Evaluation of two insulin regimens for control of glucocorticoid induced hyperglycemia during chemotherapy

Glucocorticoids are a causative factor for hyperglycemia in patients receiving
chemotherapy in malignant disease. Hyperglycemia during chemotherapy is
associated with increased chemotoxicity. Especially nonhematologic
chemotoxicity is more common in patients who develop hyperglycemia during
glucocorticoid containing chemotherapy.
Glucocorticoids are synthetic adrenal glucocorticoid hormones that inhibit
pro-inflammatory gene expression. By influencing gene expression,
glucocorticoids can induce DNA fragmentation and apoptosis, and are therefore a
key element in therapy against hematologic neoplasms. Besides its
antineoplastic effects, glucocorticoids are used as an adjuvant in treatment of
neoplasm- or therapy-related symptoms like nausea, pain and edema. Depending on
the specific neoplasm and chemotherapy, dosing and scheme of glucocorticoids
can vary between 10mg till 500mg prednisone-equivalent daily, on a continuous
or intermittent base.
Depending on the dose and duration of glucocorticoid therapy, 40-98% of
nondiabetic patients on glucocorticoid-containing chemotherapy develop
hyperglycemia. In patients diagnosed with diabetes, this rate is even higher.
Glucocorticoid induced hyperglycemia (GCIH) has a specific pattern, with normal
or near to normal fasting glucose, and pronounced postprandial hyperglycemia.
Hyperglycemia is minimal present during night and early morning, probably by
suppression of early morning endogenous cortisol peak GCIH may lead to severe
glucose excursions, but in most cases glucose levels return to normal when
glucocorticoid therapy has finished.
Counteracting acute, GCIH is usually achieved by insulin therapy. Insulin is
suitable for acute GCIH because the effect sets in within minutes till hours,
depending on the specific type of insulin. Evidence for specific schemes of
insulin therapy for GCIH is scarce, and reports are limited to non-randomized
or retrospective studies, pilot studies, case-reports and expert opinions. Best
described regimens are sliding scale insulin (SSI) therapy and once daily
administration of intermediate acting insulin.
In SSI therapy, insulin is dosed according to the current grade of
hyperglycemia. Drawbacks of SSI therapy are failure to prevent glucose
excursions and thereby high glucose variability. Furthermore, it carries the
need for frequent measurements and insulin administrations.

The rationale for the use of intermediate acting insulin in glucocorticoid
induced hyperglycemia is based on a parallel in duration of action of
intermediate acting insulin and the pattern of glucocorticoid induced
hyperglycemia. Once daily administration of intermediate acting insulin has a
duration of action of 14-18 hours. When administered in early morning,
concurrent with the morning dose of glucocorticoids, it covers the period from
approximately 7:00am untill 21:00pm-1:00am. This period parallels the part of a
natural day in which glucose metabolism is mostly affected by glucocorticoid
therapy.

In this study, we aim to determine whether intermediate acting basal insulin or
SSI results in superior glycemic control during glucocorticoid containing
chemotherapy. For this study we will recruit patients with GCIH and prescribe
them premeal aspart insulin in a sliding scale regimen and once daily NPH
insulin in random order during consecutive cycles of chemotherapy. Besides our
primary objective of glycemic control, we compare safety, patient satisfaction
and clinical outcomes between the two treatment strategies.

Primary Objective:
Compare achievement of glycemic control in SSI therapy and NPH insulin

Glycemic control is defined as the proportion of glucose measurements within
target range (Fasting target glucose 3.9 * 7.8 mmol/l. Random target glucose
3.9-10 mmol/l) after 24h of treatment

As a secondary objective, we compare patient satisfaction, clinical outcomes
and toxicity.

Randomized open label cross-over study.
Subjects will be consecutively treated by NPH insulin once daily and by short
acting insulin in a sliding scale regimen. The order of the treatment regimens
will be determined by randomization.

Subjects will be consecutively treated by (A) NPH insulin once daily and by (B)
short acting insulin in a sliding scale regimen. The order of the treatment
regimens will be determined by randomization.

Dosing of NPH (A)
0.01 IU insulin per mg prednison-equivalent per kg bodyweight, with a dose
reduction of 40% in case of age >70years old or kidney failure (eGFR < 60ml/min)

Dosing of short acting sliding scale insulin (B)
capillary glucose 7.8-12 mmol/l --> 2 supplemental units of short acting insulin
capillary glucose 12.1-17 mmol/l --> 4 supplemental units of short acting
insulin
capillary glucose *17.1 mmol/l --> 6 supplemental units of short acting
insulin

Both study treatments are currently already prescribed in regular care for
glucocorticoid induced hyperglycemia. Glycemic control is likely to improve due
to treatments and increased counselling. All subjects will receive both
treatment regimens.
The burden of participation consists of 1 venipuncture (only if HbA1c and
creatinin are not determined in routine laboratory within 3 months before start
of study treatment), and 1 randomization visit to the outpatient clinic (we try
to schedule the randomization visit subsequent to a regular visit to the
outpatient clinic). Potential risk is the occurrence of hypoglycemia, as is
present in any (new or adjusted) insulin therapy. We will account for this risk
by supplying all subjects with dietary advice, and education how to prevent,
recognize and treat hypoglycemia.