Ertugliflozin: A suitable add-on for inadequately controlled T2D

Ertugliflozin may be a suitable add-on therapy in patients with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD) whose glucose levels are inadequately controlled by a metformin-sulfonylurea or insulin regimen, substudies of the phase III VERTIS* CV trial showed.

“Ertugliflozin as add-on therapy to metformin and sulfonylurea in patients with T2DM and ASCVD resulted in significantly greater reductions in HbA_1c, fasting plasma glucose (FPG), and body weight than placebo,” said the researchers at ENDO 2021.

This substudy involved 330 patients aged ≥40 years (mean age 63.2 years) with T2DM (HbA_1c 7.0–10.5 percent; mean 8.3 percent) and ASCVD who were on stable metformin (≥1,500 mg/day) and moderate-to-high dose sulfonylurea. They were randomized 1:1:1 to receive oral ertugliflozin (5 or 15 mg once/day; n=100 and 113, respectively) or placebo (n=117) and were followed up for 18 weeks.

Mean duration of T2DM was 11.4 years. Estimated glomerular filtration rate (eGFR) was 83.5 mL/min/1.73 m² at baseline.

At week 18, patients on both ertugliflozin doses experienced greater reductions in HbA_1c from baseline than those on placebo (least squares [LS] mean difference, -0.66 [5 mg] and -0.75 [15 mg]; p<0.001 for each vs placebo). [ENDO 2021, abstract P16-5]

A greater proportion of ertugliflozin 5 and 15 mg than placebo recipients achieved HbA_1c <7 percent at 18 weeks (adjusted odds ratios, 6.0 and 4.1, respectively, vs placebo).

There were also significantly greater reductions in FPG levels (LS mean difference, -30.5 and -31.4 for ertugliflozin 5 and 15 mg, respectively; p<0.001 vs placebo) and body weight (LS mean difference, -1.6 and -1.9, respectively; p<0.001) from baseline with ertugliflozin vs placebo. However, the reduction in systolic blood pressure (SBP) with ertugliflozin 15 mg was not greater than that with placebo (p>0.05).  

Fewer ertugliflozin than placebo recipients required glycaemic rescue therapy by week 18 (7.0, 2.7, and 10.3 percent of patients in the ertugliflozin 5 mg, 15 mg, and placebo groups, respectively).

Adverse events (AEs) occurred in 48.0, 54.9, and 47.0 percent of patients in the ertugliflozin 5 mg, 15 mg, and placebo groups, respectively, and serious AEs in 7.0, 7.1, and 5.1 percent. Genital mycotic infections were significantly more common among male ertugliflozin than placebo recipients (4.2 percent [5 mg] and 4.8 percent [15 mg] vs 0 percent; p≤0.05) and only numerically higher in female ertugliflozin 15 mg recipients (10.3 percent vs 3.8 percent [placebo]; p=0.36).

Urinary tract infections (UTIs) occurred in 2.0, 3.5, and 3.4 percent of patients in the ertugliflozin 5 mg, 15 mg, and placebo groups, respectively. Symptomatic hypoglycaemia occurred in 11.0, 12.4, and 7.7 percent, and severe hypoglycaemia in 2.0, 1.8, and 0.9 percent. There was one AE-related death in the ertugliflozin 15 mg group.

“Ertugliflozin was generally well tolerated with a safety profile consistent with the SGLT2** inhibitor class,” the researchers said.

“Ertugliflozin is a suitable candidate for add-on therapy in patients with T2DM who are inadequately controlled with metformin and sulfonylurea,” they concluded.

 

Improved outcomes in insulin recipients

The benefits of ertugliflozin were also noted in another VERTIS CV substudy, this time involving 1,065 patients (mean age 64.8 years) with T2DM and ASCVD with glucose levels inadequately controlled with stable insulin (≥20 units/day; median 58 units/day). They were randomized to receive ertugliflozin (5 or 15 mg once/day; n=348 and 370, respectively) or placebo (n=347). Of these, 59.4 percent were also receiving metformin (≥1,500 mg/day). [ENDO 2021, abstract P16-6]

Mean baseline HbA_1c and eGFR levels were 8.4 percent and 73.7 mL/min/1.73 m², respectively, and patients had T2DM for a mean 16.7 years.

At 18 weeks, change from baseline in HbA_1c levels was greater in the ertugliflozin compared with placebo group (LS mean change, -0.58 percent [5 mg] and -0.65 percent [15 mg]; p<0.001 for both vs placebo).

HbA_1c <7 percent at week 18 was achieved by 20.7, 21.1, and 10.7 percent of patients on ertugliflozin 5 mg, 15 mg, and placebo recipients, respectively.

At week 18, ertugliflozin recipients demonstrated significant reductions in FPG levels (LS mean change, -19.2 and -25.4 mg/dL for ertugliflozin 5 and 15 mg, respectively; p<0.001 vs placebo), body weight (LS mean change, -1.6 and -1.9 kg, respectively; p<0.001), and SBP (LS mean change, -2.9 and -2.3 mmHg, respectively; p<0.01 and p<0.05, respectively) compared with placebo. Ertugliflozin 15 mg led to a small reduction in daily insulin dose (LS mean change, -2.1 units/day).

AEs and serious AEs occurred at a comparable rate between the ertugliflozin 5 and 15 mg and placebo groups (AEs: 59.2, 62.4, and 61.1 percent, respectively; serious AEs: 9.5, 7.3, and 10.7 percent). Genital mycotic infections were more common in female ertugliflozin compared with placebo recipients (3.4 percent [5 mg] and 3.6 percent [15 mg] vs 0 percent; p=0.05 and p=0.04, respectively).

UTIs (3.2–4.1 percent), symptomatic hypoglycaemia (26.4–28.5 percent), and severe hypoglycaemia (3.5–5.1 percent) occurred at similar rates across the treatment groups. Hypovolemia incidence was low (1.4–2.4 percent) and comparable between groups. Four, six, and one deaths occurred in the ertugliflozin 5 mg, 15 mg, and placebo groups, respectively.

Fewer ertugliflozin than placebo recipients received rescue therapy by week 18 (6.9, 5.7, and 11.5 percent of ertugliflozin 5 mg, 15 mg, and placebo recipients, respectively).

“SGLT2 inhibitors are a potentially attractive add-on treatment for patients with T2DM inadequately controlled on insulin [± metformin], as [they] have a complementary mechanism of action to exogenous insulin to reduce blood glucose, are not associated with an increased risk of hypoglycaemia, and promote weight loss,” noted the researchers.

“[In this substudy,] ertugliflozin added to insulin ± metformin in patients with T2DM and ASCVD provided clinically meaningful improvements in glycaemic control and benefits in body weight and SBP vs placebo,” they said.