Ertugliflozin Proved Effective in Patients with Type 2 Diabetes and ASCVD

A VERTIS CV sub study on T2D and ASCVD showed significant improvements in glycemic control after adding ertugliflozin to insulin-based regimens.

SGLT2 inhibitors have risen in popularity due to various studies that showed benefits for other conditions besides diabetes mellitus. For example, the FDA approved dapagliflozin for heart failure and CKD regardless of diabetes status due to results from DAPA-HF and DAPA-CKD. Another study that looked at an SGLT2 inhibitor was the VERTIS CV trial. This trial showed how ertugliflozin might reduce heart failure hospitalizations in patients with type 2 diabetes (T2DM) and atherosclerotic cardiovascular disease (ASCVD). In addition to the main study, the investigators also performed an 18-week sub study of VERTIS CV to determine if ertugliflozin added to insulin-based regimens in patients with T2DM and ASCVD would improve glycemic control. After almost a year after publication of VERTIS CV, the results of the sub study are now available.

The VERTIS CV trial was a randomized double-blinded placebo-control trial that initially enrolled 8,246 patients with T2DM and ASCVD. Of those patients, 1,065 patients participated in the sub study. To be eligible, patients must have been on insulin ≥ 20 units/day with or without metformin ≥ 1500 mg/day at baseline, with no other antihyperglycemic agents. Furthermore, patients must have been on a stable dose of insulin for ≥ eight weeks before randomization. Finally, they must remain on the same dose of insulin for the duration of the study unless they required glycemic rescue therapy or experienced clinically significant hypoglycemia. Patients only on prandial insulin were excluded. Eligible patients either received ertugliflozin 5 mg, ertugliflozin 15 mg, or a placebo for 18 weeks. The primary outcome was efficacy based on changes in A1c. Secondary outcomes included effects on fasting plasma glucose (FPG), weight, the proportion of patients with A1c <7%, SBP, DBP, changes in insulin dose after 18 weeks, and safety. Safety outcomes included adverse events (AEs), serious AEs, deaths, and discontinuations. Pertinent AEs (known as Tier 1 AEs) included the following: genital mycotic infections (GMIs), urinary tract infections (UTIs), symptomatic hypoglycemia, and hypovolemia.

Patients were assessed at baseline and every six weeks after that until 18 weeks. The authors used a longitudinal data analysis model to evaluate changes in outcomes from baseline. Logistic regression analysis measured the proportion of patients who achieved an A1c <7% after 18 weeks. Log-rank tests analyzed the proportion of patients requiring glycemic rescue therapy. Furthermore, the authors performed subgroup analyses based on baseline A1c, age, sex, and antidiabetic meds at baseline to see their effects on A1c reductions from baseline to 18 weeks. For each efficacy outcome, the investigators used a stepdown hierarchy approach where they compared ertugliflozin 15 mg daily to placebo to test for a significant difference before analyzing the 5 mg group.

Of 1,065 patients randomized, 979 patients (91.9%) completed the study. At baseline, patients had a mean A1c of 8.4% (±1.0%), the average total daily insulin dose was 70.3 (±45.1) units/day, and the median metformin dose (~60% of patients taking metformin with insulin) was 2000 mg/day. Regarding glycemic control, both ertugliflozin 5 mg (-0.58% [-0.71 to -0.44]) and ertugliflozin 15 mg (-0.65% [-0.78 to -0.51]) were effective in reducing A1c from baseline as compared to placebo (p<0.001 for both). Furthermore, more patients were able to achieve an A1c goal of <7% in the 5 mg and 15 mg groups (20.7% and 21.1% of patients, respectively) than the placebo group (10.7%). They also saw significant reductions in FBG (p<0.001), body weight (p<0.001), and SBP (p<0.01 and p<0.05, respectively) by week 18 in both groups. Improvements in glycemic control may explain reductions in insulin dose observed at week 18 in the ertugliflozin groups. Safety outcomes were comparable between all three groups for GMIs, UTIs, hypoglycemia, and hypovolemia. However, the authors did observe a higher incidence of hypoglycemic episodes on a per-patient basis with ertugliflozin than placebo. Rates of AEs were similar to those observed in studies with other SGLT2 inhibitors.

To summarize, this trial showed that ertugliflozin added to an insulin-based regimen effectively improves glycemic control, weight, and SBP in patients with T2DM and ASCVD. These findings in efficacy and safety are consistent with other SGLT2 inhibitors as well. In the CANVAS trial, canagliflozin showed similar results to ertugliflozin in patients with T2DM and ASCVD. With SGLT2 inhibitors continuing to offer clinically significant benefits, it will be interesting to see what the future holds for them, especially with results from EMPEROR-Preserved just around the corner.

Practice Pearls

• Ertugliflozin is useful for improving A1c, SBP, and weight in patients with T2DM and ASCVD who require insulin ≥20 units/day.
• The safety profile was similar to other SGLT2 inhibitors and was well tolerated by patients.
• Reductions in total daily insulin dose may offset a potential increase in hypoglycemia.

Lingvay, Ildiko et al. “Efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus and established cardiovascular disease using insulin: A VERTIS CV substudy.” Diabetes, obesity & metabolism vol. 23,7, July 2021: 1640-1651.

McMurray, John J V et al. “Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.” The New England journal of medicine vol. 381,21, 21 Nov. 2019: 1995-2008.

Heerspink, Hiddo J L et al. “Dapagliflozin in Patients with Chronic Kidney Disease.” The New England journal of medicine vol. 383,15, 8 Oct. 2020: 1436-1446.

Cannon, Christopher P et al. “Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.” The New England journal of medicine vol. 383,15, 8 Oct. 2020: 1425-1435.

Neal, Bruce et al. “Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.” The New England journal of medicine vol. 377,7, 17 August 2017: 644-657. doi:10.1056/NEJMoa1611925

Andy Dao, PharmD Candidate, University of South Florida Taneja College of Pharmacy