Articles 2262 www.thelancet.com Vol 379 June 16, 2012 Lancet 2012; 379: 2262–69 Published Online June 9, 2012 DOI:10.1016/S0140- 6736(12)60439-5 See Comment page 2220 *Equal contributions Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia (Prof P Aschner MD); The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong Special Administrative Region, China (Prof J Chan FRCP); Centre for Endocrine and Diabetes Science, Cardiff University, Cardiff, UK (Prof D R Owens MD); Point Medical Rond Point de la Nation, Dijon, France (S Picard MD); Sanofi, Bridgewater, NJ, USA (E Wang PhD); Sanofi, Paris, France (M-P Dain MD, V Pilorget MD); Rafic Hariri University Hospital, Beirut, Lebanon (A Echtay MD); and Tulane University Medical Center, New Orleans, LA, USA (Prof V Fonseca MD) Correspondence to: Prof Pablo Aschner, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia paschner@cable.net.co Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial Pablo Aschner*, Juliana Chan*, David R Owens, Sylvie Picard, Edward Wang, Marie-Paule Dain, Valérie Pilorget, Akram Echtay, Vivian Fonseca, on behalf of the EASIE investigators Summary Background In people with type 2 diabetes, a dipeptidyl peptidase-4 (DPP-4) inhibitor is one choice as second-line treatment after metformin, with basal insulin recommended as an alternative. We aimed to compare the efficacy, tolerability, and safety of insulin glargine and sitagliptin, a DPP-4 inhibitor, in patients whose disease was uncontrolled with metformin. Methods In this comparative, parallel, randomised, open-label trial, metformin-treated people aged 35–70 years with glycated haemoglobin A 1c (HbA 1c ) of 7–11%, diagnosis of type 2 diabetes for at least 6 months, and body-mass index of 25–45 kg/m² were recruited from 17 countries. Participants were randomly assigned (1:1) to 24-week treatment with insulin glargine (titrated from an initial subcutaneous dose of 0·2 units per kg bodyweight to attain fasting plasma glucose of 4·0–5·5 mmol/L) or sitagliptin (oral dose of 100 mg daily). Randomisation (via a central interactive voice response system) was by random sequence generation and was stratified by centre. Patients and investigators were not masked to treatment assignment. The primary outcome was change in HbA 1c from baseline to study end. Efficacy analysis included all randomly assigned participants who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable. This trial is registered at ClinicalTrials.gov, NCT00751114. Findings 732 people were screened and 515 were randomly assigned to insulin glargine (n=250) or sitagliptin (n=265). At study end, adjusted mean reduction in HbA 1c was greater for patients on insulin glargine (n=227; –1·72%, SE 0·06) than for those on sitagliptin (n=253; –1·13%, SE 0·06) with a mean difference of –0·59% (95% CI –0·77 to –0·42, p<0·0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4·21 [SE 0·54] vs 0·50 [SE 0·09] events per patient-year; p<0·0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event. Interpretation Our results support the option of addition of basal insulin in patients with type 2 diabetes inadequately controlled by metformin. Long-term benefits might be expected from the achievement of optimum glycaemic control early in the course of the disease. Funding Sanofi. Introduction In type 2 diabetes, large-scale randomised clinical trials have shown that early achievement of glycaemic control with glycated haemoglobin A 1c (HbA 1c ) less than 7% resulted in long-term benefits in reduction of micro- vascular complications and might reduce macrovascular problems. 1–3 With the exception of patients with sub- stantial renal impairment or gastrointestinal intol- erance, metformin is the mainstay of treatment in type 2 diabetes. However, most people eventually need additional treatment to achieve their glycaemic goal. 4–6 In view of the low associated risk of hypogly- caemia and neutral effect on bodyweight, dipeptidyl peptidase-4 (DPP-4) inhibitors are increasingly added to metformin as an alternative second agent to sulpho- nylureas. 7,8 Alternatively, randomised clinical trials 9,10 and meta-analysis 11 have suggested that the early addition of basal insulin to metformin treatment can lower HbA 1c effectively with good tolerability. To date, no studies have compared the use of DPP-4 inhibitors versus basal insulin in people with type 2 diabetes who have not responded to metformin monotherapy. In the EASIE (Evaluation of insulin glargine versus Sitagliptin in Insulin-naive patients) trial, we aimed to compare the efficacy, safety, and tolerability of basal insulin (insulin glargine) versus a DPP-4 inhibitor (sitagliptin) in such a population during a 24-week period. Methods Study design EASIE was a multicentre, 6-month, comparative, two- arm, parallel, randomised, open-label trial undertaken in 17 countries (appendix p 1) from Nov 12, 2008, to July 28, 2011. It included an initial 2-week screening See Online for appendix