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Reducing Hyperglycemia While Preserving Insulin Secretion—SGLT2 Inhibition in Diabetes
glucose concentrations and improved insulin levels. Subsequent human serum glucose was reduced by 11.7% (p<0.05), 13.3% (p<0.05), and
studies were conducted to further evaluate the safety, tolerability, 21.8% (p<0.0001) for doses of 5, 25, and 100mg, respectively, compared
pharmacokinetics, and pharmacodynamics of sergliflozin.
28,29
with subjects receiving placebo, who showed no significant reductions.
No serious adverse events were reported and negative effects were
Two small double-blind, randomized, placebo-controlled clinical studies comparable between participants given dapagliflozin or placebo.
were conducted using single oral doses of sergliflozin.
29
In the first study,
sergliflozin doses ranging from 5 to 500mg were administered to 14 Results from a phase III trial were recently presented at the European
healthy males; in the second, eight subjects with type 2 diabetes were Association for the Study of Diabetes Annual Meeting.
35
A total of 546
given 50–500mg of the drug. In both study groups, dose proportionality patients 18–77 years of age with type 2 diabetes inadequately controlled
was observed, with a dose-dependent increase in urinary glucose with metformin alone were enrolled in this double-blind, placebo-
excretion. The amount of glucose excreted in the urine reached a plateau controlled, multicenter trial. After a two-week lead-in phase, subjects
at higher doses of sergliflozin, suggesting that the SGLT2 molecules were were randomized on a 1:1 basis to receive once-daily dapagliflozin 2.5,
maximally inhibited.
29
Similarly, the higher the concentration of active 5, or 10mg or placebo in addition to metformin. The primary end-point
drug in the system, the longer the duration of glucosuria. An oral glucose was change in HbA
1c
after 24 weeks, with secondary end-points being
tolerance test in the subjects with diabetes showed a reduction of fasting plasma glucose and change in total bodyweight.
35
plasma glucose concentrations from 18.3 to 11.2mmol/h/l over four
hours after receiving 500mg of sergliflozin. All doses of this SGLT2 At week 24, mean HbA
1c
levels were significantly reduced from baseline
inhibitor were well tolerated, with the most common adverse events in all add-on dapagliflozin groups compared with the placebo group.
35
being headache, sore throat, and dyspepsia. Sergliflozin therefore led to Fasting plasma glucose was also significantly lowered for all
expected pharmacodynamic changes in the body based on lowered dapagliflozin groups versus placebo. More patients in the dapagliflozin
hyperglycemia effects, and had a favorable safety profile.
29
groups reached an HbA
1c
<7.0% than those on placebo, and the SGLT2
inhibitor was associated with continuous and progressive weight loss.
Remogliflozin Overall, adverse events were comparable between all groups, with rates
Remogliflozin is currently under development. It has a 365-fold greater of urinary tract infections being similar or lower with dapagliflozin
selectivity for SGLT2 versus SGLT1 than sergliflozin and is structurally (placebo 8.0%; dapagliflozin 2.5mg 4.4%; dapagliflozin 5mg 7.3%;
unrelated to phlorizin.
30
In both non-diabetic and diabetic rats, dapagliflozin 10mg 8.1%). Conversely, genital infections were lower in
remogliflozin reduced plasma glucose levels and decreased circulating the placebo group (placebo 5.1%; dapagliflozin 2.5mg 8.0%; dapagliflozin
insulin levels compared with placebo.
30
These antihyperglycemic effects 5mg 13.1%; dapagliflozin 10mg 8.9%). Hypoglycemic events were similar
were much more significant in the diabetic animals. Over six weeks, across all groups and none resulted in discontinuation of the study
remogliflozin led to lower fasting plasma glucose and lower HbA
1c
levels medication. Therefore, patients with type 2 diabetes whose glycemic
in obese diabetic rats. Furthermore, remogliflozin reduced circulating levels are not sufficiently controlled by metformin alone can benefit
insulin levels and produced weight loss compared with the control from the addition of the SGLT2 inhibitor dapagliflozin to their treatment
group.
30
From these findings, it appears that this SGLT2 inhibitor is regimen. A once-daily dose of this drug had a favorable safety profile
capable of reversing the many effects of hyperglycemia through the and was associated with clinically meaningful weight loss over the 24
induction of urinary glucose excretion. weeks relative to placebo.
35
Dapagliflozin Currently, of the SGLT2 inhibitors, dapagliflozin is the closest to
Dapagliflozin is another SGLT2-specific inhibitor showing a 200–1,200- achieving marketing approval. If phase III trials continue to show
fold greater selectivity for SGLT2 compared with SGLT1 in in vitro positive results and favorable safety profiles, dapagliflozin could be
studies with animal cells.
16,31
Unlike T-1095 or sergliflozin, dapagliflozin is approved as early as 2011.
active in its ingested form and, due to its c-glucoside structure, it has a
half-life that is approximately 4.6 hours longer than the other two Safety and Tolerability of Sodium-coupled
drugs.
16,31
This will enable dapagliflozin to be developed as a once-daily Glucose Co-transporter 2 Inhibitors
oral antidiabetic drug. There have been no human trials that have assessed the long-term
safety of SGLT2 inhibitors. However, short-term trials have revealed no
Preliminary animal and human studies illustrated the potential of particular safety issues. In the 24-week phase III trial discussed above,
35
dapagliflozin to lower plasma glucose levels and improve glycemic which is the longest study performed in patients with type 2 diabetes to
control in diabetics.
31,32
This justified dapagliflozin proceeding into larger- date, no serious adverse events were reported. Contrary to logical
scale clinical studies, including two phase II trials.
33,34
In the first trial, 64 expectations, no excessive loss of electrolytes was observed and
healthy subjects were recruited to determine the pharmacokinetic urinary volume increase was minimal. Furthermore, because these
properties and safety of dapagliflozin.
33,34
This drug demonstrated dose- inhibitors are specific for SGLT2, they should not affect SLGT1 in the
dependent glucosuria and SGLT2 inhibition for at least 24 hours. This small intestine, avoiding any gastrointestinal side effects such as
encouraged its study as a once-daily treatment in patients with type 2 diarrhea and abdominal cramps.
36
diabetes. A trial with 47 subjects with diabetes showed that the
medication was effective both as a monotherapy and when administered A major concern regarding diabetes treatment is the possible
in combination with metformin.
34
After 13 days of treatment, fasting occurrence of hypoglycemic events if glycemic levels decrease below
US ENDOCRINOLOGY 77
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