VERIFY – Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes
Chantal Mathieu, MD
Department of Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium Michael Stumvoli, MD
Diabetes, University Hospital Leipzig, Leipzig, Germany David R. Matthews, MD
Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK Stefano del Prato, MD
Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Pisa, Italy
The VERIFY study showed that early intervention with a combination of vildagliptin plus metformin is associated with greater and more durable long-term benefits vs initial metformin monotherapy for patients with newly diagnosed type 2 diabetes.
Thus, this trial provides solid evidence that early combination therapy is superior to the current standard of care, i.e. sequential addition of medications to maintain glycaemic control.
Previous studies have established that use of early glucose-lowering treatments with metformin for the management of type 2 diabetes is associated with a reduction in morbidity and mortality, as well as continued benefit. Recent short-term studies on metformin combinations with different anti-hyperglycaemic medications have suggested improvements in glycaemic outcomes, although the validity of such an approach in the long-term has not been demonstrated.
The Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) trial assessed the long-term benefits and glycaemic durability of an early combination treatment strategy with metformin and vildagliptin.
Type 2 diabetes diagnosed within 2 years prior to enrolment, centrally confirmed by HbA1c of 48–58 mmol/mol (6.5–7.5%), and BMI 22–40 kg/m².
Patients were randomly assigned in a 1:1 ratio either to early combination treatment or to initial metformin monotherapy.
In study period 1, patients received either early combination treatment with metformin (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and vildagliptin 50 mg twice daily, or standard-of-care initial metformin monotherapy (stable daily dose of 1000 mg, 1500 mg, or 2000 mg) and placebo twice daily.
If the initial treatment did not maintain HbA1c <53 mmol/mol (7.0%), patients in the metformin monotherapy group received vildagliptin 50 mg twice daily in place of placebo and entered study period 2, during which all patients received combination therapy.
Total patients randomised: 2001.
Early combination treatment (n = 998).
Initial metformin monotherapy (n = 1003).
Primary outcome measure
Time from randomisation to initial treatment failure, defined as HbA1c of at least 53 mmol/mol (7.0%) at two consecutive scheduled visits, 13 weeks apart from randomisation through period 1.
A total of 1598 (79.9%) patients completed the 5-year study: 811 (81.3%) in the early combination therapy group and 787 (78.5%) in the monotherapy group.
The rate of initial treatment failure during period 1 was 43.6% for patients in the combination treatment group and 62.1% for patients in the monotherapy group.
The median time to treatment failure in the monotherapy group was 36.1 months, while the median time to treatment failure time for those receiving early combination therapy could only be estimated to be beyond the study duration at 61.9 months.
A significant reduction in the relative risk for time to initial treatment failure was observed with early combination treatment vs monotherapy over the 5-year study duration (HR 0.51 (95% CI 0.45–0.58); P <0.0001).
Both treatment approaches were well tolerated, with no unexpected or new safety findings.
When all patients were receiving combination therapy, the risk for time to second treatment failure was reduced by 26%.
Median time to treatment failure was 3 years with initial monotherapy vs 5 years for an initial combination strategy.
An early combination treatment strategy significantly reduced the relative risk of time to initial treatment failure vs initial monotherapy.
Key Messages/Clinical Perspectives
Early intervention with a combination of vildagliptin plus metformin provides greater and durable long-term benefits compared with the current standard-of-care (i.e. initial metformin monotherapy) for patients with newly diagnosed type 2 diabetes.
There is now evidence that early combination therapy is superior to sequential addition of medications to maintain glycaemic control and slow progression of diabetes.