Randomized, double-blind, placebo-controlled trial on the effectiveness and
safety of dapagliflozin for blood glucose control during glucocorticoid
treatment for acute exacerbation COPD

Glucocorticoids are a causative factor for severe hyperglycaemia in patients
treated for acute exacerbation of chronic obstructive pulmonary disease
(AECOPD). Hyperglycaemia during AECOPD is associated with increased risk for
death or prolonged hospitalization, and this risk is independent of age, sex
and disease stage. Also, GCIH may increase disease burden and costs in patients
with COPD by the need for frequent monitoring of glucose levels, and the need
for frequent contact with caregivers to adjust glucose lowering treatment. In
preclinical studies, acute hyperglycaemia has been shown to cause immune
dysfunction and a procoagulant state which might explain the association
between hyperglycaemia and adverse outcomes in AECOPD.
The world-wide prevalence of chronic obstructive pulmonary disease (COPD) is
10% in adult patients. Patients with COPD frequently need high dose
glucocorticoid agents to combat sudden worsening of COPD symptoms - AECOPD. In
international guidelines, treatment with 30-40mg prednisone for 5-14 days is
advised for such episodes.
Glucocorticoids are synthetic adrenal glucocorticoid hormones that inhibit
pro-inflammatory gene expression. This inhibition of inflammation is beneficial
for the outcome of AECOPD. A complication of short-term high dose
glucocorticoids in AECOPD is acute hyperglycaemia. Glucocorticoids cause
hyperglycaemia by inducing insulin resistance, diminishing beta cell function
and increasing hepatic glucose production. These effects lead to a
glucocorticoid-specific pattern of hyperglycaemia with pronounced postprandial
hyperglycaemia and normal or near to normal fasting glucose. Forty percent of
patients with AECOPD develops severe hyperglycaemia, and in patients with known
diabetes the incidence is even higher.
There is little evidence on how to treat GCIH. Sliding scale insulin regimens
are most frequently used to treat GCIH (Gerards et al., manuscript in
preparation), although guidelines recommend against it. In SSI therapy,
subcutaneously short-acting insulin is prescribed in a variable dose based on
the current grade of hyperglycaemia. A major limitation of SSI is the failure
to prevent glucose excursions and thereby high glucose variability. The
reactive approach of SSI is especially popular in residents with low level of
clinical experience. Barriers for proactive treatment of inpatient GCIH are
absence of easily applicable treatment options, vigilance for hypoglycaemia and
the difficulty that an inpatient therapy regimen needs to be combined with
eventual pre-existing glucose lowering therapy.

SGLT-2 inhibitors lower blood glucose by blocking glucose reabsorption in the
proximal tubule leading to urinary glucose excretion, and thereby to a
reduction of blood glucose. There are 3 important reasons why SGLT-2 inhibitors
are an interesting treatment option for acute GCIH. In contrast to other
classes of glucose lowering agents the efficacy of SGLT2-inhibitors is
insulin-independent, and therefore can have a complementary instead of a
competing action to other glucose lowering agents. Secondly, SGLT-2 inhibitors
have a rapid onset of action compared to other oral glucose lowering drugs.
Thirdly, SGLT-2 inhibitors have a strong capacity to reduce postprandial
glucose. Most importantly, SGLT-2 inhibitors carry a lower risk of
hypoglycaemia in contrast to sulfonylurea derivatives and insulin. Altogether,
this make SGLT-2 inhibitors an ideal agent for treatment of temporary high dose
glucocorticoid induced hyperglycaemia that can be prescribed irrespective of
eventual pre-existing insulin resistance or glucose lowering therapy.

The purpose of this study is to investigate the effectiveness and safety of
dapagliflozin for glucose control in patients with exacerbation COPD on high
dose glucocorticoids.
Effectiveness of glucose control in clinical practice is measured by the time
spent within target range between 2nd and 7th day of study, as measured by
subcutaneous continuous glucose measurement (hypothesis that dapagliflozin
treatment is superior to placebo).
Safety is measured by as incidence rate of hypoglycaemic events (hypothesis
that dapagliflozin treatment is non-inferior to control treatment).

Multi-centre, double-blind placebo-controlled clinical trial with the objective
to investigate the difference in control of high-dose GCIH between subjects
treated with dapagliflozin 10mg or placebo

Dapagliflozin 10mg or placebo

The burden of participation consists of the extra capillary glucose
measurements that will be done 3-4 times daily and wearing a coin size glucose
sensor. Furthermore, patients have to fill out a treatment satisfaction
questionnaire. There will be no extra site visits for participants.
Dapagliflozin (experimental group) carries a risk of hypoglycaemia, especially
for patient who have concomitant therapy with insulin or sulfonylurea
derivatives. Patients will be instructed to anticipate, and if required dosing
of glucose lowering therapy will be adjusted. Furthermore, dapagliflozin
carries an increased risk of urogenital infections, increased haematocrit and
LDL cholesterol.