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CHICAGO – Even as dapagliflozin’s resubmitted application for marketing approval for treatment of type 2 diabetes is being scrutinized by the Food and Drug Administration, the drug is under study as a novel potential oral therapy for type 1 diabetes.
"For type 1 diabetes there are no approved oral agents, although some people use metformin off label. But I would predict if the numbers we saw with dapagliflozin in this short-term study persist out to 3 months, it would mean a reduction in hemoglobin A1c of 0.7-1.0 percentage points in type 1 diabetic patients who started at 8.0%," Dr. Robert R. Henry said in an interview at the annual scientific sessions of the American Diabetes Association.
He presented a small, proof-of-concept, multicenter, double-blind, phase IIa study aimed at establishing the safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT-2) inhibitor, in the management of patients with type 1 diabetes on background insulin. The study also showed early evidence of efficacy.
The five-center trial involved 62 patients who had suboptimally controlled type 1 diabetes despite being on basal bolus insulin or continuous infusion pump therapy. Their mean baseline HbA1c was 8.5%. Since this was the first study of an SGLT-2 inhibitor in patients with type 1 diabetes, it was conducted on an inpatient basis. For the first 3 days, patients were stabilized. Then they were randomized to insulin plus dapagliflozin at 1, 2.5, 5, or 10 mg once daily or to placebo.
The SGLT-2 inhibitor–treated patients demonstrated a dose-dependent increase in 24-hour urine glucose excretion. At the most effective 5- and 10-mg doses, by day 7 the 24-hour urine glucose excretion reached 84 and 100 g, respectively, representing mean 72-g and 89-g increases from baseline, compared to a 22-g decrease from baseline in the placebo group. Yet the dapagliflozin-treated patients showed no significant change in daily urine volume.
Continuous glucose monitoring showed mean 30- and 41-mg/dL reductions in daily average blood glucose levels in the 5- and 10-mg dapagliflozin groups, from a baseline of 174 mg/dL. Daily blood glucose variability decreased by 16%-25% as well, reported Dr. Henry, professor of medicine at the University of California, San Diego, and chief of the section of endocrinology, metabolism, and diabetes at Veterans Affairs Health Care System in San Diego.
Total daily insulin dosing on day 7 was down from baseline by 19% and 16%, respectively, in the 5- and 10-mg dapagliflozin-treated patients.
"This is just what I would have predicted, that dapagliflozin would be very effective in type 1 diabetes," he said.
Hypoglycemia was common in all study arms. The one case of serious hypoglycemia occurred in the dapagliflozin 10-mg group and led to study discontinuation. Two genital infections occurred in the dapagliflozin-treated patients.
Larger, longer-term clinical trials of the SGLT-2 inhibitor in patients with type 1 diabetes are planned.
The FDA initially rejected the New Drug Application that would have made dapagliflozin the first SGLT-2 inhibitor approved for the treatment of patients with type 2 diabetes. The agency requested more data on the risk/benefit ratio. Since then, dapagliflozin received marketing approval in the European Union, and the FDA granted approval to canagliflozin (Invokana) as the first SGLT-2 inhibitor to reach the U.S. market. AstraZeneca and Bristol-Myers Squibb have resubmitted the application for dapagliflozin with additional data. The FDA has indicated a decision will be announced by January.
Dr. Henry reported serving as an adviser to AstraZeneca and Bristol-Myers Squibb, which sponsored the study.
CHICAGO – Even as dapagliflozin’s resubmitted application for marketing approval for treatment of type 2 diabetes is being scrutinized by the Food and Drug Administration, the drug is under study as a novel potential oral therapy for type 1 diabetes.
"For type 1 diabetes there are no approved oral agents, although some people use metformin off label. But I would predict if the numbers we saw with dapagliflozin in this short-term study persist out to 3 months, it would mean a reduction in hemoglobin A1c of 0.7-1.0 percentage points in type 1 diabetic patients who started at 8.0%," Dr. Robert R. Henry said in an interview at the annual scientific sessions of the American Diabetes Association.
He presented a small, proof-of-concept, multicenter, double-blind, phase IIa study aimed at establishing the safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT-2) inhibitor, in the management of patients with type 1 diabetes on background insulin. The study also showed early evidence of efficacy.
The five-center trial involved 62 patients who had suboptimally controlled type 1 diabetes despite being on basal bolus insulin or continuous infusion pump therapy. Their mean baseline HbA1c was 8.5%. Since this was the first study of an SGLT-2 inhibitor in patients with type 1 diabetes, it was conducted on an inpatient basis. For the first 3 days, patients were stabilized. Then they were randomized to insulin plus dapagliflozin at 1, 2.5, 5, or 10 mg once daily or to placebo.
The SGLT-2 inhibitor–treated patients demonstrated a dose-dependent increase in 24-hour urine glucose excretion. At the most effective 5- and 10-mg doses, by day 7 the 24-hour urine glucose excretion reached 84 and 100 g, respectively, representing mean 72-g and 89-g increases from baseline, compared to a 22-g decrease from baseline in the placebo group. Yet the dapagliflozin-treated patients showed no significant change in daily urine volume.
Continuous glucose monitoring showed mean 30- and 41-mg/dL reductions in daily average blood glucose levels in the 5- and 10-mg dapagliflozin groups, from a baseline of 174 mg/dL. Daily blood glucose variability decreased by 16%-25% as well, reported Dr. Henry, professor of medicine at the University of California, San Diego, and chief of the section of endocrinology, metabolism, and diabetes at Veterans Affairs Health Care System in San Diego.
Total daily insulin dosing on day 7 was down from baseline by 19% and 16%, respectively, in the 5- and 10-mg dapagliflozin-treated patients.
"This is just what I would have predicted, that dapagliflozin would be very effective in type 1 diabetes," he said.
Hypoglycemia was common in all study arms. The one case of serious hypoglycemia occurred in the dapagliflozin 10-mg group and led to study discontinuation. Two genital infections occurred in the dapagliflozin-treated patients.
Larger, longer-term clinical trials of the SGLT-2 inhibitor in patients with type 1 diabetes are planned.
The FDA initially rejected the New Drug Application that would have made dapagliflozin the first SGLT-2 inhibitor approved for the treatment of patients with type 2 diabetes. The agency requested more data on the risk/benefit ratio. Since then, dapagliflozin received marketing approval in the European Union, and the FDA granted approval to canagliflozin (Invokana) as the first SGLT-2 inhibitor to reach the U.S. market. AstraZeneca and Bristol-Myers Squibb have resubmitted the application for dapagliflozin with additional data. The FDA has indicated a decision will be announced by January.
Dr. Henry reported serving as an adviser to AstraZeneca and Bristol-Myers Squibb, which sponsored the study.
CHICAGO – Even as dapagliflozin’s resubmitted application for marketing approval for treatment of type 2 diabetes is being scrutinized by the Food and Drug Administration, the drug is under study as a novel potential oral therapy for type 1 diabetes.
"For type 1 diabetes there are no approved oral agents, although some people use metformin off label. But I would predict if the numbers we saw with dapagliflozin in this short-term study persist out to 3 months, it would mean a reduction in hemoglobin A1c of 0.7-1.0 percentage points in type 1 diabetic patients who started at 8.0%," Dr. Robert R. Henry said in an interview at the annual scientific sessions of the American Diabetes Association.
He presented a small, proof-of-concept, multicenter, double-blind, phase IIa study aimed at establishing the safety of dapagliflozin, a sodium glucose cotransporter 2 (SGLT-2) inhibitor, in the management of patients with type 1 diabetes on background insulin. The study also showed early evidence of efficacy.
The five-center trial involved 62 patients who had suboptimally controlled type 1 diabetes despite being on basal bolus insulin or continuous infusion pump therapy. Their mean baseline HbA1c was 8.5%. Since this was the first study of an SGLT-2 inhibitor in patients with type 1 diabetes, it was conducted on an inpatient basis. For the first 3 days, patients were stabilized. Then they were randomized to insulin plus dapagliflozin at 1, 2.5, 5, or 10 mg once daily or to placebo.
The SGLT-2 inhibitor–treated patients demonstrated a dose-dependent increase in 24-hour urine glucose excretion. At the most effective 5- and 10-mg doses, by day 7 the 24-hour urine glucose excretion reached 84 and 100 g, respectively, representing mean 72-g and 89-g increases from baseline, compared to a 22-g decrease from baseline in the placebo group. Yet the dapagliflozin-treated patients showed no significant change in daily urine volume.
Continuous glucose monitoring showed mean 30- and 41-mg/dL reductions in daily average blood glucose levels in the 5- and 10-mg dapagliflozin groups, from a baseline of 174 mg/dL. Daily blood glucose variability decreased by 16%-25% as well, reported Dr. Henry, professor of medicine at the University of California, San Diego, and chief of the section of endocrinology, metabolism, and diabetes at Veterans Affairs Health Care System in San Diego.
Total daily insulin dosing on day 7 was down from baseline by 19% and 16%, respectively, in the 5- and 10-mg dapagliflozin-treated patients.
"This is just what I would have predicted, that dapagliflozin would be very effective in type 1 diabetes," he said.
Hypoglycemia was common in all study arms. The one case of serious hypoglycemia occurred in the dapagliflozin 10-mg group and led to study discontinuation. Two genital infections occurred in the dapagliflozin-treated patients.
Larger, longer-term clinical trials of the SGLT-2 inhibitor in patients with type 1 diabetes are planned.
The FDA initially rejected the New Drug Application that would have made dapagliflozin the first SGLT-2 inhibitor approved for the treatment of patients with type 2 diabetes. The agency requested more data on the risk/benefit ratio. Since then, dapagliflozin received marketing approval in the European Union, and the FDA granted approval to canagliflozin (Invokana) as the first SGLT-2 inhibitor to reach the U.S. market. AstraZeneca and Bristol-Myers Squibb have resubmitted the application for dapagliflozin with additional data. The FDA has indicated a decision will be announced by January.
Dr. Henry reported serving as an adviser to AstraZeneca and Bristol-Myers Squibb, which sponsored the study.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: Patients with suboptimally controlled type 1 diabetes on insulin therapy who were randomized to add-on once-daily oral dapagliflozin excreted up to 100 g of glucose in their urine daily, while their average 24-hour blood glucose level fell by 41 mg/dL.
Data source: A randomized, double-blind, placebo-controlled, multicenter, short-term, inpatient, phase IIa study in 62 patients with type 1 diabetes suboptimally controlled with basal bolus insulin or insulin pump therapy.
Disclosures: AstraZeneca and Bristol-Myers Squibb sponsored the study. The presenter is an adviser to those pharmaceutical companies and about a dozen others.
