Zidovudine/lamivudine contributes to insulin resistance within 3 months of starting combination antiretroviral therapy
Blümer, Regje MEa; van Vonderen, Marit GAb,d; Sutinen, Jussif,g; Hassink, Ellye; Ackermans, Mariettec; van Agtmael, Michiel Ad; Yki-Jarvinen, Hannelef; Danner, Sven Ad; Reiss, Peterb,e; Sauerwein, Hans Pa
From the aDepartment of Endocrinology and Metabolism, the Netherlands
bDepartment of Infectious Diseases, Tropical Medicine and AIDS (Center for Infection and Immunity Amsterdam), the Netherlands
cDepartment of Clinical Chemistry, Laboratory of Endocrinology and Radiochemistry, Academic Medical Center, the Netherlands
dDepartment of General Internal Medicine, VU University Medical Center, the Netherlands
eInternational Antiviral Therapy Evaluation Center, Amsterdam, the Netherlands
fDivision of Diabetes, Helsinki University Central Hospital, Helsinki, Finland
gDivision of Infectious Diseases, Helsinki University Central Hospital, Helsinki, Finland.
Received 21 April, 2007
Revised 30 September, 2007
Accepted 9 October, 2007
Correspondence to Dr R. Blümer, Department of Endocrinology and Metabolism, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, the Netherlands. E-mail: email@example.com
Background: Patients with antiretroviral therapy (ART)-associated lipodystrophy frequently have disturbances in glucose metabolism associated with insulin resistance. It is not known whether changes in body composition are necessary for the development of these disturbances in ART-naive patients starting treatment with different combination ART regimens.
Methods: Glucose metabolism and body composition were assessed before and after 3 months of ART in a prospective randomized clinical trial of HIV-1-positive ART-naive men taking lopinavir/ritonavir within either a nucleoside reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine/lamivudine; n = 11) or a NRTI-sparing regimen (nevirapine; n = 9). Glucose disposal, glucose production and lipolysis were measured after an overnight fast and during a hyperinsulinaemic–euglycaemic clamp using stable isotopes. Body composition was assessed by computed tomography and dual-energy X-ray absorptiometry.
Results: In the NRTI-containing group, body composition did not change significantly in 3 months; insulin-mediated glucose disposal decreased significantly (25%; P < 0.001); and fasting glycerol turnover increased (22%; P < 0.005). Hyperinsulinaemia suppressed glycerol turnover equally before and after treatment. The disturbances in glucose metabolism were not accompanied by changes in adiponectin or other glucoregulatory hormones. In contrast, glucose metabolism did not change in the NRTI-sparing arm. Glucose disposal significantly differed over time between the arms (P < 0.01).
Conclusions: Treatment for 3 months with a NRTI-containing, but not a NRTI-sparing, regimen resulted in a 25% decrease in insulin-mediated glucose disposal and a 22% increase in fasting lipolysis. In the absence of discernable changes in body composition, NRTI may directly affect glucose metabolism, the mechanism by which remains to be elucidated.
Combination antiretroviral treatment (cART) has remarkably improved the prognosis of patients with HIV-1-infection  but has become associated with changes in body fat distribution or lipodystrophy  and metabolic disturbances, which include dyslipidaemia and alterations in glucose metabolism [3–8]. The pathogenesis of the disturbances in glucose metabolism is likely multifactorial, and both HIV protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI) may play a role [9–23]. Prospective studies showed a decrease in insulin sensitivity and beta-cell dysfunction in HIV-1-infected patients several months after starting a PI-containing regimen [10,14,22]. In healthy volunteers, administration of a single dose of the PI indinavir reduced peripheral glucose uptake during a hyperinsulinaemic clamp .
NRTI drugs are thought to contribute mainly indirectly to disturbances in glucose metabolism by inducing changes in body fat distribution [24,25]. This could explain why cumulative exposure to particular NRTI was found to be independently associated with markers of insulin resistance . It has also been reported, however, that in ART-naive, HIV-1-infected patients insulin resistance develops as early as 4 weeks after initiating cART containing didanosine and stavudine, but not after abacavir plus lamivudine (3TC) . This could suggest that particular NRTI drugs may also disturb glucose metabolism more directly.
In contrast to PI and NRTI, nonnucleoside reverse transcriptase inhibitors have not been implicated in alterations in glucose metabolism.
This study has sought to obtain more insight into the contribution of individual drug classes, NRTI in particular and into the sequence of onset of metabolic disturbances by examining body composition and glucose metabolism in detail in a subset of 20 participants from a randomized clinical trial in ART-naive, HIV-1-infected patients. This trial compares a NRTI-containing regimen of zidovudine (ZDV) plus 3TC plus ritonavir-boosted lopinavir (LPV/r) with a NRTI-sparing regimen of nevirapine (NVP) plus LPV/r. The primary objective of the substudy was to assess the impact of both regimens on glucose metabolism (peripheral glucose disposal, endogenous glucose production) and body composition over time, as well as to compare the effects between both arms. Secondary objectives included the effects and comparisons of these two arms on lipolyis, free fatty acids (FFA), glucoregulatory hormones and lipids. The results reported here cover the first 3 months of treatment.
Subjects and study design
Subjects were participants in the MEDICLAS (metabolic effects of different classes of antiretrovirals) trial. This is an ongoing, multicentre, multinational, single-blinded, randomized trial over 144 weeks in 50 previously antiretroviral drug-naive male patients, 18–70 years of age, with an indication to start cART. The trial compares a NRTI-containing regimen of LPV/r (400/100 mg twice daily) plus ZDV/3TC (300/150 mg twice daily) with a NRTI-sparing regimen of LPV/r (533/133 mg twice daily) plus NVP (200 mg twice daily). Subjects with obesity (body mass index > 35 kg/m2), a history of hyperlipidaemia (according to the treating physician) or diabetes mellitus were excluded, as well as patients using medication that could affect glucose metabolism, for example systemic corticosteroids. For the purpose of the substudy, patients with active infections in the preceding 2 months and/or patients with wasting (defined as a recent loss of > 10% of body weight) were also excluded.
In the subgroup, glucose metabolism was investigated by hyperinsulinaemic–euglycaemic clamps using stable isotopes at baseline and at 3, 12, 24 and 36 months following the start of treatment. Body fat distribution was assessed at these same timepoints by abdominal computed tomography and dual-energy X-ray absorptiometry. Patients could be recruited into the substudy if they were followed at the Academic Medical Center, the Netherlands, or could be referred there from neighbouring participating centres, or at the Helsinki University Central Hospital, Finland, as these were the only sites able to perform the clamp studies according to a common protocol (see below). The study was approved by the medical ethical committees of all participating centres. Written informed consent was obtained from all participants prior to study entry.
At the central study coordinating centre, a treatment allocation sequence (1: 1 for LPV/r+ZDV/3TC and LPV/r+NVP) was generated using the minimization variable body mass index (≤ 25 versus > 25 kg/m2). Treatment allocation was stratified for patients participating only in the main study or patients participating in both the main and the substudy.
Hyperinsulinaemic–euglycaemic clamp protocol
All participants used a balanced diet, containing at least 250 g carbohydrates for 3 days prior to each metabolic study. After fasting for 12 h, subjects were admitted to the metabolic clinical research centre at 10 a.m. and studied in supine position. They fasted till the end of the study day and were only allowed to drink water. Antiretroviral medication was taken without food on the study day. A catheter was inserted in the antecubital vein of each arm. One catheter was used for sampling arterialized blood, using a thermoregulated (60°C) box and the other for infusion of [6,6-2H2]-glucose, [2H5]-glycerol, insulin and glucose 20%. At t = −2.30 (10 a.m.), after drawing a blood sample for background enrichment of plasma glucose and glycerol, a continuous infusion of [6,6-2H2]-glucose (> 99% enriched, Cambridge Isotopes, Massachusetts, USA) was started at a rate of 0.11 μmol/min per kg body weight, after a priming dose of 8.8 μmol/kg. At t = −1.30, a continuous infusion of [2H5]-glycerol at a rate of 0.11 μmol/min per kg was started, after a priming dose of 1.6 μmol/kg. From t = −0.30 until t = 0, blood samples were drawn every 10 min for determination of the rate of appearance of glucose and glycerol. Subsequently at t = 0, a primed continuous infusion of insulin (Actrapid 100 U/ml, Novo-Nordisk Farma BV, Alphen a/d Rijn, the Netherlands) was started for 2.5 h at a rate of 20 mU/min per m2 body surface area. Plasma glucose concentration was measured every 5 min (Beckman glucose analyzer-2, Palo Alto, California, USA) and glucose 20% was infused at a variable rate to maintain euglycaemia. [6,6-2H2]-Glucose was added to the 20% glucose solution to achieve glucose enrichments of 1% to minimize changes in isotopic enrichment caused by changes in the infusion rate of exogenous glucose [28,29]. During the last hour of insulin infusion, samples were drawn every 10 min for determination of the rate of appearance of glucose and glycerol. Blood for measurement of concentrations of cortisol, catecholamines, glucagon, insulin, FFA, soluble tumour necrosis factor-α receptors (sTNFR) 1 and 2 and adiponectin was collected at t = −0.30 and t = 0 and at the end of the hyperinsulinaemic clamp at t = 2.00 and t = 2.30. LPV concentrations were measured in the week preceding and at the end of each hyperinsulinaemic clamp. Blood samples were kept on ice immediately after collection and subsequently centrifuged for 10 min at 3000 rpm at 4°C. All plasma samples were stored at −20°C.
Total and regional fat mass were quantified in all patients by dual-energy X-ray absorptiometry (Hologic QDR-4500W, software version whole body v8.26A:5; Bedford, Massachusetts, USA) providing a quantitative assessment of peripheral (sum of arm and leg fat) and trunk fat mass in kilograms. A standardized single-slice abdominal computed tomographic scan through the level of the third lumbar vertebra was performed from which the surface area of visceral adipose tissue and subcutaneous adipose tissue was determined and expressed in square centimetres.
Plasma insulin, cortisol, catecholamines, glucagon, FFA, sTNFR-1, sTNFR-2 and adiponectin concentrations were measured as described before [30,31]. Plasma HIV-1 RNA was measured in the participating centres by various tests with a lower limit of quantification of 50 copies/ml. LPV concentration was analysed using a validated high-pressure liquid chromatography method using diode-array detection: coefficient of variation 1.6% at 1.98 mg/l and 1.7% at 7.96 mg/l; detection limit 0.008 mg/l. Plasma samples for enrichments of [6,6-2H2]-glucose and [2H5]-glycerol were determined as described before [32,33].
Calculations and statistical analysis
The rate of appearance of glucose, peripheral glucose disposal and rate of appearance of glycerol were calculated with a modified form of Steele equations, as described before [6,34]. LPV concentration ratios were calculated by dividing the measured concentration by the expected concentration from the reference curve.
All participants were evaluated as their own control. Analyses were by intent to treat. Mean within-group changes were analysed by paired Student's t-tests. In both groups, for each parameter, the difference was calculated between the value at month 3 and at baseline. Subsequently, the mean differences between the two treatment arms were analysed by Wilcoxon tests. Alpha < 0.05 was considered statistically significant. Data are presented as median with interquartile range (IQR). SPSS statistical software version 12.0.1 (SPSS, Chicago, Illinois, USA) was used for all analyses.
A total of 50 patients were included in the MEDICLAS study between February 2003 and June 2005. Twenty of these patients were also enrolled in the substudy; 11 were randomly assigned to LPV/r+ZDV/3TC and 9 to LPV/r+NVP. Their demographic and clinical characteristics are shown in Table 1. For one patient in the LPV/r+ZDV/3TC group, data on glucose metabolism during the hyperinsulinaemic clamp could not be included in the analysis because of technical failure during conduct of the clamp. In the LPV/r+NVP group, data at 3 months were not included in the analysis from two patients, one because he did not return for the visit and the second because of acute hepatitis A infection. One patient in the LPV/r+NVP arm discontinued ART after 4 weeks because of toxic hepatitis. Following complete recovery, just after the 3 month visit, he resumed LPV/r, with efavirenz instead of NVP. The data of this patient were included in the analysis. None of the patients started concomitant medication that could be expected to influence glucose metabolism between start of cART and the visit at 3 months.
Virological and immunological parameters
Patients in both groups exhibited an immunological and virological response to cART with similar increases in CD4 cell count and decreases in HIV-1 RNA (Table 1). At month 3, there were no significant differences in concentration ratios of LPV taken in the week preceding the clamp between the two arms. LPV concentrations and concentration ratios during the last hour of the hyperinsulinaemic clamp, although slightly low because the previous LPV dose had been taken while fasting, did not differ between the arms.
There were no significant changes in any of the body composition parameters over the course of 3 months, with the exception of a minor decline in abdominal subcutaneous adipose tissue (P < 0.05) and in trunk fat (P < 0.05) in patients randomized to LPV/r+NVP (Table 2). Of note, limb fat did not change significantly in either arm, whereas visceral adipose tissue showed a declining trend in both the ZDV/3TC and the NVP arms (P = 0.06 and P = 0.15, respectively).
There were no significant changes in fasting plasma glucose or insulin levels after 3 months compared with baseline in either of the two treatment arms (Table 3). In addition, there were no changes in fasting endogenous glucose production in either arm. During hyperinsulinaemia, glucose production could also be suppressed equally at month 3 when compared with baseline in both groups. Treatment with LPV/r+NVP did not result in a significant change of peripheral glucose disposal during the hyperinsulinaemic clamp. In contrast, in the LPV/r+ZDV/3TC arm, insulin-stimulated peripheral glucose disposal decreased significantly by 25% after 3 months of therapy (P < 0.001; Fig. 1). This resulted in a significant difference in glucose disposal over time between patients in the two treatment arms (P < 0.01).
After a 12 h fast as well as during the hyperinsulinaemic clamp, glycerol turnover did not change in the LPV/r+NVP group over the course of 3 months (Table 3). In contrast, in the LPV/r+ZDV/3TC group, fasting glycerol turnover had significantly increased, by 22%, 3 months after starting therapy (P < 0.005). During hyperinsulinaemia, however, glycerol turnover was suppressed equally at month 3 as at baseline in the LPV/r+ZDV/3TC arm. In agreement with the enhanced glycerol turnover after an overnight fast, fasting plasma FFA levels were 84% higher in the LPV/r+ZDV/3TC group after 3 months (P < 0.001). In the LPV/r+NVP group, fasting FFA did not change over time. As a result, the change in fasting FFA was significantly different when comparing the treatment arms (P < 0.05). Additionally, after 3 months of treatment with LPV/r+ZDV/3TC, FFA concentrations were slightly but significantly higher during the clamp (P < 0.05). There was no significant correlation between the change in insulin-mediated glucose disposal and the change in fasting glycerol turnover (r = 0.13).
Glucoregulatory hormones and lipid profile
There were no significant differences in fasting plasma concentrations of cortisol or epinephrine over time in either treatment group (Table 2). In the LPV/r+NVP group, fasting plasma glucagon significantly decreased (P < 0.05), whereas norepinephrine levels decreased in the LPV/r+ZDV/3TC group after starting treatment (P < 0.05). Plasma adiponectin concentrations did not change significantly after 3 months of therapy. Concentrations of sTNFR-1 and sTNF-2 decreased in both arms, but the declines were only significant in the LPV/r+ZDV/3TC arm (P < 0.005 and P < 0.001, respectively). Plasma total cholesterol, high density lipoprotein (HDL)-cholesterol and triglycerides were significantly higher after treatment in both groups (P < 0.05) with no significant differences between groups.
Dyslipidaemia, body fat redistribution and disturbed glucose homeostasis are frequently seen in HIV-1-infected patients treated with cART [3,7]. Once patients have developed clinically overt signs of lipodystrophy, the disturbances in glucose metabolism have been shown to include insulin resistance at the level of peripheral glucose disposal, hepatic glucose production and lipolysis [5,6,9,35]. The present study, to our knowledge, is the first prospective randomized clinical trial that attempts to investigate the onset of the derangements in glucose kinetics and body composition in relation to commencing treatment with different cART regimens, with and without NRTI, in HIV-1-infected, ART-naive patients, by conducting hyperinsulinaemic–euglycaemic clamps. Our results show that treatment with a NRTI-containing regimen of LPV/r+ZDV/3TC, in the absence of significant changes in body fat distribution, led to a 25% decrease in insulin-mediated peripheral glucose disposal and a 22% increase in fasting lipolysis after as little as 3 months of therapy, while this was not the case in patients randomized to a NRTI-sparing regimen of LPV/r+NVP.
Results from detailed prospective studies on the metabolic side-effects of ART in HIV-1-infected patients are limited. Only a few studies have tried to investigate the effects of the PI class on insulin sensitivity, measured by intravenous glucose tolerance test, the homeostatic model assessment (HOMA) index and the hyperglycaemic clamp. These studies showed that insulin resistance was detectable only a few months after starting a PI-containing regimen in HIV-1-infected patients [10,14,22]. Since these studies contained a mixture of ART-naive and ART-experienced patients and the regimens included NRTI drugs, it is impossible to conclude whether the observed reduction in insulin sensitivity could be attributed only to the use of a PI. The effect of different PI on glucose metabolism has been studied in HIV-1-uninfected volunteers. Administration of the PI indinavir, both as a single dose and during 4 weeks, reduced peripheral glucose disposal and increased endogenous glucose production during a hyperinsulinaemic clamp [16,17,19]. The effects observed with short-term exposure to LPV/r differ however; insulin sensitivity with respect to glucose disposal decreased after a single dose and after 5 days of exposure [13,18], but not after 4 weeks of LPV/r treatment . In line with these human studies, studies in healthy rodents showed an acute reduction in peripheral glucose uptake after administration of several PI drugs, including LPV/r [12,23]. Moreover, these studies showed that glucose transport in both skeletal muscle and adipose tissue was affected. In-vitro research has shown that several PI, including ritonavir, are able to acutely inhibit the activity of glucose transporter-4 [11,15], thereby offering a possible explanation for the peripheral insulin resistance found in healthy volunteers and HIV-1-infected patients with lipodystrophy. Besides PI, NRTI drugs have also been associated with insulin resistance in patients with HIV-1-infection. Duration of exposure to NRTI has been reported to be independently associated with insulin resistance, as measured by fasting insulin levels and the QUICKI index in a number of observational studies [26,37]. These findings could potentially be explained as indirect effects of NRTI by virtue of their association with the development of changes in body fat distribution, especially lipoatrophy [24,25]. However, evidence from a randomized trial conducted in previously ART-naive subjects demonstrated early and sustained increases in fasting serum insulin levels and in HOMA indices, as short as 4 weeks after treatment initiation with cART containing a thymidine analogue, including stavudine plus didanosine, but not with a thymidine analogue-sparing combination of abacavir plus 3TC . These results suggested that thymidine analogue NRTI, in particular, may contribute to the early onset of insulin resistance before any clinically noticeable changes in body fat distribution are present. A recent placebo-controlled study in healthy HIV-uninfected volunteers demonstrated that administration of stavudine during 4 weeks indeed resulted in a significant decrease in insulin sensitivity measured by hyperinsulinaemic–euglycaemic clamps, without changes in body composition. Interestingly, 31P magnetic resonance spectroscopy revealed reduced mitochondrial function in skeletal muscle, which correlated significantly with insulin sensitivity. In addition, mitochondrial DNA content was reduced in muscle biopsies of stavudine recipients .
The present study which employed serial hyperinsulinaemic–euglycaemic clamps, found a reduction in peripheral insulin sensitivity study in the absence of significant changes in body fat distribution, after only 3 months in patients taking LPV/r+ZDV/3TC, as opposed to those treated with LPV/r+NVP. The latter may seem in contrast with the findings from earlier studies assessing changes in insulin sensitivity following the introduction of PI in antiretroviral regimens [10,14,22]. Of note however, the PI in those studies did not include LPV/r. Furthermore, patients were concomitantly receiving an NRTI in most instances, which could have contributed to the reported changes in glucose metabolism. Nonetheless, LPV/r did result in a change in insulin sensitivity when administered as monotherapy to healthy HIV-1-uninfected persons [13,18]. The difference in duration of LPV/r exposure between our study (3 months) and the studies conducted in healthy volunteers (single dose and 5 days) may be relevant and an earlier reduction in insulin sensitivity in our patients on LPV/r+NVP, which had disappeared after 3 months, cannot be ruled out.
The changes in glucose metabolism in the NRTI-containing arm, as opposed to the NRTI-sparing arm, suggest that exposure to ZDV/3TC may have contributed to the development of alterations in glucose metabolism. This is in accordance with a number of observations concerning the potential contribution of NRTI to the development of insulin resistance [26,27,37]. NRTI, particularly the thymidine analogues stavudine and ZDV, have been shown to play an important role in the onset of lipoatrophy . Since lipoatrophy has independently been associated with insulin resistance, NRTI drugs have been suggested to affect glucose metabolism indirectly via a decrease in peripheral fat [24,25]. In the present study, however, LPV/r+ZDV/3TC treatment resulted in disturbed glucose metabolism in the absence of changes in fat distribution. We cannot rule out the possibility of having missed a small decline in peripheral fat because of a concomitant increase in fat through recovery from HIV-wasting, as has been described before in patients starting ART [40,41], but find it an unlikely confounding factor as patients with wasting were excluded and LPV/r+NVP treatment, which is not expected to result in lipoatrophy, likewise did not result in increased fat amounts. This suggests that ZDV/3TC may have directly contributed to the development of reduced insulin sensitivity, through several possible mechanisms. Some NRTI drugs have been shown to disturb the production and secretion of adipocytokines, which, in turn, could affect glucose metabolism. In 3T3 culture adipocytes, stavudine and ZDV both decreased adiponectin production, whereas the production of TNF-α and interleukins 1 and 6 was enhanced . However, in the present study, adiponectin levels were unchanged after 3 months, whereas sTNFR-1 and sTNF-2 decreased rather than increased in the LPV/r+ZDV/3TC arm. These results argue against abnormal adipocytokine secretion as an explanation for insulin insensitivity. In our study, LPV/r+ZDV/3TC treatment resulted in stimulation of fasting lipolysis with increased plasma FFA levels, which may indicate resistance to insulin's suppressive effect on lipolysis. As FFA have a negative influence on the signalling pathway of insulin [43,44], increased FFA levels could have contributed to insulin resistance with respect to peripheral glucose disposal in the LPV/r+ZDV/3TC arm. However, since patients with HIV-associated lipodystrophy remained insulin resistant (albeit less so) after FFA levels were acutely lowered by administration of the lipolysis inhibitor acipimox , additional factors are involved. There might be an important role for mitochondria in fat and muscle in the development of insulin insensitivity. NRTI have been associated with mitochondrial toxicity [38,46–49]. A decline in oxidative phosphorylation, resulting from mitochondrial dysfunction, could result in accumulation of FFA (metabolites), which, in turn, could have a negative effect on the signalling cascade of insulin [43,44] and may reinforce mitochondrial dysfunction [44,50]. NRTI-induced mitochondrial dysfunction as a cause for insulin insensitivity has been suggested by a recent study in healthy volunteers .
With respect to plasma lipids, total cholesterol and triglyceride levels increased significantly in both arms after 3 months, which was not unexpected given the presence of LPV/r in both regimens [51,52]. Compatible with observations in other trials of potent cART in ART-naive, HIV-1-infected individuals, HDL-cholesterol likewise increased in both arms [53,54]. Further follow-up of lipid changes in all MEDICLAS trial participants will be needed to determine whether the rise in HDL-cholesterol will be significantly greater in the NVP-containing arm.
In conclusion, treatment with the NRTI-containing regimen LPV/r+ZDV/3TC, as opposed to the NRTI-sparing regimen LPV/r+NVP, resulted in a 25% decrease in insulin-mediated peripheral glucose disposal and a 22% increase in fasting lipolysis after only 3 months, in the absence of discernable changes in body composition. These findings suggest that certain NRTI may directly contribute to ART-associated disturbances in glucose metabolism, the precise underlying mechanism of which remains to be elucidated but could include NRTI-induced mitochondrial dysfunction. Follow-up of participants in our trial is ongoing and will need to determine to what extent these regimens will continue to differ with respect to their effects on peripheral insulin sensitivity and, over the longer term, potentially also on other aspects of glucose metabolism, body fat distribution and lipid abnormalities. Meanwhile avoiding thymidine analogue NRTI might be appropriate, particularly in patients with (a predisposition to develop) diabetes mellitus.
We are indebted to Katja Tuominen, Rob Simonse, Gerrit-Jan Ilbrink and Ingrid Knufman for their great help during the clamps and their assistance in planning all study days. We would like to thank An Ruiter, Barbara Voermans and Erik Endert from the department of Clinical Chemistry, Laboratory of Endocrinology and Radiochemistry for excellent analytical assistance.
Sponsorship: This study was supported by Abbott International and Boehringer Ingelheim by an independent scientific grant.
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