November/December 2009
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Sodium Glucose Cotransport Inhibition in Type 2 Diabetes Treatment
Dapagliflozin selectively inhibits renal glucose reabsorption, lowers hyperglycemia,
and leads to weight loss among type 2 diabetes patients.
By Conni Bergmann Koury, Editor in Chief
Intensive glycemic control has been associated with
a marked decrease in the risk of microvascular
complications associated with type 2 diabetes.1-5
Data from the UKPDS (United Kingdom
Prospective Diabetes Study) also revealed a trend
toward a reduction in macrovascular complications
associated with intensive glycemic control.3 Subsequent
long-term follow-up of the UKPDS cohort confirmed
the reduction in microvascular risk and risk of myocardial
infarction.4 Then the ADVANCE (Action in Diabetes
and Vascular Disease)2 and ACCORD (Action to Control
Cardiovascular Risk in Diabetes) studies,1 however,
failed to demonstrate macrovascular benefits in
patients assigned to intensive glycemic control.
It has been suggested that the use of sulfonylureas
may have obviated any benefit of achieving A1C levels
of 6.5% in ADVANCE, based on a greater risk of mortality
observed with these agents.6 Experts now believe
that the failure of achieving benefit by aiming for goal
A1C <6.0% in ACCORD was likely due to a failure of the
process of control in these patients, which resulted in
weight gain and a three- to four-fold increase in hypoglycemia.
7 This issue continues to be studied.
Based on the pathophysiology of hyperglycemia, the
current guidelines of the American Diabetes Association8
and the European Association for the Study of
Diabetes (EASD)9 have set a goal of achieving near-normal
levels of A1C while managing the risks of hypoglycemia.
Based on this evidence for reduced A1C targets
and tighter glycemic control, development of new
therapeutic strategies that achieve significant reductions
in A1C while minimizing risk of therapeutic complications—
such as hypoglycemia and weight gain—
remains a priority.
SGLT2 INHIBITION
A novel approach that shows promise in achieving
these goals are agents that induce renal glycosuria by
selectively blocking sodium glucose cotransporter 2
(SGLT2). 10-14 According to preclinical models, SGLT2 inhibition
lowers blood glucose independently of insulin.
Kipnes15 reported that inhibition of SGLT2 by new agents,
such as dapagliflozin (joint development by Bristol-Myers
Squibb Company and AstraZeneca), has the potential to
reduce hyperglycemia by inhibiting glucose reabsorption
in the kidney. Preclinical trials demonstrated that
dapagliflozin is indeed a potent and selective inhibitor of
SGLT2. It has shown linear pharmacokinetics over the
dose range of 2.5 to 5.0 mg/day, it is not significantly influenced
when taken with food, and is primarily eliminated
via urinary excretion. Clinical trials have shown that
dapagliflozin treatment induces glucosuria and improves
glycemic parameters in patients with type 2 diabetes.
Bakris et al16 discussed the importance of the kidneys’
role in regulating glucose. The group also reported that
evidence has suggested selective inhibition of SGLT2
induces glucosuria in a dose-dependent manner and may
have beneficial effects on glucose regulation in individuals
with type 2 diabetes. Preclinical data on dapagliflozin and
sergliflozin, confirm that these compounds are highly
selective inhibitors for SGLT2, have beneficial effects on
the glucose utilization rate, and reduce hyperglycemia
while having no hypoglycemic adverse effects. These compounds
represent a very promising approach for the
treatment of diabetes, investigators concluded.
PHASE 3 TRIAL
Results from a 24-week study presented at the 45th
EASD Annual Meeting17 revealed that dapagliflozin added to metformin— was associated with significant
mean reductions in the primary endpoint, A1C, and in the
secondary endpoint, fasting plasma glucose (FPG), in
patients with type 2 diabetes who were inadequately controlled
with metformin alone, as compared with placebo
plus metformin.
Dapagliflozin is currently in phase 3 trials.18 The study
also showed that individuals receiving dapagliflozin had statistically
greater mean reductions in body weight compared
with individuals taking placebo. According to the company,
these 24-week data represent the first public presentation
of dapagliflozin phase 3 results.
“Given the continued rising prevalence of type 2 diabetes,
development of novel treatments such as SGLT2
inhibitors are needed to help improve glycemic control.
The preliminary data on weight loss and blood pressure
may be important adjuvants to glycemic control,” said Cliff
Bailey, Professor of Clinical Science and Head of Diabetes
Research at Aston University, Birmingham, UK, in a news
release from the drug’s manufacturers. “We look forward to
additional data from pivotal dapagliflozin studies which
will explore the potential benefits of this new class of medicine
for type 2 diabetes patients.”
Study design. A group of 546 type 2 diabetes patients
aged 18 to 77 years were included in this randomized,
double-blind, placebo-controlled investigation. At baseline,
patients’ A1C was ≥7% and ≤10%. Following a
2-week lead-in phase, patients were randomized to one of
four separate treatment arms: dapagliflozin 2.5 mg
(n=137), dapagliflozin 5 mg (n=137), dapagliflozin 10 mg
(n=135), or placebo (n=137). Patients in all arms were also
receiving metformin (≥1,500 mg/d). The primary endpoint
of the study compared mean A1C change from
baseline for each dapagliflozin treatment arm versus
placebo after 24 weeks. Secondary endpoints included
change from baseline in FPG and body weight at week
24 versus placebo, and adjusted percentage of individuals
treated with dapagliflozin who achieved A1C <7% at
24 weeks. Additional exploratory endpoints included
body weight decrease of ≥5% or ≥10% as well as body
weight percent change from baseline. The study includes
an extension phase for a total duration of 2 years.
Study results. After 24 weeks, individuals receiving
dapagliflozin 2.5, 5, and 10 mg plus metformin demonstrated
a statistically significant adjusted mean change in A1C
from baseline of -0.67%, -0.70%, and -0.84%, respectively,
compared with -0.30% for placebo (P<.0005 for all treatment
arms). Individuals treated with dapagliflozin demonstrated
a statistically significant adjusted mean change in
FPG, from baseline at week 24: -17.8 mg/dL for dapagliflozin
2.5 mg, -21.5 mg/dL for dapagliflozin 5 mg, and
-23.5 mg/dL for dapagliflozin 10 mg, compared with
-6.0 mg/dL for placebo (P<.005 for all treatment arms). The
adjusted percentage of patients treated with dapagliflozin
who achieved A1C <7% at 24 weeks, a secondary endpoint,
was 33% for dapagliflozin 2.5 mg (P=NS), 37.5% for dapagliflozin
5 mg, and 40.6% for dapagliflozin 10 mg (both P<.05)
versus 25.9% for placebo.
The study also evaluated the potential impact of
dapagliflozin on weight loss. These findings included data
measuring changes in total body weight over the 24-week
study period. At 24 weeks, the change in total body weight
in kilograms, a secondary endpoint, was -2.21 kg for dapagliflozin
2.5 mg, -3.04 kg for dapagliflozin 5 mg, and
-2.86 kg for dapagliflozin 10 mg, compared with -0.89 kg for
placebo (P<.0001). Overall, more patients taking dapagliflozin
achieved weight losses ≥5% versus placebo, an
exploratory endpoint (24% for dapagliflozin 2.5 mg, 25.4%
for dapagliflozin 5 mg, 28.0% for dapagliflozin 10 mg vs
5.9% for placebo).
Adverse events were generally balanced across all groups.
Overall, the number of individuals reporting at least one
adverse event for dapagliflozin 2.5 mg, dapagliflozin 5 mg,
dapagliflozin 10 mg, and placebo were 89, 95, 98, and 88,
respectively. Rates of urinary tract infections were similar
for dapagliflozin 2.5 mg, 5 mg, 10 mg and placebo (4.4%,
7.3%, 8.1%, and 8.0%, respectively). Rates of genital infections
were higher for the 2.5-mg, 5-mg, and 10-mg
dapagliflozin treatment arms versus placebo (8.0%, 13.1%,
8.9%, and 5.1%, respectively. The investigators reported that
genital tract infections were mild or moderate in nature
and did not lead to discontinuation from the study. There
were no clinically meaningful changes in markers for renal
impairment, increases in mean serum creatinine, or increases
in electrolyte abnormalities associated with dapagliflozin
therapy.
The number of reported hypoglycemic events was similar
across all treatment arms: 2.2% for dapagliflozin
2.5 mg, 3.6% for dapagliflozin 5 mg, 3.7% for dapagliflozin
10 mg, and 2.9% for placebo. There was no occurrence of
hypoglycemia that led to discontinuation of the study.
Reductions in blood pressure were observed without
associated signs of hypotension. Changes in blood pressure
at week 24 ranged from -3.1 to -5.9 systolic/-2.1 to
-2.7 diastolic mm Hg with dapagliflozin, compared with
-0.3 systolic/-0.4 diastolic mm Hg with placebo. A similar
proportion of patients across all treatment arms, including
placebo, had measured orthostatic hypotension.
DAPAGLIFLOZIN PLUS INSULIN,INSULIN SENSITIZERS
Wilding et al20 sought to determine whether
dapagliflozin would lower hyperglycemia in patients with
type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs). They found
that, in patients receiving high insulin doses plus insulin
sensitizers who had their baseline insulin reduced by 50%,
dapagliflozin decreased A1C, produced better FPG and
postprandial glucose (PPG) levels, and lowered weight
more than placebo.
Study design. This randomized, double-blind, threearm
parallel-group, placebo-controlled, trial was conducted
in 26 centers in the United States and Canada.
Investigators wrote that, based on data from an insulin
dose-adjustment setting cohort (n=4), patients in the
treatment cohort (n=71) were randomized in a 1:1:1 fashion
to placebo, 10 or 20 mg dapagliflozin, plus OAD(s)
and 50% of their daily insulin dose. The primary outcome
studied was a change from baseline in A1C at week 12
(dapagliflozin vs. placebo, last observation carried forward
[LOCF]).
Included patients had type 2 diabetes, were aged 18 to
75 years, had body mass index ≤45 kg/m2, and A1C 7.5%
to 10%. They were receiving stable-dose insulin sensitizer
therapy (metformin ≥1,000 mg and/or pioglitazone
[Actos, Takeda] ≥30 mg or rosiglitazone [Avandia,
GlaxoSmithKline] 4 mg) for ≥6 weeks and insulin therapy
for ≥12 weeks before enrollment (insulin dose must have
been ≥50 units of U-100 daily and stable for ≥6 weeks).
Study results. At week 12 (LOCF), patients assigned to
the 10- and 20-mg dapagliflozin groups had -0.70 and
-0.78% mean differences in A1C change from baseline versus
placebo. In both dapagliflozin groups, 65.2% of
patients achieved a decrease from baseline in A1C
≥0.5% compared with 15.8% in the placebo group. Mean
changes from baseline in FPG were +17.8, +2.4, and
-9.6 mg/dL (placebo, 10, and 20 mg dapagliflozin, respectively).
PPG reductions with dapagliflozin also showed
dose dependence, the investigators found. Mean changes
in total body weight were -1.9, -4.5, and -4.3 kg (placebo,
10, and 20 mg dapagliflozin). Overall, adverse events were
balanced across all groups, although more genital infections
occurred in the 20-mg dapagliflozin group than in
the placebo group.
CONCLUSIONS
The progression of type 2 diabetes is defined by a cycle
of deteriorating glycemic control due to declining betacell
function. It is known that therapies that employ
insulin supplementation or secretion carry with them
hypoglycemia risk, weight gain, decreased insulin sensitivity,
and an eventual loss of effectiveness. Wilding et al
wrote that this “frustrating clinical setting is exemplified
most dramatically by patients with late-stage type 2 diabetes
who require escalating insulin doses, often with oral
agents such as metformin and/or thiazolidinediones, to maintain glycemic control.” More than 25% of patients are
ultimately treated with insulin-based regimens, often in
combination with OADs. A novel strategy for controlling
glycemia independently of insulin involves limiting glucose
reabsorption in the proximal tubule of the kidney, where
glucose is reabsorbed via SGLT2 receptors. Dapagliflozin
selectively inhibits SGLT2, thereby limiting glucose reabsorption.
Recent results with dapagliflozin establish that SGLT2
inhibition can improve glycemic control and weight in
patients with diabetes that is poorly controlled with metformin,
as well as among those who are poorly controlled
with high insulin doses and oral insulin sensitizer therapy.
Additionally, this therapeutic approach may lend itself to
reducing the weight gain that often occurs when insulin
therapy is intensified in this population.
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