Insights from VERIFY: Early Combination Therapy Provides Better Glycaemic Durability Than a Stepwise Approach in Newly Diagnosed Type 2 Diabetes

Abstract

The treatment aims for type 2 diabetes are to prevent complications and premature mortality, and improve quality of life. Glycaemic control is central to these aims; clinical guidelines have sought to achieve this with a stepwise approach starting with lifestyle measures and metformin, adding further medications once glycated haemoglobin (HbA1c) levels rise above a predefined threshold. However, treatment intensification can be delayed when HbA1c levels increase, and HbA1c levels become inadequately controlled in many patients. Clinical inertia can result in sustained elevated levels of HbA1c; when combined with a late diagnosis, this negatively impacts patients' prognosis. Early combination therapy using medications with complementary modes of action could achieve optimal glycaemic targets and alter the course of the disease more than metformin alone. The multinational VERIFY study (clinicaltrials.gov NCT01528254) provided evidence accrued over 5 years, demonstrating the potential of early combination therapy: time to loss of glycaemic control was nearly doubled, and more than twice the number of patients experienced extended glycaemic control, with a vildagliptin-metformin combination therapy versus metformin alone. The study also showed a delay in secondary treatment failure in patients receiving the combination. Early combination therapy therefore offers a different trajectory to the stepwise approach. Translating these findings into clinical practice will require early detection and diagnosis of type 2 diabetes plus a shift in disease management. Nonetheless, the potential benefits of sustained and continuous disease control that early combination therapy offers represent the start of a new era in early diagnosis and intensive management, to achieve the treatment aims of type 2 diabetes.

Keywords: Combination therapy; Glycaemic control; Type 2 diabetes; VERIFY; Vildagliptin.

Figures

Fig. 1

An abbreviated overview of ADA and EASD recommendations over the last decade for stepwise therapy for patients with type 2 diabetes. 1Nathan DM, et al. Diabetologia 2009;52:17–30 [4]. 2Inzucchi SE, et al. Diabetologia 2012;55:1577–96 [6]. 3Inzucchi SE, et al. Diabetologia 2015;58:429–42 [5]. 4Davies MJ, et al. Diabetologia 2018;61:2461–98 [1]. 5Buse JB, et al. Diabetologia 2020;63:221–8 [7]. *Well-validated core therapies. †GLP-1 receptor agonist not to be used with either a DPP4 inhibitor or an SGLT2 inhibitor. ADA American Diabetes Association, ASCVD atherosclerotic cardiovascular disease, CKD chronic kidney disease, CVD cardiovascular disease, EASD European Association for the Study of Diabetes, HbA1c glycated haemoglobin

Fig. 2

The VERIFY study design. Adapted from Del Prato S, et al. Diabet Med. 2014;31;1178–84 [16]

Fig. 3

A 26% reduction in risk of time to secondary treatment failure following early combination therapy in the VERIFY study [14]; i.e. approx. 1 in 4 patients treated and initially experiencing failure with early combination treatment did not require addition of a third treatment (usually insulin), versus delayed combination therapy. *Defined as loss of glycaemic control: two consecutive values of HbA1c ≥ 53 mmol/mol (7.0%). †Defined by the need to maintain glycaemic control with a third treatment (usually insulin) in patients receiving combination therapy, according to local diabetes treatment guidelines and as per investigators discretion

Fig. 4

Early combination strategy and evolution of the patient journey from early diagnosis of type 2 diabetes. Adapted from Reach G, et al. Diabetes Metab. 2017;43:501–11, Strain WD, et al. Diabetes Res Clin Pract. 2014;105:302–12 and Pantalone KM, et al. Diabetes Care. 2016;39:1527–34 [–12]

Fig. 5

Guiding principles: the six most important actions for the physician in an early combination strategy