Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial

Abstract

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.

Keywords: cardiovascular; clinical trial; diabetes; diabetes mellitus; hyperglycemia; kidney transplantation; organ transplant; randomized controlled trials; renal transplantation.

Graphical abstract

Figure 1.

Consolidated standards of reporting trial (CONSORT) flow chart of the trial. Structural outline of the Insulin Therapy for the Prevention of New Onset Diabetes after Transplantation (ITP-NODAT) trial. Reasons for trial discontinuation are listed at the bottom of the figure, for control versus treatment group participants. ITT, intention-to-treat; PP, per-protocol.

Figure 2.

Antihyperglycemic therapy and PTDM incidence (framed for month 12 = contributing to the primary end point) in the control versus treatment groups. (A) and (D) Absolute numbers of participants who were treated with antihyperglycemics (insulin and/or oral antidiabetics) through 730 days of follow-up in the control group (dotted line, grey) versus in the treatment group (bold line). (B) and (E) ORs and their 95% confidence intervals for antidiabetic therapy in the treatment versus control group at months 6, 12, and 24. (C) and (F) Absolute numbers of participants who were treated with antidiabetics at months 6, 12, and 24.

Figure 3.

Oral glucose tolerance tests outcomes at 6, 12, and 24 months after transplantation. (A) and (C) Diabetes (red) was defined by requirement for antidiabetic treatment, 2 hour plasma glucose ≥200 mg/dl or HbA1c ≥6.5% in participants who missed their oral glucose tolerance test, as specified in the Methods (n=18 control and n=9 treatment in month 6, n=13 control and n=13 treatment in month 12, n=25 control and n=20 treatment in month 24). Absence of diabetes (tan) was defined by 2 hour plasma glucose <200 mg/dl or HbA1c <6.5% in participants who missed their oral glucose tolerance test. Fasting plasma glucose ≥126 mg/dl in participants with 2 hour plasma glucose <200 mg/dl is shown above the tan part of the bar chart. Missing data for oral glucose tolerance test or HbA1c (white) are presented at the bottom, and a more detailed presentation of the glucose metabolism is provided in Supplemental Figure 1. (B) and (D) ORs and their 95% confidence intervals for diabetes in the treatment versus control group at months 6, 12, and 24 (framed for month 12 = primary end point). Diabetes was defined as described for (A) and (C) (red). (A) and (B) Intention-to-treat population. (C) and (D) Per-protocol population. Adjustment variables: polycystic kidney disease and glomerular disease. Statistically significant ORs are marked (bold).

Figure 4.

Postoperative capillary blood glucose. Mean±SD capillary blood glucose levels >730 days of follow-up in treatment group participants (intention-to-treat population). The color coding of the four different time points (fasting [A], lunch [B], afternoon [C], evening [D]) represents the mean capillary blood glucose course of the respective time point, described at the y-axis. The grey lines are for comparison of the other time points.

Figure 5.

Association between exploratory measures of early protocol adherence and diabetic outcome in the treatment group. (A) Diabetes at months 6, 12, and 24 by the sum of days during the first week after transplantation with missed insulin initiation (when basal insulin therapy initiation was mandated per intervention protocol, but not performed) and with missing afternoon glucose measurements in a combined “Treatment Adherence Score,” in the intention-to-treat population. (B) ORs (95% confidence intervals) for PTDM at months 6, 12, and 24 in the intention-to-treat population. ORs were calculated with days of the “Treatment Adherence Score” as the independent variable. In these models, the odds for diabetes rise by the factor of the corresponding OR, for each additional day on the adherence score. PTDM definitions are analogous to Figure 2, as explained in the Methods section. For further methodological details, see Supplemental Figure 4.