Plenty of information has been released recently about the
sodium-glucose transporter-2 inhi-bitors, commonly known as SGLT2s, leading
endocrinologists to ask, What is all the excitement?
These agents represent a potentially promising approach to treating
diabetes because they have no effect on insulin secretion and insulin
resistance. Instead, SGLT2 inhibitors block reabsorption of glucose by the
At the American Diabetes
Association 70th Scientific Sessions in June, nine abstracts were presented
on canagliflozin and three were presented on dapagliflozin. To date, three
clinical trials of the most studied SGLT2 inhibitor dapagliflozin
have been published. Several SGLT2 inhibitors are currently being studied in
phase 2 and 3 clinical trials for patients with type 2 diabetes.
A crucial evolutionary adaption to retain calories, renal glucose
absorption by the kidney contributes to hyperglycemia, and is a crucial
evolutionary adaption to retain calories. Paradoxically, patients with diabetes
may have this process accentuated. Historically, glycosuria has been regarded
as a sign of metabolic decompensation and adverse clinical consequences.
Diminishing renal glucose reabsorption and elevating urinary glucose excretion
as a strategy for treating diabetes, thus, represents a paradigm shift. SGLT is
responsible for renal glucose reabsorption, with 90% mediated by SGLT2, a
high-capacity, low-affinity carrier found mainly in the S1 segment of the
proximal convoluted tubule. SGLT1 coordinates the remaining 10% of glucose
reabsorption in the kidney; these co-transporters are situated in the S2 and S3
segment of the proximal convoluted tubule. The high plasma glucose levels that
are the hallmark of uncontrolled type 2 diabetes exceed the maximum threshold
of glucose reabsorption, thus leading to saturation of the SGLT receptors and,
in turn, resulting in glycosuria.
The development of SGLT2 inhibitors extends to 1835, when phlorizin was
first isolated. This compound, derived from the root bark of the apple tree,
was an inhibitor of both SGLT2 and SGLT1. Phlorizin was not feasible for
further development, due to being quickly degraded and because it had low
bioavailability secondary to being poorly absorbed from the gastrointestinal
tract. Other agents were tested, which provided more specificity, but were
discontinued for reasons that were not entirely known, but likely included
suboptimal safety and efficacy.
In one abstract presented at the ADA meeting, Wilding and colleagues
examined dapagliflozin (AstraZeneca and Bristol-Myers Squibb); this agent has
progressed the furthest in development among the SGLT2 inhibitors. For 48
weeks, 808 patients with type 2 diabetes who were suboptimally controlled on
insulin were administered this SGLT2 inhibitor. HbA1c levels declined by
0.43% (standard error 0.07%) in the placebo group; 0.74% (0.06%) in
the dapagliflozin 2.5 mg group; 0.94% (0.06%) in the dapagliflozin 5-mg
group; and 0.93% (0.06%) in the dapagliflozin 10-mg group. Urinary tract
infections were observed in 7.9% to 10.8% of patients assigned to dapagliflozin
vs. 5.1% of patients assigned to placebo. Genital infections were also more
common in the dapagliflozin group vs. placebo group (6.4% to 10.7% vs. 2.5%).
Canagliflozin (Johnson & Johnson) is another SGLT2 inhibitor that is
in clinical trials and was presented at the ADA meeting. In a randomized,
double blind, placebo-controlled study by Schwartz and colleagues, 29 people
with type 2 diabetes suboptimally controlled on stable insulin doses were
administered canagliflozin 100-mg daily, 300-mg twice daily or placebo. The
HbA1c decrease was 0.19% from a baseline level of 8.27% in the placebo
group; 0.73% from 8.38% in the canagliflozin 100-mg daily group; and
0.92% from 8.42% in the canagliflozin 300 mg twice-daily group. Weight
decreases ranged from 0.7 kg with canagliflozin at 100 mg per day to
1.2 kg with canagliflozin 300 mg twice daily.
In another study, Rosenstock and colleagues randomly assigned 451
patients with type 2 diabetes who were not optimally controlled on metformin to
daily canagliflozin 50 mg, 100 mg, 200 mg or 300 mg; to twice-daily
canagliflozin 300 mg; to daily sitagliptin 100 mg (Januvia, Merck); or to
placebo. HbA1c declined between 0.45% and 0.73% in all patients assigned to
canagliflozin compared with a 0.56% decrease in patients assigned to
sitagliptin. Weight was reduced by 1.3% to 2.3% with canagliflozin. In
addition, fasting plasma glucose changed from 16.2 mg/dL to 32.4
mg/dL vs. an increase of 0.4 mg/dL with sitagliptin. The overnight urine
glucose-creatinine ratio ranged from 36.1 to 60.3 vs. 3/3 with
sitagliptin. These changes were all statistically significant.
Also in the study, hypoglycemia was observed in up to 6% of the
canagliflozin patients compared with 2% with placebo and 5% with sitagliptin.
Urinary tract infections occurred in 3% to 9% of the canagliflozin groups, 6%
of the placebo group and 2% of the sitagliptin group. The researchers noted no
dose-response effect for hypoglycemia or urinary tract infection.
Non-dose-dependent elevations in symptomatic genital infections were also
observed: 3% to 8% with canagliflozin and 2% with placebo and sitagliptin.
Further studies are needed to address safety issues associated with
SGLT2 inhibitors, such as risks for hypoglycemia, electrolyte imbalance,
urinary and genital infections and the inhibitors effect on bone
metabolism. How to best use these medications to attain greater glycemic
control while minimizing adverse effects also awaits further research.
Whether these agents will be best used for type 1 diabetes or type 2
diabetes will depend on studies that have examined use in both. The role of
SGLT2 inhibitors in combination with oral agents must also be further explored
in large trials of longer duration.
These are just some of the unanswered questions that remain. The data
generated thus far appear to suggest that SGLT2 inhibitors represent a
promising approach to tackling hyperglycemia.
Edward C. Chao, DO, is assistant clinical professor of medicine at
University of California, San Diego, and staff physician at VA Medical Center,
For more information:
- Rosenstock J. Canagliflozin, an inhibitor of sodium glucose co
transporter 2 (SGLT2), improves glycemic control and lowers body weight in
subjects with type 2 diabetes (T2D) on metformin.
- Schwartz S. Canagliflozin improves glycemic control in subjects
with type 2 diabetes (T2D) not optimally controlled on stable doses of
- Wilding J. Sustained effectiveness of dapagliflozin over 48 weeks
in patients with type 2 diabetes poorly controlled with insulin. All presented
at: American Diabetes Association 70th Scientific Sessions; June 24-29, 2010;