A1C reductions seen in therapy combined with metformin
The use of SGLT-2 inhibitors has increased over the past few years because of their efficacy in type 2 diabetes mellitus. All the currently approved agents — canagliflozin, dapagliflozin, and empagliflozin — have been shown to significantly reduce HbA1c levels when used in combination with other antidiabetic agents. The unique mechanism of action of these agents makes them a feasible option for combination therapy in diabetes management. Current studies are focusing on understanding the safety and efficacy of SGLT-2 inhibitors in conjunction with other agents. It has been shown that dual therapy with metformin and empagliflozin reduces HbA1c while providing weight loss, blood pressure reductions, and reductions in fasting blood glucose. The use of these agents has been well-tolerated and have provided a low risk of hypoglycemia.
Recently, Samy Hadjadj from the University of Poitiers (Université de Poitiers) in France and his colleagues expanded on this topic. In a randomized, double-blind, parallel phase III study, Hadjadj and colleagues compared the safety and efficacy of empagliflozin and metformin in patients with type 2 diabetes. The study included 1,364 patients with HbA1c of 7.5-12% who had not received any treatment for diabetes. Patients were randomized to receive empagliflozin 12.5 mg twice daily with metformin 1000 mg twice daily, empagliflozin 12.5 mg twice daily with metformin 500mg twice daily, empagliflozin 5 mg twice daily with metformin 500 mg twice daily, empagliflozin 5 mg twice daily with metformin 1000 mg twice daily, empagliflozin 25 mg daily, metformin 500 mg twice daily, or metformin 1000 mg twice daily for a total of 24 weeks. The primary endpoint was reduction from baseline in HbA1c. Changes in weight and fasting glucose were used as secondary endpoints.
At 24 weeks, all groups obtained significant reduction in HbA1c. Those patients who received empagliflozin and metformin twice daily obtained A1c reductions of less than 7% (~8.6% at baseline) when compared to those patients receiving monotherapy. Patients who received empagliflozin 12.5 mg twice daily with metformin 100 mg twice daily obtained a 2.08% reduction in A1c (p=0.006 vs metformin 1000 mg twice daily and p<0.001 when compared to empagliflozin 25 mg daily). Similar reductions (-2.07%) were seen in those receiving empagliflozin 5 mg twice daily with metformin 1000 mg twice daily (p=0.006 when compared to metformin 1000 mg twice daily vs p<0.001 when compared to empagliflozin 10 mg daily). The empagliflozin 12.5 mg with metformin 500 mg twice daily regimen provided a 1.93% reduction in HbA1c (p<0.001 when compared to each drug as monotherapy). Similarly, a 1.98% reduction was obtained in those patients receiving empagliflozin 5 mg twice daily and metformin 500 mg twice daily (p<0.001 when compared to each agent as monotherapy). Metformin 500 mg twice daily provided the least HbA1c reduction (-1.18%) followed by empagliflozin 10 mg daily when compared to empagliflozin 25 mg daily, -1.35% and -1.36%, respectively. Moreover, those regimens containing empagliflozin provided significant reductions in fasting plasma glucose and weight (greater than 5% reduction).
Based on these findings, the observed reductions of dual therapy were clinically significant when compared to metformin or empagliflozin monotherapy regimens. Hadjadj and colleague say that “utilizing combination therapy could be useful in providing glycemic control in newly diagnosed patients, especially those with an HbA1c of greater than 8.5%.” Dual therapy with empagliflozin provides a means for initial management in those patients unable to obtain adequate control upon initial diagnosis of type 2 diabetes. Hadjadj does not report any major events leading to discontinuation of treatment. The incidence of hypoglycemia was low in these patients and the most common side effect reported was urinary tract infections and genital infections. It is therefore why it is important to stress the importance of using these regimens that include empagliflozin – and other SGLT-2 inhibitors — with caution in patients with predisposing factors for these infections and/or suffering from other immune deficiencies. As more studies continue to highlight the importance of SGLT-2 inhibitors, it can be concluded that empagliflozin provides significant HbA1c reductions when used in combination with metformin.
- Utilizing empagliflozin with metformin as an initial regimen for glycemic control, provides significant HbA1c reductions.
- Close monitoring should be done in newly diagnosed patients due to the risk of hypoglycemia.
- HbA1c reductions of less than 7% can be obtained with empagliflozin and metformin when used in combination.
Hadjadj, Samy, Julio Rosenstock, Thomas Meinicke, Hans J. Woerle, and Uli C. Broedl. “Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes.” Diabetes Care Dia Care (2016): Dc160522. Web.
Romera, Irene, Ramon Gomis, Susanne Crowe, Pedro De Pablos-Velasco, Unai Aranda, Arantxa García, Sanja Giljanovic Kis, and Ebrahim Naderali. “Empagliflozin in Combination with Oral Agents in Young and Overweight/obese Type 2 Diabetes Mellitus Patients: A Pooled Analysis of Three Randomized Trials.” Journal of Diabetes and Its Complications (2016): n. pag. Web.
Researched and prepared by Christian Gill, Pharm.D. Candidate, Class of 2017. Reviewed by Michelle Caetano, Pharm.D., BCPS, BCACP, CDOE, CVDOE