Dapagliflozin improves glycemic index; SGLT shown as useful adjunctive agent when insulin monotherapy fails, but decrease in insulin use may prove harmful.
Dapagliflozin is a selective sodium glucose cotransporter (SGLT2) inhibitor, a class of oral glucose-lowering agents often used in conjunction with insulin in patients with type 1 diabetes who are not sufficiently managing their diabetes on insulin monotherapy. SGLT2 inhibitors work via blocking the SGLT2 protein, which allows for glucose reabsorption in the proximal renal tubule of the kidneys. This blockage allows for increased glucose excretion and in turn a lowered glucose level.. While standards of care in diabetes promote the use of SGLT2 inhibitors alongside insulin in patients with type 1 diabetes, few studies have focused their attention on diabetic ketoacidosis as an adverse effect of this therapy.
In a 24-week multicenter trial, investigators examined the efficacy and safety of dapagliflozin as an adjunctive therapy to insulin in people with insufficiently managed type 1 diabetes. The phase 3 study was conducted at 137 sites in the USA, South America, Europe, and Asia, and focused specifically on change in HbA1c from baseline. Eligible patients were between the ages of 18–75 years and were considered to have insufficiently managed diabetes if they had a HbA1c between 7.5% and 10.5%. All patients enrolled had been prescribed insulin for at least 12 months prior to the onset of the study.
Included in the analysis were 813 patients who were randomly assigned 1:1:1 to three different treatment groups. Group 1 was given dapagliflozin 5 mg once daily (n=271), group 2 was given dapagliflozin 10 mg once daily (n=270), and the third group was given a placebo (n=272). Randomization of each group was stratified by method of insulin administration, current use of glucose monitoring, and baseline HbA1c. Insulin doses were adjusted throughout the study according to glucose readings, local guidance, and individual conditions.
Mean baseline HbA1c was 8.53% at the onset of the study. At 24 weeks, both the 5 mg and 10 mg dapagliflozin groups showed a statistically significant reduction in HbA1c from baseline compared with placebo. Participants in the 5 mg dapagliflozin group saw a HbA1c reduction of 0.37% on average, and the 10 mg group saw an average reduction of 0.4%. In addition to the enhanced glycemic lowering, investigators also noted a reduction in the amount of insulin needed in each of the treatment groups.
While the focus of the study was to examine the change in HbA1c using an adjunctive therapy in patients whose diabetes was not well-managed on insulin alone, the study unveiled a much more serious outcome. Diabetic ketoacidosis (DKA) occurred in 2.6% of patients in the 5 mg dapagliflozin group and 2.2% in the 10 mg dapagliflozin group, with 0% of patients experiencing DKA in the placebo group. While those numbers may seem inadequate, DKA is a serious and life-threatening complication and remains as the most common cause of death in young patients with type 1 diabetes.
Overall, investigators of the study concluded that using dapagliflozin as an adjunct therapy to insulin has promising results in improving glycemic control in patients with type 1 diabetes when monotherapy has failed. Investigators of this study also noted, however, that the benefits of adding a SGLT2 inhibitor to a pre-existing insulin regimen must be weighed against the increased risk of DKA before prescribing practices can be altered.
- Dapagliflozin as an adjunct therapy can help lower HbA1c and improve glucose levels in patients with type 1 diabetes unable to achieve their goals with insulin alone.
- The risk of developing DKA may be increased in patients with type 1 diabetes when insulin doses are decreased due to addition of SGLT2 inhibitors.
- Further studies need to be conducted over a longer period of time in order to assess the incidence of DKA when SGLT2s are added to pre-existing insulin therapy in patients with type 1 diabetes.
Mathieu, Chantal, et al. (2018). Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial. Diabetes Care. PubMed, doi:10.2337/dc18-0623.
Kirkwood, Michelle. “Dapagliflozin as Adjunct Therapy to Insulin for People with Type 1 Diabetes May Improve Glycemic Control.” American Diabetes Association, Diabetes.Org, 24 June 2018, www.diabetes.org/newsroom/press-releases/2018/dapagliflozin-as-adjunct-therapy-to-insulin-for-people-with-t1-d-may-improve-glycemic.html.
Clarke Powell, Pharm.D. Candidate 2019, LECOM School of Pharmacy