Systematic review and meta-analysis of Statins-Fibrates ...

Systematic review and meta-analysis of Statins-Fibrates therapy in diabetic dyslipidemia patients

Shuang Zheng, Yang-Xue Li, Ting-Ting Han, Yao Zhang, Dong-Dong Jiang, Yao-Min Hu

Shuang Zheng, Yang-Xue Li, Ting-Ting Han, Yao Zhang, Dong-Dong Jiang, Yao-Min Hu, Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong Univer-sity, Shanghai 200127, ChinaAuthor contributions: Hu YM designed the review; Zheng S and Li YX collected the data; Han TT, Zhang Y and Jiang DD analyzed the data; Zheng S and Hu YM wrote the paper.Supported by The National Scientific Foundation of China, No. 81270946, No. 81170758, No. 30670988Correspondence to: Yao-Min Hu, PhD, Department of Endo-crinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NO.160 Pujian Road, Shanghai 200127, China. [email protected]: +86-21-68383447 Fax: +86-21-58394262Received: June 6, 2014 Revised: June 24, 2014Accepted: September 6, 2014Published online: November 26, 2014

AbstractAIM: To evaluate the efficacy, effect of preventing cardio-vascular diseases and safety of statins-fibrates combination therapy in diabetic dyslipidemia patients.

METHODS: We searched the databases of MEDLINE, EM-BASE, web of knowledge and Cochrane central register of Controlled Trials for literatures about the coadministration of statins and fibrates as the treatment of patients with dyslipidemia and type 2 diabetes mellitus. We included re-lated randomized controlled trials, controlled clinical trials and cross-sectional studies and excluded animal trials and clinical observations. The primary endpoints outcomes were the concentration of plasma total cholesterol (TC), triglyc-eride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). The secondary outcomes were cardiovascular diseases (CVD) and adverse events.

RESULTS: Ten studies were included in this meta-analysis. For lipid modifying efficacy, the combination of statins and fibrates therapy had more significant effect

on reducing TC [P = 0.004, weighted mean difference (WMD) = -8.19, 95%CI: -13.82--2.56] and TG concentra-tion (P < 0.001, WMD = -47.29, 95%CI: -68.66--25.92) and increasing HDL-C concentration (P < 0.00001, WMD = 3.79, 95%CI: 2.25-5.33) when compared with statins monotherapy, while the effect of reducing LDL-C concen-tration (P = 0.50, WMD = -2.52, 95%CI: -9.76-4.72) was insignificant. To fibrates monotherapy, the combination therapy was more effective on reducing TC (P < 0.00001, WMD = -48.51, 95%CI: -57.14--39.89), TG (P < 0.00001, WMD = -26.07, 95%CI: -30.96--21.18), LDL-C concentra-tion (P < 0.00001, WMD = -45.74, 95%CI: -53.35--38.13) and increasing HDL-C concentration (P = 0.04, WMD = 1.38, 95%CI: 0.04-2.73). For cardiovascular diseases, the coad-ministration therapy had no significant effect on reducing the incidence of these events when compared with mono-therapy (For primary clinical endpoints, P = 0.12, OR = 0.61, 95%CI: 0.33-1.14); for secondary clinical endpoints, P = 0.13, OR = 0.66, 95%CI: 0.38-1.14). For adverse events happened during the follow-up, both the incidence of hepatic-related (alanine aminotransferase and/or aspartate aminotransferase of patients were ≥ 3 times of upper limit of normal) (P = 0.38, OR = 0.55, 95%CI: 0.15-2.06) and muscular-related (myopathy and/or creatine phosphokinase ≥ 3 times of upper limit of normal) adverse events (P = 0.10, OR = 1.62, 95%CI: 0.91-2.86) had no significant dif-ference between these two therapies.

CONCLUSION: The results showed statins-fibrates com-bination therapy was more effective on lipid modification and well tolerated but there was no significant effect on preventing cardiovascular diseases.

© 2014 Baishideng Publishing Group Inc. All rights reserved.

Key words: Statin; Fibrate; Dyslipidemia; Type 2 diabetes; Combination therapy

Core tip: Both dyslipidemia and type 2 diabetes were es-tablished risk factors of cardiovascular diseases. Statins therapy was highly effective at lowering low density lipo-

META-ANALYSIS

November 26, 2014|Volume 2|Issue 4|WJMA|www.wjgnet.com

World Journal ofMeta-AnalysisW J M A

Submit a Manuscript: http://www.wjgnet.com/esps/Help Desk: http://www.wjgnet.com/esps/helpdesk.aspxDOI: 10.13105/wjma.v2.i4.194

World J Meta-Anal 2014 November 26; 2(4): 194-203ISSN 2308-3840 (online)


194

protein cholesterol (LDL-C). However, despite the increas-ing use of statins as monotherapy for LDL-C reduction, a significant residual cardiovascular risk was still presented in patients with diabetic dyslipidemia. At the same time, Fenofibrate failed to alter the primary clinical endpoints significantly. How about the efficacy of statins-fibrates combination therapy in patients with diabetic dyslipidemia? The results of this meta-analysis showed the combination therapy was more effective on lipid modification and well tolerated but there was no significant effect on preventing cardiovascular diseases.

Zheng S, Li YX, Han TT, Zhang Y, Jiang DD, Hu YM. Systemat-ic review and meta-analysis of Statins-Fibrates therapy in diabetic dyslipidemia patients. World J Meta-Anal 2014; 2(4): 194-203 Available from: URL: http://www.wjgnet.com/2308-3840/full/v2/i4/194.htm DOI: http://dx.doi.org/10.13105/wjma.v2.i4.194

INTRODUCTIONCardiovascular diseases (CVD) represent the leading cause of mortality worldwide. Many researches have confirmed that both dyslipidemia and type 2 diabetes have tight rela-tionship with CVD[1,2]. The combination of dyslipidemia and diabetes could be called diabetic dyslipidemia, which is a well-recognized reason for atherosclerotic cardiovascular diseases[3]. Elevated low density lipoprotein cholesterol (LDL-C) is a major risk factor for CVD[4]. As a result, cur-rent guidelines recommend management of LDL-C as the primary goal of therapy for diabetic dyslipidemia[5]. Statins are the drug of first choice for aggressive lipid lowering ac-tions and reducing risk of CVD in these patients[6]. Howev-er, current therapeutic use of statins as monotherapy is still leaving many patients with diabetic dyslipidemia at high risk for CVD[7]. Some studies have come up with the conclu-sion that the coadministration of statins and fibrates may be more effective with no more adverse events as the treat-ment to patients with mixed dyslipidemia than statins or fibrates monotherapy[8-12], which may reduce the incidence of CVD at the same time. So we are curious about the ef-ficacy and safety of the combined statins-fibrates therapy and their benefits in reducing CVD incidence in patients with dyslipidemia and type 2 diabetes.

MATERIALS AND METHODSSearch strategy and selection criteriaThe search was performed using database of MED-LINE from 1980 to March 2014, EMBASE from 1980 to March 2014, the forth quarter 2014 Cochrane central register of controlled trials and web of knowledge from 1980 to March 2014. We conducted a comprehensive and systematic search of the published literature for trials of coadministration of statins and fibrtaes as the treatment of dyslipidemia with type 2 diabetes. The initial search terms were “statin”, “fibrate”, “dyslipidemia’’, “diabetes” and their combination [statin AND fibrate /“combina-

tion therapy” AND dyslipidemia/dyslipidemia AND diabetes/(statin AND fibrate) AND dyslipidemia/(statin AND fibrate) AND diabetes/“diabetic dyslipidemia”/(statin AND fibrate) AND “diabetic dyslipidemia”/“combination therapy” AND “diabetic dyslipidemia”].

We included randomized controlled trials, controlled clinical trials and cross-sectional studies those investigated the efficacy and safety of coadministration of statins and fibrates in patients with diabetic dyslipidemia and excluded animal trials and clinical observations. The treatment group involved the coadministration of statins and fibrates. The control group used statins or fibrates monotherapy. The statins included Simvastatin, Fluvastatin, Atorvastatin, Pravastatin, Rosuvastatin and Cerivastatin. The fibrates in-cluded Fenofibrate, Bezafibrate and Fenofibric acid.

Two reviewers independently evaluated the articles and any disagreement was resolved by consensus.

Statistical analysis Study design data including design synopsis, duration of treatment and basic characteristics of patients. The primary endpoints outcomes were the concentration of total cholesterol (TC), triglyceride (TG), high density lipo-protein cholesterol (HDL-C) and LDL-C. The second-ary outcomes were cardiovascular diseases and adverse events. For cardiovascular diseases, the primary clinical endpoints included death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke. The secondary clinical endpoints included the combination of the primary outcome plus revascularization or hospital-ization for congestive heart failure (termed the “expanded macrovascular outcome”); a combination of a fatal coro-nary event, nonfatal myocardial infarction, or unstable angina (termed “major coronary disease events”); nonfa-tal myocardial infarction; fatal or nonfatal stroke; nonfatal stroke; death from any cause; death from cardiovascular causes; and hospitalization or death due to heart failure. For adverse events, if the alanine aminotransferase and/or aspartate aminotransferase of patients were ≥ 3 times of upper limit of normal during follow-up, it would be counted as hepatic-related adverse events. While the muscular-related adverse events included myopathy and CK (creatine phosphokinase) ≥ 3 times of upper limit of normal during follow-up.

We combined the results and expressed them as odds radio (OR) or weighted mean difference (WMD) with corresponding 95%CIs, using a fixed effect (FE) or ran-domized effect (RE) model for the studies with sufficient data (in this article, if the homogeneity was no more than 50%, FE model was used, else RE model was used). The homogeneity was assessed with I2 and χ 2 test. The above statistical calculations were performed on Revman Manager 5.0 Software (Copenhagen, Denmark) for meta-analysis.

RESULTSWe searched 107 potentially relevant studies and retrieved 62 full-text articles. 52 of the full-text articles were exclud-


Zheng S et al . Efficacy and safety of combination therapy

195

ed because the patients were not having both dyslipidemia and diabetes or the data were not complete (Figure 1). Finally only 10 studies[13-22] were included in our research and their basic characteristics were shown in Table 1.

Comparisons of lipid modifying efficacy between coadministration and monotherapyFigure 2 showed the comparisons of lipid modifying ef-ficacy between coadministration of statins and fibrates and statins monotherapy. Figure 2A presented the results of plasma TC concentration in two different therapies; six trials investigated it with a total of 721 patients. From this figure we observed that compared with statins monotherapy, the coadministration of statins and fibrates had more strong function on reducing the concentration of plasma TC in patients with diabetic dyslipidemia (P = 0.004, WMD = -8.19, 95%CI: -13.82--2.56). Figure 2B presented the results of plasma TG concentration in two different therapies, four trials with 663 patients were included, which had the similar results with TC (P < 0.001, WMD = -47.29, 95%CI: -68.66--25.92). Both of them showed a beneficial and statistically significant ef-fect of coadministration on diabetic dyslipidemia. Figure 2C presented the results of plasma HDL-C concentra-tion with six trials and 721 patients. From this figure we observed the concentration of HDL-C was lower in

statins monotherapy group (P < 0.00001, WMD = 3.79, 95%CI: 2.25-5.33). Figure 2D presented the results of plasma LDL-C concentration with four trials and 691 pa-tients, which showed the modification of LDL-C was not significant between coadministration and statins mono-therapy (P = 0.50, WMD = -2.52, 95%CI: -9.76-4.72). In conclusion, for lipid modifying efficacy, the combination of statins and fibrates therapy had more significant ef-fect on reducing plasma TC and TG concentration and increasing HDL-C concentration when compared with statins monotherapy, while the effect of reducing LDL-C concentration was insignificant.

Figure 3 showed the comparisons of lipid modifying efficacy between coadministration of statins and fibrates and fibrates monotherapy. Figure 3A, B and D presented the results of plasma TC, TG and LDL-C concentration respectively. All of them showed a beneficial and statisti-cally significant effect on reducing TC, TG and LDL-C with combination therapy (P < 0.00001). Figure 3C presented the results of plasma HDL-C concentration with three trials and 302 patients. From this figure we ob-served the concentration of HDL-C was lower in fibrates monotherapy group (P = 0.04, WMD = 1.38, 95%CI: 0.04-2.73). In conclusion, the combination therapy was more effective on reducing TC, TG, LDL-C concentra-tion and increasing HDL-C concentration than fibrates monotherapy.

Comparisons of cardiovascular diseases between coadministration and monotherapyFigure 4 showed the incidence of cardiovascular dis-eases between coadministration and statins or fibrates monotherapy. Three identified studies were included in this analysis with 8875 patients. Figure 4A showed the primary clinical endpoints, Figure 4B showed the second-ary clinical endpoints. From Figure 4 we observed that in patients with diabetic dyslipidemia, the coadministration therapy had insignificant effect on reducing the incidence of cardiovascular diseases when compared with statins or fibrates monotherapy. For primary clinical endpoints, P = 0.12, OR = 0.61, 95%CI: 0.33-1.14); for secondary clini-cal endpoints, P = 0.13, OR = 0.66, 95%CI: 0.38-1.14).

November 26, 2014|Volume 2|Issue 4|WJMA|www.wjgnet.com 196

Ref. Type Number (T/C1/C2)

Age (mean)(T/C1/C2)

Men (%) Treatment Contral 1 Contral 2 Duration(mo)

Athyros et al[19] 2002 RCT 40/40/40 58/57/58 56.7 A + Fe A Fe 6 Durrington et al[22] 2004 RCT 115/53/48 60/60/60 53.0 R + Fe R Fe 6 Rosenson et al[21] 2011 RCT 177/173/123 60/58/58 41.4 R + FA R FA 3

Derosa et al[18] 2004 RCT 25/23/0 61/59/0 50.0 F + Fe F 6 Farnier et al[16] 2011 RCT 145/146/0 56/57/0 48.1 P + Fe S 3 Hamilton et al[17] 2010 RCT 15/0/15 63/0/63 86.7 A/S/P/R + Fe Fe 3 Ginsberg et al[20] 2010 RCT 2765/2753/0 62/62/0 69.3 S + Fe S 56.4 Gavish et al[13] 2000 CCT 146/100/48 59/58/60 57.4 S + B S B 21 Constantinides et al[15] 2012 CCT 14/14/14 > 18/> 18/> 18 100 S + B S B 2 Klempfner et al[14] 2014 CSS 225/2838/0 60/65/0 71.0 A/S/P/C/F + B B 12

Table 1 Basic characteristics of included studies

RCT: Randomized controlled trial; CCT: Controlled clinical trial; CSS: Cross-sectional study; T/C1/C2: Treatment/Control 1/Control 2; S: Simvastatin; B: Bezafibrate; F: Fluvastatin; Fe: Fenofibrate; A: Atorvastatin; P: Pravastatin; R: Rosuvastatin; C: Cerivastatin; FA: Fenofibric acid.

107 potentially relevant studies

45 were not full-text articles

62 full-text articles

10 studies included in meta-analysis

Excluded (n = 52) Patients with only dyslipidemia (n = 42) Patients with dyslipidemia and prediabetes (IFG + IGT) (n = 1) No relevant data were reported (n = 8) Three drug combination therapy (n = 1)

Figure 1 Flow diagram of study screening process. IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance.



riod of two different therapies. Four related trials were included in meta-analysis with a total of 1274 patients. Figure 5A presented the hepatic-related adverse events. Figure 5B presented the muscular-related adverse events. There was no significant difference between the two therapies (P = 0.38 and 0.10 respectively). In conclusion, statins-fibrates combination therapy was tolerated as well

In conclusion, the coadministration therapy had no sig-nificant effect on reducing the incidence of these events when compared with monotherapy.

Comparisons of adverse events between coadministration and monotherapyFigure 5 showed the adverse events happened in the pe-

197

Statin and fibrate Statin Mean difference Mean differenceStudy or subgroup Mean SD Total Mean SD Total Weight Ⅳ, Random, 95%CI Ⅳ, Random, 95%CI

Athyros et al 2002Constantinides et al 2012Derosa et al 2004Farnier et al 2011Gavish et al 2000Hamilton et al 2010

159143.21

196191.8

208.44131.24

724.7

3840.819.33.86

401425

14414615

174135.1

208200.1

208.44142.82

1028.56

2837.4

23.163.86

401423

14510015

24.1%6.2%6.7%

16.0%21.5%25.4%

-15.00 (-18.78, -11.22)8.11 (-11.67, 27.89)

-12.00 (-30.78, 6.78)-8.30 (-17.33, 0.73)

0.00 (-5.51, 5.51)-11.58 (-14.34, -8.82)

Total (95%CI)Heterogeneity: Tau2 = 30.46; χ 2 = 23.58, df = 5 (P = 0.0003; I 2 = 79%)Test for overall effect: Z = 2.85 ((P = 0.004)

384 337 100.0% -8.19 (-13.82, -2.56)

-50 -25 0 25 50Favours coadministration Favours statin


Total (95%CI)

Heterogeneity: Tau2 = 384.37; χ 2 = 44.30, df = 3 (P < 0.00001; I 2 = 93%)

Test for overall effect: Z = 4.34 ((P < 0.0001)Favours coadministration Favours statin

Athyros et al 2002

Derosa et al 2004

Farnier et al 2011

Gavish et al 2000

139

109

182.9

78.75

12

37

124.2

18.9

40

25

144

146

195

124

281.8

110.25

22

49

156.8

18.9

40

23

145

100

29.7%

21.9%

18.0%

30.4%

-56.00 (-63.77, -48.23)

-15.00 (-39.73, 9.73)

-98.90 (-131.50, -66.30)

-31.50 (-36.31, -26.69)

-100 -50 0 50 100

355 308 100.0% -47.29 (-68.66, -25.92)


Total (95%CI)

Heterogeneity: Tau2 = 2.15; χ 2 = 15.46, df = 5 (P = 0.009; I 2 = 68%)

Test for overall effect: Z = 4.81 ((P < 0.00001) Favours statin Favours coadministration

Athyros et al 2002

Constantinides et al 2012

Derosa et al 2004

Farnier et al 2011

Gavish et al 2000

Hamilton et al 2010

43

39.3

55

48.6

30

35.7

4.3

11.4

6

12.7

6

1.5

40

14

25

144

146

15

37.7

36.9

48

45.6

27

33.6

4.5

11.4

4

11.1

6

1.5

40

14

23

145

100

15

19.8%

3.0%

14.4%

15.0%

22.4%

25.3%

5.30 (3.37, 7.23)

2.40 (-6.05, 10.85)

7.00 (4.14, 9.86)

3.00 (0.25, 5.75)

3.00 (1.47, 4.53)

2.10 (1.03, 3.17)

384 337 100.0% 3.79 (2.25, 5.33)


Total (95%CI)


Test for overall effect: Z = 0.68 ((P = 0.50) Favours coadministration Favours statin

Athyros et al 2002


Derosa et al 2004

Farnier et al 2011

Gavish et al 2000

89

82.46

125

117.3

121.6

6

22.8

20

33.5

19

40

14

25

144

146

97

73.34

140

117.2

117.8

7

24.32

25

32.7

22.8

40

14

23

145

100

27.6%

10.8%

15.1%

21.8%

24.8%

-8.00 (-10.86, -5.14)

9.12 (-8.34, 26.58)

-15.00 (-27.88, -2.12)

0.10 (-7.53, 7.73)

3.80 (-1.63, 9.23)

-10 -5 0 5 10

369 322 100.0% -2.52 (-9.76, 4.72)

-50 -25 0 25 50

A

B

C

D

Figure 2 Summary of results of meta-analysis on the lipid modifying function between coadministration of statins and fibrates and statins monotherapy. A: Comparison of plasma TC concentration between coadministration and statins monotherapy; B: Comparison of plasma TG concentration between coadministration and statins monotherapy; C: Comparison of plasma HDL-C concentration between coadministration and statins monotherapy; D: Comparison of plasma LDL-C concentration between coadministration and statins monotherapy. LDL-C: Low density lipoprotein cholesterol; HDL-C: High density lipoprotein cholesterol; TG: Triglyceride.



as statins or fibrates monotherapy.

DISCUSSIONCVD continues the leading cause of death worldwide. Both dyslipidemia and type 2 diabetes were established risk factors for CVD[1,2]. Moreover, dyslipidemia was strikingly common in patients with type 2 diabetes, af-fecting almost 50% of this population[2]. So it was easy to understand that CVD was more common in patients with diabetic dyslipidemia than in the general populations[23].

Several researches had come out with the idea that el-evated LDL-C was a major risk factor for CVD[4,24,25]. As a result, management of LDL-C was the primary goal of therapy for patients with dyslipidemia and type 2 diabe-tes[5,26].

Statins therapy was highly effective at lowering LDL-C. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) have emerged as the cornerstone for LDL-C lowering since the first agent, lovastatin, was approved in 1987[27]. However, despite the increasing use of statins as monotherapy for LDL-C reduction, a

198

Statin and fibrate Fibrate Mean difference Mean difference

Study or subgroup Mean SD Total Mean SD Total Weight Ⅳ, Random, 95%CI Ⅳ, Random, 95%CI

Total (95%CI)


Test for overall effect: Z = 11.02 ((P < 0.00001) Favours coadministration Favours fibrate

Athyros et al 2002


Gavish et al 2000

159

143.21

208.44

7

24.7

19.3

40

14

146

213

171.77

258.62

14

24.7

19.3

40

14

48

44.2%

15.5%

40.3%

-54.00 (-58.85, -49.15)

-28.56 (-46.86, -10.26)

-50.18 (-56.47, -43.89)

200 102 100.0% -48.51 (-57.14, -39.89)

-100 -50 0 50 100

Statin and fibrate Fibrate Mean difference Mean difference

Study or subgroup Mean SD Total Mean SD Total Weight Ⅳ, Fixed, 95%CI Ⅳ, Fixed, 95%CI

Total (95%CI)

Heterogeneity: χ 2 = 1.25, df = 1 (P = 0.26; I 2 = 20%)

Test for overall effect: Z = 10.44 ((P < 0.00001)Favours coadministration Favours fibrate

Athyros et al 2002

Gavish et al 2000

139

78.75

12

18.9

40

146

167

100.8

15

28.35

40

48

67.5%

32.5%

-28.00 (-33.95, -22.05)

-22.05 (-30.64, -13.46)

186 88 100.0% -26.07 (-30.96, -21.18)

-50 -25 0 25 50

Statin and fibrate Fibrate Mean difference Mean differenceStudy or subgroup Mean SD Total Mean SD Total Weight Ⅳ, Fixed, 95%CI Ⅳ, Fixed, 95%CI

Athyros et al 2002


Gavish et al 2000

Total (95%CI)


Test for overall effect: Z = 2.02 ((P = 0.04) Favours fibrate Favours coadministration

43

39.3

30

4.3

11.4

6

40

14

146

40.3

38.1

30

4.38

10.5

6

40

14

48

50.0%

2.7%

47.3%

2.70 (0.80, 4.60)

1.20 (-6.92, 9.32)

0.00 (-1.96, 1.96)

200 102 100.0% 1.38 (0.04, 2.73)

-10 -5 0 5 10

Statin and fibrate Fibrate Mean difference Mean differenceStudy or subgroup Mean SD Total Mean SD Total Weight Ⅳ, Random, 95%CI Ⅳ, Random, 95%CI

Athyros et al 2002


Gavish et al 2000

Total (95%CI)


Test for overall effect: Z = 11.78 ((P < 0.00001)

89

82.46

121.6

6

22.8

19

40

14

146

140

110.96

167.2

15

26.6

15.2

40

14

48

43.9%

13.1%

43.0%

-51.00 (-56.01, -45.99)

-28.50 (-46.85, -10.15)

-45.60 (-50.89, -40.31)

Favours coadministration Favours fibrate-100 -50 0 50 100

200 102 100.0%-45.74 (-53.35, -38.13)

A

B

C

D

Figure 3 Summary of results of meta-analysis on the lipid modifying function between coadministration of statins and fibrates and fibrates monotherapy. A: Comparison of plasma TC concentration between coadministration and fibrates monotherapy; B: Comparison of plasma TG concentration between coadministration and fibrates monotherapy; C: Comparison of plasma HDL-C concentration between coadministration and fibrates monotherapy; D: Comparison of plasma LDL-C concentration between coadministration and fibrates monotherapy. LDL-C: Low density lipoprotein cholesterol; HDL-C: High density lipoprotein cholesterol; TG: Triglyceride.



significant residual cardiovascular risk was still presented in patients with diabetic dyslipidemia[7]. The reason was that LDL-C could not reflect the classic “diabetic dys-lipidemia”, which consisted of hypertriglyceridemia and low levels of HDL-C[28,29]. In patients with type 2 dia-betes, LDL particles were small and dense, carrying less cholesterol per particle; therefore, at any given LDL-C concentration, there were more LDL particles present in an individual with type 2 diabetes relative to an individual without the disease, which might make the LDL-C level a

misleading measure of risk in patients with type 2 diabe-tes[5]. It was increasingly recognized that insulin resistance contributed to the characteristic dyslipidemia associated with type 2 diabetes[30]; and this dyslipidemia associated with insulin resistance was also referred to as atherogenic dyslipidemia.

Since diabetic dyslipidemia was characterized by mod-erately increased TG levels and reduced HDL-C, fibrates therapy should be considered as the option. Several large clinical and angiographic trials had evaluated the efficacy

199

Statin and fibrate Statin or fibrate Odds Ratio Odds RatioStudy or subgroup Events Total Events Total Weight Ⅳ, Random, 95%CI Ⅳ, Random, 95%CI

Total (95%CI)

Total events


Test for overall effect: Z = 1.54 ((P = 0.12)0.01 0.1 1 10 100

Favours coadministration Favours monotherapy

Gavish et al 2000

Ginsberg et al 2010

Klempfner et al 2014

2

291

18

146

2765

225

10

310

402

148

2753

2838

12.4%

49.0%

38.6%

0.19 (0.04, 0.89)

0.93 (0.78, 1.10)

0.53 (0.32, 0.86)

3136 5739

311 722

100.0% 0.61 (0.33, 1.14)

Statin and fibrate Odds Ratio Odds Ratio

Study or subgroup Events Total Events Total Weight Ⅳ, Random, 95%CI Ⅳ, Random, 95%CI

Statin or fibrate

Gavish et al 2000

Ginsberg et al 2010

Klempfner et al 2014

Total (95%CI)

Total events

Heterogeneity: Tau2 = 0.15; χ 2 = 10.34, df = 2 (P = 0.006); I 2 = 81%

Test for overall effect: Z = 1.49 ((P = 0.13) Favours coadministration Favours monotherapy

0

1400

39

146

2765

225

2

1475

842

148

2753

2838

3.1%

52.9%

44.1%

0.20 (0.01, 4.20)

0.89 (0.80, 0.99)

0.50 (0.35, 0.71)

3136

1439 2319

5739 100.0% 0.66 (0.38, 1.14)

0.01 0.1 1 10 100

Figure 4 Summary of results of meta-analysis on cardiovascular diseases. A: Primary clinical endpoints events; B: Secondary clinical endpoints events.

A

B

Statin and fibrate Statin or fibrate Odds Ratio Odds Ratio

Study or subgroup Events Total Events Total Weight Ⅳ, Fixed, 95%CI Ⅳ, Fixed, 95%CI

Durrington et al 2004

Farnier et al 2011

Gavish et al 2000

Rosenson et al 2011

Total (95%CI)

Total events


Test for overall effect: Z = 0.89 ((P = 0.38)

0

0

2

1

3

101

145

146

177

569

12

1

2

0

15

115

146

148

296

705

21.6%

16.9%

44.6%

16.9%

100.00%

0.04 (0.00, 0.70)

0.33 (0.01, 8.25)

1.01 (0.14, 7.30)

5.04 (0.20, 124.38)

0.55 (0.15, 2.06)

Favours coadministration Favours monotherapy0.01 0.1 1 10 100

Statin and fibrate Statin or fibrate Odds Ratio Odds RatioStudy or subgroup Events Total Events Total Weight Ⅳ, Fixed, 95%CI Ⅳ, Fixed, 95%CI

Durrington et al 2004

Gavish et al 2000

Rosenson et al 2011

Total (95%CI)

Total events

Heterogeneity: χ 2 = 4.00, df = 2 (P = 0.14); I 2 = 50%

Test for overall effect: Z = 1.64 ((P = 0.10)

7

17

8

32

101

146

177

424

3

7

16

26

115

148

296

559

17.2%

39.4%

43.3%

100.00%

2.78 (0.70, 11.05)

2.65 (1.07, 6.61)

0.83 (0.35, 1.98)

1.62 (0.91, 2.86)

Favours coadministration Favours monotherapy0.01 0.1 1 10 100

Figure 5 Summary of results of meta-analysis on adverse events. A: Hepatic-related adverse events; B: Muscular-related adverse events.

A

B



of fibrates as monotherapy in halting the progression of atherosclerotic diseases[31-33]. The Fenofibrate Interven-tion and Event Lowering in Diabetes study was a 5-year, randomized, placebo-controlled trial testing the safety and efficacy of fenofibrate 200 mg in 9795 type 2 dia-betic patients[34]. In this trial Fenofibrate failed to alter the primary clinical endpoints significantly.

Although LDL-C levels didn’t differ substantially from individuals with or without type 2 diabetes, data had demonstrated that lowering LDL-C levels reduced the risk for major CVD in patients with type 2 diabetes[5]. It was well accepted that statins were the primary and more efficient method of reducing LDL-C levels even at low doses[35]. However, statins manifested minimal effects on raising HDL-C levels (5%-15%) and on decreasing TG levels (7%-30%)[36]. Fibrates had small or minimal effects on LDL-C levels, which depended on baseline TG lev-els[35]. These data implied that a combination of statins and fibrates may have additional benefits, especially in patients with dyslipidemia and type 2 diabetes.

Some researches have shown the efficacy of statins-fibrates combination therapy in patients with mixed dyslipidemia. Research by Goldberg et al[8] focused on the efficacy of fenofibric acid plus statins on multiple lipid parameters in women with mixed dyslipidemia and the results showed the coadministration could increase the HDL-C level and decrease TG level more effecctive than statin monotherapy. Similar results could observed from Research by Pepine et al[9] showed that in elderly patients with mixed dyslipidemia, rosuvastatin 5, 10, or 20 mg in combination with fenofibric acid 135 mg improved the overall lipid profile. Farnier et al[10] also found in high-risk patients with mixed hyperlipidemia not controlled by pravastatin 40 mg monotherapy, the fenofibrate 160 mg/pravastatin 40 mg fixed-dose combination therapy significantly improved the global atherogenic lipid profile. So it was easy for us to suppose that combination therapy was more effective on patients with mixed dyslipidemia than statins or fibrates monotherapy. How about patients with diabetic dyslipidemia?

From our meta-analysis, we observed that in patients with both dyslipidemia and type 2 diabetes, compared with statins or fibrates monotherapy, the coadministra-tion of statins and fibrates had more significant effect on lowering TG concentration. For plasma LDL-C concen-tration, combination therapy had statistically significant effect on lowering it than fibrates monotherapy. These data gave us the implication that the coadministration may be more effective on lipid modification than statins or fibrates monotherapy in diabetic dyslipidemia patients.

Since the combination therapy had additional benefit than monotherapy on lipid modifying efficacy in diabetic dyslipidemia patients, it was reasonable for us to give the hypothesis that the combination therapy would result in an additional cardiovascular benefit, as compared with statins therapy alone. One study focused on cardiovascu-lar events in patients received combined fibrates/statins treatment versus statin monotherapy had showed that a

significantly lower risk of 30-d major adverse cardiovas-cular events rate was observed in patients receiving com-bined fibrates/statins treatment following acute coronary syndrome compared with statins monotherapy[37]. How-ever, from the results of our meta-analysis, there was no significant difference on the incidence of cardiovascular diseases, no matter the primary or the secondary clini-cal endpoints, between the coadministration therapy and monotherapy in diabetic dyslipidemia patients. So our analysis did not support the use of combination therapy to reduce cardiovascular risk in the majority of patients with type 2 diabetes who were at high risk for cardiovas-cular diseases. But this evidence was not so robust since only three identified studies were included in this part of meta-analysis. Further studies should continue focus on the rate of CVD and maybe we could find different an-swers to this kind of questions.

In addition to lipid modifying efficacy, safety was an important issue influencing the selection of combina-tion therapy or monotherapy. Common adverse events associated with statins use included gastrointestinal up-set and muscle aches, although dose related hepatoxic-ity and myotoxicity were the most clinically significant adverse events[38]. Common adverse events associated with fibrates included gastrointestinal disturbance, rash, headache, pancreatitis, myalgia, and myotoxicity (in rare instances-and possibly more likely with gemfibrozil than with fenofibrate)[23]. Combination therapy with statins and gemfibrozil was more likely to be accompanied by severe myopathy[39,40]. This might due to the fact that gemfibrozil had significant pharmacokinetic interactions with statins that lead to increased plasma levels of statins[41]. This limitation was not observed with fenofibrate, bezafibrate, or ciprofibrate and no significant side effects had been observed with combination treatment with statins and fibrates[23]. Same conclusions could be driven from our meta-analysis, both incidence of hepatic-related adverse events and muscular-related adverse events had no obvi-ous difference between coadministration and monothera-py. So the combination therapy could be well tolerated in diabetic dyslipidemia patients.

In conclusion, diabetic dyslipidemia was associated with elevated serum TG, low serum HDL-C levels, and a preponderance of small, dense LDL particles. Distur-bance of lipid metabolism linked to insulin resistance may be the primary event in the development of type 2 diabetes, which had the tight relationship with CVD. The present meta-analysis had shown that the coadministra-tion was more effective on lipid modification than mono-therapy and it was well tolerated, though the rate of CVD had no significant difference when combination therapy was given.

However, our meta-analysis had several potential limi-tations. Firstly, most studies included in this mate-analysis were of small sample size and didn’t describe withdraw-als or dropouts. Secondly, few studies were included in the analysis of the incidence of CVD, for few related published articles were found, so our meta-analysis may

200



be affected by publication bias. Thus, more high quality studies were needed to evaluate the efficacy of coadmin-istration therapy on reducing the rate of CVD in patients with diabetic dyslipidemia. Finally, our results showed there was no significant difference between combina-tion therapy and statins monotherapy for reducing the incidence of CVD in patients with diabetic dyslipidemia. However, considering the limited literatures and most of the researches were not focus on dyslipidemia patients who need the combination therapy to prevent CVD and residual atherogenic risk after statins monotherapy, there may be some potential bias. As a result, further study aiming at these patients in need for combination therapy was necessary for a more precise and reliable comparison.

COMMENTSBackgroundStatins-fibrates combination therapy has been suggested to be more effective with no more adverse events as the treatment to patients with mixed dyslip-idemia than statins or fibrates monotherapy, which may reduce the incidence of cardiovascular diseases (CVD) at the same time. However, it is still unclear of the efficacy and safety of the combined statins-fibrates therapy and their benefits on reducing CVD incidence in patients with dyslipidemia and type 2 diabetes.Research frontiersStatins therapy was highly effective at lowering low density lipoprotein choles-terol (LDL-C). However, despite the increasing use of statins as monotherapy for LDL-C reduction, a significant residual cardiovascular risk was still pre-sented in patients with diabetic dyslipidemia. The Fenofibrate Intervention and Event Lowering in Diabetes study was a 5-year, randomized, placebo-controlled trial testing the safety and efficacy of fenofibrate 200 mg in 9795 type 2 diabetic patients. In this trial Fenofibrate failed to alter the primary clinical endpoints significantly. Some researches have shown the efficacy and safety of statins-fibrates combination therapy in patients with mixed dyslipidemia. But no consensus was reached among patients with diabetic dyslipidemia of using the combination therapy.Innovations and breakthroughsThis meta-analysis included 10 articles and more than 10 thousand patients were contained. Most of the included studies were randomized controlled trials. The authors found that the combination therapy was more effective on lipid modification and well tolerated but there was no significant effect on preventing cardiovascular diseases.Applications Statins-fibrates combination therapy may potentially be used for the therapy of diabetic dyslipidemia; however, more high quality studies are required for further estimate of the efficacy of combination therapy on reducing the rate of CVD.TerminologyStatins are Hydroxymethylglutaryl-coenzyme A reductase inhibitors, which may inhibit HMG-CoA reductase, a precursor to the formation of cholesterol, and up-regulate the LDL-C-receptor. What’s more, statins could reduce the hepatic cholesterol synthesis. Fibrates exert their primary effects on lipid metabolism via the activation of peroxisome proliferator activated receptor-alpha. It is able to reduce plasma triglyceride levels by inhibiting their synthesis and stimulating their clearance.Peer reviewIn this article, Zheng et al present evidence that the coadministration of statins and fibrates in the treatment of patients with dyslipidemia and type 2 diabetes was more effective on lipid modification than statins or fibrates monotherapy. They also present evidence that statins-fibrates combination therapy was toler-ated as well as statins or fibrates monotherapy. This is an interesting report for the clinical practice. Overall the report appears to be carefully examined and data adequately discussed.

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P- Reviewer: Cicero AFG, Sakabe K S- Editor: Song XX L- Editor: A E- Editor: Wu HL

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