Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes:The DEPICT-1 52-Week Study

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Clinical Question

In patients with uncontrolled type 1 diabetes, does the addition of Dapagliflozin to adjustable insulin as opposed to adjustable insulin alone improve glycemic control without causing adverse effects?


Bottom Line

In patients with type 1 diabetes, the addition of Dapagliflozin leads to a decrease in HbA1c over a 52-week period, promotes weight loss, and allows for a decrease in the dose of insulin administered, however, it lead to an increase in incidence of diabetic ketoacidosis (DKA). All incidences of DKA were managed with standard care, so the benefits of Dapagliflozin therapy in addition to normal insulin therapy outweigh the risks when the patient is properly educated on the signs and management of DKA.

Major Points

Despite the strides being made to improve insulin and its delivery, there continues to be many patients with Type 1 diabetes that still cannot keep their blood glucose levels within range. This may be attributed to the fact that there are currently no approved adjunct oral therapies to be used alongside insulin for Type 1 diabetes. Dapagliflozin has been used largely for Type 2 diabetes to reduce glucose absorption and promote its urinary excretion, thus improving blood glucose control while also promoting weight loss and lower blood pressure. A phase 3 study was performed on Dapagliflozin to determine if it can be used with adjustable insulin in patients with uncontrolled Type 1 diabetes. This study focused on analyzing the safety of long term use of medication in the long term, specifically in occurrences of hypoglycemia and diabetic ketoacidosis while determining its effectiveness at assisting Type 1 diabetics in maintaining adequate glycemic control. The DEPICT-1 52-Week Study was a randomized, three-arm, parallel-group, multicenter Phase 3 study. This study evaluated the “efficacy and safety of dapagliflozin 5 mg and 10 mg as an add-on to adjustable insulin in patients with type 1 diabetes”1. The results of the 52 week study include the 24-week double blind short-term period and the 28-week long-term subject- and study sites–blinded extension period. Patients were randomized into 3 groups including: dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo. There was 833 patients randomized into the 24-week short-term study. There were 747 patients who entered the 28-week long-term treatment period after the 24-week short-term study. During the 28-week long extension period, patients continued to receive their randomly assigned medications. All participants, including the patients and study sites, followed the same criteria as the 24-week short term study and remained blinded to the study medications. The study site visits occurred at weeks 32, 40, 48, and 52 with an additional 30-day posttreatment follow-up at week 56. The outcome of the 52-week long study concluded with improvements in HbA1c levels that were observed in both the 24-week short-term and 28-week long-term study with dapagliflozin 5 mg and 10 mg. Those in the dapagliflozin 5 mg and 10 mg group showed reduced total insulin daily doses at week 2 and this reduced total insulin daily dose continued over the 52 weeks when compared to those in the placebo group. This study showed that dapagliflozin was well-tolerated and did improve glycemic control while simultaneously reducing weight and amount of insulin needed. However, these did come with the risk of adverse events such as infections and hypersensitivity reactions, and serious events such as hypoglycemia and DKA. However, there was no increase in severe hypoglycemia or in the overall incidence of hypoglycemia. Because more patients experienced DKA with treatment than with placebo, providers must be aware of the risk and benefit for the specific patients and how to report and manage these events. This study had limitations that may have prevented the full glycemic potential of the medication, made it impossible to compare the 52 week and 24 week study, and also did not include enough diverse ethnicities to see if the results are applicable in different ethnic groups.


Guidelines

Design

Trial Type: Randomized (1:1:1), double-blind, placebo-controlled Phase 3 study N= There was 833 patients randomized into the 24-week short-term study. There was 747 patients who continued into 28-week long-term study. Experimental Arm: three-arm Standard: Patients were randomized into 3 groups - dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260). Setting: double-binded Enrollment: “In the full analysis set, 85%, 86%, and 84% of randomized patients in the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively, completed the entire 52-week study”1 Mean Follow-up: The study site visits occurred at weeks 32, 40, 48, and 52 with an additional 30-day posttreatment follow-up at week 56. Analysis: All patients who received at least one dose of study medication during the 24-week short-term period were included in the full analysis set which assessed efficacy. Due to a randomized error, the first 55 patients were excluded from the full analysis set. The patients were excluded because they were only allocated to one of the dapagliflozin treatment arms. Patient-recorded basal and bolus insulin dose ranges for each week between the visits on week 2 and week 10, week 12 and week 22, and week 24 to week 56 were used to summarize insulin dose data. Patients with daily dose data was “converted into weekly ranges and then combined for analyses” 1 No p value was calculated for treatment group comparisons between the 24-week short-term and 28-week long-term study because 52-week efficacy analyses were investigative. The effects of treatment as if all patients had completed the 52-week long study was evaluated by: “longitudinal repeated-measures analysis (which included a model including fixed categorical effects of treatment), week, randomization stratification factors (one term for each combination of all stratification factors), treatment-by-week interaction, and also the continuous fixed covariates of baseline measurement and baseline measurement-by-week interaction, was performed for analyses of variables in terms of change or percentage change (using log transformation for the end point) from baseline.”1 No statistical tests were performed to compare safety variables between the treatment groups. Safety outcomes comprised all patients who received at least one dose of study drug. Primary Outcome: Improvements in glycemic control and weight loss without the risk of additional adverse events


Population

Inclusion Criteria

Patients were eligible if they were “adult patients with inadequately controlled type 1 diabetes (HbA1c, 7.7–11.0% [61–97 mmol/mol] at screening; 7.5–10.5% [58–91 mmol/mol] at randomization)”1 “Participants had to be prescribed insulin for >12 months and be given a dose of >0.3 IU/kg/day for >3 months”1 “C-peptide had to be <0.7 nl/mL and BMI >18.5kg/m2”1

Exclusion Criteria

The exclusion criteria for patients included: “a history of type 2 diabetes, pancreatic surgery, or chronic pancreatitis or other pancreatic disorders resulting in decreased b-cell capacity, DKA requiring medical intervention, or hospitalization for hyperglycemia or hypoglycemia within 1 month before screening, if they had frequent episodes of severe hypoglycemia, showed symptoms of poorly controlled diabetes, or had previously used any SGLT2 inhibitor.”1

Baseline Characteristics

“Participants had to be prescribed insulin for >12 months and be given a dose of >0.3 IU/kg/day for >3 months”1 “C-peptide had to be <0.7 nl/mL and BMI >18.5kg/m2”1

Interventions

Patients continued to receive their injectable insulin therapy for type 1 diabetes and were divided into dapagliflozin 5 mg, 10 mg, or placebo treatment groups (randomized 1:1:1). These patients were started on the regimens designated for their study group for a 24 week short-term period. After the first two weeks, patients on the insulin and dapagliflozin treatments reduced their insulin dosing by 20%. A 28 week extension of study was performed with study visits at weeks 32, 40, 48, and 52. At week 56, a 30-day posttreatment follow up was performed.

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

The addition of Dapagliflozin leads to a decrease in HbA1c.


Secondary Outcomes

Lower amount of insulin, weight loss and increased risk of definite diabetic ketoacidosis.


Subgroup Analysis

Reduction in HbA1c levels in patients in the dapagliflozin subgroups was greater than that in the control group in both the 24 week short-term and 28 week extension trials. Four weeks after the discontinuation of treatments, patients returned to baseline HbA1c values. An adjusted average change in HbA1c from baseline to week 52 values for dapagliflozin 5 mg was -0.27% (p=0.06), for dapagliflozin 10 mg it was -0.31% (p=0.06), and for placebo it was 0.06% (p=0.06). Insulin doses were reduced by 20% in the dapagliflozin groups in week 2 to prevent adverse reactions. Weight loss was also greater in the dapagliflozin subgroups, but there was no correlation to baseline HbA1c or BMI values. Adjusted average changes from baseline weight to week 52 values in the dapagliflozin 5 mg, 10 mg, and placebo respectively was -2.31 kg, -3.65 kg, and 0.25 kg (p=0.27).

Adverse Events

The number of patients with AEs were higher in the dapagliflozin treatment groups than with the placebo group. Infections and infestation events occurred in 55.6% (NNH= 13), 53.7% (NNH= 18), and 48.1% of the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively. Discontinuations due to AEs occurred in 4.0%, 4.4%, and 3.5% in the 5 mg, 10 mg, and placebo group, respectively. SAEs were reported in 13.4%, 13.5%, and 11.5% of patients in the 5 mg, 10 mg, and placebo group, respectively with the SAEs related to the study drug being 2.9%, 4.4%, and 0.8%. The proportion of patients experiencing a SAE of hypoglycemia was comparable among the 3 groups: 1.1% for 5 mg, 1.4% for 10 mg, and 1.2% for placebo group. DKA events occurred most frequently in the 5 mg dapagliflozin group with 11 participants (4.0%) having a definite event. 10 participants (3.4%, NNH= 67) in the 10 mg group and 5 participants (1.9%) in the placebo group experienced a definite DKA event. All DKA events were successfully managed and did not cause any further complications.

Criticisms

This phase 3 study was done over a period of 52 weeks. It may be argued that 52 weeks is not the appropriate amount of time to determine possible long term side effects of this medication.

Limitations: There was not a protocol-mandated algorithm in which insulin was titrated. Due to the lack of protocol, the full glycemic potential of dapagliflozin may not have been observed. The insulin dose reductions between the 24-week short-term study and the 28-week long-term study cannot be directly compared because two different methods were used for reporting insulin dose. For the 52-week study, patients recorded the midpoint for basal and bolus insulin dose for each week. For the 24-week short-term study, each insulin dose taken was recorded daily at set times so that the total daily insulin dose may be calculated. This study may not be applicable to all ethnicities because the the population of this study was predominantly Caucasian. “The DEPICT-2 study in patients with dapagliflozin in patients with type 1 diabetes included a large number of Asian patients from Japan in addition to countries with predominantly Caucasian patients”1 and thus may also not be applicable to all ethnicities.

Funding

AstraZeneca and Bristol-Myers Squibb funded the study. AstraZeneca is a manufacturer of Farxiga, Qtern, and Xigduo all of which employ Dapagliflozin in their formulations.

Further Reading

Dandona, P. et.al. (2018). Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes: The DEPICT-1 52-Week Study. Diabetes Care, [online] 41(12), pp.2552-2559. Available at: http://care.diabetesjournals.org/content/41/12/2552 [Accessed 11 Apr. 2019].