Dapagliflozin vs. Saxagliptin: Durability of Glycemic Control

The persistence of benefits of dapagliflozin vs. saxagliptin might change therapy choices in patients with type 2 diabetes.

Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has been established to have higher glycemic efficacy, reduction in weight, and reduction in systolic blood pressure than the dipeptidyl peptidase-4 (DPP4) inhibitor saxagliptin. Previous studies have not compared both medications in head-to-head trials in the aspects of the durability of control of HbA1c, fasting plasma glucose, systolic blood pressure, and body weight. This study aimed to assess the durability of HbA1c lowering by reviewing three randomized trials of dapagliflozin vs. saxagliptin in patients with type 2 diabetes over short- and long-term follow-up periods.

For the short-term follow-up period (direct statistical comparison of both medications), patients who are on 1500 mg metformin daily or higher were randomized to either receive dapagliflozin 10 mg daily or saxagliptin 5 mg daily. Open-label rescue medication protocol was put in place if patients had not achieved glycemic control in week six until week 24. The first endpoint was assessed as the number of patients with HbA1c >9% at week 24, patients who received rescue medication, or patients who discontinued treatment because of a lack of glycemic control. The second endpoint was time to rescue medication use or study discontinuation as a result of failure to achieve glycemic control up to 24 weeks. The coefficient of failure (CoF) methodology was used to assess the durability of glycemic control using HbA1c. CoF was measured using the slope from a random coefficient model of changes in HbA1c over weeks 18-24. CoF analysis excluded the data of rescue medication use. Regarding the long-term follow-up period (indirect statistical comparison of both medications), patients were randomized to receive dapagliflozin 10 mg daily or saxagliptin 5 mg daily or placebo plus metformin ≥1500 mg daily for more than eight weeks. Patients who did not achieve glycemic control from weeks of 4 – 102 received open-label rescue medication. The use of rescue medication before week 20 or after excluded patients from the CoF analysis. At least three HbA1c values were collected at three different visits. The first endpoint that was assessed was the time to study discontinuation (TTSD) because of a lack of glycemic control or rescue medication use up to 102 weeks. The second endpoint was the durability of glycemic control between week 20 to 102. Additional endpoints were fasting blood glucose, systolic blood pressure, and body weight in weeks of 20-102 in the CoF population. Kaplan-Meier method was used to assess TTSD. All randomized patients and CoF populations were assessed. The area-under-the-curve estimates assessed the long-term analysis. Random-coefficient- models analysis was used to compare the additional endpoints vs. baseline in the long-term analysis.

Over 24 weeks, 6% fewer discontinuations in the dapagliflozin group had occurred as a result of inadequate glycemic control (95% CI, 1.0-11.0; P<0.05). When HbA1c >9% at 24 weeks was added to the above criteria, the difference in discontinuation increased to 12.3% (4.5,20.0; P<0.01). Dapagliflozin use caused a delay in TTSD and HbA1c improvements in contrast to saxagliptin. Mean CoF in the dapagliflozin group was -0.93%/year vs. 0.45%/year in the saxagliptin group. The difference in CoF estimates was −1.38%/year (−2.41, −0.35; P =0.009). Regarding weeks 20-102, dapagliflozin’s group had 3% fewer discontinuations than the saxagliptin group. Restricting the analysis to weeks 96-102, Discontinuations were 6% (unweighted) more often in the saxagliptin group. Significant negative difference was found in HBA1c (placebo-adjusted) CoF with dapagliflozin vs. saxagliptin (mean difference [95% CI], −0.37 [−0.73, −0.02]; P = 0.04). FPG, SBP, and body weight over weeks 20-102 were maintained significantly in the dapagliflozin’s group vs. the saxagliptin’s group. Regarding safety, incidences of hypoglycemia were low in both groups. Dapagliflozin’s group experienced more genital and urinary tract infections.

In conclusion, they found that dapagliflozin offered higher durability of glucose control than saxagliptin when used for the short term and in the long term. Patients who were in the dapagliflozin group required fewer rescue medications and had fewer discontinuations in addition to a higher reduction in HbA1c, blood pressure, and body weight when used long term. Limitations of the study include the potential confounding variable in long term analysis because of intercurrent illnesses and changes in medications. Additionally, the CoF method doesn’t evaluate the conditions of maintained efficacy that can be worsened or improved over time. Future studies should incorporate an alternative method to incorporate those conditions. Finally, the HbA1c range that was used in the study was between 8%-12%. Therefore, it may not be generalized to patients outside those ranges.

Practice Pearls:

• Dapagliflozin was found to be associated with greater glycemic durability when compared to saxagliptin when used for a short or a long period.
• When used long term, reduction in systolic blood pressure, body weight, and fasting blood glucose is maintained.
• Inadequate glycemic control was decreased in the group that used dapagliflozin.

Bailey, Clifford J., et al. “Durability of Glycaemic Control with Dapagliflozin, an SGLT2 Inhibitor, Compared

with Saxagliptin, a DPP4 Inhibitor, in Patients with Inadequately Controlled Type 2 Diabetes.” Diabetes,

Obesity and Metabolism, 2019

Nour Salhab, Pharm.D. Candidate, USF College of Pharmacy