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Efficacy And Safety When Adding Ertugliflozin to Metformin and Sitagliptin

Dec 16, 2017

New SGLT-2 inhibitor can be used as add-on therapy to provide better improvement in HbA1C in patients with type 2 diabetes.

Metformin is the standard first line therapy for patients with type 2 diabetes. DPP-4 inhibitors such as sitagliptin are occasionally added as an add-on treatment for increasing the incretins action and achieving better glycemic control. As diabetes progresses a third agent could be added to the treatment if the patient does not meet his or her glycemic goals. SGLT-2 Inhibitors are safe and effective anti-diabetic agents that are well tolerated with minimal risk of hypoglycemia, and work differently from the other two agents. Some studies have shown that SGLT-2 Inhibitors also lower blood pressure and reduce body weight.


Ertugliflozin is an SGLT-2 selective agent that is currently being evaluated on the VERTIS clinical trial program. For Phase 3, a study included the administration of ertugliflozin to patients already taking metformin and sitagliptin. The trial was conducted across 12 countries and included 462 patients from April 2014 until June 2016. Patients with major cardiovascular conditions such as history of MI, stroke, class III-IV heart failure, CKD stage 3 or higher, were all excluded.  The participants were randomized to either ertugliflozin 5mg, ertugliflozin 15mg or placebo (1:1:1). The study had two phases, A and B, and each one lasted 26 weeks. Primary and secondary endpoints included: HbA1C, fasting plasma glucose (FPG), proportion with HbA1C <7.0%, body weight and systolic BP.

At the end of Phase A, significantly greater reductions in HbA1C from baseline were observed in the ertugliflozin groups compared to placebo; the mean HbA1C reductions were as follows: 5mg (-0.7%),10 mg (-0.8%) vs placebo (-0.1%) (p <0.01). Higher proportion of ertugliflozin-treated patients had HbA1c <7.0% at week 26 compared to the placebo group. The odds of having HbA1c <7.0% at week 26 were significantly greater in the ertugliflozin groups versus placebo (p < 0.001). Fewer ertugliflozin-treated patients received glycemic rescue medication at or before the end of Phase A (1.3% and 2.0% for the ertugliflozin 5 mg and 15 mg groups, respectively) compared with placebo (16.3%) Both comparisons were statistically significant.

There were no major adverse effects reported and discontinuation rates were low and similar across all treatment groups. The incidence of hypoglycemia was low and similar between ertugliflozin and placebo (2-7%) After 52 weeks of treatment, relevant adverse effect in the treatment groups were nasopharyngitis (placebo: 3.3%; ertugliflozin 5 mg: 5.1%; ertugliflozin 15 mg: 3.9%) and urinary tract infections (placebo: 5.2%; ertugliflozin 5 mg: 1.3%; ertugliflozin 15 mg: 3.3%). No patient had an event that reflected ketoacidosis and incidences pancreatitis were reported. Genital mycotic infections were relevant for both males and females taking ertugliflozin (up to 14% incidence vs 1% in placebo group). The mean reduction of weight in the treatment group was significant, consistent with SGLT-2 mild benefit of inducing weight loss.

This Phase 3 placebo-controlled trial found substantial improvement in glycemic control with the addition of ertugliflozin added to metformin and sitagliptin. This agent added a greater reduction in HbAc1 compared to placebo. More patients taking the ertugliflozin reached the HbA1C of <7.0%, which represents the standard goal for patients with diabetes, according to the American Diabetes Association. The incidences of UTI were not significant in the treatment group, which contrasts with the SGLT-2 inhibitors reputation of increasing such risk. The authors remarked that diabetes is a progressive disease, which will require intensification of treatment, eventually leading to the use of insulin, thus, the addition of an effective third agent could potentially delay this progression and keep the patient on oral therapy for a longer time while achieving an optimal glycemic control. The significant higher incidence of genital mycotic infections in the treatment group may constitute a risk factor of ertugliflozin, and it should be included in the risk vs benefits information provided to patients prior to starting therapy. Patients with eGFR <60 were not included because SGLT-2 inhibitors are dependent on renal function, so their effects are most likely to be diminished, even though it might still result in beneficially decreasing BP and body weight for that population.

Practice Pearls:

  • The addition of ertugliflozin to standard treatment of metformin with sitagliptin may provide better glycemic control and delay the need for injectable insulin.
  • Patients should be warned that ertugliflozin may increase the risk of mycotic genital infections.
  • Ertugliflozin has not been proven safe nor effective in patients with CKD stage 3+.


Samuel Dagogo-Jack, Jie Liu. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: the VERTIS SITA2 placebo-controlled randomized study

Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy