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MUNICH -- For type 2 diabetes patients uncontrolled on metformin and sitagliptin (Januvia), adding the novel sodium/glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin improved glycemic levels, a trial showed.

HbA1c improved by 0.7 percentage points with the lower 5 mg dose and by 0.8 percentage points with the higher dose compared with placebo on a background of metformin and the dipeptidyl peptidase-4 (DPP-4) inhibitor , both significant at P<0.001 for the primary endpoint at 26 weeks.

Those were "clinically meaningful reductions," , of drug developer Merck in Kenilworth, N.J., and colleagues reported in the VERTIS SITA2 trial here at the European Association for the Study of Diabetes meeting.

Secondary endpoints also showed significant differences from placebo for the following:

• Weight was lower by 2.0 and 1.7 kg, or 4.4 and 3.7 lb, for the 5-mg and 15-mg dose groups, respectively
• More participants reached the less than 7% HbA1c goal at week 26 (32.1% lower dose and 39.9% higher dose versus 17.0%)
• Fasting plasma glucose was lower by 1.4 and 1.7 mmol/L, 25 and 31 mg/dL, respectively
• Systolic blood pressure came in 2.9 and 3.9 mm Hg lower with the two doses, respectively

With three SGLT2 inhibitors already available, one member of the audience questioned why develop yet another.

"With more agents, there's more choice on the marketplace for patients," answered Lauring, who added that differences have emerged among agents in some classes, like the DPP-4 drugs, and it's possible that the large cardiovascular outcomes trial program with ertugliflozin will be required to see if there is such a difference in the SGLT2s too given the "pretty compelling efficacy with this agent."

Also, a fixed dose combination is attractive for patients, he added, having noted that "SGLT2 and DPP-4 inhibitors have differing, complementary mechanisms of action, and additive efficacy is expected."

, of Aston University in Birmingham, England, called the findings "consistent with effects of other members of class" but cautioned that it's "not possible to make specific comparisons with other members of the class in other studies as populations and other aspects of the studies will differ."

The included 263 type 2 diabetes patients with inadequate glycemic control (A1c of 7.0% to 10.5%) on metformin dosed at 1,500 mg/day or greater and sitagliptin at 100 mg/day. They were randomized to the addition of ertugliflozin at either 5 or 15 mg or placebo for 26 weeks.

Adverse event rates were not higher overall with the drug than placebo, but there were more events deemed treatment related with both doses (10.9% and 14.4% versus 8.5%) and more discontinuations with the lower dose only (5 cases, 3.2%, versus one in the other groups, 0.7% each).

Of the events of interest based on what has been seen with other SGLT2 inhibitors, there was a fairly high rate of genital mycotic infection in women (12.7% with the higher dose and 8.0% with the lower dose versus 1.9% with placebo, P<0.05) and a similar trend in men (3.7% and 4.9% vs 0.0%). Urinary tract infections occurred in 4.6% of the higher dose, 2.6% of the lower dose, and 2.0% of the placebo groups.

Symptomatic hypoglycemia occurred in just 0.7% of the higher dose group but 3.8% of the lower dose and 2.6% of the placebo groups.

"SGLT2 inhibitors are known to result in transient reductions in eGFR," Lauring noted. "And that's what we saw. There were reductions on order of 2 mL/min, which returned to baseline by week 26."

There have also been associations with increases in LDL cholesterol but in the study "we didn't observe meaningful differences."

Two other pivotal trials in the VERTIS series also reported recently, in presentations at the American Diabetes Association meeting this year: VERTIS Mono with ertugliflozin as monotherapy against placebo and VERTIS Factorial, showing greater reductions in A1C with the ertugliflozin-sitagliptin combination than with ertugliflozin or sitagliptin alone.

Merck and Pfizer have announced plans to file for FDA approval of ertugliflozin and two fixed-dose combinations (ertugliflozin plus sitagliptin and ertugliflozin plus metformin) by the end of this year.

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