Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial

Aims/hypothesis As glycaemia and the incidence of microvascular diabetes complications follow a log-linear relationship, it becomes increasingly difficult to demonstrate a microvascular benefit of glucose-lowering when the HbA(1c) level is close to normal. Methods The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomised 12,537 people with diabetes, impaired glucose tolerance or impaired fasting glucose to receive standard glycaemic care or standard care with the addition of basal insulin glargine (A21Gly,B31Arg,B32Arg human insulin), targeting a fasting plasma glucose level <= 5.3 mmol/l. Microvascular outcomes during a median follow-up of 6.2 years were examined in participants whose baseline HbA(1c) was above or below the median of 6.4% (46.4 mmol/mol). Results Allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA(1c) level was >= 6.4% (46.4 mmol/mol; HR 0.90 [95% CI 0.81, 0.99]) but not in participants with a lower baseline HbA(1c) (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). In people whose baseline HbA(1c) level was >= 6.4% (46.4 mmol/mol), the median post-randomisation change in HbA(1c) was -0.65% (interquartile range -0.16, -0.91%) after allocation to insulin glargine and -0.33% (-0.83, 0.13%) after allocation to standard care (median HbA(1c) difference 0.33%; p<0.0001). A smaller median difference of 0.22% was noted in people whose baseline HbA(1c) was <6.4% (p<0.0001). Conclusions/interpretation In patients with dysglycaemia, intervention targeting normal fasting glucose levels reduced HbA(1c) and attenuated the risk of microvascular outcomes in participants with a baseline HbA(1c) level >= 6.4% (46.4 mmol/mol). A neutral effect was seen in those with a lower baseline HbA(1c) level.