Copyright ª Blackwell Munksgaard 2007
Clin Transplant 2007: 21: 246–251 DOI: 10.1111/j.1399-0012.2006.00634.x
Nateglinide improves postprandial hyperglycemia and insulin secretion in renal transplant recipients Voytovich MH, Haukereid C, Hjelmesæth J, Hartmann A, Løvik A, Jenssen T. Nateglinide improves postprandial hyperglycemia and insulin secretion in renal transplant recipients. Clin Transplant 2007: 21: 246–251. ª Blackwell Munksgaard, 2007 Abstract: Background: Postprandial hyperglycemia (PPHG) frequently occurs among renal transplant recipients (RTR). Reduced early insulin response (EIR) after a meal leads to impaired suppression of endogenous glucose production and subsequently PPHG, which is a risk factor for cardiovascular disease. Nateglinide is a rapid acting insulin secretagogue inducing an EIR after a meal. Our main objective was to investigate the safety and effect of nateglinide treatment on postprandial plasma glucose excursions and insulin secretion in RTR with PPHG. Patients and methods: A total of 14 Caucasian RTR with new-onset diabetes mellitus (NODM; n ¼ 6) or impaired glucose tolerance (IGT; n ¼ 8) were included. The insulin response and glucose excursions were measured for 240 min after a standardized liquid meal at baseline and after two-wk treatment with nateglinide. Results: Treatment with nateglinide was followed by a significant decrease in mean two-h plasma glucose from 10.5 mmol/L (3.1) to 7.6 mmol/L (2.1; p < 0.001) and a decline in total postprandial area under the curve (AUC) of glucose concentration (p < 0.001). Both estimated EIR and the late insulin response increased significantly (p ¼ 0.008 and p ¼ 0.003, respectively). No serious adverse event was observed during the study period. Conclusions: Treating RTR with nateglinide for two-wk significantly improved PPHG, increased the insulin response following a standardized meal and was well tolerated.
Monica Hagen Voytovicha, Cecilie Haukereida, Jøran Hjelmesætha, Anders Hartmanna, Astrid Løvikb and Trond Jenssena,c Section of aNephrology and bClinical Nutrition, Department of Medicine, Rikshospitalet Radiumhospitalet HF, University of Oslo, Oslo and cInstitute of Clinical Medicine, Faculty of Medicine, University of Tromsø, Tromsø, Norway
Key words: hyperglycemia – impaired glucose tolerance – insulin secretion – new-onset diabetes mellitus – renal transplantation Corresponding author: Monica Hagen Voytovich, Section of Nephrology, Department of Medicine, Rikshospitalet Radiumhospitalet HF, University of Oslo, Sognsvannsveien 20, Oslo, Norway. Tel.: +47 23 07 35 44; fax: +47 23 07 38 65; e-mail:
[email protected] or
[email protected] Accepted for publication 23 October 2006
Cardiovascular disease is the main cause of death in renal transplant recipients (RTR) (1, 2). Impaired glucose tolerance (IGT) and new-onset diabetes mellitus (NODM) frequently develop after transplantation (3, 4). We have recently shown that RTR with NODM as diagnosed by an oral glucose tolerance test, had a three-fold increased long-term (eight yr) risk of major cardiac events (cardiac death or non-fatal myocardial infarction) (5). In the general population several studies indicate that postprandial hyperglycemia, as seen in, e.g., IGT and mild diabetes, is an independent and clinical significant risk factor for cardiovascular morbidity and mortality (6, 7). Therefore, there has been an increased focus on the importance of
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controlling postprandial glycemia to avoid cardiovascular complications (8, 9). The early insulin response (EIR) after a meal is essential to control PPHG. EIR suppresses endogenous glucose production and reduces the increase in plasma glucose (10). The ideal oral drug should normalize EIR without inducing postprandial hyperinsulinemia and hypoglycemia (11). Traditional antidiabetic drugs like the sulfonylurea (glibenclamide and glipizide) stimulate insulin secretion but dissociate slowly from the SU1receptor and may cause hypoglycemia between meals. Nateglinide is a new d-phenylalanine derivate, also binding to the SU1-receptor but its mode of
Nateglinide and renal transplant recipients action is different from that of the traditional sulfonylureas in several ways. It has a fast-acting effect, which causes an early insulin release. It dissociates from its receptor very quickly, which reduces the risk for sustained hyperinsulinemia and hence hypoglycemia (11). Nateglinide is therefore assumed to have a ÔÔfast on-fast offÕÕ-effect. Furthermore, the effect of nateglinide is glucose sensitive in the sense that the action of the drug is increased with hyperglycemia (12). In total, nateglinide works mainly by restoring the EIR during hyperglycemia and, accordingly, suppressing endogenous glucose production. Consequently, the postprandial hyperglycemia declined approximately 40% in a non-transplant diabetes population (13,14). Another short-acting insulin secretion drug repaglinide has recently been shown to be effective in RTR with NODM (15). However, the effects and safety of nateglinide have not yet been explored in transplanted patients receiving immunosuppressant drugs. The main objectives of the present study were to investigate the safety and effect of two-wk treatment with nateglinide on postprandial plasma glucose excursions and insulin response in RTR with IGT or NODM.
Patients and methods Patients
A total of 14 Caucasian RTR (11 men, three women) were included in the study. None of the patients had diabetes prior to transplantation. All the subjects were found to have post-load hyperglycemia by an oral glucose tolerance test (OGTT) performed at time of inclusion. Based on the WHO criteria (16) six recipients had NODM and eight had IGT. Demographic data are presented in Table 1. The recipients received prednisolone (n ¼ 14; mean: 9.8 mg/d, SD: 2.9 mg/d), a calcineurin inhibitor [cyclosporin A (CsA, Sandimmun Neoral Novartis, Basel, Switzerland, n ¼ 10) or tacrolimus (Prograf Astellas Pharma GmbH, Mu¨nchen; Germany, n ¼ 1)], and mycophenolate mofetil (CellCept Roche, Basel, Switzerland, n ¼ 9) or azathioprine (Imurel GlaxoSmith Kline, London, UK, n ¼ 1). The daily prednisolone dose was not changed during the study (Table 2). The included subjects were 40–7 yr of age, had a mean fasting plasma glucose concentration of 5.5 mmol/ L (1.2) and a mean body mass index (BMI) of 27.2 kg/m2 (3.1) at the time of inclusion. The study was approved by the Regional Ethics Committee and by the Norwegian Medicines Control Agency. Each subject gave written informed consent before participating in the study, according
Table 1. Demographic data at inclusion. The values are given as mean (SD) All Age (yr) IGT/NODM (number) Sex (male/female) Time after transplantation (month) Fasting plasma glucose (mmol/L) HbA1C (%) Body mass index (BMI, kg/m2) GFR (mL/min) Blood pressure Systolic (mmHg) Diastolic (mmHg)
IGT
NODM
57 (12) 59 (13) 54 (11) 14 8 6 11/3 6/2 5/1 3 (2–136) 5 (2–36) 3 (3–136) 5.5 (1.0) 5.0 (0.6) 6.3 (1.1)* 6.6 (0.8) 6.4 (0.5) 6.7 (1.2) 27.2 (3.1) 27.4 (3.3) 27.1 (3.1) 66.1 (16.3) 66.3 (19.7) 67.0 (13.7) 137 (22) 87 (13)
142 (29) 89 (15)
130 (7) 84 (7)
Values are given as mean (SD) or median (range). *p < 0.05.
Table 2. BMI and immunosuppression at baseline and follow-up
BMI (kg/m2) Prednisolone dose (mg/d) CsA concentration (C0) (lg/L)
Baseline
Follow-up
p-value
27.2 (3.1) 9.8 (2.9) 182 (86)
27.1 (3.3) 9.5 (2.5) 167 (97)
0.34 0.50 0.34
Values are given as mean (SD).
to the Declaration of Helsinki (17). The study has been registered at http://www.ClinicalTrials.gov. Study design
All recipients were treated with nateglinide (Starlix; Novartis) for two wk. They received 120 mg (one tablet) nateglinide four times daily, each tablet was taken 10 min before the main meals (breakfast, lunch, dinner, and supper). After an overnight fast, each patient completed a meal tolerance test and indirect calorimetric measurements (IC), both at baseline and at follow-up. Blood samples for analyzing plasma glucose, insulin, C-peptide, free fatty acids (FFA), triglycerides, total-, LDL- and HDL-cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine were drawn at baseline and following two wk of treatment. Also, 24-h urine was collected. During the study period, the subjects were instructed to measure their blood glucose three d a wk, both fasting and two h after breakfast, lunch, dinner, and supper. The individual measurements were performed with Medisense Precision Xtra (Abbot, Norway). Nateglinide was given in blister packages, and compliance was controlled by tablet count at day 7 and day 14. Oral glucose tolerance test
For categorizing the recipients a 75 g oral glucose load in 300 mL of tap water was given to the
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patients at time of inclusion. Venous blood samples were drawn immediately before and at 30, 60, 90, and 120 min. Whole blood glucose was analyzed using HemocueAB B-glucose Analyzer (A¨ngelholm, Sweden) and calculated to plasma values (18). The recipients were diagnosed according to the WHO criteria (16): NODM was diagnosed with fasting plasma glucose ‡7.0 mmol/L or two h plasma glucose ‡11.1 mmol/L (n ¼ 6 in the present study), and IGT with fasting plasma glucose
