Chronic kidney disease (CKD) is characterised by specific lipoprotein abnormalities and insulin resistance. Dual activation of the peroxisome proliferators-activated receptors (PPAR)
Chronic renal insufficiency is characterized by specific lipoprotein abnormalities [
It is well documented that patients with chronic renal insufficiency as well as patients with diabetes mellitus are at high cardiovascular risk and that the characteristic lipoprotein abnormalities play an important role in atherogenesis [
Tesaglitazar is a dual PPAR
The aim of the present analyses was to investigate the effects of a dual PPAR
The study was an open-label study in two parallel groups. The primary aim of the study was to evaluate pharmacokinetics of tesaglitazar in patients with renal impairment [
One mg of tesaglitazar was given once daily during six weeks to patients with various degrees of renal impairment (renal impaired group) and to subjects with normal renal function (reference group). After completion of active drug treatment, the groups were followed for an additional three weeks. No dietary advice was given during the study and followup.
The aim was to include eight patients in each of the three groups of varying severities of renal impairment: mild renal impairment (GFR 51–80 mL/min × 1.73 m2 BSA), moderate renal impairment (GFR 31–50 mL/min × 1.73 m2 BSA), and severe renal impairment (GFR 10–30 mL/min × 1.73 m2 BSA). Twenty-three patients were finally included (
A group of 18 age- and sex-matched subjects with normal renal function was included as a reference group. One subject was withdrawn during the treatment period. Baseline characteristics of the groups are presented in Table
Baseline characteristics of patient and reference groups. Mean and standard deviation (in parenthesis).
CKD patients | Healthy reference group | |
---|---|---|
Age (years) | 54.9 (11.9) | 55.6 (10.3) |
Male/female ( |
17/6 | 13/4 |
Body mass index (kg/m2) | 27.1 (3.9) | 25.0 (2.4) |
S-creatinine (µmol/L) | 201 (66) | 71 (11) |
Glomerular filtration rate (mL/min × 1.73 m2 BSA) | 43.2 (24.0) | 94.6 (13.2) |
Blood pressure (mm Hg) | 140 (17)/81 (10) | 135 (14)/81 (7) |
The study was conducted according to the Declaration of Helsinki and in accordance with the Guideline of Good Clinical Practice and was approved by independent ethics committee. Signed informed consent was received from all subjects.
Blood samples to determine plasma lipids, apolipoproteins, lipoproteins, and their sizes were drawn in all subjects at start and after six weeks, that is, at the end of active treatment. Plasma lipids were also determined after three-week followup of study drug. In addition, fasting plasma insulin and blood glucose were measured. All samples were taken after an overnight fast. To plasma samples for the lipoprotein measurements were added preservatives containing thimerosal and a protease inhibitor,
Total cholesterol and triglyceride concentrations were determined by enzymatic methods [
Lipoproteins A-I and A-I : A-II and the major classes of apoB-containing lipoprotein families, cholesterol-rich Lp-B and triglyceride-rich Lp-B : C, Lp-B : C : E, and Lp-A-II : B : C : D : E were isolated by immunoaffinity chromatography and determined according to a previously described electroimmunoassay of apoB [
Lipoprotein particle size and concentration were analyzed by nuclear magnetic resonance (NMR) technique [
Glomerular filtration rate (GFR) was measured by plasma iohexol clearance at start and end of treatment and after three weeks of followup [
Standard statistics were used to illustrate the salient features of data. Changes in metabolic and renal outcome variables from baseline were calculated for each group (renal impaired group and reference group) and analyzed in a linear model, using a fixed-effect analysis with the baseline value as covariate. A
Plasma lipid levels (mmol/L) in patients with chronic renal insufficiency (
CKD patients | Healthy reference group | |||||||
---|---|---|---|---|---|---|---|---|
At entry | After 6 weeks | Estimated change | After 3 weeks of drug | At entry | After 6 weeks | Estimated change | After 3 weeks of drug | |
Total cholesterol | 6.4 (1.3) | 5.7 (1.3) | −12%*** | 6.3 (1.2) | 5.3 (0.7) | 4.6 (0.5) | −14%*** | 5.0 (0.6) |
Triglycerides | 2.0 (1.9) | 1.2 (0.9) | −40%*** | 1.7 (1.1) | 1.1 (0.4) | 0.7 (0.3) | −34%*** | 1.1 (0.4) |
VLDL-cholesterol | 0.8 (0.4) | 0.5 (0.3) | −40%*** | 0.8 (0.5) | 0.5 (0.2) | 0.3 (0.1) | −34%*** | 0.5 (0.2) |
LDL-cholesterol | 4.2 (0.81) | 3.5 (1.2) | −21%*** | 4.2 (1.0) | 3.4 (0.7) | 2.7 (0.6) | −20%** | 3.1 (0.6) |
HDL-cholesterol | 1.2 (0.2) | 1.6 (0.4) | +24%*** | 1.4 (0.3) | 1.5 (0.4) | 1.5 (0.4) | +2% | 1.4 (0.3) |
The plasma concentrations of triglycerides, total cholesterol, VLDL-cholesterol, and LDL-cholesterol were all significantly reduced by treatment with tesaglitazar in both the renal impaired group and the reference group. HDL-cholesterol increased significantly in subjects with renal impairment. The plasma lipids returned to baseline levels after three weeks of treatment.
Plasma apolipoprotein concentrations levels (mg/dL) in patients with chronic renal insufficiency (
CKD patients | Healthy reference group | |||||
---|---|---|---|---|---|---|
At entry | After 6 weeks | Estimated change | At entry | After 6 weeks | Estimated change | |
Apo A-I | 141 (16) | 153 (21) | +9%** | 145 (23) | 154 (20) | +7% |
Apo B | 126 (34) | 104 (31) | −18%*** | 105 (16) | 87 (17) | −17%*** |
Apo B/Apo A-I | 0.9 (0.3) | 0.7 (0.3) | −24%*** | 0.7 (0.2) | 0.6 (0.1) | −22%*** |
Apo C-III | 16.6 (5.4) | 17.4 (3.9) | +6% | 11.4 (2.4) | 11.1 (2.5) | −3% |
Apo C-III-HS | 9.1 (2.3) | 11.4 (3.8) | +30%*** | 8.3 (2.5) | 8.1 (2.3) | +2% |
Apo C-III-HP | 6.8 (3.0) | 5.7 (2.6) | −13%** | 3.6 (1.0) | 3.2 (1.2) | −14%** |
Apo C-III ratio | 1.5 (0.7) | 2.5 (1.6) | +55%** | 2.3 (0.9) | 2.9 (1.6) | +19% |
Apo A-I/Apo C-III | 9.0 (2.0) | 9.2 (2.0) | +9% | 13.2 (2.7) | 14.3 (2.5) | +2% |
Apo E | 7.8 (2.9) | 8.2 (2.6) | +5% | 5.5 (1.2) | 6.0 (1.8) | +8% |
In the subjects with renal impairment apoA-I increased significantly by 9%, and apoB decreased by 18%. The total plasma concentration of ApoC-III did not change. However, there was a significant change in the apolipoprotein content of apoC-III, that is, an increase in apoC-III in HDL by 30% and a parallel decrease in apoC-III in VLDL + LDL by 13% in subjects with renal impairment. This resulted in a significant increase in the apoC-III ratio by 55%. Although the level of apoC-III in VLDL + LDL also increased in the reference group, the apoC-III ratio did not change significantly. The total plasma concentration of apoE was unaltered in both groups.
Plasma concentrations of lipoprotein subclasses (mg/dL) in patients with chronic renal insufficiency (
CKD patients | Healthy reference group | |||||
---|---|---|---|---|---|---|
At entry | After 6 weeks | Estimated change | At entry | After 6 weeks | Estimated change | |
Lp-A-I | 36 (5) | 40 (6) | +11%** | 37 (7) | 37 (7) | −1% |
Lp-A-I : A-II | 105 (12) | 114 (17) | +8%** | 108 (20) | 117 (15) | +10% |
Lp-B | 79 (18) | 67 (19) | −17%*** | 67 (11) | 58 (10) | −13%** |
Lp-B : C | 10 (8) | 7 (3) | −26%* | 6 (2) | 5 (2) | −19% |
Lp-B : E + Lp-B : C : E | 20 (8) | 14 (6) | −28%** | 13 (6) | 10 (4) | −11% |
Lp-A-II : B : C : D : E | 17 (7) | 16 (9) | −9% | 20 (9) | 15 (8) | −29%* |
Plasma concentrations of Apo-B-containing lipoprotein particles (mg/dL) in patients with various degrees of chronic renal insufficiency (mild;
At entry | After 6 weeks | At entry | After 6 weeks | |
---|---|---|---|---|
Lp-B | Lp-B : C | |||
| ||||
Reference group | 67 (12) | 58 (10) | 6 (2) | 5 (2) |
Mild CRF | 66 (9) | 59 (13) | 6 (1) | 7 (2) |
Moderate CRF | 85 (21) | 70 (22) | 9 (5) | 6 (2) |
Severe CRF | 86 (17) | 70 (20) | 15 (12) | 8 (4) |
| ||||
Lp-B : E + Lp-B : C : E | Lp-A-II : B : C : D : E | |||
| ||||
Reference group | 13 (6) | 10 (4) | 20 (9) | 15 (8) |
Mild CRF | 14 (5) | 15 (3) | 16 (6) | 9 (3) |
Moderate CRF | 22 (7) | 14 (5) | 17 (6) | 17 (7) |
Severe CRF | 24 (9) | 14 (10) | 16 (9) | 20 (10) |
Lp A-I and A-I : A-II particles increased, and the apoB-containing cholesterol-rich subclass Lp-B and the triglyceride-rich subclasses LP-B : E + LP-B : C : E + LP-A-II : B : C : D : E decreased significantly (−17% and −32%, resp.) in the patients with CKD. The decrease of the apoB-containing triglyceride-rich lipoprotein subclasses was due to a significant decrease in the individual Lp-B : C (−26%) at the Lp-B : E + Lp-B : C : E (−28%), whereas no significant changes were observed in the Lp-A-II : B : C : D : E subclass concentrations. In the reference group there was a significant reduction of 13% in Lp-B, whereas the reduction of 26% of apoB-containing triglyceride-rich subclasses did not reach statistical significance (95% CI: −46%, +2%).
The effect of tesaglitazar on apoB-containing lipoproteins increased with reduced renal function (Table
The lipoprotein particle size did not change during treatment. The LDL diameter was 21.0 (range 19.0–22.0) nm at baseline and 21.2 (range 20.1–22.0) after six weeks in the renal impaired group. The corresponding LDL diameters were 21.6 (range 20.9–22.0) and 21.6 (range 21.0–22.0), respectively, in the reference group.
After 6 weeks of treatment, fasting insulin was reduced by 40% in the group with CKD (
Glomerular filtration rate and serum creatinine at entry, after administration of 1 mg tesaglitazar for 6 weeks, and at followup 3 weeks after drug administration. Mean and standard deviation (in parenthesis).
CKD patients | Healthy reference group | |||||
---|---|---|---|---|---|---|
At entry | After 6 weeks | After 3 weeks of drug | At entry | After 6 weeks | After 3 weeks of drug | |
GFR (mL/min × 1.73 m2 BSA) | 43.2 (24.0) | 37.7 (21.1) | 43.4 (28.3) | 94.6 (13.2) | 91.9 (15.5) | 91.8 (10.4) |
S-creatinine (µmol/L) | 201 (66) | 249 (93) | 226 (89) | 71 (11) | 79 (8) | 72 (10) |
Glomerular filtration rate decreased in both study groups. In subjects with normal renal function it decreased from 94.6 to 91.9 mL/min × 1.73 m2 body surface area (BSA) and in the CKD patients from 43.2 to 37.7 mL/min × 1.73 m2 BSA. This reduction in GFR of 13% in the CKD patients was of the same magnitude in all three subgroups of mild, moderate, and severe renal impairment, respectively. With one exception GFR returned to the baseline value three weeks after the tesaglitazar treatment was stopped.
Ten subjects in the renal impaired group reported a total of 15 adverse events. One was a gastrointestinal bleeding episode requiring hospitalisation, whereas the remaining 14 adverse events were mild. Twelve subjects in the reference group reported a total of 27 adverse events. One subject in the reference group was withdrawn from active treatment due to a herpes zoster infection. The other reported adverse events were all mild.
The main finding of this study was that treatment with a dual PPAR
Since the primary purpose of the study was to evaluate the pharmacokinetics of the dual PPAR
It is well documented that there is a typical accumulation of apoB-containing triglyceride-rich lipoproteins early in mild to moderate renal impairment, which is first detected in specific alterations in the apolipoprotein profile [
All plasma lipids were significantly, and positively, altered in the patients with renal impairment. In fact, the lipid profile in the renal impaired group was normalised after six-week treatment when compared with the baseline profile of the subjects with normal renal function, illustrated in Figure
Plasma lipid concentrations at baseline and after six-week treatment with 1 mg tesaglitazar o.d. (mean and standard error of the mean).
In accordance with the increased plasma concentrations of apoA-I the plasma levels of the Lp-A-I and the Lp-A-I : A-II subclasses were significantly increased. The plasma concentrations of the atherogenic apoB-containing cholesterol-rich subclass, Lp-B, and the atherogenic apoB-containing triglyceride-rich subclasses carrying also apoC-III, that is, Lp-B : C and Lp-B : C : E, were reduced to the same levels seen at baseline in the reference group. This differs from previous findings by our group in the same category of subjects in which we found that fluvastatin treatment had a good effect on Lp-B but was less effective in reducing apoB-containing triglyceride-rich subclasses carrying also apoC-III [
Although the elevated total plasma concentration of apoC-III was not affected by treatment with the dual PPAR
Chronic renal disease is associated with a high cardiovascular risk [
The changes in the lipoprotein profile observed in this study by the dual PPAR
Whether the unaffected high plasma concentration of the apoC-III still implies an increased risk of atherosclerosis remains to be clarified. Studies on nonrenal patients have shown that apoC-III is an independent risk factor for coronary heart disease [
The clinical development of tesaglitazar was discontinued in 2006 when data from a 24-week randomised, controlled study of patients with type 2 diabetes mellitus clearly showed that the previously observed increase in serum creatinine concentrations was due to a true reduction in GFR and not to a reduction in the tubular secretion of creatinine [
In conclusion, this study suggests that by improving insulin sensitivity a dual PPAR
Dr. I. Gause-Nilsson is currently an employee of AstraZeneca and Dr. M. K. Svensson was employed by AstraZeneca at the time of the study. Drs. O. Samuelsson, P. O. Attman, and P. Alaupovic have no conflicts of interest.
The AstraZeneca Company financially supported the study. The results and views of the present study represent the authors, and not any official views of the Medical Products Agency where one author currently is employed (M. K. Svensson).