Triple Therapy: Dapagliflozin, Saxagliptin, Metformin

Triple therapy with dapagliflozin added to metformin and saxagliptin has sustained efficacy compared to placebo, and is well-tolerated over 52 weeks in patients with T2DM, according to results from a study published online in Diabetes Obesity & Metabolism.¹

“Treatment with dapagliflozin versus placebo as add-on therapy to saxagliptin plus metformin improved A1C and FPG [fasting plasma glucose] and resulted in a larger proportion of patients achieving A1C <7%. The favourable effects on glycaemic measures were accompanied by a reduction in body weight,” wrote first author Chantal Mathieu, MD, PhD, of Katholieke Universiteit Leuven, (Leuven, Belgium), and colleagues.

A shorter 24-week study by this research group also reported that dapagliflozin added to saxagliptin plus metformin results in greater HbA1c, FPG, and body weight reductions than placebo in patients with T2DM.² The current study provides longer term results at 52 weeks for this triple therapy combination.

The randomized, double blind, placebo-controlled phase 3 study began with a 24-week period in which patients received open label therapy with the DPP-4 inhibitor saxagliptin (5 mg/day) plus metformin.  After that, patients with stable, adequate glycemic control were randomized to placebo or dapagliflozin 10 mg/day added to open label saxagliptin and metformin for 24 weeks. The blinded period was followed by a 28-week extension period in which participants remained on the blinded medication. At the end of the study, 281/320 (87.8%) patients completed both 24- and 28-week blinded treatment periods.

Key results at week 52:

• HbA1c change from baseline: Greater for dapagliflozin vs placebo (−0.74% vs. 0.07%)

♦ More patients achieved a goal HbA1C <7% with dapagliflozin (29.4%) vs placebo (12.6%)

• FPG change from baseline: Greater for dapagliflozin vs placebo (−27 vs. 10 mg/dL)

• Body weight change from baseline: Greater for dapagliflozin vs placebo (−2.1 vs. −0.4 kg)

• Adverse events: Similar with dapagliflozin (66%) and placebo (71%)

♦ Genital infections: More common with dapagliflozin (6%) than placebo (1%)

♦ Urinary tract infections: Similar frequency for dapagliflozin (9%) vs. placebo (10%)

• Hypoglycemia: Rare (≤2%)

The authors pointed out that the US Food and Drug Administration (USFDA) has issued a warning about increased risk for severe and disabling joint pain with DPP-4 inhibitor use.³ The FDA has also issued a warning about diabetic ketoacidosis (DKA) and urinary tract infection serious enough to cause urosepsis and pyelonephritis with SGLT2 inhibitor use.⁴

However, in June 2016 the American Association of Clinical Endocrinologists and American College of Endocrinology issued a position statement and review of the evidence regarding SGLT2 inhibitor use and DKA. The statement concluded that DKA is infrequent with SGLT2 inhibitor use, and that the risk-benefit ratio overwhelmingly favors continued SGLT2 inhibitor use, without any changes to current recommendations.⁵

That, combined with results from this study, lead the authors to conclude: “[T]riple therapy with dapagliflozin added on to saxagliptin plus metformin therapy provides a new, durable and well-tolerated treatment for patients with T2D.”

Take-home Points

• A phase 3 study found that triple therapy with dapagliflozin added to saxaglitpin plus metformin has sustained efficacy compared to placebo, and is well-tolerated over 52 weeks in patients with T2DM.

• Dapagliflozin was associated with a greater decrease in body weight and fasting plasma glucose than placebo.

• Adverse events were similar with dapagliflozin and placebo, and hypoglycemia was rare.

The study was funded by Bristol-Myers Squibb and AstraZeneca.

One or more authors reports advisory board membership, serving on speakers’ bureau, institutional support, serving as a principal investigator XXX for one or more of the following: Novo Nordisk, Sanofi, Merck Sharp & Dohme, Eli Lilly and Company, Novartis, Bristol-Myers Squibb, AstraZeneca, Pfizer, Johnson and Johnson, Boehringer Ingelheim, Hanmi, Mannkind, Roche, Abbott

Dr Hansen is an employee of Bristol-Myers Squibb. Drs Chen, Johnsson, and Garcia-Sanchez are employees of AstraZeneca.

References:

1. Mathieu C, et al. Efficacy and safety of triple therapy with dapagliflozin add-on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes. Diabetes Obes Metab. 2016 Jul 7.

2. Mathieu C, et al. A randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38: 2009-2017.

3. US Food and Drug Administration.  FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Accessed September 6 2016 at: http://www.fda.gov/Drugs/DrugSafety/ucm459579.htm

4. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. Accessed September 6, 2016 at: http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm

5. Handelsman Y, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT2 inhibitors and diabetic ketoacidosis. Accessed Sepetmber 6, 2016 at: https://www.aace.com/files/position-statements/SGLT-2-position-statement.pdf