Early basal insulin therapy decreases new-onset diabetes after renal transplantation

Abstract

No effective interventions to reduce risk for new-onset diabetes after transplantation (NODAT), a condition associated with postoperative hyperglycemia and reduced patient and graft survival, have been established. In this 1-year, proof-of-concept clinical trial, we randomly assigned 50 renal transplant recipients to immediate-postoperative isophane insulin for evening blood glucose ≥140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose ≥180-250 mg/dl (standard-of-care control group). We included only patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose ≥140 mg/dl and were subsequently treated with basal insulin; during the first 3 weeks after transplantation, the mean ± SD daily insulin dosage was 17±11 IU/d. Among controls, 23 (92%) of 25 had blood glucose ≥200 mg/dl and 18 (72%) of 25 received standard-of-care antihyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 (28%) of 25 controls required antidiabetic agents. The groups did not differ for insulin sensitivity, but the treatment group showed better β-cell function throughout the 1-year follow-up. In conclusion, this study suggests regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of β cells.

Figure 1.

CONSORT (Consolidated Standards of Reporting Trials) flow chart of the study. tx, transplantation.

Figure 2.

Postoperative mean blood glucose profiles and insulin dosage. (A) Daily mean glucose levels ± SE of the means; P<0.001 (ANOVA of repeated measures). (B) Mean glucose levels ± SD at 4 daily time points from postoperative days 1–21. Overall blood glucose was obtained by averaging all measurements; all P values <0.0001 (two-tailed t test). (C) Daily mean insulin doses ± SE of the means (total daily insulin used); P<0.001 (ANOVA of repeated measures). (D) Mean insulin dose profile: mean insulin levels ± SD at five daily time points from postoperative days 1–21. Overall insulin dose was obtained by averaging all total daily insulin doses, including zeros. Patients not receiving insulin were included (and the respective days were counted as zero). P values were determined using a two-tailed t test. Numbers of patients in the control group and treatment group, respectively, were as follows: postoperative days 1–9: 25 and 25; day 10: 23 and 25; days 11–13: 22 and 25; day 14: 21 and 23; day 15: 20 and 21; day 16: 18 and 21; day 17: 17 and 21; days 18 and 19: 17 and 18; day 20: 16 and 18; day 21: 14 and 15.

Figure 3.

Post-transplantation antidiabetic treatment in the treatment and control groups. Bold lines represent patients known to be receiving antidiabetic therapy (including basal insulin for treatment group). Thin lines reflect periods of changes in antidiabetic treatment. Antidiabetic therapy in the control group was at the discretion of physicians unrelated to the study. ctr, control group; treat, treatment group.

Figure 4.

OGTT outcomes at 3, 6, and 12 months after transplantation. ^{^}Patients receiving antidiabetics were counted as diabetic (without OGTT being performed). ^{^^}Generalized estimating equations were used to determine overall odds ratios over the 1-year follow-up period, accounting for within-patient repeated measures. Boldface numbers indicate findings with P<0.05. CI, confidence interval; imp. glc. tol., impaired glucose tolerance.

Figure 5.

HbA1c, insulin sensitivity, and β-cell function. (A) Mean HbA1c ± SD in control versus treatment group at baseline and 3, 6, and 12 months. (B) Mean change in HbA1c from baseline ± SD in control versus treatment group at 3, 6, and 12 months. P values were determined using a two-tailed t test (*P<0.05). °Generalized estimating equations accounting for within-patient repeated measures. Estimated differences with 95% confidence intervals between study groups were determined using a two-tailed t test and generalized estimating equation. (C and D) Mean insulin sensitivity and β-cell function (by OGIS index in C) and IGI (D) ±SD in control group versus treatment group at 3, 6, and 12 months. P values were determined using a two-tailed t test (for OGIS index, all P≥0.19; for IGI, *P<0.05, ⁺P=0.107, and 2 other P≥0.13). °°Missing values in all patients requiring antidiabetic agents were conservatively predicted, as explained in the text.

Figure 6.

Renal function, as reported with mean ± SD serum creatinine levels at 3, 6, and 12 months. P values were determined using a two-tailed t test.