (preinsulin) and feeding,
mentation of a change to detemir. Dogs previously with additional measurements optional at midday

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and bedtime. Owners were provided with a diary to 1 or 12 hours. Dogs with blood glucose concentra-
record daily blood glucose concentrations and dose tions for preinsulin and 12 hours (missing value for 1
of detemir administered and the respective times. hour) were only included in the analysis of preinsu-
Adverse events and health-related problems such lin versus 12 hours. Similarly, dogs with a preinsulin,
as lethargy, weakness, inappetence, vomiting, and 1-hour, and missing 12-hour blood glucose concen-
inappropriate urination were also recorded. Owners tration were only included in the analysis of preinsu-
performed blood glucose measurements at home lin versus 1 hour. Glucose concentrations were aver-
with 2 to 4 measurements/day for the first 6 to 8 aged for each dog first and then over dogs to obtain
weeks as dose was adjusted in the initial stabilization the reported concentrations.
period, and twice daily thereafter. The blood glucose Generalized LMMs were used to compare odds
log was collected and reviewed at each visit and a of glucose being controlled or having a biochemi-
new blood glucose log provided to the owner. cal hypoglycemic event during the last month of the
shorter-acting insulin to the first, third, sixth, and last
In-hospital monitoring month of detemir. For control, a multinomial distri-
Dogs were evaluated by the veterinarian ev- bution with a cumulative logit link function was as-
ery 7 to 14 days for the first 30 days and every 90 sumed. For hypoglycemic event, a binomial distribu-
days thereafter. The blood glucose and dosing log tion with a logit link function was assumed.
was reviewed, and a history was obtained, includ- All LMMs and generalized LMMs had random in-
ing the owner’s perception of changes (increased, tercepts for each dog to account for within dog cor-
decreased, or no change) in their dog’s frequency relation of glucose levels. Histograms and Q-Q plots
of urination, water consumption, and appetite com- of LMM conditional model residuals were examined
pared to the previous visit, as well as any adverse to evaluate the assumption of normality. Plots of
events they had observed. At each visit, a complete LMM conditional residuals versus predicted values
physical examination was performed and abnormali- of measurements were examined to evaluate the as-
ties and body weight documented. Results of blood sumption of homogeneity of variances.
and urine analysis for hematology, serum biochemis- Data were averaged by insulin per month by dog
try, serum fructosamine concentration, and urinaly- for descriptive statistics and graphs. Histograms and
sis were reviewed. Q-Q plots for each insulin per month were examined
In addition to the insulin dose adjustments based and confirmed the assumption of normality of daily
on the insulin dosing chart provided to the owners, mean, peak, nadir, and preinsulin AM and PM blood
adjustments in insulin dose were at the veterinarian’s glucose values. Mean, median, SD, minimum, and
discretion based on the owner’s perception of pres- maximum were reported.
ence and severity of clinical signs of diabetes, the
results of the physical examination, change in body
weight, and home blood glucose measurements and Results
previous response to insulin dose. Insulin dose was
adjusted by the veterinarian (SLF) to maintain blood Study animals
glucose concentration between 4.4 mmol/L (80 mg/ Seven diabetic dogs (2 spayed females and 5
dL) and 16.7 mmol/L (300 mg/dL) and the blood neutered males) met the inclusion criteria of a his-
glucose nadir between 4.4 mmol/L (80 mg/dL) and tory of poor glycemic control with intermediate-
8.3 mmol/L (150 mg/dL). acting insulins such as NPH and porcine lente in-
sulin and were subsequently changed to detemir
Statistical analysis insulin. Dogs were determined to have poor glyce-
All analyses were performed using SAS version mic control on the basis of the presence of polyuria,
9.4 (SAS Institute Inc). A significance threshold of polydipsia, persistent hyperglycemia (peak blood
0.05 was used. glucose > 19.4 mmol/L [> 350 mg/dL] based on
Linear mixed models (LMMs) were used to com- home monitoring), and glucosuria, with or without
pare daily mean, peak, nadir, and preinsulin morning polyphagia or anorexia, despite insulin being ad-
(AM) and evening (PM) blood glucose concentrations ministered for a minimum of 4 weeks at appropriate
obtained during the last month of treatment with the doses (0.5 U/kg, q 12 h, in 5/7 dogs and 0.36 U/kg,
shorter-acting insulin(s) to those obtained during the q 12 h in 2/7 dogs; Appendix 2). Dogs were a vari-
first, third, and sixth months of treatment with de- ety of breeds. Age ranged from 7.5 to 16 years (me-
temir. The models included a single fixed factor for dian, 10 years), and median body weight was 23 kg
insulin per month. Similarly, LMMs were used to com- (range, 5.6 to 43.8 kg). All study dogs had concur-
pare glucose concentrations obtained during the last rent diseases, which included the following: chronic
month of treatment with the shorter-acting insulin(s) pancreatitis (n = 3) diagnosed via ultrasound or ca-
to the last month of treatment with detemir. nine pancreas-specific lipase, suspected inflamma-
When detemir was withheld because preinsulin tory bowel disease (1), cholangiohepatopathy (2),
blood glucose concentration in the morning or eve- hyperlipidemia (1), osteoarthritis (3), urinary tract
ning was < 6.7 mmol/L (< 120 mg/dL), LMMs were infection (2) (chronic recurrent, 1; acute, 1), hypo-
also used to compare between preinsulin, 1-hour, thyroidism (1), pituitary-dependent hyperadreno-
and 12-hour (next preinsulin) blood glucose con- corticism (1), neoplasia (1) (anal sac adenocarcino-
centrations on days insulin was withheld for either ma with metastasis), and chronic intervertebral disc

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disease (IVDD; 1). One patient was euthanized at 4 ing effect (n = 4) or short duration of action (3). At
months after being started on detemir because of the time of change to detemir, clinical signs such as
metastatic anal sac carcinoma and was the only dog polyuria (n = 6), polydipsia (6), polyphagia (5), an-
that did not have 6 months of data. Age at diagno- orexia/weight loss (3), lethargy, weakness, inappe-
sis, signalment, duration and dose of initial insulin, tence, and vision loss were present despite previous
persistent clinical signs, and concurrent diseases insulin therapy (Appendix 2). The median initial de-
for the 7 dogs are shown (Appendix 2). temir insulin dose was 0.2 U/kg (range, 0.09 to 0.74
U/kg) twice daily. Data were available for a median
Insulin treatment of 14 months (average, 17 months; range, 4 to 51
After initial diagnosis of diabetes, dogs were months) during treatment with detemir. Median in-
started on NPH (n = 6) and porcine lente insulin (1), sulin dose of detemir in the final month of treatment
and 1 dog was initially placed on NPH for 18 weeks was 0.33 U/kg (range, 0.017 to 1.1 U/kg).
but switched to porcine lente insulin. Two diabetic
dogs were initially placed on porcine lente insulin Mean, peak, nadir, and preinsulin
and then changed to NPH. Data from both insulins glucose concentrations
were included in the evaluation for both dogs. Medi- Mean, peak, and nadir blood glucose concentra-
an dose immediately prior to the change to detemir tions were all significantly lower after dosing with
was 0.69 U/kg (range, 0.37 to 1.2 U/kg) twice daily. detemir for 1, 3, or 6 months and during the last
Median duration of treatment with intermediate-act- month of treatment for which data were available,
ing insulin was 17 weeks (mean, 48 weeks; range, 4 compared with concentrations during the last month
to 154 weeks). Patient’s insulin therapy was changed of dosing with an intermediate-acting insulin (P val-
to detemir because of an inadequate glucose lower- ues from .021 to < .0001; Table 1; Figures 1 and 2).

Table 1—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 previ-
ously treated with intermediate-acting insulin and then switched to detemir. Data shown for last month on interme-
diate-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.

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 P values from .024 to < .001. However, there were no
significant differences between the mean blood glu-
cose concentrations with detemir between months
1, 3, or 6 (P > .3). Morning and evening preinsulin
daily blood glucose concentrations were also sig-
nificantly 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 intermedi-
Figure 1—Mean blood glucose concentrations (+ SE)
were significantly lower after dosing with detemir for ate-acting insulin (mean, 17.5 mmol/L [316 mg/dL])
1, 3, or 6 months (P < .0001 for all) than during dosing was significantly higher than detemir at month 1, 3, or
with an intermediate-acting insulin. Mean daily blood 6 or the last month (mean, 12.9, 12.0, 12.8, and 12.0
glucose levels were also significantly lower during the mmol/L [232, 216, 230, and 217 mg/dL]; P values
last month of detemir administration than during dos- from .0003 to .017), but there were no significant dif-
ing with an intermediate-acting insulin (P = .0003).
There were no significant differences between mean ferences between months 1, 3, or 6 (P > .2).
glucose concentrations after dosing with detemir for 1,
3, or 6 months (P > .70 for all). Glycemic control
Intermediate-acting insulins resulted in signifi-
cantly 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 treat-
ment (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, moder-
ate, and poor control categories was 11%, 23%, and
67% compared to the sixth month of detemir treat-
ment when the corresponding proportions were 30%,
34%, and 36%. When glycemic control was assessed
by the proportion of days in each month that the na-
dir 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, >
Figure 2—Nadir daily blood glucose levels (+ SE) were 8.3 to 11.1 mmol/L [> 150 to 200 mg/dL]; and poor,
significantly lower after dosing with detemir for 1, 3, or > 11.1 mmol/L [> 200 mg/dL]), intermediate-acting
6 months (P < .0001 for all) and during the last month
(P < .0001) than during dosing with an intermediate- insulins also had significantly worse control based on
acting insulin. There were no significant differences in the nadir than detemir at month 1 (P = .006), 3 (P =
nadir glucose concentrations after dosing with detemir .0003), or 6 (P = .017) or the last month (P = .0006;
for 1, 3, or 6 months (P > .30 for all). Table 2). For example, the proportion of nadir glucose
concentrations in the respective categories in the last
For example, mean blood glucose concentrations month of treatment with intermediate-acting insu-
after 1, 3, and 6 months of treatment with detemir lin was 0.5%, 14%, 12%, and 74% of days compared to
were 16.8, 16.3, and 16.9 mmol/L (302, 294, and 305 1.6%, 27%, 17%, and 55% in the sixth month of detemir
mg/dL) compared to the mean during intermediate- treatment. There were no significant differences be-
acting insulin treatment of 21.8 mmol/L (393 mg/dL; tween months 1, 3, or 6 of detemir treatment (P > .2).

Table 2—Proportion of days in each month that mean and nadir glucose concentrations were in 1 of 3 categories of
glycemic control.
Control Nadir control

Insulin/mo Good Moderate Poor Hypoglycemia Good Moderate Poor

< 14 mmol/L 14-1.49 mmol/L > 19.4 mmol/L < 3.3 mmol/L 3.3–8.3 mmol/L > 8.3–11 mmol/L > 11 mmol/L
(< 250 mg/dL) (250–350 mg/dL) (350 mg/dL) (60 mg/dL) (60–150 mg/dL) (150–200 mg/dL) (200 mg/dL)
N Mean N Mean N Mean N Mean N Mean N Mean N Mean
Intermediate-acting
7 11% 7 23% 7 67% 7 0.5% 7 14% 7 12% 7 74%
insulin last mo
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%

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Hypoglycemia
The odds of having a biochemical hypoglycemic
measurement (< 3.3 mmol/L [< 60 mg/dL]) were not
significantly different after month 1 (marginally signif-
icant, 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 treat-
ment with intermediate-acting insulin, the average num-
ber 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 pa-
tients had a documented history of clinical hypoglyce-
mia when treated with intermediate-acting insulin. The Figure 3—Mean glucose concentrations when insulin
average percentage of blood glucose measurements was withheld in the morning because glucose concen-
per month that were in the hypoglycemic range were tration was < 6.7 mmol/L (< 120 mg/dL). Dogs were fed
higher with detemir versus intermediate-acting insulins at the time insulin was withheld. Glucose concentration
except for the last month of detemir treatment. For ex- was significantly higher 1 hour later (P < .0001).
ample, the average percentage of biochemical hypogly-
cemic 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 morn-
ing 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 near-
ly 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 Figure 4—Mean glucose concentrations after 12 hours
12 hours (P < .0001 for both). Glucose concentrations when insulin was withheld for 1 or 12 hours because
were significantly higher if insulin was withheld for 12 preinsulin blood glucose was < 6.7 mmol/L (120 mg/
dL). Glucose concentrations were significantly higher 12
hours (mean, 24.5 mmol/L [442 mg/dL]) compared hours later on days when insulin was withheld for either 1
to 1 hour only (mean, 12.9 mmol/L [233 mg/dL]; P or 12 hours (P < .0001 for both). Glucose concentrations
< .0001; Table 3) and were on average 4 times higher were significantly higher if insulin was withheld 12 hours
than initial blood glucose (Figure 4). compared to for only 1 hour (P < .0001).

Table 3—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.
Glucose 12 hours later when insulin was withheld
Glucose concentrations preinsulin (0) at preinsulin (0) and 1 hour later (no insulin given for 12 hours),
and 1 hour (1) later after eating or was withheld preinsulin and given 1 hour later

Mean glucose mmol/L (mg/dL) Mean glucose mmol/L (mg/dL)

Insulin within 12 h N/A N/A Yes (insulin was No (insulin dose
given 1 h later) 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 8.8 mmol/L 4.7 mmol/L 9.7 mmol/L 4.1 mmol/L 16.9 mmol/L
(81 mg/dL) (159 mg/dL) (85 mg/dL) (174 mg/dL) (74 mg/dL) (304 mg/dL)
Maximum 6.7 mmol/L 18.2 mmol/L 6.5 mmol/L 21.3 mmol/L 7.8 mmol/L 30.5 mmol/L
(120 mg/dL) (328 mg/dL) (118 mg/dL) (384 mg/dL) (140 mg/dL) (550 mg/dL)

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Discussion manufactured with 24 nmol of detemir, whereas 1 unit
of human insulin consists of 6 nmol of insulin. The lower
Seven diabetic dogs with concurrent disease and poor molar potency of detemir compared to human insulin is
glycemic control were evaluated after being changed from attributed to the addition of the fatty acid myristic acid,
an intermediate-acting insulin to the long-acting insulin de- which is covalently bound to lysine and postulated to in-
temir. This is the first report of the use of detemir in dogs terfere with receptor binding, as well as possible differ-
with poor diabetic regulation and concomitant disease. ences between species in detemir’s binding to albumin,
The most important findings were that administration of which influences its duration of action.28
detemir improved glycemic control compared to treat- Given that no clinical hypoglycemia was observed in
ment with intermediate-acting insulin and, at the doses the dogs in our study, it is recommended that, in the future,
used, did not increase the probability of hypoglycemia. cautious dosage increments are continued to be made
Our patients had multiple diseases that contributed to in dogs, as with other insulins, with the aim of all blood
their poor glycemic control and were consistent with the glucose measurements being < 13.9 mmol/L (250 mg/
reported causes of insulin resistance in diabetic dogs. For dL) and > 4 mmol/dL (72 mg/dL). It is likely that with a
example, 1 study15 reported that hyperadrenocorticism, less conservative dosing regimen, further improvements
urinary tract infections, acute pancreatitis, neoplasia, and in glycemic control over the treatment period would have
hypothyroidism were associated with insulin resistance. been noted. It is recommended that home blood glucose
One dog in our study had chronic IVDD. Although no measurements be made at a minimum twice daily before
studies in veterinary medicine exist to demonstrate an as- each insulin dose and feeding (preinsulin and preprandial)
sociation between IVDD and insulin resistance, in our clini- on a daily basis to inform dose adjustments, particularly in
cal experience, IVDD is associated with a requirement for dogs with concomitant disease and poor glycemic control
higher insulin doses to control glycemia, suggesting insulin or requiring higher than normal insulin doses, suggesting
resistance. However, there are reports that diabetes melli- insulin resistance.
tus could potentially be a risk factor for IVDD disease in hu- Intermediate-acting insulins resulted in significantly
mans and rodents with type 2 diabetes. An experimental worse glycemic control than detemir. This is likely due to
study in rodents showed a positive link between IVDD and faster release of insulin into the blood after injection, lead-
type 2 diabetes mellitus.25 Also, humans with type 2 diabe- ing to a rapid peak and shorter duration of action for por-
tes for > 10 years and who were poorly controlled were at cine lente and NPH.29 In our study, no significant difference
risk for developing lumbar disc disease.26 was noticed in the odds of biochemical hypoglycemia or
Average dose of intermediate-acting insulin in well- the average number of biochemical hypoglycemic mea-
controlled diabetic dogs is approximately 0.5 U/kg for surements per month compared to intermediate-acting
porcine lente and 0.25 to 0.5 U/kg for NPH, but the dogs insulin throughout the course of treatment. However, de-
in our study had poor glycemic control despite a median temir had a slightly higher percentage of blood glucose
dose of 0.7 U/kg prior to being changed to detemir.27 Al- measurements that were in the hypoglycemic range. This
though 2 dogs were on 0.4 U/kg for their final doses of could be attributed to owners taking more glucose mea-
intermediate-acting insulin, both dogs had poor glycemic surements around the time of a low blood glucose mea-
control and were polydipsic or polyuric at that dose. De- surement because they were doing home monitoring.
temir is reported to be 4 times more potent on a unit basis Owners were instructed to recheck the blood glucose con-
than other insulins in dogs, and the recommended starting centration to verify the measurement if the blood glucose
dose is 0.1 to 0.2 U/kg for newly diagnosed diabetics.23,24 was low. If the concentration was persistently low, owners
When changing from intermediate-acting insulin to insulin were instructed to feed their pet and recheck the blood
detemir, the dose advised is one-fourth the dose of inter- glucose concentration in 1 hour (Appendix 1). No clinical
mediate insulin and dosed twice daily compared to 0.25 to hypoglycemia was reported in our study dogs.
0.5 U/kg twice daily for most other insulins. Dogs in our Our study showed that withholding insulin if prein-
study were started on a median dose of 0.2 U/kg on the sulin blood glucose was < 6.7 mmol/L (120 mg/dL) ei-
basis of their previous doses on intermediate-acting insu- ther in the morning or evening resulted in a mean glucose
lin, and none had clinical evidence of hypoglycemia associ- concentration of 13.5 mmol/L (244 mg/dL) 1 hour later
ated with this dose. and, when withheld both initially and 1 hour later, a con-
Overall, all patients had an improvement in the mean, centration of 24.5 mmol/L (442 mg/dL) 12 hours later.
peak, and nadir blood glucose concentrations after being Therefore, the results of our study suggest glycemic con-
changed to detemir at 1, 3, and 6 months of treatment, trol would be improved if insulin is not withheld in diabetic
compared to treatment with a previous intermediate in- patients with preinsulin glucose concentrations above the
sulin. However, no further improvement in any measure upper limit of the normal range (6.5 mmol/L [117 mg/
of glycemic control was observed after the first month. dL]). This is consistent with our subsequent clinical ex-
At the time the first 5 dogs in our study were started on perience with detemir. If blood glucose is in the normal
detemir, there were no reports in the literature of detemir range (3 to < 6.5 mmol/dL [54 to < 117 mg/dL]), it is
being used in diabetic dogs. Conservative dose increases recommended that insulin be withheld and the response
were made by the clinician (SLF) because detemir is ap- in the individual dog to eating be evaluated. If blood glu-
proximately 4-fold more potent in dogs than other insu- cose increases above the normal range within 1 hour after
lins on a unit basis. In initial trials with detemir, the molar feeding, it is recommended that in subsequent situations
potency in humans was approximately one-fourth that when preinsulin glucose is in the normal range that insu-
of human insulin, but in dogs, detemir was found to be lin and food be administered and the glycemic response
equipotent on a molar basis to human insulin. To main- evaluated to ensure that hypoglycemia does not occur.
tain a similar glucose lowering effect in humans per unit For the dogs in our study, no diet changes were im-
of detemir compared to other human insulins, 1 unit was plemented throughout the course of the study. Detemir

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reversibly binds to albumin via its fatty chain, resulting in 3. Verdon DR. Banfield releases major veterinary study
a slower and more gradual release of insulin and a longer showing spike in diabetes, dental disease, and otitis ex-
terna. dvm360. Accessed October 22, 2019. https://
duration of action compared to intermediate-acting insu-
www.veterinarynews.dvm360.com/banfield-releases-
lins. The insulin peak is more pronounced in NPH, and it is major-veterinary-study-showing-spike-diabetes-dental-
recommended that the timing of feeding and injection of disease-and-otitis-externa?rel=canonical
NPH be coordinated so the postprandial glucose peak cor- 4. Hoenig M. Comparative aspects of diabetes mellitus in
responds with the insulin peak to minimize the postprandi- dogs and cats. Mol Cell Endocrinol. 2002;197(1-2):221–
al hyperglycemia.25 Glargine has a similarly long duration of 229. doi:10.1016/s0303-7207(02)00264-2
5. Ettinger S, Feldman E. Diabetes mellitus. In: Textbook of
action as detemir in cats, and low-carbohydrate diets (≤ 3.7
Veterinary Internal Medicine. 6th ed. Elsevier Saunders;
g/100 kcal) have been developed for diabetic cats and re- 2005:1563–1591.
duce the postprandial glucose peak, but low-carbohydrate 6. Palm CA, Boston RC, Refsal KR, Hess RS. An investiga-
diets are not generally available for diabetic dogs.30 tion of the action of Neutral Protamine Hagedorn hu-
Our study had several limitations. The primary limita- man analogue insulin in dogs with naturally occurring
tion was that it was a retrospective pilot study, and com- diabetes mellitus. J Vet Intern Med. 2009;23(1):50–55.
doi:10.1111/j.1939-1676.2008.0249.x
plete data were not collected for each patient. In addition,
7. Lathan P, Fleeman L. Comparing lente insulin and NPH in-
an a priori power analysis was not performed. This study sulin for treating diabetic dogs. Vet Rec. 2018;183(8):260–
was a retrospective study and as such was practically lim- 261. doi:10.1136/vr.k3636
ited to the number of patients available that met the in- 8. Nelson RW. Disorders of the endocrine pancreas. In: Nelson
clusion criteria for the study. Since there were clinically sig- RW, Couto CG, eds. Small Animal Internal Medicine. 5th ed.
nificant differences in glucose concentrations (the primary Elsevier Saunders; 2014:777–798.
9. Fracassi F, Linari G, Del Baldo F, et al. Comparison of lente
end point of the study) that were also found to be statisti-
insulin and NPH insulin therapy for the treatment of newly
cally significant in this study, despite the small sample size, diagnosed diabetic dogs: a randomised study. Vet Rec.
there was adequate power. The number of dogs was small 2018;183(8):262. doi:10.1136/vr.104818
(7 dogs), and they were not a homogenous cohort, with 10. Eigenmann JE, Eigenmann RY, Rijnberk A, van der Gaag
differing comorbidities, likely contributing different levels I, Zapf J, Froesch ER. Progesterone-controlled growth
of poor glycemic control. This decreased the power to hormone overproduction and naturally occurring canine
diabetes and acromegaly. Acta Endocrinol (Copenh).
demonstrate a difference in glycemic variables if one was
1983;104(2):167–176. doi:10.1530/acta.0.1040167
present. Another limitation was that the insulin-dosing 11. Fall T, Johansson Kreuger S, Juberget A, Bergström A,
protocol was likely too conservative to achieve further im- Hedhammar A. Gestational diabetes mellitus in 13 dogs.
provements in glycemic control after the first month, limit- J Vet Intern Med. 2008;22(6):1296–1300. doi:10.1111/
ing evaluation of detemir’s effectiveness over time. Lastly, j.1939-1676.2008.0199.x
one of our major limitations was that not every patient had 12. Fleeman LM, Rand JS. Management of canine diabetes.
Vet Clin North Am Small Anim Pract. 2001;31(5):855–880,
sufficient blood glucose measurements to appropriately
vi. doi:10.1016/S0195-5616(01)50003-0
assess insulin dose. 13. Miceli DD, Pignataro OP, Castillo VA. Concurrent hyperad-
In conclusion, detemir was a useful and safe insulin for renocorticism and diabetes mellitus in dogs. Res Vet Sci.
treatment in diabetic dogs with various comorbidities and 2017;115:425–431. doi:10.1016/j.rvsc.2017.07.026
improved glycemic control in dogs that had poor control 14. Catchpole B, Ristic JM, Fleeman LM, Davison LJ. Canine dia-
when treated with intermediate-acting insulin. In dogs fed betes mellitus: can old dogs teach us new tricks? Diabetologia.
2005;48(10):1948–1956. doi:10.1007/s00125-005-1921-1
diets similar to those of our cohort, it is not recommended
15. Hess RS. Insulin resistance in dogs. Vet Clin North Am
to withhold insulin if preinsulin glucose is above the up- Small Anim Pract. 2010;40(2):309–316. doi:10.1016/j.
per limit of the reference range (> 6.5 mmol/L [> 117 mg/ cvsm.2009.12.001
dL]), because it will lead to worsening glycemia. Further 16. Richter M, Guscetti F, Spiess B. Aldose reductase activ-
prospective studies are needed to develop insulin-dosing ity and glucose-related opacities in incubated lenses from
protocols for detemir that achieve excellent glycemic con- dogs and cats. Am J Vet Res. 2002;63(11):1591–1597.
doi:10.2460/ajvr.2002.63.1591
trol in otherwise healthy diabetic dogs, and dogs with poor
17. Beam S, Correa MT, Davidson MG. A retrospective-cohort
glycemic control with other insulins, other comorbidities, study on the development of cataracts in dogs with diabe-
and insulin resistance. It is recommended that low-carbo- tes mellitus: 200 cases. Vet Ophthalmol. 1999;2(3):169–
hydrate diets be developed for diabetic dogs, as they have 172. doi:10.1046/j.1463-5224.1999.00073.x
for cats, for use in conjunction with long-acting insulins. 18. Niessen SJM, Hazuchova K, Powney SL, et al. The Big
Pet Diabetes Survey: perceived frequency and trig-
gers for euthanasia. Vet Sci. 2017;4(2):27. doi:10.3390/
Acknowledgments vetsci4020027
19. Maggiore AD, Nelson RW, Dennis J, Johnson E, Kass PH.
The authors declare that there were no conflicts of inter- Efficacy of protamine zinc recombinant human insulin for
est relative to this work. controlling hyperglycemia in dogs with diabetes melli-
Comprehensive statistical analysis was provided by tus. J Vet Intern Med. 2012;26(1):109–115. doi:10.1111/
Deborah A. Keys, PhD, with Kaleidoscope Statistics. 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
References Rec. 2012;170(2):52. doi:10.1136/vr.100070
21. Hess RS, Drobatz KJ. Glargine insulin for treatment
1. Mattin M, O’Neill D, Church D, McGreevy PD, Thomson PC, of naturally occurring diabetes mellitus in dogs. J Am
Brodbelt D. An epidemiological study of diabetes mellitus Vet Med Assoc. 2013;243(8):1154–1161. doi:10.2460/
in dogs attending first opinion practice in the UK. Vet Rec. javma.243.8.1154
2014;174(14):349. doi:10.1136/vr.101950 22. Chapman TM, Perry CM. Insulin detemir: a review of its
2. Davison LJ, Herrtage ME, Catchpole B. Study of 253 dogs use in the management of type 1 and 2 diabetes mellitus.
in the United Kingdom with diabetes mellitus. Vet Rec. Drugs. 2004;64(22):2577–2595. doi:10.2165/00003495-
2005;156(15):467–471. doi:10.1136/vr.156.15.467 200464220-00008

334 JAVMA | MARCH 2023 | VOL 261 | NO. 3

Unauthenticated | Downloaded 03/28/23 08:10 PM UTC

23. Fracassi F, Corradini S, Hafner M, Boretti FS, Sieber- 27. Thompson A, Lathan P, Fleeman L. Update on insulin treat-
Ruckstuhl NS, Reusch CE. Detemir insulin for the treat- ment for dogs and cats: insulin dosing pens and more. Vet
ment of diabetes mellitus in dogs. J Am Vet Med Assoc. Med (Auckl). 2015;6:129–142. doi:10.2147/VMRR.S39984
2015;247(1):73–78. doi:10.2460/javma.247.1.73 28. Roomp K, Rand J. Evaluation of detemir in diabetic
24. Sako T, Mori A, Lee P, et al. Time-action profiles of in- cats managed with a protocol for intensive blood glu-
sulin detemir in normal and diabetic dogs. Res Vet Sci. cose control. J Feline Med Surg. 2012;14(8):566–572.
2011;90(3):396–403. doi:10.1016/j.rvsc.2010.07.001 doi:10.1177/1098612X12446211
25. Mahmoud M, Kokozidou M, Auffarth A, Schulze-Tanzil 29. Donner T, Sarkar S. Insulin – pharmacology, therapeutic
G. The relationship between diabetes mellitus type II regimens, and principles of intensive insulin therapy. In:
and intervertebral disc degeneration in diabetic rodent Feingold KR, Anawalt B, Boyce A, eds. Endotext. MDText.
models: a systematic and comprehensive review. Cells. com Inc; 2019:2000.
2020;9(10):2208. doi:10.3390/cells9102208 30. Coradini M, Rand JS, Morton JM, Rawlings JM. Effects of
26. Liu X, Pan F, Ba Z, Wang S, Wu D. The potential effect two commercially available feline diets on glucose and in-
of type 2 diabetes mellitus on lumbar disc degeneration: sulin concentrations, insulin sensitivity and energetic ef-
a retrospective single-center study. J Orthop Surg Res. ficiency of weight gain. Br J Nutr. 2011;106(suppl 1):S64–
2018;13(1):52. doi:10.1186/s13018-018-0755-8 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 calcu-
lated on the basis of the previous insulin dose of inter-
mediate-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.
Last dose
Duration of (units/kg/12 h)
Age at initial insulin of initial insulin
diagnosis Weight treatment Initial before change Persistent Concurrent
Patient (y) Breed Sex (kg) (wks) insulin to detemir clinical signs 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, Anal sac adenocarcinoma with
polyphagia 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, Cholangiohepatopathy
inappetence, PU/PD
6 9 Yorkie MN 5.6 17 NPH/PL 0.53/0.36 PU/PD,/PP vision loss, Cholangiohepatopathy
weight loss
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.

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