Better glucose control with early combination therapy in patients newly diagnosed with T2DM
The VERIFY (Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes) study is the first to show that early combination therapy using vildagliptin and metformin in patients newly diagnosed with type 2 diabetes (T2D) leads to better long-term blood sugar control and a reduced rate of treatment failure than metformin alone. The VERIFY data were presented at this year’s Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain (16-20 Sept, 2019), and published simultaneously in The Lancet.
Vildagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor. By inhibiting this key enzyme, DPP-4 inhibitors promote secretion of insulin by the pancreas, and inhibit production of glucagon, and thus help control blood sugar and avoid hyperglycaemia.
This study included 2001 patients from 254 centres in 34 countries, with 998 randomised to receive early combination therapy using vildagliptin and metformin, and 1003 randomised to receive initial metformin alone, across a 5-year treatment period (enrolment occurred between 2012 and 2014 and follow-up of the final patients was completed in 2019).
The study was divided into 3 periods. In study period 1, patients received either the early combination treatment with metformin (individual, stable daily dose of 1000 to 2000 mg, depending on the patient’s tolerability) and vildagliptin 50 mg twice daily, or standard-of-care initial metformin monotherapy (individual, stable daily dose of 1000 to 2000 mg) and placebo twice daily.
Treatment response was monitored by patients visiting their centre every 13 weeks, when the patients’ HbA1c level was assessed. If the initial treatment did not maintain levels of HbA1c <53 mmol/mol [7·0%]) during period 1, confirmed at two consecutive scheduled visits, 13 weeks apart, then this was defined as treatment failure and patients in the metformin monotherapy group received vildagliptin 50 mg twice daily in place of the placebo and patients in the early combination therapy group continued on combination.
This second period was thus a phase of two arms where allocated early combination therapy approach was being tested against a later, metformin with vildagliptin-if-necessary combination strategy. Subsequent failure requiring insulin treatment was assessed as an end-point for second failure by two further visits with loss of glycaemic control. Physicians would then move patients onto insulin therapy. However, patients who did not fail in period 1 but maintained good glycaemic control (HbA1c <53 mmol/mol, 7%), continued their randomised study medication for up to five years.
The primary efficacy endpoint was the time from randomisation to initial treatment failure, defined as HbA1c measurement of >53 mmol/mol (7·0%) at two consecutive scheduled visits, 13 weeks apart, during 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 incidence of initial treatment failure during period 1 was 429 (43.6%) patients in the combination treatment group and 614 (62.1%) patients in the monotherapy group. The median observed 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 5-year study duration at 61.9 months. Both treatment approaches were safe and well tolerated.
The risk of losing blood sugar control (going above HbA1c 53 mmol/mol (7.0%), twice) was approximately halved in the early combination treatment group compared with the monotherapy group over the 5-year study duration (a statistically significant 49% relative risk (RR) reduction). During period 2 when patients in both groups were (or could be) receiving combination treatment, the relative risk of losing blood sugar control was also reduced by 26% among those randomised to receive the early combination treatment, compared with those who transferred to combination therapy after their first treatment failure.
This showed that the early combination therapy strategy approach was superior to a sequential strategy approach involving later intensification of the failing monotherapy with a combination therapy, as demonstrated by a durable effect on blood glucose levels. The authors believe the better long term ‘durability’ of blood sugar control seen in the combination group could be due to the complementary mechanism of action between the two drugs.
Source: Press release EASD September 18, 2019