Clinical Impact of Initiation of U-500 Insulin vs Continuation of U-100 Insulin in Subjects With Diabetes

Discussion

The purpose of the study was to compare subjects with obesity and T2DM using U-500 concentrated insulin with similarly matched subjects using U-100 insulin. Available studies using U-500 insulin, including prospective trials, have reported the experience after transitioning patients who “failed” U-100 regimens.^{13-16,18,21-24} This failure is a relative and transient condition that, in theory, could be improved with medical intervention and lifestyle changes. Such changes cannot be easily quantified in a clinical trial or retrospective study without a control group. This study was an attempt to fill this knowledge gap.

The U-500 intervention resulted in a 0.8% overall reduction in Hb A_1C and a significant 0.4% reduction compared to subjects using U-100. While both groups had improvement in Hb A_1C , U-500 was associated with superior reductions in Hb A_1C . This finding confirms prior assertions that U-500, compared with U-100, is associated with larger Hb A_1C improvement.^14-16

The preintervention and postintervention Hb A_1C means were > 8% in both groups. This finding suggests that lowering Hb A_1C is challenging, similar to published results demonstrating that Hb A_1C levels < 7% are achieved by fewer than one-third of U-500 users.^16-18 The explanation for this finding remains elusive, due to the methodologic limitations of a retrospective analysis. A possible explanation is the high prevalence of CKD and ASCVD among the study population, conditions which, according to guidelines justify less aggressive glycemic control efforts.²⁵ Multiple prior studies using retrospective data^8,13-16 and 2 prospective trials^18,22 demonstrated similar Hb A_1C reductions after failure of U-100 regimens.

In this study, U-500 resulted in a nominal increase in the risk of severe hypoglycemic episodes. A detailed review of the events found that most of these patients had preestablished CKD and ASCVD, and half of the subjects with sever hypoglycemic episodes had new vascular events during the study (Appendix). These findings suggest a possible correlation between CKD and ASCVD complications and the risk of severe hypoglycemic events. Pharmacokinetic profiles for U-500 have not been studied in subjects with CKD, but the clinical effect of CKD is likely prolonged by the expected reduction in insulin clearance. Similarly, the frailty associated with preexisting ASCVD, or the related polypharmacy, could be factors increasing the risk of hypoglycemia and deserve further study.

Most of the U-500 subjects used it twice daily in this study, which could have contributed to the higher hypoglycemia rate. In a prospective randomized trial Hood and colleagues reported a rate of symptomatic hypoglycemia exceeding 90% in the 2 study groups, and 8 subjects (of 325 total) had severe hypoglycemia during the 6-month observation. The group assigned to 2 daily injections had a significantly higher rate of hypoglycemic events compared with a group that had 3 injections per day.¹⁸ Additional studies are required to ascertain whether U-500, compared with specific U-100 regimens (basal-bolus vs premixed; human vs insulin analogs), results in a higher risk of severe hypoglycemia.

This study also investigated the incidence of new cardiovascular events, and no difference was found between the 2 groups. A longer observation would be required to better assess whether U-500 therapy can reduce the incidence of microvascular and macrovascular complications. The similar incidence of complications is further evidence of the similarity between the 2 studied groups. It was also reassuring to find that weight gains were small and nearly identical in both insulin groups.