Exploring early combination strategy in Latin American patients with newly diagnosed type 2 diabetes: a sub-analysis of the VERIFY study

Abstract

Background: Patients with type 2 diabetes mellitus (T2DM) from Latin American countries face challenges in access to healthcare, leading to under-diagnosis, under-achievement of glycemic target, and long-term complications. Early diagnosis and treatment initiation are of paramount importance in this population due to the high prevalence of risk factors such as obesity and metabolic syndrome. The VERIFY study in patients with newly diagnosed T2DM (across 34 countries), assessed the normoglycemic durability (5 years), with early combination (EC) therapy approach versus the traditional stepwise approach of initiating treatment with metformin monotherapy (MET). Here we present the results from the VERIFY study for participants from eight countries in Latin America.

Methods: Newly diagnosed adult patients with T2DM, HbA1c 6.5-7.5% and body-mass index (BMI) of 22-40 kg/m2 were enrolled. The primary endpoint was time to initial treatment failure (TF; HbA1c ≥ 7.0% at two consecutive scheduled visits 13 weeks apart). Time to second TF was evaluated when patients in both groups were receiving and failing on the vildagliptin combination. Safety and tolerability were also assessed for both treatment approaches during the study.

Results: A total of 537 eligible patients (female, 58.8%) were randomly assigned to receive either EC (n = 266) or MET (n = 271). EC significantly reduced the relative risk of time to initial TF by 47% versus MET [HR (95% CI) 0.53 (0.4, 0.7) p < 0.0001]. Overall, 46.4% versus 66.3% of patients achieved the primary endpoint in the EC and MET groups, with a median [interquartile range (IQR)] time to TF of 59.8 (27.5, not evaluable) and 33.4 (12.2, 60.1) months, respectively. The risk for time to second TF was 31% lower with EC (p < 0.0092). A higher proportion of patients receiving EC maintained durable HbA1c < 7.0%, < 6.5%, and < 6.0%. Both treatment approaches were well tolerated, and only 3.2% of participants discontinued the study due to adverse events. All hypoglycemic events (EC: n = 7 and MET: n = 3) were single, mild episodes and did not lead to study discontinuation.

Conclusion: Similar to the global population, long-term clinical benefits were achieved more frequently and without tolerability issues with EC versus standard-of-care MET in this Latin American sub-population. This study is registered with ClinicalTrials.gov, NCT01528254.

Keywords: Early combination; Latin America; Type 2 diabetes mellitus; Vildagliptin.

Conflict of interest statement

PMP was the medical lead of the VERIFY study and employed by Novartis (till Jan 2020) and received grants from Juselius Foundation and UPM Biomedicals, outside the submitted work. CM, SV and YLH declare that they have no competing interests. PP and JMP are employed by and own stocks in Novartis.

Figures

Fig. 1

Patients disposition. HbA1c glycated haemoglobin. * intolerant to at least 1000 mg daily metformin or not compliant

Fig. 2

a Primary treatment failure* among Latin American patients randomized to early combination versus initial monotherapy. CI confidence interval, HR hazard ratio, LatAm Latin America. *Primary treatment failure is defined as HbA1c ≥ 7.0% at two consecutive scheduled visits, starting from 13 weeks after randomization. The time to initial treatment failure is the time from randomization to the second consecutive scheduled visits with HbA1c ≥ 7.0%. Patients who discontinued the study for any reason during period 1 were censored at the date of discontinuation. Patients with HbA1c < 7.0% (or whose measurement ≥ 7.0% was not confirmed at next scheduled visit) were censored at the date of last study visit. The Kaplan–Meier estimates were performed for patients who had received at least one randomized medication and one post-randomization efficacy parameter assessed. b Primary treatment failure* among all patients from VERIFY randomized to early combination versus initial monotherapy. CI, confidence interval; HR, hazard ratio. *Primary treatment failure is defined as HbA1c ≥ 7.0% at two consecutive scheduled visits, starting from 13 weeks after randomization. The time to initial treatment failure is the time from randomization to the second consecutive scheduled visits with HbA1c ≥ 7.0%. Patients who discontinued the study for any reason during period 1 were censored at the date of discontinuation. Patients with HbA1c < 7.0% (or whose measurement ≥ 7.0% was not confirmed at next scheduled visit) were censored at the date of last study visit. The Kaplan–Meier estimates were performed for patients who had received at least one randomized medication and one post-randomization efficacy parameter assessed

Fig. 3

Subgroup analysis of time to initial treatment failure. BMI body mass index, CI confidence interval, eGFR estimated glomerular filtration rate, HR hazard ratio. HRs and the associated CIs and p values were obtained from a Cox proportional hazards model containing terms for treatment approach, geographical region, and baseline HbA1c. Significance was established on the basis of a two-sided 0.05 significance level. The treatment-by-subgroup interaction p values are provided for tests of homogeneity of between-group differences among subgroups, with no adjustment for multiple testing. The p value for treatment comparison in the overall population is also provided. BMI body mass index, CI confidence interval, GFR glomerular filtration rate, HbA1c glycated hemoglobin, HR hazard ratio, N total number of patients considered for each subgroup analysis, n number of patients with relevant results within each subgroup

Fig. 4

Secondary treatment failure* among patients with early combination versus initial monotherapy followed by vildagliptin addition. CI confidence interval, HbA1c glycated hemoglobin; HR, hazard ratio. *Secondary treatment failure is defined as two consecutive scheduled visits with HbA1c ≥ 7.0% during period 2 (i.e., after period 1 comparing metformin monotherapy versus early combination therapy with metformin and vildagliptin and up to end of period 2 when both groups are on combination therapy after primary treatment failure. The time to secondary treatment failure is the number of days from randomization to the second confirmed HbA1c ≥ 7.0% during consecutive scheduled visits, three months apart, in period 2. The Kaplan Meier estimates were performed for patients who had received at least one randomized medication and one post-randomization efficacy parameter assessed. Patients who had no event and discontinued the study for any reason during period 1 or period 2 were censored at the date of discontinuation. Patients who entered period 3 from period 1 were censored to last study visit prior to start of period 3. Two-sided p value was obtained from a Cox proportional hazards model containing terms for treatment approach. Baseline HbA1c was the value obtained on Day 1, or the value obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if Day 1 measurement was missing

Fig. 5

a Success rate of early combination and initial monotherapy approaches at cut-off HbA1c 7.0%. HbA1c glycated hemoglobin. b Success rate of early combination and initial monotherapy approaches at cut-off HbA1c 6.5%. HbA1c, glycated hemoglobin. c Success rate of early combination and initial monotherapy approaches at cut-off HbA1c 6.0%. HbA1c glycated hemoglobin