Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study

Abstract

Aims/hypothesis: This long-term study was designed to further characterise the retinal safety profile of insulin glargine and human neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus.

Methods: An open-label, 5 year, randomised (1:1), multicentre, stratified, parallel-group study conducted in the USA and Canada enrolled individuals with type 2 diabetes and either no or non-proliferative retinopathy (less than severe; Early Treatment Diabetic Retinopathy Study [ETDRS] level less than 53 in both eyes) who were treated with oral hypoglycaemic agents (OHAs) alone, insulin alone or OHAs with insulin for >/=3 months prior to study entry and a baseline HbA(1c) level of 6.0-12.0%. Patients were randomised by the investigator according to the centralised interactive voice response system to receive twice-daily NPH insulin (n = 509) or once-daily basal insulin glargine (n = 515). The investigator was not blinded to the treatment group to which each participant had been assigned. The main objective of this study was to compare the progression of diabetic retinopathy between treatment groups by analysing the percentage of patients with three or more step progression in the ETDRS retinopathy patient-level severity scale after treatment with either basal insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used.

Results: Similarly sustained glycaemic control was observed in both the insulin glargine and NPH insulin treatment groups. Despite a slightly greater severity of diabetic retinopathy for the insulin glargine group at baseline, three or more step progression in ETDRS score from baseline to end-of-study was similar between treatment groups (14.2% [53/374] of insulin glargine-treated patients vs 15.7% [57/363] of NPH-treated patients); the difference in the incidence of progression was -1.98% (95% CI -7.02, 3.06%). Other measures of retinopathy-the development of proliferative diabetic retinopathy and progression to clinically significant macular oedema-occurred to a similar degree in both treatment groups. No other safety issues, such as unexpected adverse events for either insulin emerged during the 5 year study. However, NPH insulin treatment was associated with a higher incidence of severe hypoglycaemia compared with insulin glargine.

Conclusions/interpretation: This study shows no evidence of a greater risk of the development or progression of diabetic retinopathy with insulin glargine vs NPH insulin treatment in patients with type 2 diabetes mellitus.

Trial registration: ClinicalTrials.gov NCT00174824

Funding: This study was sponsored by sanofi-aventis.

Fig. 1

Summary of participant randomisation and disposition. This study was conducted between June 2001 and April 2007. Patients entering the screening phase (1,413 participants were screened at 46 sites in the USA and 16 sites in Canada) received a participant number and, following fulfilment of inclusion criteria (at the end of the screening phase), were randomised by the investigator according to the centralised interactive voice response system (IVRS). The randomisation schedule (1:1) was stratified by investigational centre and baseline HbA_1c levels (6.0–9.0% and >9.0–12.0%). The investigator was not blinded to the treatment group to which each participant had been assigned. ^aOne patient who was randomised to receive NPH insulin received insulin glargine throughout the study, and is consequently counted in the ITT population as an NPH patient, but in the safety population as an insulin glargine patient, leading to a discrepancy in the numbers for the ITT and safety populations in both the insulin glargine and NPH insulin arms

Fig. 2

Metabolic changes (mean ± SD) during the course of the study from baseline to endpoint (last observation carried forward) in the insulin glargine and NPH insulin groups. a Change in FPG levels over time with twice-daily NPH insulin (squares) and once-daily insulin glargine (triangles; ITT population). b Change in HbA_1c levels over time with twice-daily NPH insulin (squares) and once-daily insulin glargine (triangles; ITT population). c Change in HbA_1c levels over time with twice-daily NPH insulin (squares) and once-daily insulin glargine (triangles) in patients treated with basal insulin plus OHAs only (ITT population). d Summary of patient mean yearly rate of hypoglycaemia with twice-daily NPH insulin (black bars) and once-daily insulin glargine (white bars) (ITT population). Yearly rate of hypoglycaemia was calculated by 365.25 × (number of episodes in the period)/(number of days in period)

Fig. 3

Primary and secondary retinopathy outcomes following treatment with either twice-daily NPH insulin (black bars) or once-daily insulin glargine (white bars; PP population). a Prevalence of three or more step progression on the ETDRS retinopathy severity scale during the course of the study. Percentage of patients calculated using the number of PP population as denominator. b Proportion of patients with three or more step progression on the ETDRS scale at endpoint. Percentage of patients calculated using the number of participants in the PP population as the denominator. There were 57/363 (15.7%) of NPH insulin-treated patients and 53/374 (14.2%) of insulin glargine-treated patients with three or more step progression on the ETDRS. The difference in progression rate between treatment groups was −1.98 (95% CI −7.02, 3.06)