Metformin is the recommended first-line pharmacological treatment for type 2 diabetes. However, as type 2 diabetes progresses, metformin monotherapy often fails to maintain glycaemic control. In such cases, there is often a failure to intensify treatment as appropriate.
Metformin acts mainly by reducing hepatic glucose production via inhibition of gluconeogenesis and also increases glucose uptake in peripheral tissue. Metformin is associated with a low risk of hypoglycaemia and is weight neutral or can lead to weight loss.
In a retrospective cohort study of more than 81 000 patients with type 2 diabetes, the median time to the addition of another oral glucose-lowering agent after a patient exceeded his or her HbA1c target ranged from 1.6 to 2.9 years.
The reasons for this are unclear but could include a reluctance to initiate more complex drug regimens. Hadjadj et al compared the efficacy and safety of initial combinations of empagliflozin + metformin with empagliflozin and metformin monotherapy in 1 364 drug-naïve patients with type 2 diabetes.
At week 24, reductions in HbA1c (mean baseline 8.6–8.9% [70–73 mmol/mol]) were -1.9% to -2.1% with empagliflozin +metformin twice-daily regimens, -1.4% with both empagliflozin once-daily regimens, and -1.2 to -1.8% with metformin twice-daily regimens.
Reductions in HbA1c were significantly greater with empagliflozin + metformin twice-daily regimens than with empagliflozin once-daily regimens (P <0.001) and with metformin twice-daily regimens (P <0.01). Reductions in weight at week 24 were significantly greater with empagliflozin + metformin twice-daily regimens (range -2.8 to -3.8kg) than with metformin twice-daily regimens (-0.5 to -1.3kg) (P < 0.001 for all). Adverse event (AE) rates were similar across groups (56.7–66.3%). No hypoglycaemic AEs required assistance.
The study found initial combinations of empagliflozin and metformin IR given twice daily for 24 weeks in patients with type 2 diabetes led to statistically significant and clinically meaningful reductions in HbA1c compared with the corresponding empagliflozin once-daily and metformin twice-daily regimens. In the combination therapy groups, changes in HbA1c of ~2% were observed at week 24, irrespective of the dose of empagliflozin or metformin.
Importantly, 57%–70% of patients with HbA1c ≥7% at baseline who received combination therapy reached HbA1c <7% at week 24, and 37%–52% reached HbA1c <6.5%. Even in very poorly controlled patients with type 2 diabetes (mean HbA1c of 11.5% at baseline in the open-label group), 53% reached HbA1c <7% at week 24, suggesting that an initial combination of empagliflozin and metformin may provide substantial benefits in this patient population. In conclusion, twice-daily combinations of empagliflozin and metformin for 24 weeks led to rapid, pronounced reductions in HbA1c and weight loss, with 57–70% of patients reaching HbA1c <7% and 26–41% achieving weight loss of >5% at week 24.
These data suggest that the initial combination of empagliflozin and metformin could represent a valuable treatment option for newly diagnosed patients with type 2 diabetes, particularly those with HbA1c >8.5%, irrespective of the dose of metformin that a patient can tolerate.
REFERENCES: Samy Hadjadj, Julio Rosenstock, Thomas Meinicke, et al. Initial Combination of Empagliflozin and Metformin in Patients WithType 2 Diabetes. Diabetes Care 2016;39:1718–1728 | DOI: 10.2337/dc16-0522.