LISBON, PORTUGAL — Dapagliflozin (Farxiga/Forxiga, AstraZeneca) improves glycemic control and induces weight loss in patients with inadequately controlled type 1 diabetes, shows the first phase 3 clinical trial of a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor in type 1 disease.
And importantly, incidence of diabetic ketoacidosis was approximately the same across the dapagliflozin and placebo groups, reported Paresh Dandona, MD, from the State University of New York at Buffalo, who presented the results here at the European Association for the Study of Diabetes (EASD) 2016 Annual Meeting. They were also published simultaneously in Lancet Diabetes and Endocrinology.
The 24-week results of the Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes (DEPICT-1) trial of dapagliflozin as an oral adjunct to insulin in type 1 diabetes showed that both doses of dapagliflozin (5-mg and 10-mg) provided clinically relevant benefits as add-on to adjustable insulin, compared with placebo.
“Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycemic control in patients with inadequately controlled type 1 diabetes,” said Dr Dandona.
He added that the trial showed dapagliflozin was well tolerated with no new safety signals identified. “The 24-week results are important as they represent the first phase 3 trial in type 1 diabetes of the newer selective SGLT-2 class of diabetes medicines as an oral adjunct to insulin.”
Writing in an accompanying editorial, John Petrie, MD, from the Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland, says that DEPICT-1 “provides encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized.”
However, he adds that regulators are likely to await longer-term results before SGLT2 inhibitors — currently approved only for type 2 diabetes — are cleared for use in type 1 diabetes.
Still, he told Medscape Medical News, these results with dapagliflozin in DEPICT-1 appear more encouraging than those of the investigational SGLT1/2 inhibitor, sotagliflozin (Lexicon/Sanofi), in type 1 diabetes in inTandem3, reported here at the conference yesterday.
First Phase 3 Trial of a SGLT2 Inhibitor in T1D
Dr Dandona explained the need for improved therapy in type 1 diabetes. He said that “the intensification of insulin therapy necessary to achieve tight glycemic control is often associated with hypoglycemia…[and does not] address glucagon imbalances and increased rate of gastric emptying.”
Weight gain and blood-pressure rises are also associated with insulin therapy. “As such, there is a need for an adjunct treatment that provides sustained improvement across key parameters including HbA1c, time in glycemic range, body weight, and risk of hypoglycemia.”
DEPICT-1 aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. The double-blind, randomized, parallel-controlled, three-arm, phase 3, multicenter trial was conducted at 143 sites in 17 countries, with eligible patients aged 18 to 75 years having inadequately controlled type 1 diabetes (HbA1c between ≥7.7% and ≤11.0% [mean baseline HbA1c was 8.53%]) who had been on insulin for at least 12 months prior to enrolment.
Patients were randomized (1:1:1) to oral dapagliflozin 5 mg or 10 mg once daily or matched placebo, plus insulin. For safety analyses, 833 patients were randomized to groups (dapagliflozin 5 mg n=277; dapagliflozin 10 mg, n=296; placebo, n=260), and 778 of these patients were included in the full analysis set for efficacy (259 vs 259 vs 260, respectively).
The primary efficacy outcome was the change from baseline in HbA1c. Secondary end points included percentage change in total daily insulin dose; percentage change in body weight; change in mean value of 24-hour glucose readings, and change in mean amplitude of glucose excursion of 24 hours.
HbA1c, BMI, and Insulin Reduced; Hypoglycemia Similar Across Arms
Both doses of dapagliflozin significantly reduced HbA1c compared with placebo: mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was -0.42% (P < .0001) and for dapagliflozin 10 mg vs placebo was -0.45% (P < .0001]).
Change in body mass index (BMI) from baseline to week 24 was -2.96% (P < .0001) for dapagliflozin 5 mg vs placebo and -3.72% (P < .0001) for dapagliflozin 10 mg vs placebo
Total daily insulin dose changed over the 24 weeks by -8.8% (P < .0001) and -13.2% (P < .0001) in the 5-mg and 10-mg dapagliflozin groups, respectively.
Overall, the most common adverse events were nasopharyngitis (14% vs 12% vs 15%); urinary-tract infection (7% vs 4% vs 5%); upper-respiratory-tract infection (5% vs 5% vs 4%); and headache (4% vs 6% vs 4%).
Hypoglycemia occurred in 79%, 79%, and 80% of patients in the dapagliflozin 5-mg, dapagliflozin 10-mg, and placebo groups, respectively; severe hypoglycemia occurred in 8%, 6%, and 7% patients, respectively.
“Clearly, no increase in hypoglycemia is seen in this large clinical trial, so we can conclude this drug can be used safely without increase in hypoglycemia,” highlighted Dr Dandona.
Diabetic Ketoacidosis Approximately Same Across Groups
Adjudicated definite diabetic ketoacidosis (DKA) occurred in four (1%) patients in the dapagliflozin 5-mg group, five (2%) in the dapagliflozin 10-mg group, and three (1%) in the placebo group. Severe ketoacidosis (incidence rate per 100 patient-years) was one vs one vs one.
“Really, DKA was equal across the three arms,” said Dr Dandona.
Results of the inTANDEM3 trial in sotagliflozin, also reported at this year’s EASD meeting, showed that acidosis-related adverse events at week 24 occurred in 8.6% with sotagliflozin vs 2.4% with placebo, and one or more adjudicated DKA episodes occurred in 3.0% vs 0.6%. Discontinuation due to DKA occurred in 1.6% of the sotagliflozin group vs 0.1% of the placebo group.
In his editorial, Dr Petrie explains that initial enthusiasm for off-label use of SGLT2 inhibitors in type 1 diabetes was affected by reports of ketoacidosis and as such the US Food and Drug Administration (FDA) has not encouraged the use of this class of drugs in type 1 diabetes, with warning labels in place since May 2015.
Clinical Practice Employed Helped Mitigate DKA
In his editorial, Dr Petrie adds that the DEPICT-1 investigators kept real-world clinical practice in mind by “providing a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back toward the initial dose.”
He points out that this approach was effective in mitigating ketoacidosis and is feasible to implement in modern clinical practice.
Maciej Malecki, MD, from Jagiellonian University, Medical College, Krakow, Poland, provided formal comment after presentation of the DEPICT-1 results.
He raised a couple of unanswered questions around the results — first in relation to the reduction in HbA1c accompanied by weight loss: “Would this weight loss be desirable in type 1 diabetes patients with normal BMI?”
And then, “would the systolic blood-pressure decrease be wanted in patients with lower initial values?”
Also, with respect to safety, he wondered whether “the insulin-dose reduction would be equally safe in type 1 diabetes patients with a lower initial daily insulin dose.”
Nevertheless, “These results give hope for a prompt registration of dapagliflozin as adjunct therapy in this form of diabetes, but further postregistration observations will be required to fully define its safety profile in type 1 diabetes,” he noted, adding that it will also be necessary to determine whether the drug will reduce CV mortality in type 1 diabetes.
CV-Outcomes Trial With Dapagliflozin in T2D and Perhaps T1D?
Providing further exclusive comment for Medscape Medical News, Dr Petrie remarked, “What we need now are longer-term data and ideally a cardiovascular-outcomes trial [in type 1] — this would be an exciting prospect, as there has never been one in type 1 diabetes, and there is growing momentum for this in the diabetes community.
“We also need to work out how to predict which people with type 1 are more prone to ketosis when given an SGLT2 inhibitor, whether via baseline blood ketone levels, or more sophisticated techniques, or novel biomarkers.”
Dr Petrie added, “SGLT2 inhibitors are back on the road toward approval for an indication in type 1 diabetes,” pointing out that in comparison with sotagliflozin, the investigational SGLT1/2 inhibitor, “the ketoacidosis rates are reassuring, but we have to remember that this [DEPICT-3] was a phase 3 trial in which participants were closely supervised.
“The sotagliflozin data from inTandem3 derived from a more pragmatic design, but this does not in my view account for higher rates of ketoacidosis in that study on active medication, as rates were lower on placebo — and ketoacidosis was classified in an almost identical manner.”
This study was funded by AstraZeneca and Bristol-Myers Squibb. Dr Pandona serves on the advisory boards of AstraZeneca, Novo Nordisk, Sanofi, Boehringer Ingelheim, Merck Intarcia, and AbbVie and has received research grants from all of these companies, apart from Intarcia. Disclosures for the coauthors are listed in the paper. Dr Petrie has received personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi, Quintiles, and Janssen; nonfinancial support from Merck (Germany) and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
Lancet Diabetes Endocrinol Metab. Published online September 14, 2017. Abstract, Editorial
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