Quadruple therapy with empagliflozin/dapagliflozin affords long-term glycaemic control

A four-drug combination that includes either empagliflozin or dapagliflozin helps keep glucose in check through 3 years for patients with type 2 diabetes (T2D), in addition to its positive effect on weight and tolerable safety profile, as shown in an open-label randomized controlled study.

At 3 years, HbA1c and fasting plasma glucose (FPG) decreased by 1.7 percent and 60.0 mg/dL with empagliflozin (p=0.001) and –1.1 percent and –48.1 mg/dL with dapagliflozin (p=0.055), respectively. [Diabetes Res Clin Pract 2021;doi:10.1016/j.diabres.2021.109123

The proportions of patients who achieved HbA1c <7.0 percent and <8.0 percent were 29.4 percent and 79.0 percent in the empagliflozin group, respectively. In the dapagliflozin group, the corresponding number of patients who achieved each level of HbA1c was considerably less, 22.3 percent and 58.9 percent, respectively.

Generally, empagliflozin performed better than dapagliflozin, yielding greater reductions in weight (–4.5 vs –1.0 kg; p=0.024) and both high- (HDL) and low-density lipoprotein (LDL) cholesterol (both p<0.05).

“To the best of our knowledge, this is the first prospective study describing the long-term (3 years) effectiveness and safety of empagliflozin and dapagliflozin as a quadruple oral antidiabetic drugs combination therapy in patients with T2D,” the investigators said.

“The reason for the superior effect of empagliflozin to control patient glycaemia and body weight reduction compared to the dapagliflozin group remains to be determined. One possibility is the higher dose of empagliflozin being administered to the patients compared to dapagliflozin,” they added.

There was no significant between-group difference in the overall incidence of adverse events (AEs), cardiovascular events, and mortality. During the study period, 18 out of 185 (9.7 percent) patients in the empagliflozin group and 11 out of 177 patients (6.2 percent) in the dapagliflozin group withdrew from the study as per the recommendation by their physician due to a lack of glycaemic control or the required treatment with a rescue drug.

The reasons for treatment discontinuation regardless of the drug was AE, loss of patient follow-up, missing values for HbA1c, and economic issues. The main AEs leading to treatment discontinuation were hypoglycaemia and volume depletion in the empagliflozin (5.6 percent) and the dapagliflozin (7.9 percent) groups, respectively. 

The cohort comprised 362 patients (mean age 58 years, 60.7 percent male, body mass index 26 kg/m², mean disease duration ≥12 years) with inadequately controlled T2D despite combined treatment with metformin, glimepiride, and a dipeptidyl peptidase-4 inhibitor. They were given a sodium-glucose co-transporter 2 (SGLT2) inhibitor as a fourth drug in their regimen, with 185 randomly assigned to empagliflozin 25 mg/day and 177 to dapagliflozin 10 mg/day.

More than half of the patients in the population had hypertension, and more than a quarter had cardiovascular disease. As background glucose-lowering agents, mean daily doses of metformin and glimepiride were 1,800 mg and 7.3 mg, respectively, and sitagliptin and vildagliptin were the most prescribed DPP-4 inhibitors. For statins and other antihypertensive drugs, the distribution of prescription between the two groups was comparable.

“As T2D is a progressive complex disease, maintenance of glycaemic goals for extended periods of time with monotherapy is often challenging in many patients. Current guidelines recommend that treatment intensification should not be delayed for patients who do not meet their treatment goals,” according to the investigators. [Diabetes Care 2021;44:S111-S124; Diabetes Metab J 2021;45:461-481; Diabetologia 2020;63:221-228]

“Injectable therapy with insulin or GLP-1RA can effectively improve glycaemic control in patients who have failed with oral antidiabetic drugs (OADs), but there is a population of patients that are often reluctant to initiate injectable therapy for a variety of personal reasons. Therefore, a significant number of patients need an alternate regimen where they are now being recommended for quadruple OADs therapy in clinical practice,” they added.

The investigators believed that the SGTL2 inhibitor-based quadruple OADs, given their durable effects, may be a viable therapeutic option for patient-centred strategies to treat poorly controlled T2D.