Results from a 12-week study demonstrated that the investigational drug
dapagliflozin, a novel, selective, sodium glucose co-transporter 2
(SGLT2) inhibitor, produced greater improvements across all key glycemic
measures studied [glycosylated hemoglobin level (HbA1c), fasting plasma
glucose (FPG) and post-prandial glucose (PPG)] in type 2 diabetes
patients who were treated with high doses of insulin and commonly used
oral anti-diabetes medications (OADs), compared to placebo (placebo plus
OADs plus insulin). Overall adverse events across the dapagliflozin
treatment arms were reported at a similar rate to placebo. The study
also showed that individuals receiving dapagliflozin had greater
reductions in body weight compared to individuals taking placebo, and
support the findings from a previous 12-week, Phase 2b study. Results
from the 12-week study were presented at the 69th American
Diabetes Association Annual Scientific Sessions.
Dapagliflozin is an investigational SGLT2 inhibitor currently in Phase 3
trials under joint development by Bristol-Myers
Squibb Company (NYSE: BMY) and AstraZeneca
(NYSE: AZN) as a once-daily therapy for the treatment of type 2
diabetes. SGLT2 facilitates the reabsorption of glucose in the kidney,
thereby returning filtered glucose to the circulation.
“Currently, more than 20 percent of individuals with type 2 diabetes are
treated with insulin, and significant proportions of patients are unable
to adequately control their blood sugar despite high doses of insulin,”
said John Wilding, DM, FRCP, Professor of Medicine & Honorary Consultant
Physician, Head of Diabetes and Endocrinology Clinical Research Unit,
University Hospital Aintree (UK). “The results presented today on
glycemic and weight parameters suggest that further study of
dapagliflozin in this patient population is warranted.”
About the Study
The study was designed to assess the efficacy and safety of
dapagliflozin in patients with inadequately controlled type 2 diabetes,
despite treatment with at least 50 units of U100 insulin per day plus
one or two baseline OADs (at least 1000 mg of metformin and/or at least
30 mg of pioglitazone or 4 mg of rosiglitazone). The data represent
findings from a randomized, double-blind, placebo-controlled study of 71
individuals with type 2 diabetes (ages 18 —75) whose HbA1c was greater
than or equal to 7.5 percent and less than or equal to 10 percent.
Individuals were randomized to one of three separate treatment arms:
dapagliflozin 10 mg (n= 24), dapagliflozin 20 mg (n= 24) or placebo (n=
23), given once daily. Baseline OAD doses were maintained during the
study but initial insulin doses in all study participants were reduced
to 50 percent of each individual’s daily baseline dose to reduce the
risk of hypoglycemia. The primary endpoint of the study compared mean
HbA1c change from baseline for each dapagliflozin treatment arm compared
to placebo. The secondary endpoints included proportion of individuals
achieving the American Diabetes Association recommended HbA1c target of
less than 7 percent, proportion of patients achieving HbA1c decrease
from baseline of at least 0.5 percent and FPG change from baseline as
compared to placebo. Changes in body weight were also assessed.
Study Results
After 12 weeks, individuals receiving dapagliflozin demonstrated an
adjusted mean decrease in HbA1c from baseline of 0.61 percent for
dapagliflozin 10 mg and 0.69 percent for dapagliflozin 20 mg, compared
to an increase of 0.09 percent for placebo.
The percentage of individuals treated with dapagliflozin that achieved
HbA1c of less than 7 percent after the 12-week treatment period was 13
percent for dapagliflozin 10 mg and 4.3 percent for dapagliflozin 20 mg,
compared to 5.3 percent for placebo. The percentage of individuals that
achieved HbA1c decrease from baseline of at least 0.5 percent was 65.2
percent for dapagliflozin 10 mg and 65.2 dapagliflozin 20 mg, compared
to 15.8 percent for placebo. The change from baseline in FPG at 12 weeks
was +2.4 mg/dL for dapagliflozin 10 mg and -9.6 mg/dL for dapagliflozin
20 mg, compared to +17.8 mg/dL for placebo.
Overall adverse events across the dapagliflozin treatment arms were
reported at a similar rate to placebo. The number of individuals
reporting at least one adverse event for dapagliflozin 10 mg,
dapagliflozin 20 mg, and placebo were 18, 16, and 15, respectively. The
most commonly reported (greater than or equal to 5 percent overall)
adverse events for dapagliflozin 10 mg, 20 mg and placebo were: urinary
frequency (pollakiuria), back pain, nasopharyngitis, nausea, headache,
and upper respiratory tract infection. Reported adverse events of
special interest for dapagliflozin 10 mg, 20 mg and placebo, were
urinary tract infection [0, 1, 0] and genital tract infection [0, 5, 1].
The number of reported hypoglycemic events was 7 for dapagliflozin 10
mg, 6 for dapagliflozin 20 mg, and 3 for placebo. There was no
occurrence of major hypoglycemia (neurological symptoms of hypoglycemia
such as confusion, fingerstick glucose less than or equal to 54 mg/dL
and needing external treatment).
Effect of Dapagliflozin on Weight Loss
The study also evaluated the potential impact of dapagliflozin-induced
glucosuria on weight loss in this type 2 diabetes patient population.
These findings included data measuring changes in total body weight and
body mass index over the 12-week study period.
Overall, greater decreases in body weight occurred in the dapagliflozin
treatment groups: 4.51 kg for dapagliflozin 10 mg and 4.3 kg for
dapagliflozin 20 mg, compared to 1.88 kg for placebo.
About Type 2 Diabetes
Diabetes (diabetes mellitus) is a chronic disease in which the body does
not produce or properly use insulin (a hormone that is needed for the
cells of the body to properly take up glucose). This leads to elevated
blood glucose levels (hyperglycemia) that are sustained over time.
Sustained hyperglycemia, the hallmark of diabetes, is associated with
long-term complications that can affect almost every part of the body.
The genesis of diabetes continues to be investigated, and both genetic
and environmental factors such as obesity and lack of exercise appear to
play a role. There are two primary underlying causes associated with
type 2 diabetes: the body does not produce enough insulin (insulin
deficiency), and the cells are resistant to the effect of insulin
(insulin resistance).
The kidneys play a key but underappreciated role in the overall
regulation of blood glucose levels in the body. Normally, in healthy
individuals, the kidneys filter a large volume of glucose and actively
reabsorb virtually all of it. Glucose reabsorption is necessary to
retain calories, but becomes counterproductive in type 2 diabetes. In
patients with type 2 diabetes who have hyperglycemia, a greater amount
of glucose is filtered and reabsorbed by the kidneys despite the fact
that this retention process contributes to sustaining the hyperglycemia
of diabetes.
Over time, sustained hyperglycemia leads to glucotoxicity, which worsens
insulin resistance and contributes to dysfunction in the beta cells of
the pancreas. The degree of sustained hyperglycemia is directly related
to diabetic microvascular complications and may also contribute to
macrovascular complications. In this way, hyperglycemia appears to
perpetuate a vicious cycle of deleterious effects that exacerbate type 2
diabetes control and complications.
About SGLT2 Inhibitors
The kidney continuously filters glucose through the glomerulus; however,
nearly all of this glucose is reabsorbed. A protein called SGLT2 is
responsible for the majority of glucose reabsorption and helps the body
retain glucose for its energy requirements. For patients with diabetes,
retention of excess glucose by this pathway contributes to persistent
hyperglycemia.Suppressing the activity of SGLT2 inhibits
renal-glucose reabsorption in the body, thereby leading to the excretion
of glucose in the urine
Bristol-Myers Squibb and AstraZeneca Collaboration
Bristol-Myers Squibb and AstraZeneca entered into collaboration in
January 2007 to enable the companies to research, develop and
commercialize two investigational drugs for type 2 diabetes — ONGLYZA
and dapagliflozin. The Bristol-Myers Squibb/AstraZeneca diabetes
collaboration is dedicated to global patient care, improving patient
outcomes and creating a new vision for the treatment of type 2 diabetes.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to extend and enhance human life. For more information, visit www.bms.com.
About AstraZeneca
AstraZeneca is a major international healthcare business engaged in the
research, development, manufacturing and marketing of meaningful
prescription medicines and supplier for healthcare services. AstraZeneca
is one of the world's leading pharmaceutical companies with healthcare
sales of US $31.6 billion and is a leader in gastrointestinal,
cardiovascular, neuroscience, respiratory, oncology and infectious
disease medicines. For more information about AstraZeneca, please visit: www.astrazeneca.com.