How conclusive is the CONCLUDE trial?

The development of basal insulin analogues has reduced the risk of hypoglycaemia in insulin-treated individuals with type 2 diabetes. Insulin degludec and insulin glargine 300 U/ml (glargine U300) represent an evolution of basal insulin analogues, both of them reducing the risk of hypoglycaemia as compared with that associated with glargine U100. However, whether degludec and glargine U300 are equivalent with respect to glycaemic control and risk of hypoglycaemia remains to be fully ascertained. In the CONCLUDE trial, 1609 individuals with type 2 diabetes were randomised to either degludec 200 U/ml (degludec U200) or glargine U300. In this issue of Diabetologia (10.1007/s00125-019-05080-9) the investigators report that during the maintenance period, HbA(1c) improved to a similar extent in the two groups with no significant difference in the rate of overall hypoglycaemia (the primary endpoint of the study), while rates of nocturnal symptomatic and severe hypoglycaemia (secondary endpoints) were lower with degludec U200 than with glargine U300. These results, although of great interest to the clinician, need to be carefully interpreted as they cannot be considered as conclusive. First, the primary endpoint was not met and, therefore, analyses of secondary endpoints remain exploratory. Even assuming that degludec is superior to glargine in reducing the risk of hypoglycaemia, the mechanism(s) accounting for such an advantage remain elusive and potential differences in pharmacokinetics and pharmacodynamics difficult to appreciate because of methodological issues. The study design had to be amended because of lack of reliability of the glucometers initially used in the trial, particularly in the low blood glucose ranges, so the potential implications of these changes in the subsequent conduct of the trial cannot be excluded. Finally, comparison with the BRIGHT trial, the only other available head-to-head study, is complicated by differences between the two studies in the primary endpoint (HbA(1c) reduction vs reduction of the risk of hypoglycaemia), study population (insulin-experienced vs insulin-naive) and concomitant glucose-lowering medications. In spite of all this, CONCLUDE teaches us an important lesson regarding the need, particularly in the clinical setting, to monitor the reliability of the glucometers the diabetic individual uses to adjust his/her insulin dose. Insufficient precision or inappropriate use of the glucometer can easily offset any minute advantage a new insulin can offer with respect to glycaemic control and risk of hypoglycaemia.