VERIFY: Early Vildagliptin and Metformin Combination Therapy Associated with Greater and Long-term Glycemic Durability vs. Metformin Monotherapy

Table of Content

Newly diagnosed type 2 diabetes mellitus patients treated with an early combination therapy of vildagliptin plus metformin experience greater clinical and long-term glycemic durability benefits vs. those treated with standard-of-care initial metformin monotherapy or late combination therapy, according to the VERIFY trial.

Background

Some evidence suggests that achieving early glycemic control within the first 12 months of diagnosis of type 2 diabetes mellitus (T2DM), may improve long-term glycemic durability and potentially alleviate the risk of associated complications. Introducing combination therapy at an early stage of T2DM diagnosis may potentially result in better achievement and management of glycemic control as compared to the traditional stepwise approach. Nevertheless, the validity of this approach is yet to be determined.

Aim 

The Vildagliptin Efficacy in combination with metfoRmIn For earlY treatment of type 2 diabetes (VERIFY) trial compared the efficacy and safety of early combination therapy with vildagliptin plus metformin as against the standard of care metformin monotherapy over a period of five years in newly diagnosed T2DM patients.

Patient Profile

  • Patients with newly diagnosed T2DM (diagnosis established within 2 years before study enrolment; age: 18–70 years), having glycated hemoglobin (HbA1c) of 6·5–7·5% and a body-mass index of 22–40 kg/m² (n=4524)
  • All patients received appropriate lifestyle modification advice including diet counseling and exercise training before enrolment

Methods

Study Design

  • A multinational, randomized, double-blind, parallel-group study conducted in 254 centers across 34 countries

Study Phases

  • A 2-week screening visit
  • A 3-week metformin-alone run-in period (target dose; maximum 1500 mg/day)
  • A 5-year treatment period further split into study periods 1, 2, and 3 (results of study periods 1 and 2 reported in this study)

Treatment Strategy

  • Patients tolerating 1000 mg/day metformin during run-in phase (n=2001) were randomized 1:1 either to early combination therapy (n=998) or metformin monotherapy (n=1003)
  • Study period 1: Patients were treated with early combination therapy 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.
  • Study period 2: For cases that failed to  maintain HbA1c below 7·0% with initial treatment failed (as confirmed at two consecutive scheduled visits 13 weeks apart), placebo was replaced with vildagliptin 50 mg twice daily amongst patients in the metformin monotherapy group.

Endpoints

Primary Endpoint

  • The time from randomization to initial treatment failure (defined as HbA1c measurement of at least 7·0% at two consecutive scheduled visits, 13 weeks apart from randomization through study period 1)

Secondary Endpoints

  • The time to second treatment failure (defined as HbA1c measurement of at least 7.0% at two consecutive scheduled visits, 13 weeks apart)
  • Safety and tolerability

Results

  • The five-year study period was completed by 79.9% (n=1598) patients: 81·3% (n=811) in the early combination therapy group and 78·5% (n=787) in the monotherapy group.
  • The median follow-up time for patients in the early combination treatment group as well as those in the monotherapy group was 59.8 months.
  • The incidence of initial treatment failure during period 1 was lesser in the combination therapy group vs. the monotherapy group (43·6% vs. 62.1%) (Figure 1). This translates to a 49% relative risk reduction in time to initial treatment failure with early combination of vildagliptin and metformin compared to metformin monotherapy over the five-year study duration {hazard ratio (HR); 0·51, 95% CI 0·45–0·58, p<0·0001}
Figure 1: Incidence of primary endpoint in the study groups

  • The median observed time to treatment failure was higher in the early combination treatment group, in fact, it could be estimated only beyond study duration when compared to the monotherapy group ). This resulted in a gain of therapeutic window of least 2 years with vildagliptin and metformin combination compared to metformin alone, over the study duration (Figure 2).
Figure 2: Time to treatment failure in the study groups

  • Furthermore, early combination therapy was also associated with a significant 26% RR in time to second treatment failure during period 2 (HR; 0.74, 95% CI0.63-0.86, p<0.0001)
  • Patients treated with early combination therapy vs. those treated with monotherapy consistently had lower HbA1c throughout the study period, with greater proportion of these patients in the early combination group with HbA1c below 7%, 6.5% and 6%.
  • Patients treated with monotherapy had a more rapid deterioration of glycemic control as compared to those treated with early combination therapy.  
  • Both treatment approaches were equally safe and well tolerated, with no unexpected or new safety findings, and no treatment-related deaths.
  • The incidence of hypoglycemic events was low and similar in both the study groups . Mild reduction in body weight was observed in both the study groups, over the 5-year period.
  • The rate of treatment discontinuation was low and similar in both the study groups

Conclusions

  • Early combination therapy with vildagliptin and metformin improved glycemic durability in newly diagnosed T2DM patients compared to standard-of-care initial metformin monotherapy or sequential vildagliptin combination.
  • Early combination treatment not only reduced the probability of initial treatment failure, but also reduced the time to second treatment failure compared with monotherapy throughout the five-year study duration.
  • The early combination therapy was safe and well-tolerated in T2DM patients.

Lancet. Sep18, 2019 (Published Online); DOI: 10.1016/S0140-6736(19)32131-2.