Effects of change in high-density lipoprotein cholesterol by statin switching on glucose metabolism and renal function in hypercholesterolemia

Journal of Clinical Lipidology (2015) 9, 709–715

Effects of change in high-density lipoprotein cholesterol by statin switching on glucose metabolism and renal function in hypercholesterolemia Hirokazu Kakuda, MD*, Munetoshi Matoba, MD, Hideaki Nakatoh, MD, Shin Nagao, MD, Noboru Takekoshi, MD, PhD Kakuda Clinic, Kahoku, Ishikawa, Japan (Dr Kakuda); Matoba Clinic, Kanazawa, Ishikawa, Japan (Dr Matoba); Nakatoh Clinic, Kanazawa, Ishikawa, Japan (Dr Nakatoh); Nagao Clinic, Hakusan, Ishikawa, Japan (Dr Nagao); and Division of Cardiology, Kanazawa Medical University, Ishikawa, Japan (Dr Takekoshi) KEYWORDS: Statin; HDL cholesterol; Glucose metabolism; Renal function

BACKGROUND: Recent reports have suggested that high-density lipoprotein (HDL) is metabolically related to glucose metabolism and renal function. Statin administration clinically increases HDL cholesterol (HDL-C). OBJECTIVE: To confirm that change in HDL-C by statin switching is associated with glucose metabolism and renal function in hypercholesterolemic patients. METHODS: In hypercholesterolemic outpatients (n 5 129) who had taken either statin, as atorvastatin, pitavastatin, or rosuvastatin and switched to another statin, the relationship of change in HDL-C to glycated hemoglobin and estimated glomerular filtration rate (eGFR) was assessed. RESULTS: Change in HDL-C did not significantly correlate with change in HbA1c, eGFR calculated from creatinine (eGFRcre), and eGFR calculated from cystatin C (eGFRcys). The subjects were then divided into 2 groups by change in HDL-C: no change or decrease in HDL-C (HD group) and increase in HDL-C (HI group). In the HI group, apolipoprotein A-1 (Apo A-1) and eGFRs were significantly increased by statin switching. There were significant differences in changes in HDL-C, Apo A-1, lipoprotein lipase, glycated hemoglobin, and eGFR calculated from creatinine between the groups. In the patients with impaired glucose tolerance or diabetes, change in HbA1c was also significant between the groups. CONCLUSIONS: Our data suggest that an increase in HDL-C due to statin switching is associated with improvement in glucose metabolism and renal function. Ó 2015 National Lipid Association. All rights reserved.

The authors declare that there is no conflict of interest regarding the publication of this article. * Corresponding author. Kakuda Clinic, Takamatsu Na 15-1, Kahoku, Ishikawa 929-1215, Japan. E-mail address: [email protected] Submitted January 23, 2015. Accepted for publication July 18, 2015.

1933-2874/Ó 2015 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2015.07.007

Introduction High-density lipoprotein (HDL) plays a major role in reverse cholesterol transport and also has antiatherogenic properties, including antioxidative stress, anti-inflammation, and improvement of endothelial function.1–3 A low level of

710 HDL cholesterol (HDL-C) is a strong risk factor for cardiovascular disease,4–6 in spite of a low level of low-density lipoprotein cholesterol (LDL-C). Statins, LDL-C–lowering agents, reduce the incidence of cardiovascular events. Despite their use, residual cardiovascular risk still remains with a low level of HDL-C.7–9 Recent reports have suggested that HDL and apolipoprotein A-1 (Apo A-1) are related to glucose metabolism and renal function. HDL and Apo A-1 stimulate insulin secretion by interaction with ATP-binding cassette sub-family A member 1 (ABCA1), ATP-binding cassette sub-family G member 1 (ABCG1), or scavenger receptor class B type I (SR-BI) and also inhibit apoptosis of pancreatic beta cells (b-cells).10 In multivariate analyses of the GREek Atorvastatin and Coronary heart disease Evaluation study11 and LIvalo Effectiveness and Safety study,12 change in HDL-C was identified as a significant factor in increasing estimated glomerular filtration rate (eGFR) during statin treatment. Besides preventing cardiovascular disease, HDL is associated with glucose metabolism and renal function. Although statin administration is one of the medical treatment strategies for elevating HDL-C, there have been few reports that have investigated the relationship between change in HDL-C by statin switching and glucose homeostasis and renal function in hypercholesterolemic patients who take statins. We previously compared the effect on residual risk factors of 3 statins (atorvastatin [ATO], pitavastatin [PIT], and rosuvastatin [ROS]) by statin switching and reported that the effects on HDL-C and Apo A-1 were significantly different between the statins.13 In this report, PIT had a favorable effect on the level of HDL-C and Apo A-1 compared with other statins. In the present report, using the data of a previous study,13 we analyzed whether an increase in HDL-C by statin switching ameliorates glucose homeostasis and renal function.

Journal of Clinical Lipidology, Vol 9, No 5, October 2015 were switched to another statin at the discretion of the physicians without any washout period. The study protocol was approved by the Research Ethics Committee of Kanazawa Medical University. Of the 136 eligible patients enrolled, 7 refused to allow publication of their data. Of the 129 enrolled outpatients, 40 subjects receiving ATO switched to PIT (n 5 19) or ROS (n 5 21), 39 subjects receiving PIT switched to ATO (n 5 19) or ROS (n 5 20), and 50 subjects receiving ROS switched to ATO (n 5 20) or PIT (n 5 30). The laboratory values before and 3 months after switching were measured in nonfasting serum. In the present analysis, the relationship between change in HDL-C and change in glucose metabolism and renal function is investigated.

Measurements and calculations Nonfasting blood was collected before and 3 months after switching statins. Serum and plasma were separated and stored at each clinic, then measured by an external laboratory (ALP, Kanazawa, Ishikawa, Japan). Total cholesterol, direct method LDL-C, HDL-C, triglyceride, remnantlike lipoprotein particles cholesterol, malondialdehydemodified LDL, Apo A-1, Apo B, Apo E, preheparin lipoprotein lipase (LPL) mass, glycated hemoglobin (HbA1c), serum creatinine, and cystatin C were measured. Serum cystatin C has also been used to assess renal function and serum creatinine.14 In the recent report, cystatin C is superior in predicting GFR to creatinine in Japanese subjects with normal and mildly reduced GFR.15 HDL-C was evaluated as an HDL-related factor. HbA1c was evaluated as a glucose homeostasis–related factor, and eGFRs calculated by creatinine and cystatin C were evaluated as a renal function–related factor. eGFR calculated by creatinine (eGFRcre) was assessed using the standard Japanese equation16:
eGFRcre mL=min=1:73m2 5194!ðserumcreatinineÞ21:094 20:287

!ðAgeÞ !ð0:739; if femaleÞ

Methods Study design and data collection The present study is a subanalysis of a previous report, a prospective, open-labeled, multicenter study performed at 4 clinics in Ishikawa, Japan, that evaluated the effects of 3 statins on cardiovascular residual risks.13 Patients were recruited between June 2010 and October 2010. Eligible patients were men and women aged 20 years or older who were administrated 10-mg/d ATO, 2-mg/d PIT, or 2.5-mg/d ROS, which are regular dose in Japanese practice and have comparable effect on LDL-C lowering, for at least 6 months. Major exclusion criteria were type III hyperlipidemia, secondary hyperlipidemia, severe renal or liver impairment or dysfunction, and type I diabetes mellitus. After informed consent was obtained, eligible patients

eGFR calculated by cystatin C (eGFRcys) was assessed using following equation15:
21:019 eGFRcys mL=min=1:73m2 5104!ðserumcystatin CÞ !0:9962ðageÞ !ð0:929; if femaleÞ28

Statistical analysis Data are expressed as mean 6 standard deviation. Student t test or chi-squared test was used where appropriate. Statistical tests were 2-sided with a 5% significance level.

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Results

Subject background of the 2 groups

Change in HDL-C and glucose metabolism and renal function

Of the 129 enrolled outpatients, there were 65 subjects in the HD group and 64 subjects in the HI group (Table 1). There was not a significant difference in patient characteristics or concomitant drugs between the 2 groups except regarding the number of patients switched to ATO and PIT. In the previous report, HDL-C significantly increased in the groups who switched to PIT, but not in the other groups. Mean age was higher in the HI group vs the HD group, but this was not statistically significant. At baseline, before statin switching, the only significant difference in laboratory measurement between the 2 groups was eGFRcre (Table 2). At baseline, eGFRcre was lower in the HI group than in the HD group (70.6 vs 64.1 mL/min/ 1.73 m2, P 5 .033).

Change in HDL-C did not significantly correlate with change in HbA1c (r 5 20.09, P 5 .34), eGFRcre (r 5 0.15, P 5 .09), and eGFRcys (r 5 0.15, P 5 .10; Fig. 1). The subjects were then divided into 2 groups by change in HDL-C: no change or decrease in HDL-C (HD group) and increase in HDL-C (HI group). We compared change in glucose metabolism and renal function between the 2 groups.

Change in parameters after switching Compared with baseline, HDL and Apo A-1 significantly decreased in the HD group (23.49 mg/dL Table 1

Figure 1 The relationship between change in high-density lipoprotein cholesterol (HDL-C) level and each parameter changes in parameters (A) HbA1c, (B) estimated glomerular filtration rate calculated from creatinine (eGFRcre), and (C) estimated glomerular filtration rate calculated from cystatin C (eGFRcys).

Patient characteristics and concomitant drugs P value

Characteristics

HD

HI

N Age (y) Gender (males/females) Body mass index (kg/m2) Number of BMI .25 Hypertension Impaired glucose tolerance/diabetes mellitus Coronary heart disease Stroke Statin after switching Atorvastatin Pitavastatin Rosuvastatin Concomitant drugs ARB/ACE inhibitor Diuretic Calcium blocker Sulfonylurea a-Glucosidase inhibitor Biguanide Thiazolidine DPP4 inhibitor

65 64 69.8 6 11.1 73.4 6 9.9 .054 23/42 16/48 n.s. 25.6 6 4.1 25.1 6 4.2 n.s. 33 (51) 51 (78) 33 (51)

28 (43) 52 (81) 27 (42)

n.s. n.s. n.s.

5 (8) 3 (5)

8 (13) 1 (2)

n.s. n.s.

27 (42) 13 (20) 25 (38)

12 (19) 36 (56) 16 (25)

.016 ,.01 n.s.

39 20 30 12 14

34 16 30 9 8

(53) (25) (47) (14) (13)

n.s. n.s. n.s. n.s. n.s.

7 (11) 2 (3) 1 (2)

n.s. n.s. n.s.

(60) (31) (46) (18) (22)

6 (9) 6 (9) 5 (8)

ARB, angiotensin II receptor antagonist; ACE inhibitor: angiotensin-converting enzyme inhibitor; BMI, body mass index; DPP4 inhibitor, dipeptidyl peptidase 4 inhibitor; HD, no change or decrease in high-density lipoprotein cholesterol; HI, increase in highdensity lipoprotein cholesterol; n.s., not significant. Values are presented by mean 6 standard deviation or n (%). Chisquared test was used to compare the differences between the HD and the HI groups.

712 Table 2

Journal of Clinical Lipidology, Vol 9, No 5, October 2015 Laboratory results HD

HI

Variables

Baseline

TC (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) non–HDL-C (mg/dL) RLP-C (mg/dL) MDA-LDL (U/L) Apo A-1 (mg/dL) Apo B (mg/dL) Apo E (mg/dL) LPL (ng/mL) HbA1c (%) eGFRcre (mL/min/1.73 m2) eGFRcys (mL/min/1.73 m2) Urinary albumin (mg/gCr)

180.5 99.6 54.6 164.1 125.9 6.5 67.2 146.6 87.9 4.36 64.2 6.4 70.6 68.2 57.9

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

Change 27.3 19.6 12.2 93.3 23.56 5.2 19.5 22.9 16.3 0.98 21.7 0.8 17.6 19.2 152.0

22.66 0.62 23.49 23.58 0.83 0.29 6.74 25.66 0.62 0.05 22.43 0.05 20.65 1.04 7.52

Baseline 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

19.69 16.78 3.44** 53.03 19.56 3.43 19.80** 10.82** 13.48 0.64 14.83 0.27 7.17 7.57 70.41

182.3 100.9 54.9 137.0 127.4 5.5 68.2 145.2 87.7 4.28 72.8 6.4 64.1 62.1 89.0

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

P value between the groups

Change 34.2 26.2 14.1 54.4 31.0 2.9 29.8 28.3 20.8 0.91 23.6 1.3 16.3*** 17.9 253.1

1.72 20.58 5.72 0.55 24.00 0.18 20.59 11.20 20.72 0.02 2.98 20.09 2.06 1.94 21.98

6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

24.35 20.46 4.24** 56.03 24.17 3.42 27.27 11.77** 15.20 0.67 12.56 0.41 6.39** 7.34* 73.31

n.s. n.s. ,.01 n.s. n.s. n.s. n.s. ,.01 n.s. n.s. .028 .018 .026 n.s. n.s.

eGFRcre, estimated glomerular filtration rate calculated from serum creatinine value; eGFRcys, estimated glomerular filtration rate calculated from serum cystatin C; HbA1c, glycated hemoglobin; HD, no change or decrease in high-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; HI, increase in high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LPL, preheparin lipoprotein lipase mass; MDA-LDL, malondialdehyde-modified LDL; n.s., not significant; RLP-C, remnant-like lipoprotein particles cholesterol; TC, total cholesterol; TG, triglyceride. Values are presented as mean 6 standard deviation. Student paired t test was used to compare difference between before and after statin switching. Student unpaired t test was used to compare difference between the HD and the HI group. *P , .05 vs baseline; **P , .01 vs baseline; ***P , .05 HD baseline vs HI baseline.

and 25.66 mg/dL, respectively) and increased in the HI group (5.72 mg/dL and 11.20 mg/dL, respectively) after switching, whereas LDL-C did not show any significant changes, remaining approximately 100 mg/dL in both groups (Table 2). In the HI group, eGFRcre and eGFRcys were significantly increased (2.06 mL/min/1.73 m2 and 1.94 mL/min/1.73 m2, respectively). There was no significant change in HbA1c, LPL, and urinary albumin in the both groups.

Discussion The present analysis showed a relationship of change in plasma HDL to glucose metabolism and renal function after statin switching. Statin doses are lower in Japanese practice than in Western one. In a recent report, Japanese patients treated with ATO 10-mg/day, PIT 2-mg/day, or ROS 2.5-mg/day and suppressed LDL-C approximately 2.5 mmol/L (95 mg/dL).17 This is comparable with the present analysis.

Change in parameters between the groups HDL and glucose metabolism Change in parameters between the HD and HI groups after statin switching was compared (Table 2) (Fig. 2). Changes in HDL-C (23.49 6 3.44 vs 5.72 6 4.24 mg/ dL, P , .01), Apo A-1 (25.66 6 10.82 vs 11.20 6 11.77 mg/dL, P , .01), LPL (22.43 6 14.83 vs 2.98 6 12.56 ng/mL, P 5 .028), HbA1c (0.05 6 0.27 vs 20.09 6 0.41%, P 5 .018), and eGFRcre (20.65 6 7.17 vs 2.06 6 6.39 mL/min/1.73 m2, P 5 .026) were significant between the 2 groups. In the patients with impaired glucose tolerance or diabetes (IGT/DM), changes in HbA1c were also significant between the 2 groups (0.10 6 0.33 vs 20.17 6 0.48%, P 5 .033). In the patients without IGT/DM, changes in HbA1c were not significant between the 2 groups (Table 3).

The present analysis did not show the relationship between change in HDL-C and change in HbA1c before and after statin switching (Fig. 1). The subjects were then divided into 2 groups by change in HDL-C. The HbA1c significantly decreased in the HI group compared with that in the HD group (Table 2) (Fig. 2). In the subjects with IGT/DM, HbA1c exhibited a similar tendency (Table 3). LPL significantly increased in the HI group compared with that in the HD group (2.98 6 12.56 vs 22.43 6 14.83, P 5 .028). It is well known that LPL activity is dependent on insulin resistance and mediates triglyceride-rich lipoprotein catabolism. In the previous study, there was a slight but significant association between change in HDL-C and change in LPL in all

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Figure 2 Change in parameters in the no change or decrease in high-density lipoprotein cholesterol (HDL-C; HD) group and the increase in HDL-C (HI) group before (solid bar) and after (white bar) statin switching. Parameters before and after statin switching: HbA1c (A), estimated glomerular filtration rate calculated from creatinine (eGFRcre) (B), and estimated glomerular filtration rate calculated from cystatin C (eGFRcys) (C). Change in parameters between the HD group and the HI group (dot bar): HbA1c (D), eGFRcre (E), eGFRcys (F).

subjects (r 5 0.34, P , .01).10 LPL activity is also associated with HDL-C level.18 Therefore, it has been suggested that change in HDL-C by statin switching may be related to change in insulin activity. Other recent reports have suggested that HDL may modulate glucose metabolism, and the underlying mechanisms have been investigated. In patients with type II diabetes mellitus, intravenous reconstituted HDL injection reduces plasma glucose by increasing serum insulin and by activating AMP-activated protein kinase.19 Islet cholesterol accumulation and lack of ABCA1 function, which regulates islet cholesterol efflux, leads to reduced b-cell function.20 Apo A-1 and Apo A-2 stimulate insulin secretion from b-cell via ABCA1 or ABCG1.21,22 In type II diabetes mellitus, b-cell function is related to HDL function, and better HDL functionality is important in maintaining b-cell function.23

In the present study, HDL-C and Apo A-1 increased in the HI group. Increased HDL-C level by statin switching may affect b-cell function and glucose metabolism.

HDL and renal function In the present analysis, there is a significant difference in baseline eGFRcre between the HD group and HI group. This was because of mean age difference between the groups. In the HI group, eGFRcre and eGFRcys significantly increased after statin switching. The first role of HDL in renal function is its cholesterol efflux capacity. Lipid nephrotoxicity may worsen glomerular and tubuleinterstitial disease,24 and cholesterol efflux from glomerulus by HDL may reduce the nephrotoxicity. The second role of HDL in renal function is its antioxidative effect and endothelial function improvement. In hypertensive

714 Table 3

Journal of Clinical Lipidology, Vol 9, No 5, October 2015 Laboratory results with or without IGT/DM and with or without BMI .25 HD

Variables

HI

Baseline

HbA1c (%) IGT/DM 6.88 Non-IGT/DM 5.82 BMI .25 6.50 BMI #25 6.21 eGFRcre (mL/min/1.73 m2) IGT/DM 72.3 Non-IGT/DM 68.8 BMI .25 71.6 BMI #25 69.6 eGFRcys (mL/min/1.73 m2) IGT/DM 70.4 Non-IGT/DM 65.9 BMI .25 69.3 BMI #25 66.9

Change

Baseline

P value between the groups

Change

6 6 6 6

0.84 0.36 0.83 0.82

0.01 0.01 0.09 0.01

6 6 6 6

0.33 0.16 0.28 0.25

7.23 5.75 6.74 6.09

6 6 6 6

1.65 0.27 1.63 0.89

20.17 20.04 20.04 20.14

6 6 6 6

0.60 0.15 0.33 0.46

.033 n.s. n.s. n.s.

6 6 6 6

18.1 16.8 17.2 17.9

0.30 21.63 20.93 20.37

6 6 6 6

6.85 7.35 8.43 5.55

68.1 61.2 66.2 62.5

6 6 6 6

17.3 15.2 17.2 15.4

2.88 1.47 2.87 1.44

6 6 6 6

7.20 5.73 7.18* 5.62

n.s. .056 .070 n.s.

6 6 6 6

19.3 18.8 17.7 20.5

0.93 1.15 0.93 1.15

6 6 6 6

6.79 8.30 8.22 6.84

64.0 60.7 62.6 61.7

6 6 6 6

17.4 18.5 18.2 17.7

0.92 2.69 3.45 0.77

6 6 6 6

7.60 7.20* 8.12* 6.49

n.s. n.s. n.s. n.s.

BMI, body mass index; eGFRcre, estimated glomerular filtration rate calculated from serum creatinine value; eGFRcys, estimated glomerular filtration rate calculated from serum cystatin C; IGT/DM, impaired glucose tolerance or diabetes; HbA1c, glycated hemoglobin; HD, no change or decrease in highdensity lipoprotein cholesterol; HI, increase in high-density lipoprotein cholesterol. Values are presented by mean 6 standard deviation. Student unpaired t test was used to compare difference between the HD and the HI group. The number of subjects with IGT/DM in HD was 33, subjects without IGT/DM was 32. The number of subjects with IGT/DM in HI was 27, subjects without IGT/ DM was 37. The number of subjects who’s BMI above 25 in HD was 33, subjects without below 25 was 32. The number of subjects who’s BMI above 25 in HI was 28, subjects without below 25 was 36. *P , .05 vs baseline.

patients, endothelial dysfunction is related to eGFR decline.25 Because different estimations denote the same tendency, increased HDL-C may be associated with improvement in renal function.

Conclusion Increase in HDL-C because of statin switching is associated with improvement in glucose metabolism and renal function when the level of LDL-C was maintained. An increase in HDL-C by statin switching may be beneficial in suppressing cardiovascular risk via improvement in glucose metabolism and renal function (Fig. 3).

Limitations Some limitations exist in the present analysis. As the present study was not a randomized controlled study,

selection biases might exist. As the HI group was older than the HD group, and there were more subjects with IGT/ DM in the HI group, baseline eGFR was lower in the HI group than in the HD group. And as we examined 1 sample per measurement in each participant, a measurement deviation might exist. Therefore, we have taken various steps to remove biases as much as possible. Another limitation is that the mechanism of change in HDL-C level by statin switching is not investigated in the present study. In a recent report, an increase in adiponectin secondary to statin treatment resulted in an increase in HDL-C.26 The final limitation is that HDL functions, such as cholesterol efflux capacity and antioxidative effect of HDL, are not investigated in the present study. In addition to the level of HDL-C, HDL functionality is likely to be important in preventing cardiovascular disease and improving glucose metabolism and renal function. Apo A-1 is one of the indicators of HDL function,1 and statins increase Apo A-1 levels. Randomized, large, clinical studies are needed to clarify the multiple effects of HDL, including its association with glucose metabolism and renal function.

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Figure 3 Hypothesis of functional high-density lipoprotein (HDL) and glucose metabolism and renal function.

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