Trial results VERIFY first-line combination therapy for type 2 diabetes
medwireNews: Upfront combination therapy with vildagliptin and metformin is more durable than metformin alone, and appears to have a legacy effect, report the VERIFY investigators.
During the first phase of VERIFY, the 2001 participants were randomly assigned to receive treatment with metformin at a dose of up to 1000 mg twice daily plus vildagliptin 50 mg twice daily or placebo. All participants were diagnosed within the preceding 2 years and had glycated hemoglobin (HbA1c) levels of 48–58 mmol/mol (6.5–7.5%), to ensure they were in the relatively early stages of clinical disease. They were treatment-naïve or had used metformin for less than a month prior to study entry.
Treatment failure, defined as an HbA1c level of 53 mmol/mol (7.0%) or higher at two consecutive study visits (which were every 3 months), occurred in 62.1% of the metformin-only group, compared with just 43.6% of the combination group.
The median time to treatment failure was 36.1 months in the monotherapy group and was estimated at 61.9 months in the combination group – beyond the median 59.8 months of study follow-up. This equated to a 49% risk reduction in the time to treatment failure with combination versus monotherapy.
“You gain 2 years’ therapeutic window here,” VERIFY investigator David Matthews (University of Oxford, UK) told journalists at the 55th EASD Annual Meeting in Barcelona, Spain.
Patients who experienced treatment failure went on to receive open-label treatment with metformin plus vildagliptin, continuing until the next point of treatment failure, defined as need for insulin initiation according to local guidelines. If a different (non-insulin) medication was needed, the patients were removed from the study.
Importantly, patients who had been on combination therapy in the first phase of the trial also did better during this second phase; those who started on metformin monotherapy had a more rapid progression to insulin-dependence (secondary treatment failure), despite the addition of vildagliptin at the first point of treatment failure.
The issue of whether patients benefit in the long run from receiving more intensive therapy upfront is “a big question in diabetes,” said Matthews.
In VERIFY, those who had taken vildagliptin from the start had a significant 26% reduction in the time to secondary treatment failure, he reported.
Upfront vildagliptin treatment did not result in increased weight gain relative to metformin alone, and rates of hypoglycemia were similar between the two groups.
Although the trial was not powered to assess cardiovascular outcomes, the investigators saw some evidence of a delayed time to first adjudicated macrovascular event with upfront combination therapy, implying that the more intensive glycemic control translated into a reduced risk for cardiovascular complications. However, this was based on very small numbers of events, at 2.4% in the combination therapy group and 3.3% in the metformin group.
Co-investigator Stefano Del Prato (University of Pisa, Italy) stressed that the macrovascular outcomes analysis was purely exploratory and requires a dedicated outcomes study to replicate the findings. But he described the result as “intriguing,” given that the VERIFY study participants, with very early diabetes, are strikingly different from the high-risk populations recruited to the cardiovascular outcomes trials that have demonstrated cardioprotective benefits for some diabetes medications.
Del Prato also noted that there are many other possible first-line medication combinations besides vildagliptin and metformin. He concluded: “We do think that VERIFY is opening up a new era for investigation of what could be the potential benefit of different combinations in the population of people with type 2 diabetes.”
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