Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial
Authors: Schwaiger Elisabeth , Krenn Simon , Kurnikowski Amelie , Bergfeld Leon , Pérez-Sáez María José , Frey Alexander , Topitz David , Bergmann Michael , Hödlmoser Sebastian , Bachmann Friederike , Halleck Fabian , Kron Susanne , Hafner-Giessauf Hildegard , Eller Kathrin , Rosenkranz Alexander R. , Crespo Marta , Faura Anna , Tura Andrea , Song Peter X. K. , Port Friedrich K. , Pascual Julio , Budde Klemens , Ristl Robin , Werzowa Johannes , Hecking Manfred 
Published: July 2021

Significance Statement
Sustained (or overt) diabetes mellitus after kidney transplantation is strongly associated with hyperglycemia during the early perioperative period. In a multicenter trial with 263 participants randomized to strict blood glucose monitoring and an early basal insulin intervention versus control (a more liberal approach consisting of sporadic corrections of hyperglycemia and otherwise oral antidiabetics), overt post-transplantation diabetes mellitus (PTDM) was ascertained by antidiabetic treatment and an oral glucose tolerance test (2 hour glucose ≥200 mg/dl). The intervention resulted in modestly reduced PTDM rates at 12 months and 24 months at the cost of higher rates of hypoglycemia. In a per-protocol analysis that excluded protocol violators and accounted for baseline differences in polycystic kidney disease, the reduction in PTDM at 12 months was significant, suggesting the approach merits further study.

Background
Post-transplantation diabetes mellitus (PTDM) might be preventable.

Methods
This open-label, multicenter randomized trial compared 133 kidney transplant recipients given intermediate-acting insulin isophane for postoperative afternoon glucose ≥140 mg/dl with 130 patients given short-acting insulin for fasting glucose ≥200 mg/dl (control). The primary end point was PTDM (antidiabetic treatment or oral glucose tolerance test–derived 2 hour glucose ≥200 mg/dl) at month 12 post-transplant.

Results
In the intention-to-treat population, PTDM rates at 12 months were 12.2% and 14.7% in treatment versus control groups, respectively (odds ratio [OR], 0.82; 95% confidence interval [95% CI], 0.39 to 1.76) and 13.4% versus 17.4%, respectively, at 24 months (OR, 0.71; 95% CI, 0.34 to 1.49). In the per-protocol population, treatment resulted in reduced odds for PTDM at 12 months (OR, 0.40; 95% CI, 0.16 to 1.01) and 24 months (OR, 0.54; 95% CI, 0.24 to 1.20). After adjustment for polycystic kidney disease, per-protocol ORs for PTDM (treatment versus controls) were 0.21 (95% CI, 0.07 to 0.62) at 12 months and 0.35 (95% CI, 0.14 to 0.87) at 24 months. Significantly more hypoglycemic events (mostly asymptomatic or mildly symptomatic) occurred in the treatment group versus the control group. Within the treatment group, nonadherence to the insulin initiation protocol was associated with significantly higher odds for PTDM at months 12 and 24.

Conclusions
At low overt PTDM incidence, the primary end point in the intention-to-treat population did not differ significantly between treatment and control groups. In the per-protocol analysis, early basal insulin therapy resulted in significantly higher hypoglycemia rates but reduced odds for overt PTDM—a significant reduction after adjustment for baseline differences—suggesting the intervention merits further study.

Clinical Trial registration number: NCT03507829