Skip to content

Advertisement

Open Access

Baseline diabetes as a way to predict CV outcomes in a lipid-modifying trial: a meta-analysis of 330,376 patients from 47 landmark studies

  • Michel P. Hermans1Email author,
  • Evariste Bouenizabila2,
  • Daniel K. Amoussou-guenou3,
  • Sylvie A. Ahn4 and
  • Michel F. Rousseau4
Cardiovascular Diabetology201514:60

https://doi.org/10.1186/s12933-015-0226-z

Received: 2 March 2015

Accepted: 6 May 2015

Published: 21 May 2015

Abstract

Background

Diabetes is a major cardiovascular risk factor. However, its influence on the rate of occurrence of cardiovascular (CV) events during a clinical trial that included a diabetes subgroup has not yet been quantified.

Aims

To establish equations relating baseline diabetes prevalence and incident CV events, based on comparator arms data of major lipid-modifying trials.

Methods

Meta-analysis of primary outcomes (PO) rates of key prospective trials, for which the baseline proportion of diabetics was reported, including studies having specifically reported CV outcomes within their diabetic subgroups.

Results

47 studies, representing 330,376 patients (among whom 124,115 diabetics), were analyzed as regards the relationship between CV outcomes rates (including CHD) and the number of diabetics enrolled. Altogether, a total of 18,445 and 16,156 events occurred in the comparator and treatment arms, respectively. There were significant linear relationships between diabetes prevalence and both PO and CHD rates (%/year): y = 0.0299*x + 3.12 [PO] (p = 0.0128); and y = 0.0531*x + 1.54 [CHD] (p = 0.0094), baseline diabetes predicting PO rates between 3.12 %/year (no diabetic included) and 6.11 %/year (all patients diabetic); and CHD rates between 1.54 %/year (no diabetic) and 6.85 %/year (all patients diabetic). The slopes of the equations did not differ according to whether they were derived from primary or secondary prevention trials.

Conclusions

Absolute and relative CV risk associated with diabetes at inclusion can be readily predicted using linear equations relating diabetes prevalence to primary outcomes or CHD rates.

Keywords

DiabetesCardiovascularCoronary heart diseaseClinical trialResidual riskLipids

Introduction

Key prospective trials have demonstrated the effectiveness of long-term control of conventional risk factors (RFs) to prevent cardiovascular (CV) events. Next to decreasing tobacco use and physical inactivity, indisputable gains were achieved by targeting hypertension and hypercholesterolemia. Nevertheless, there remained a high residual risk of incident CV events in control and comparator arms of these trials, even in patients receiving appropriate standard of care [14]. This residual risk is driven by non-modifiable RFs (age; gender; familial or genetic features; and diabetes) and by modifiable conventional or emerging RFs (eg. atherogenic dyslipidemia; remnant lipoproteins; hyperglycaemia; hyperinsulinaemia; metabolic syndrome; subclinical inflammation; and chronic kidney disease).

Based on epidemiology and prospective studies, type 2 diabetes mellitus (T2DM) significantly increases the absolute risk of developing coronary heart disease (CHD), and confers a higher residual risk of large and small vessel damage. In the microcirculation, such risk is directly related to hyperglycaemia, whereas in large vessels, this residual risk is linked to hypertension, low-density lipoproteins (LDL); non-LDL dyslipidemias; and other metabolic comorbidities [510]. As a result, having T2DM, either individually or at a sub-group level (within a cohort or population) increases residual CV risk to an extent that needs to be determined. Since residual risk varies considerably from one study to another, such an evaluation would require going beyond comparing CV outcomes rates in diabetic vs. nondiabetic subgroups of individual trials.

The aim of this work was to establish equations relating baseline diabetes prevalence and incident CV events, based on comparator arms data of major clinical trials having investigated the potential CV benefit of various pharmacological or dietary interventions targeting, in the vast majority, lipids and lipoproteins. We performed a systematic meta-analysis of CV outcomes rates of those key prospective studies, for which the baseline proportion of diabetics was reported and, where available, studies having reported CV outcomes of diabetic subgroups [1190] (Table 1).
Table 1

Overview of 47 landmark prospective clinical trials with CV outcomes having included a substantial number and/or proportion of diabetic patients at baseline

 

CV prevention

Patients

Diabetes

Active arm

Comparator arm

Follow-up

Publication year

Reference

  

n

n

%

n

n

years

  

4D

PP-SP

1255

1255

100

619

636

4.0

2005

[11]

4S

SP

4444

202

5

2221

2223

5.4

1994

[1214]

 diabetes substudy

SP

202

202

100

105

97

5.4

1997

[14]

ACCORD-Lipid

PP-SP

5518

5518

100

2765

2753

4.7

2010

[15, 16]

ADDITION-Europe

PP-SP

3055

3055

100

1678

1377

5.3

2011

[17, 18]

AFCAPS/TexCAPS

PP

6605

155

2

3304

3301

5.2

1998

[19, 20]

AIM-HIGH

SP

3414

1158

34

1718

1696

3.0

2011

[21, 22]

AleCardio

SP

7226

7226

100

3616

3610

2.0

2014

[23, 24]

ALERT

PP-SP

2102

396

19

1050

1052

5.1

2003

[25]

ALLHAT-LLT

PP-SP

10355

3638

35

5170

5185

4.8

2002

[26]

Alpha-Omega

SP

4837

1754

36

2404

2433

3.4

2010

[27]

ASCOT-LLA

PP

10305

2532

25

5168

5137

3.3

2003

[28, 29]

 diabetes substudy

PP

2532

2532

100

1258

1274

3.3

2005

[29]

ASPEN

PP

2410

2410

100

1211

1199

4.0

2006

[30]

AURORA

PP-SP

2773

731

26

1389

1384

3.8

2009

[31, 32]

 diabetes substudy

PP-SP

731

731

100

388

343

2.8

2011

[32]

BIP

SP

3090

309

10

1548

1542

6.2

2000

[33, 34]

CARDS

PP

2838

2838

100

1428

1410

3.9

2004

[35]

CARE

SP

4159

586

14

2081

2078

5.0

1998

[3638]

 diabetes substudy

SP

586

586

100

282

304

5.0

1998

[38]

CDP (clofibrate)

SP

3892

1517

39

1103

2789

6.2

1975

[39, 40]

CDP (niacin)

SP

3908

1524

39

1119

2789

6.2

1975

[39, 40]

dal-OUTCOMES

SP

15871

3882

24

7938

7933

2.6

2012

[41, 42]

DIS

PP

761

761

100

379

382

5.0

1991

[43]

FIELD

PP-SP

9795

9795

100

4895

4900

5.0

2005

[4446]

GISSI-Prevenzione

SP

4271

582

14

2138

2133

2.0

2000

[47]

GREACE

SP

1600

313

20

880

720

3.0

2002

[48, 49]

 diabetes substudy

SP

313

313

100

161

152

3.0

2003

[49]

HATS

SP

107

17

16

73

34

3.0

2001

[50]

HHS

PP

4081

108

3

2051

2030

5.0

1987

[51, 52]

 diabetes substudy

PP

135

135

100

59

76

5.0

1992

[52]

HPS - MRC/BHF

PP-SP

20536

5963

29

10269

10267

5.0

2002

[53, 54]

 diabetes substudy

PP-SP

5963

5963

100

2978

2985

4.8

2003

[54]

HPS2-THRIVE

SP

25673

8299

32

12838

12835

3.9

2013

[55]

IDEAL

SP

8888

1057

12

4439

4449

4.8

2005

[56, 57]

ILLUMINATE

PP-SP

15067

6661

44.2

7533

7534

1.0

2007

[58]

JELIS

PP-SP

18645

3040

16.3

9326

9319

4.6

2007

[59]

LEADER

PP-SP

1568

268

17

783

785

4.6

2002

[60, 61]

LIPID

SP

9014

782

9

4512

4502

6.1

1998

[6264]

LIPS

SP

1677

202

12

844

833

3.9

2002

[65]

MEGA

PP

7832

1632

21

3866

3966

5.3

2006

[66]

ORIGIN

PP-SP

12536

11081

88.4

6281

6255

6.2

2012

[67]

PERFORM

SP

19120

5299

27.7

9562

9558

2.4

2011

[68]

Post-CABG

SP

1351

116

9

676

675

7.5

2000

[69, 70]

PREDIMED

PP

7447

3614

49

4997

2450

4.5

2013

[71]

PROACTIVE

SP

5238

5238

100

2605

2633

2.9

2005

[72, 73]

PROFIT-J

PP-SP

481

481

100

234

247

1.8

2014

[74]

PROSPER

PP-SP

5804

623

11

2891

2913

3.2

2002

[75]

RPS

PP-SP

12505

7494

60

6239

6266

5.0

2013

[76, 77]

SHARP

PP-SP

9270

2094

23

4650

4620

4.9

2011

[78]

STABILITY

SP

15828

5351

34

7924

7904

3.7

2014

[79, 80]

STENO-2

PP-SP

160

160

100

80

80

13.3

2008

[81]

TNT

SP

10001

1501

15

4995

5006

4.9

2005

[8286]

 diabetes substudy

SP

1501

1501

100

753

748

4.9

2006

[86]

VA Cooperative Study

SP

532

128

24

268

264

1.8

1973

[87]

VA-HIT

SP

2531

769

30

1264

1267

5.1

1999

[8890]

 diabetes substudy

SP

769

769

100

377

392

5.1

2002

[90]

Total (n)

 

330376

124115

 

165022

165354

   

Mean

      

4.4

  

CV: cardiovascular; PP and SP: primary and secondary prevention. Acronyms: 4D: Die Deutsche Diabetes Dialyse studie; 4S: Scandinavian Simvastatin Survival Study; ACCORD-Lipid: Action to Control Cardiovascular Risk in Diabetes - Lipid arm; ADDITION-Europe: Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care; AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study; AIM-HIGH: Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes; AleCardio: A Safety and Efficacy Study to Evaluate the Potential of Aleglitazar to Reduce CV Risk in CHD Patients with a Recent ACS and T2DM; ALERT: Assessment of Lescol in Renal Transplantation; ALLHAT-LLT: Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial; ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm; ASPEN: Atorvastatin as Prevention of CHD Endpoints in patients with Non-insulin dependent diabetes mellitus; AURORA: A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: an Assessment of Survival and Cardiovascular Events; BIP: Bezafibrate Infarction Prevention; CARDS: Collaborative Atorvastatin Diabetes Study; CARE : Cholesterol and Recurrent Events; CDP: Coronary Drug Project; dal-OUTCOMES: Efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome; DIS: Diabetes Intervention Study; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes; GISSI-Prevenzione: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico - Prevenzione; GREACE: Greek Atorvastatin and Coronary-heart-disease Evaluation; HATS: HDL-Atherosclerosis Treatment Study; HHS: Helsinki Heart Study; HPS - MRC/BHF: Medical Research Council and British Heart Foundation Heart Protection Study; HPS2-THRIVE: Heart Protection Study - Treatment of HDL to Reduce the Incidence of Vascular Events; IDEAL: Incremental Decrease in End Points Through Aggressive Lipid Lowering Trial; ILLUMINATE: Investigation of Lipid Level Management to Understand its Impact in Atherosclerosis Events; JELIS: Japan EPA Lipid Intervention Study; LEADER: Lower Extremity Arterial Disease Event Reduction; LIPID: Long-term Intervention with Pravastatin in Ischaemic Disease; LIPS: Lescol Intervention Prevention Study; MEGA: Primary Prevention of Cardiovascular Disease with Pravastatin in Japan; ORIGIN: Outcome Reduction with an Initial Glarigine Intervention; PERFORM: Prevention of cerebrovascular and cardiovascular Events of ischaemic origin with teRutroban in patients with a history oF ischaemic strOke or tRansient ischaeMic attack; Post-CABG (FU): Post Coronary Artery Bypass Graft Trial (follow-up); PREDIMED: Prevencion con Dieta Mediterranea; PROACTIVE: PROspective pioglitAzone Clinical Trial In macroVascular Events; PROFIT-J: PRimary preventiOn oF hIgh risk Type 2 diabetes in Japan; PROSPER: Prospective Study of Pravastatin in the Elderly at Risk; RPS: Risk and Prevention Study; SHARP: Study of Heart and Renal Protection; STABILITY: STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY; STENO-2: STENO-2 Study; TNT: Treating to New Targets; VA Cooperative Study: Veteran Administration Cooperative Study of Atherosclerosis, Neurology Section; VA-HIT: Veterans Affairs High-Density Lipoprotein Intervention Trial

Patients and methods

To be selected for inclusion, major clinical trials with CV outcomes had to meet three requirements: (i) the main purpose of the trial was to study the effect on CHD of a pharmacological or dietary intervention targeting lipids or lipoproteins, with CHD rates as sole primary outcome (PO), or with a major adverse CV event (MACE) composite PO comprising CHD; (ii) to focus exclusively on diabetic patients, or (iii) to report data on a sufficient number of diabetic patients from pre-/post-hoc analyses of DM subgroups of the main trial. Among studies conducted non-exclusively in DM patients, eligible trials had to comply with ≥1 of the following criteria: (i) the main trial had a subgroup of patients already diagnosed with DM at baseline, whose proportion was deemed sufficiently representative (>15 %); or (ii) the trial enrolled at least 100 DM patients, regardless of on-study new-onset diabetes.

For each study, the following items were analyzed: CV risk category at baseline (primary prevention [PP], secondary prevention [SP] or mixed [PP-SP]); number of patients included; number and proportion of patients with DM at baseline; number of patients in the active or comparator arms; duration of follow-up; age at inclusion; number of males; DM type and duration; HbA1c; total cholesterol (TC); low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); non-HDL-cholesterol (non-HDL-C); apolipoprotein B100 (apoB); triglycerides (TG); type of pharmacological or dietary intervention; primary trial outcome; CHD outcomes (see Table 2 for CV outcomes categories); and CV events number and rates for each trial.
Table 2

CV outcomes categories

Total mortality

all-cause death

A

Composite

all CV events (including procedures)

B

 

MACE

C

 

CV death

D

Cardiac

total CHD/major coronary events

E

 

nonfatal CHD

F

 

cardiac death/fatal CHD

G

 

ACS/ACE

H

 

all MI

I

 

nonfatal MI

J

 

fatal MI

K

 

unstable/hospitalization-requiring AP

L

 

coronary revascularization (PCI or CABG)

M

 

life-threatening arrhytmias

N

 

resuscitation for cardiac arrest

O

 

sudden death

P

 

CHF

Q

Coronary imaging

angiographic CAD progression/change in coronary atheroma volume

R

Cerebrovascular

all major cerebrovascular events

S

 

all stroke/TIA

T

 

nonfatal stroke

U

 

fatal stroke

V

 

carotid revascularization

W

Other composite

non-CHD MACE

X

Other mortality

non-CHD CV death

Y

Peripheral

any PAD event (including revascularization and leg amputation)

Z

ACE/ACS: acute coronary event/syndrome; AP angina pectoris; CABG: coronary artery bypass graft; CAD: coronary artery disease; CHD: coronary heart disease; CHF: congestive heart failure; CV: cardiovascular; MACE: major adverse cardiovascular event; MI myocardial infraction; PAD: peripheral arterial disease; PCI: percutaneous coronary intervention; TIA:transient is chemic attack (adapted from [91])

Results are presented as means (±1 standard deviation (SD)), or as proportions (%), with between-study range [BSR] described when needed. Linear regression was computed using the least-squares method. Results were considered statistically significant or non-significant (NS) for p <0.05 or p ≥0.05, respectively.

Results

Forty-seven studies were selected based on the criteria defined above [1190]. They accounted for a total of 330,376 patients. The median year of publication for all studies was 2005. Table 1 describes, for each study, the acronym’s definition; the CV prevention category; the cohort size and the number or proportion of diabetic at baseline; the number of patients randomized in the active or comparator arms; the follow-up duration; and publication year. For all studies, mean age (1SD) was 61.7 (6.4) years, and the proportion of males was 74 (17) %. Regarding ethnicity, the majority of patients studied were Caucasian (median 86.5 % [between-study range (BSR 0 %)–99.2 %] Three studies [JELIS; MEGA; and PROFIT-J] included only Japanese patients [59, 66, 74]. Among studies, 8 of 47 (17 %; n = 42,279) enrolled patients in PP at baseline; 17 of 47 (36 %; n = 131,425) included populations whose CV risk was a mix of PP and SP; and 22 of 47 (47 %; n = 156,672) were SP trials. Lipid values at baseline were (mg/dL): 209 (34) [TC]; 126 (32) [LDL-C]; 44 (7) [HDL-C]; 161 (32) [non-HDL-C]; 99 (19) [apoB] and 162 (27) [TG]. In total, these studies have included 124,115 diabetic patients, representing 42.1 % [BSR 2.3 %–100 %] of the population studied. For studies that reported diabetes duration, it averaged 7.5 (4.9) years, whereas metabolic control assessed by HbA1c was 7.49 (0.68) % (Table 3). The trials investigated the following interventions over a mean (1SD) duration of 4.4 (1.9) years [BSR: 1.0–13.3 years]: statins (21 trials); fibrates (9 trials); n-3 fatty acids and/or traditional Mediterranean diet (5 trials); niacin (4 trials); CETP-inhibitor (2 trials); PPAR-γ agonist (2 trials); ezetimibe (1 trial); PPAR-α/γ agonist (1 trial); and Lp-PLA2 inhibitor (1 trial) (Table 4).
Table 3

Baseline characteristics

Study§

Age (years)

Males (%)

Diabetes type & duration (years)

HbA1c (%)

TC (mg/dL)

LDL-C (mg/dL)

HDL-C (mg/dL)

Non-HDL-C (mg/dL)

apoB (mg/dL)

TG (mg/dL)

4D

66

54

T2DM

18

6.7

218

125

36

182

~

261

4S

59

81

~

  

260

188

46

214

~

132

 diabetes substudy

60

78

~

  

259

186

43

216

~

150

ACCORD-Lipid

62

69

T2DM

10

8.3

175

100

38

137

~

164

ADDITION-Europe

60.3

58

T2DM

0

7

214

133

46

168

~

146

AFCAPS/TexCAPS

58

85

T1DM; T2DM

  

221

150

37

184

~

158

AIM-HIGH

64

85

~

 

6.7

146

74

35

111

83

168

AleCardio

60.8

73

T2DM

8.6

7.8

152

79

42

110

~

152

ALERT

50

66

~

  

247

158

50

197

~

195

ALLHAT-LLT

66

51

T2DM

  

224

146

48

176

~

152

Alpha-Omega

69

78

~

  

183

100

50

133

~

146

ASCOT-LLA

63

81

~

  

212

131

50

162

~

150

 diabetes substudy

63.6

76

T2DM

  

205

128

46

159

~

168

ASPEN

61

66

T2DM

8

7.8

194

113

47

147

~

147

AURORA

64

62

~

  

176

100

45

131

82

157

 diabetes substudy

65

66

~

  

174

97

43

131

~

168

BIP

60

91

T2DM

  

212

148

35

177

~

145

CARDS

62

68

T2DM

8

7.9

207

117

54

153

117

173

CARE

59

86

~

  

209

139

39

170

~

156

 diabetes substudy

61

80

~

  

206

136

38

168

~

164

CDP (clofibrate)

 

100

~

  

252

~

~

~

~

183

CDP (niacin)

 

100

~

  

253

~

~

~

~

183

dal-OUTCOMES

60.2

81

~

  

145

76

42

103

81

134

DIS

46

56

T2DM

0

 

218

~

~

~

~

157

FIELD

62

63

T2DM

5

6.9

195

119

43

152

97

173

GISSI-Prevenzione

60

86

T2DM (79 %) T1DM (21 %)

  

229

152

46

183

~

166

GREACE

 

79

~

  

264

193

39

225

~

159

 diabetes substudy

55

56

T2DM (92 %) T1DM (8 %)

10.5

7.5

271

189

35

236

~

221

HATS

53

87

~

  

200

128

30

170

119

219

HHS

47

100

~

  

270

189

47

223

~

175

 diabetes substudy

49

100

T2DM

4.5

 

292

200

46

246

~

214

HPS - MRC/BHF

 

75

~

  

228

131

41

187

114

186

 diabetes substudy

62.1

70

T2DM (90 %) T1DM (10 %)

27

7

220

124

41

179

110

204

HPS2-THRIVE

64.9

82.7

~

  

128

63

44

84

68

127

IDEAL

62

81

~

  

197

122

46

151

119

151

ILLUMINATE

61.3

77.8

T2DM

  

157

80

49

108

73

127

JELIS

61

31.4

~

  

275

181

59

216

~

153

LEADER

68

100

~

  

218

131

46

172

~

213

LIPID

62

83

~

  

218

150

36

182

133

142

LIPS

60

84

T2DM; T1DM

  

200

131

38

162

~

160

MEGA

58.3

32

~

  

242

157

58

184

~

128

ORIGIN

63.5

65

T2DM

5.4

 

189

112

46

143

~

142

PERFORM

67.2

62.5

~

  

~

93

~

~

  

Post-CABG

61.7

92

~

  

226

156

39

187

~

158

PREDIMED

67

43

~

  

219

143

53

172

102

142

PROACTIVE

61.8

66

T2DM

9.5

8.1

199

114

45

154

~

198

PROFIT-J

85

65

T2DM

11.3

7.4

198

115

55

144

~

141

PROSPER

75

48

~

  

220

147

50

170

~

133

RPS

63.9

61.5

~

 

6.7

216

132

51

165

~

150

SHARP

62

63

~

  

189

107

43

146

92

205

STABILITY

65

81

~

  

~

80

45

~

  

STENO-2

54.9

74

T2DM

5.8

8.6

210

133

40

170

~

159

TNT

61

81

~

  

175

97

47

128

111

151

 diabetes substudy

63

73

~

8.5

7.4

175

96

45

130

113

171

VA Cooperative Study

55

100

~

  

244

~

~

~

~

~

VA-HIT

64

100

~

  

175

111

32

143

96

161

 diabetes substudy

65

 

~

  

172

108

31

141

~

166

mean

61.7

74

 

7.5

7.49

209

126

44

161

99

162

standard deviation

6.4

17

 

4.9

0.68

34

32

7

32

19

27

§: see legend to Table 1 for study acronyms definition; apoB: apolipoprotein B100; C: cholesterol; HbA1c: glycated haemoglobin A1c; HDL: high-density lipoprotein; LDL: low-density lipoprotein; T1DM and T2DM: type 1 and type 2 diabetes mellitus; TG: triglycerides

Table 4

Primary CV outcome rates in the active (treatment) and control (comparator/placebo) arms

Study§

Intervention

Primary; secondary CV outcomes§§

Events (n) treatment

Events (%) treatment

Rate (%.year-1) treatment

Events (n) control

Events (%) control

Rate (%.year-1) control

HR

95 % CI for HR

P

4D

statin

C; D + J

226

36.5

9.13

243

38.2

9.55

0.96

0.77-1.1

0.37

4S

statin

A

182

8.2

1.52

256

11.5

2.13

0.71

0.58-0.85

0.0003

 diabetes substudy

statin

A

15

14.3

2.65

24

24.7

4.58

0.58

NR

0.087

ACCORD-Lipid

fibrate

C; J + D

291

10.5

2.24

310

11.3

2.40

0.93

0.79-1.08

0.32

ADDITION-Europe

statin/other

B; D + J + M + Z

121

7.2

1.36

117

8.5

1.60

0.85

0.65-1.05

0.12

AFCAPS/TexCAPS

statin

C; E

116

3.5

0.68

183

5.5

1.07

0.63

0.50-0.79

<0.001

AIM-HIGH

niacin

C; G + J + H + M

282

16.4

5.47

274

16.2

5.39

1.02

0.87-1.21

0.8

AleCardio

PPAR-α/γ

C; D + J

344

9.5

4.76

360

10.0

4.99

0.95

0.83-1.11

0.57

ALERT

statin

C; G + J + M

112

10.7

2.09

134

12.7

2.50

0.84

0.64-1.06

0.14

ALLHAT-LLT

statin

A

631

12.2

2.54

641

12.4

2.58

0.99

0.89-1.11

0.88

Alpha-Omega

n-3 fatty acids

B

336

14.0

4.11

335

13.8

4.05

1.02

0.87-1.17

0.93

ASCOT-LLA

statin

J + G

100

1.9

0.59

154

3.0

0.91

0.65

0.50-0.83

0.0005

 diabetes substudy

statin

B

116

9.2

2.79

151

11.9

3.59

0.78

0.61-0.98

0.04

ASPEN

statin

C; D + J + M + O + L

166

13.7

3.43

180

15.0

3.75

0.91

0.73-1.12

0.34

AURORA

statin

C; J + D

396

28.5

7.50

408

29.5

7.76

0.97

0.84-1.11

0.59

 diabetes substudy

statin

C; G + J

85

21.9

7.82

104

30.3

10.83

0.72

0.51-0.90

0.008

BIP

fibrate

C; K + J + P

211

13.6

2.20

232

15.0

2.43

0.91

NR

0.26

CARDS

statin

C; H + M + T

83

5.8

1.49

127

9.0

2.31

0.65

0.48-0.83

0.001

CARE

statin

G + J

212

10.2

2.04

274

13.2

2.64

0.77

0.09-0.36

0.003

 diabetes substudy

statin

G + J + M

81

28.7

5.74

112

36.8

7.37

0.78

NR

<0.0001

CDP (clofibrate)

fibrate

A

281

25.5

4.11

709

25.4

4.10

1.00

NR

NR

CDP (niacin)

niacin

A

273

24.4

3.93

709

25.4

4.10

0.96

0.85-1.08

NR

dal-OUTCOMES

CETP inhibitor

C; G + J + L + O

656

8.3

3.20

633

8.0

3.09

1.04

0.93-1.16

0.52

DIS

fibrate

E

32

8.4

1.69

31

8.1

1.62

1.04

NR

NR

FIELD

fibrate

C; B + D + I + M

256

5.2

1.05

288

5.9

1.18

0.89

0.75-1.05

0.16

GISSI-Prevenzione

statin

C; A + I

120

5.6

2.77

136

6.4

3.15

0.88

0.71-1.15

0.41

GREACE

statin

C; A + J + L + Q + M

112

12.7

4.24

180

25.0

8.33

0.51

 

<0.0001

 diabetes substudy

statin

C; A + J + L + Q + M

20

12.4

4.14

46

30.3

10.09

0.41

NR

<0.0001

HATS

statin + niacin§§§

R + B; D + J + M

7

9.6

3.20

12

35.3

11.76

0.27

NR

0.02

HHS

fibrate

C; K + J + G

56

2.7

0.55

84

4.1

0.83

0.66

0.08-0.53

<0.02

 diabetes substudy

fibrate

C; K + J + G

2

3.4

0.68

8

10.5

2.11

0.32

NR

0.19

HPS - MRC/BHF

statin

C; A + G

1328

12.9

2.59

1507

14.7

2.94

0.88

0.81-0.94

0.0003

 diabetes substudy

statin

E + B

601

20.2

4.20

748

25.1

5.22

0.81

0.19-0.30

<0.0001

HPS2-THRIVE

niacin

C; G + M

1696

13.2

3.39

1758

13.7

3.51

0.96

0.90-1.03

0.29

IDEAL

statin

C; G + J + O

411

9.3

1.93

463

10.4

2.17

0.89

0.78-1.01

0.07

ILLUMINATE

CETP inhibitor

C; G + J + L

464

6.2

6.16

373

5.0

4.95

1.24

1.09-1.44

0.001

JELIS

n-3 fatty acids

E; P; I; L; M; A

262

2.8

0.61

324

3.5

0.76

0.81

0.69-0.95

0.01

LEADER

fibrate

E

150

19.2

4.95

160

20.4

5.20

0.95

0.76-1.21

0.72

LIPID

statin

G

287

6.4

1.04

373

8.3

1.36

0.77

0.12-0.35

<0.001

LIPS

statin

C; G + J + M

181

21.4

5.50

222

26.7

6.83

0.80

0.64-0.95

0.01

MEGA

statin

C; I + L + M + P

66

1.7

0.32

101

2.5

0.48

0.67

0.49-0.91

0.01

ORIGIN

n-3 fatty acids

D; D + J + U; A; I; T; M + W; Q; L; Z

574

9.1

1.47

581

9.3

1.50

0.98

0.87-1.10

0.72

PERFORM

antiplatelet

D; I

1091

11.4

4.83

1062

11.1

4.71

1.03

0.94-1.12

NS

Post-CABG

statin

C; D + J + M

207

30.6

4.08

271

40.1

5.35

0.76

NR

0.04

PREDIMED

TMD

C; D + I

179

3.6

0.80

109

4.4

1.12

0.71

  

PROACTIVE

glitazone

C; A + J + H + M

514

19.7

6.80

572

21.7

7.49

0.91

0.80-1.02

0.1

PROFIT-J

glitazone

C; A + J

9

3.8

2.09

10

4.0

2.20

0.95

0.427-2.593

0.91

PROSPER

statin

C; G + J

408

14.1

4.41

473

16.2

5.07

0.87

0.74-0.97

0.01

RPS

n-3 fatty acids

D

733

11.7

2.35

745

11.9

2.38

0.99

0.88-1.08

0.64

SHARP

statin/ezetimibe

C; J + G + M

526

11.3

2.31

619

13.4

2.73

0.84

0.74-0.94

0.0021

STABILITY

Lp-PLA2-inhibitor

C; D + J + U

769

9.7

2.62

819

10.4

2.80

0.94

0.85-1.03

0.2

STENO-2

statin/fibrate

A

24

30.0

2.26

40

50.0

3.76

0.60

0.32-0.89

0.02

TNT

statin

C; G + J + O + T

434

8.7

1.77

548

10.9

2.23

0.79

0.69-0.89

<0.001

 diabetes substudy

statin

C; G + J + O + T

103

13.7

2.79

135

18.0

3.68

0.76

0.58-0.97

0.026

VA Cooperative Study

fibrate

A + B

22

8.2

4.56

30

11.4

6.31

0.72

0.43-1.22

NR

VA-HIT

fibrate

C; J + G

219

17.3

3.40

275

21.7

4.26

0.80

0.07-0.35

0.006

 diabetes substudy

fibrate

C; J + G

96

25.5

4.99

141

36.0

7.05

0.71

0.53-0.88

0.004

Total (n)

  

16156

  

18445

     

Mean

   

12.2

3.0

 

14.8

3.6

0.85

  

§: see legend to Table 1 for study acronyms definition; §§: see Table 2 for CV outcomes definition; §§§: ±antioxidants; CETP: cholesteryl ester transfer protein; CI: confidence interval; CV: cardiovascular; HR: hazard ratio; LpPLA2: lipoprotein-associated phospholipase A2; NR: not reported; NS: non significant; PPAR: peroxisome proliferator-activated receptor; TMD: traditional Mediterranean diet

For all 47 studies, a total of 18,445 and 16,156 events occurred in the comparator and treatment arms, respectively. On an annual basis, this was equivalent to an average rate of occurrence for the primary CV outcome of 3.6 (2.4) %/year [BSR 0.5–11.8] (comparator) and 3.0 (1.9)%/year [BSR 0.3–9.1] (treatment), respectively (Table 4). The slopes of the equations relating PO rates (y) to diabetes prevalence (x) did not differ according to whether they were derived from PP or SP trials: thus, for PP trials y = 0.0208* x + 0.53 (R2 = 0.6369; p = 0.0058), whereas y = 0.0267* x +3.76 (R2 = 0.1436; p = 0.0464) for SP trials.

When comparing PO rates from the comparator arms of studies published prior to 2005 vs. those published ≥2005, average PO incidence decreased from 3.7 %/year [<2005] to 2.7 %/year [≥2005] for non-diabetic patients, ie. absolute and relative reductions of 1 % and 28 % (NS). For diabetic patients, the event rate decreased from 5.0 %/year [<2005] to 4.3 %/year [≥2005], ie. absolute and relative reductions of 0.7 % and 14 % (NS).

Among these, 33 trials, totaling 259,151 patients, are described below as predominantly non-diabetes studies [1214, 1922, 2529, 3134, 3642, 4766, 6870, 75, 7880, 8290] (Table 1). The mean age was 61.4 (5.5) years [BSR 47.0–75.0], and the proportion of males was 78.6 (17.8) % [BSR 31.4–100]. Among predominantly non-diabetes studies, 4 of 33 (12 %) enrolled patients who were in PP at baseline; 9 of 33 (27 %) included mixed populations whose CV risk was either PP or SP; and 20 of 33 (61 %) were clinical trials in SP only. Lipid values at baseline were (mg/dL): 212 (38) [TC]; 129 (36) [LDL-C]; 44 (7) [HDL-C]; 165 (36) [non-HDL-C]; 98 (21) [apoB] and 160 (25) [TG]. In total, these studies have included 63.189 diabetic patients, representing 21.3 % [BSR 2.3 %–44.2 %] of the population studied (Table 1; Table 3). These predominantly non-diabetes studies investigated the following interventions over a mean (1SD) duration of 4.3 (1.5) years [BSR: 1.0–7.5 years]: statins (19 trials); fibrates (6 trials); n-3 fatty acids (2 trials); niacin (4 trials); CETP-inhibitor (2 trials); ezetimibe (1 trial); and Lp-PLA2 inhibitor (1 trial) (Table 4).

Amongst predominantly non-diabetes studies, we identified 9 diabetes sub-studies (DSS), numbering 12,732 patients, published as pre-/post-hoc sub-group analyses of DM patients [14, 29, 32, 38, 49, 52, 54, 86, 90] (Table 1). The mean age was 60.4 (5.3) years [BSR 49.0–65.0], and the proportion of males was 74.9 (12.8) % [BSR 56.2–100]. Within DSS, 2 of 9 (22 %) enrolled patients who were in PP at baseline; 2 of 9 (22 %) included mixed populations whose CV risk was either PP or SP; and 5 of 9 (56 %) were clinical trials in SP only. Lipid values at baseline were (mg/dL): 219 (45) [TC]; 140 (41) [LDL-C]; 41 (5) [HDL-C]; 178 (44) [non-HDL-C]; and 181 (25) [TG] (Table 3). The DSS have investigated the following interventions over a mean (1SD) duration of 4.4 (1.0) years [BSR: 2.8–5.4 years]: statins (7 trials); and fibrates (2 trials) (Table 4).

Fourteen other trials, totaling 71,225 patients, dealt exclusively with DM patients, or included a very-high proportion (>45 %) of DM patients at baseline [11, 1518, 23, 24, 30, 35, 4346, 67, 7174, 76, 77, 81], and are described below as studies focusing on diabetes (Table 1). The mean age was 62.6 (8.2) years [BSR 46.0–85.0], and the proportion of males was 63.0 (8.3) % [BSR 42.5–74.4]. Mean diabetes duration was 7.5 (4.9) years [BSR 0–18.0], and HbA1c 7.6 (0.7) % [BSR 6.7–8.6] (Table 3).

Among studies focusing on diabetes, 4 of 14 (29 %) enrolled patients who were in PP at baseline; 8 of 14 (57 %) included mixed populations whose CV risk was either PP or SP; and 2 of 14 (14 %) were clinical trials in SP only. Lipid values at baseline were (mg/dL): 200 (19) [TC]; 118 (16) [LDL-C]; 46 (6) [HDL-C]; 154 (19) [non-HDL-C]; and 165 (32) [TG] (Table 3). The studies focusing on diabetes investigated the following interventions over a mean (1SD) duration of 4.8 (2.7) years [BSR: 1.8–13.3 years]: statins (5 trials); fibrates (4 trials); n-3 fatty acids and/or traditional Mediterranean diet (3 trials); PPAR-γ agonist (2 trials); and PPAR-α/γ agonist (1 trial) (Table 4).

Among the 33 predominantly non-diabetic studies, a total of 14,732 and 12,604 events occurred in the comparator and treatment arms, respectively. On an annual basis, this was equivalent to an average rate of occurrence for the primary CV outcome of 3.8 (2.4) %/year [BSR 0.5–11.8] (comparator) and 3.1 (1.8) %/year [BSR 0.3–7.5] (treatment), respectively.

Amongst the 9 DSS, a total of 1,469 and 1,119 events occurred in the comparator and treatment arms, respectively. On an annual basis, this was equivalent to an average rate of occurrence for the primary CV outcome of 6.1 (3.0) %/year [BSR 2.1–10.8] (comparator) and 4.0 (2.1) %/year [BSR 0.7–7.8] (treatment), respectively.

Among the 14 studies focusing on diabetes, a total of 3,713 and 3,552 events occurred in the comparator and treatment arms, respectively. On an annual basis, this was equivalent to an average rate of occurrence for the primary CV outcome of 3.3 (2.5) %/year [BSR 1.1–9.6] (comparator) and 2.9 (2.4) %/year [BSR 0.8–9.1] (treatment), respectively.

In addition to PO rates, which include de facto CHD, we also examined CHD rate as a separate outcome [Table 4 and Fig. 1 left panels]. Rates of CHD were issued for 21 trials and DSS for comparator and treatment arms, and amounted to [%/year]: 11.1 and 7.2 [4S-DSS]; 1.3 and 0.9 [AFCAPS/TexCAPS]; 1.5 and 1.0 [ASCOT-LLA]; 5.1 and 4.9 [AURORA]; 5.8 and 5.4 [BIP]; 12.0 and 9.3 [CARE-DSS]; 4.9 and 4.5 [CDP (clofibrate)]; 4.9 and 4.1 [CDP (niacin)]; 2.4 and 1.7 [HPS - MRC/BHF]; 2.6 and 2.0 [HPS - MRC/BHF-DSS]; 1.4 and 1.3 [HPS2-THRIVE]; 5.0 and 4.2 [IDEAL]; 2.0 and 2.4 [ILLUMINATE]; 0.8 and 0.6 [JELIS]; 3.1 and 2.5 [LEADER]; 0.5 and 0.3 [MEGA]; 1.0 and 0.9 [SHARP]; 4.3 and 4.0 [STABILITY]; 1.7 and 1.4 [TNT]; 2.6 and 2.1 [TNT-DSS]; and 1.9 and 1.7 [VA Cooperative Study] (Fig. 1; right panels).
Figure 1
Fig. 1

Relationship between proportion of diabetic patients at inclusion (%) and primary outcome rates (%/year; left panels) or total coronary heart disease (CHD) events (%/year; right panels) in comparator arms (upper panels) and in treatment arms (lower panels) of 33 landmark trials that included a substantial minority of diabetics (ranging from 2 % to 44 %), representing a total of 259,151 patients. The graphs are based on data from the following trials: 4S; AFCAPS/TexCAPS; AIM-HIGH; ALERT; ALLHAT-LLT; Alpha-Omega; ASCOT-LLA; AURORA; BIP; CARE; CDP; dal-OUTCOMES; GISSI-Prevenzione; GREACE; HATS; HHS; HPS-MRC/BHF; HPS2-THRIVE; IDEAL; ILLUMINATE; JELIS; LEADER; LIPID; LIPS; MEGA; PERFORM; Post-CABG; PROSPER; SHARP; STABILITY; TNT; VA Cooperative Study; and VA-HIT. The open diamonds represent primary outcome rates and CHD events from the following diabetes substudies: 4S; ASCOT-LLA; AURORA; CARE; GREACE; HHS; HPS-MRC/BHF; TNT; and VA-HIT. See Table 1 for acronyms definition and trials’ references, and Table 2 and Table 4 for primary outcomes classification and description

The relationship between proportion of diabetic patients at inclusion and PO or CHD rates was inferred on the basis of the comparator and treatment arms data from the 33 predominantly non-diabetic studies, including where appropriate the rates for the corresponding DSS, ie 259,151 patients. Both for PO and CHD, there was a highly significant linear relationship between the proportion of diabetics enrolled and events rates, both in comparator arms (p = 0.0128 [PO] and p = 0.0094 [CHD]; Fig. 1; upper panels) and active arms (p = 0.0470 [PO] and p = 0.0272 [CHD]; Fig. 1; lower panels). When comparing the slopes of the equations between PO and the proportion of diabetes at baseline in the comparator arm of studies published < 2005 and from 2005 to 2014, they rose from 0.0129 to 0.0162, ie a relative increase of 26 % (not shown). Such relationships were more pronounced as regards CHD events, exhibiting steeper gradients than those of PO rates, with slope coefficients higher by a relative 78 % [comparator arms] and 110 % [treatment arms]. Vis-à-vis the comparator arms, the slopes of the relationships between proportions of diabetics and events rates in the treatment arms of the same studies were attenuated, by a relative 45 % [PO rates] and 34 % [CHD events] (Fig. 1; lower panels).

Computing occurrence rates of PO and CHD in the comparator arms showed that the proportion of diabetics at inclusion predicted PO rates ranging from 3.12 %/year (no diabetic included) to 6.11 %/year (all patients diabetic). Predicted CHD rates depending on baseline diabetes prevalence ranged from 1.54 %/year (no diabetic included) to 6.85 %/year (all patients diabetic). This implies that a cohort exclusively composed of diabetic patients would present a PO rate already increased by an absolute 3 %/year due to the mere fact of being diabetic at baseline. Such an out-of-hand absolute increase in events rate due to the diabetic state would further increase to 5.3 %/year when it comes to the risk of incident CHD (Fig. 1; upper panels).

By relating incidence rates of PO and CHD in the treatment arms, it appears that the proportion of diabetics at inclusion predicts PO rates ranging from 2.65 %/year (no diabetic included) to 4.31 %/year (all patients diabetic). Predicted CHD rates based on diabetes prevalence ranged from 1.64 %/year (no diabetic included) to 5.13 %/year (all patients diabetic). It follows that a cohort exclusively composed of diabetic patients would present an on-treatment PO rate increased by an absolute 1.7 %/year solely due to the presence of DM at baseline. Such an absolute increase in events rate due to diabetes would further increase to 3.5 %/year for incident CHD risk (Fig. 1; lower panels).

The comparison of these equations linking the proportion of diabetics and outcome rates in comparator vs. treatment arms allows for determining whether being diabetic (apart from the observation that it increases the absolute rate of occurrence of CV events) is associated with an idiosyncratic on-treatment clinical response. As for PO and CHD, diabetic patients were characterized by a clinical response that was better than that calculated for a non-diabetic population that would have been subject to the same therapeutic interventions. Thus, residual CV risk persisting after treatment was further reduced in case of diabetes, in a relative proportion of 14.4 % [PO] and 31.2 % [CHD], respectively (Fig. 1; upper and lower panels).

Discussion

This meta-analysis shows that the presence of diabetics in a lipid-modifying trial is a determinant of CV events rate, the impact of which can be accurately assessed once known the proportion of diabetics enrolled, regardless of the CV risk category at baseline. Thus, the linear equations derived from this meta-analysis can be used to determine the absolute and relative enhancement of CV risk related to the inclusion of diabetics in a trial. Conversely, these algorithms can be used to estimate the proportion of diabetics to be included when designing a prospective study, in order to achieve a given number of CV events.

Major guidelines recognize a higher risk of CHD in DM patients, even in situations of primary prevention, as compared to non-diabetic subjects. The events rates in the comparator arms of randomized controlled trials and the meta-analyses of key statin trials show that CHD risk from hypercholesterolemia in non-diabetic patients is proportional to baseline LDL-C level. This is also the case for type 2 DM patients, with the additional aggravating fact that this linear relationship was shifted upward compared to non-diabetics. This underlies current recommendations for effective lowering of LDL-C as the major modifiable lipid risk factor for CHD in diabetic patients.

It should be noted that mean PO rate in studies focusing on diabetes was considerably lower (-46 %) than the risk that would be determined for diabetics if included, as a subgroup, in a clinical trial not focusing on diabetes. This follows from the fact that studies focusing on diabetes had a lower CV risk at inclusion, as well as lesser PO or CHD events during the study. As a result, the impact of DM on CV events must be qualified according to whether it is evaluated from diabetic subgroups of cohorts followed in cardiology (mostly in a macrovascular setting), or whether it is obtained in patients from clinical trials focusing on nutrition or diabetes (usually dealing with glycemic control or microvascular risk reduction). In addition, variation in residual risk related to T2DM in key trials may result from inhomogeneity in inclusion criteria; varying baseline CV risk; individual differences in diabetes duration or severity; and heterogeneous RFs exposure among diabetics.

As opposed to what occurs in microvessels, and unlike a widely held view about it, residual risk targeting large vessels is related to a limited extent only by hyperglycaemia in (pre)diabetes states. Rather, the accrued macrovascular risk is associated with the common form of T2DM (that is to say the one that expresses a MetS phenotype, including insulin resistance and hyperinsulinemia). The common pathogenic factors underlying the observed association between hyperglycemia and CHD are involved either (i) at the onset of diabetes (promoting B-cell decompensation or altering one or two variable(s) of the hyperbolic product between insulin secretion and insulin sensitivity), and/or (ii) because they embody cardiometabolic comorbidities that increase the macrovascular risk regardless of glucose levels.

It should be noted that the slopes of the relationships between CV events and percentage of included diabetics were less marked when it came to comparing PO vs. CHD events rates, both in comparator and treatment arms, on one hand, or when it came to comparing PO or CHD events rates in treated arms vs. comparator arms, on the other hand. These observations suggest (i) that the presence of diabetes at baseline has less adverse effect on the occurrence of certain constituents of the PO, such as all-cause deaths or coronary revascularization; and (ii) that diabetic patients derive more benefits from the different treatment approaches studied than non-diabetic patients as regards the occurrence of macrovascular events [91]. In this meta-analysis, we have not distinguished between studies on the basis of pharmacological or nutritional interventions, since we based our findings on patients from comparator arms, usually receiving a placebo or standard care. When comparing less recent (published <2005) and more contemporary studies (published ≥2005), a decrease in absolute and relative events rates was observed (-28 % and -1 % respectively), suggestive of a reduction in exposure to CV RFs over time and/or of improved overall CV management. Such changes were however not significant and further, diabetic patients benefited less from this trend, reducing the absolute and relative rates by only -14 % and -0.7 %. It seemed therefore appropriate to include all studies in this analysis regardless of publication year.

It is noteworthy that the increased risk of CV events due to the presence of a subgroup of diabetics had a pretty similar slope, whatever the CV risk category at baseline. It follows that the excess CV risk associated with the inclusion of people with diabetes in a lipid-modifying trial is relatively independent of study design, expanding the applicability of equations derived from this meta-analysis. There exists a positive relationship between biomarkers and occurrence of CV events [92]; our meta-analysis suggests that documenting the frequency of enlisted T2DM patients can also be used as surrogate biomarker predicting a non-modifiable component of residual CV risk. Considering that our analysis focused on populations enrolled in the comparator arms of mostly LMT studies, it would be interesting to determine the impact on residual risk arising from enlistment of diabetics in clinical trials testing several interventions in primary care [93].

This study has several limitations. Firstly, the risk estimates attributed to DM were not adjusted for age or other CV RFs comorbid to T2DM and, as in all systematic collection of published data, there is always a potential bias related to publications [94]. Secondly, the adequacy of these equations to predict CV outcomes has not been independently validated in a prospective context. Thirdly, for reasons related to the design and reporting of individual studies, it was not feasible to derive specific equations applicable to T1DM vs. T2DM subgroups, or to newly-diagnosed vs. long-standing T2DM patients [95]. We were not able to analyze the potential influence of glycaemic control in diabetic subgroups at baseline, due to the low reporting rate of HbA1c values [96]. Finally, we did not examine, for reasons of brevity, the relationship between diabetes prevalence and non-CHD outcomes, such as HF, which will require dedicated meta-analyses [97].

Conclusion

This study attempted to quantify the impact of diabetes on the occurrence of CV events during a lipid-modifying trial, based on the proportion of known diabetics included. The component of absolute and relative residual CV risk associated with diabetes can be measured from linear equations relating diabetes prevalence to primary outcomes or CHD rates. Such calculations may help clinical study designers when selecting inclusion criteria; cohort size; and planned diabetics’ enrollment, so as to achieve sufficient CV events over time.

Abbreviations

apoB: 

apolipoprotein B100

BSR: 

Between-study range

CETP: 

Cholesteryl ester transfer protein

CHD: 

Coronary heart disease

CV: 

Cardiovascular

DM: 

Diabetes mellitus

DSS: 

Diabetes substudy

HbA1c

glycated hemoglobin

HDL: 

High-density lipoprotein

HDL-C: 

High-density lipoprotein cholesterol

LDL: 

Low-density lipoproteins

LDL-C: 

Low-density lipoprotein cholesterol

Lp-PLA2: 

Lipoprotein-associated phospholipase A2

non-HDL-C: 

non-high-density lipoprotein cholesterol

NS: 

Non-significant

PO: 

Primary outcome

PP: 

Primary prevention

PPAR: 

Peroxisome proliferator-activated receptor

RF: 

Risk factor

SD: 

Standard deviation

SP: 

Secondary prevention

T1DM: 

Type 1 diabetes mellitus

T2DM: 

Type 2 diabetes mellitus

TC: 

Total cholesterol

TG: 

Triglycerides (triacylglycerols)

Declarations

Acknowledgements

This study received no financial support.

Authors’ Affiliations

(1)
Division of Endocrinology & Nutrition, Cliniques universitaires St-Luc and Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium
(2)
Service de Maladies Métaboliques et Endocriniennes, Centre Hospitalier et Universitaire de Brazzaville, Brazzaville, Congo
(3)
Service d’Endocrinologie et Métabolisme, CNHU HKM Cotonou, Université d’Abomey-Calavi, Abomey-Calavi, Bénin
(4)
Division of Cardiology, Cliniques universitaires St-Luc and Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium

References

  1. Hermans MP, Ahn SA, Rousseau MF. Effect of lipid management on coronary heart disease risk in patients with diabetes. In: McGuire DK, Nikolaus M, editors. Diabetes in Cardiovascular Disease. A Companion to Braunwald’s Heart Disease. Philadelphia: Elsevier Saunders; 2015. p. 181–202.Google Scholar
  2. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in non-diabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–34.View ArticlePubMedGoogle Scholar
  3. Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Type 2 diabetes as a ‘coronary heart disease equivalent’. An 18-year prospective population-based study in Finnish subjects. Diabetes Care. 2005;28:2901–7.View ArticlePubMedGoogle Scholar
  4. Buyken AE, von Eckardstein A, Schulte H, Cullen P, Assmann G. Type 2 diabetes mellitus and risk of coronary heart disease: results of the 10-year follow-up of the PROCAM study. Eur J Cardiovasc Prev Rehabil. 2007;14:230–6.View ArticlePubMedGoogle Scholar
  5. CTT-Cholesterol treatment trialists’ (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371:117–25.View ArticleGoogle Scholar
  6. Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet. 2008;371:1800–9.View ArticlePubMed CentralPubMedGoogle Scholar
  7. Schramm TK, Gislason GH, Køber L, Rasmussen S, Rasmussen JN, Abildstrøm SZ, et al. Diabetes patients requiring glucose-lowering therapy and non-diabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation. 2008;117:1945–54.View ArticlePubMedGoogle Scholar
  8. Fruchart JC, Sacks FM, Hermans MP, Assmann G, Brown WV, Ceska R, et al. Residual Risk Reduction Initiative (R3I). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res. 2008;5:319–35.View ArticlePubMedGoogle Scholar
  9. Hermans MP, Ahn SA, Rousseau MF. Residual vascular risk in T2DM: the next frontier. In: Mark B, editor. Recent Advances in the Pathogenesis, Prevention and Management of Type 2 Diabetes and its Complications. Croatia: Zimering, Intech, Rijeka; 2011. p. 45–66.Google Scholar
  10. Fruchart JC, Davignon J, Hermans MP, Al-Rubeaan K, Amarenco P, Assmann G, et al. Residual Risk Reduction Initiative (R3i). Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol. 2014;13:26.View ArticlePubMed CentralPubMedGoogle Scholar
  11. Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238–48.View ArticlePubMedGoogle Scholar
  12. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–9.Google Scholar
  13. Kjekshus J, Pedersen TR, For the Scandinavian Simvastatin Survival Study Group. Reducing the risk of coronary events: Evidence from the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol. 1995;76:64C–8.View ArticlePubMedGoogle Scholar
  14. Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. the 4S Study Group: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20:614–20.View ArticlePubMedGoogle Scholar
  15. The ACCORD Study Group. Action to control cardiovascular risk in diabetes (ACCORD) trial: Design and Methods. Am J Cardiol. 2007;99:21j–33.Google Scholar
  16. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.View ArticlePubMed CentralGoogle Scholar
  17. Griffin SJ, Borch-Johnsen K, Davies MJ, Khunti K, Rutten GE, Sandbæk A, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. Lancet. 2011;378:156–67.View ArticlePubMed CentralPubMedGoogle Scholar
  18. Van Den Donk Van Den Donk M, Griffin SJ, Stellato RK, Simmons RK, Sandbæk A, Lauritzen T, et al. Effect of early intensive multifactorial therapy compared with routine care on self-reported health status, general well-being, diabetes-specific quality of life and treatment satisfaction in screen-detected type 2 diabetes mellitus patients (ADDITION-Europe): a cluster-randomised trial. Diabetologia. 2013;56:2367–77.View ArticleGoogle Scholar
  19. Downs JR, Beere PA, Whitney E, Clearfield M, Weis S, Rochen J, et al. Design & rationale of the Air Force/Texas coronary atherosclerosis prevention study (AFCAPS/TexCAPS). Am J Cardiol. 1997;80:287–93.View ArticlePubMedGoogle Scholar
  20. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results from AFCAPS/TexCAPS. JAMA. 1998;279:1615–22.View ArticlePubMedGoogle Scholar
  21. The AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: Baseline characteristics of study participants. The atherothrombosis intervention in metabolic syndrome with low HDL/high triglycerides: Impact on global health outcomes (AIM-HIGH) trial. Am Heart J. 2011;161:538–43.View ArticlePubMed CentralGoogle Scholar
  22. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.View ArticleGoogle Scholar
  23. Lincoff AM, Tardif JC, Neal B, Nicholls SJ, Rydén L, Schwartz GG, et al. Evaluation of the dual peroxisome proliferator-activated receptor α/γ agonist aleglitazar to reduce cardiovascular events in patients with acute coronary syndrome and type 2 diabetes mellitus: rationale and design of the AleCardio trial. Am Heart J. 2013;166:429–34.View ArticlePubMedGoogle Scholar
  24. Lincoff AM, Tardif JC, Schwartz GG, Nicholls SJ, Rydén L, Neal B, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA. 2014;311:1515–25.View ArticlePubMedGoogle Scholar
  25. Holdaas H, Fellström B, Jardine AG, Holme I, Nyberg G, Fauchald P, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361:2024–31.View ArticlePubMedGoogle Scholar
  26. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT-LLT). JAMA. 2002;288:2998–3007.View ArticleGoogle Scholar
  27. Kromhout D, Giltay EJ, Geleijnse JM. Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010;363:2015–26.View ArticlePubMedGoogle Scholar
  28. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149–58.View ArticlePubMedGoogle Scholar
  29. Sever PS, Poulter NR, Dahlöf B, Wedel H, Collins R, Beevers G, et al. Reduction in cardiovascular events with atorvastatin in 2532 patients with type 2 diabetes. Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTT-LLA). Diabetes Care. 2005;28:1151–7.View ArticlePubMedGoogle Scholar
  30. Knopp RH, D’Emden M, Smilde JG, Pocock SJ, The ASPEN Study Group. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes. The atorvastatin study for prevention of coronary heart disease endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care. 2006;29:1478–85.View ArticlePubMedGoogle Scholar
  31. Felström BC, Jardine AG, Schmeider RE, Holdaas H, Bannister K, Beutler J, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395–407.View ArticleGoogle Scholar
  32. Holdaas H, Holme I, Schmeider RE, Jardine AG, Zannad F, Norby GE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol. 2011;22:1335–41.View ArticlePubMed CentralPubMedGoogle Scholar
  33. The BIP, Group S. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. The Bezafibrate Infarction Prevention (BIP) Study. Circulation. 2000;102:21–7.View ArticleGoogle Scholar
  34. Goldenberg I, Boyko V, Tennenbaum A, Tanne D, Behar S, Guetta V. Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate. 16-year mortality follow-up of the Bezafibrate Infarction Prevention Trial. Arch Intern Med. 2009;169:508–14.View ArticlePubMedGoogle Scholar
  35. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685–96.View ArticlePubMedGoogle Scholar
  36. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–9.View ArticlePubMedGoogle Scholar
  37. Lewis SJ, Sacks FM, Mitchell JS, East C, Glasser S, Kell S, et al. Effect of pravastatin on cardiovascular events in women after myocardial infarction: The Cholesterol and Recurrent Events (CARE) Trial. J Am Coll Cardiol. 1998;32:140–6.View ArticlePubMedGoogle Scholar
  38. Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analyses in the Cholesterol And Recurrent Events (CARE) Trial. Circulation. 1998;98:2513–9.View ArticlePubMedGoogle Scholar
  39. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360–81.View ArticleGoogle Scholar
  40. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245–55.View ArticlePubMedGoogle Scholar
  41. Schwartz GG, Olsson AG, Ballantyne CM, Barter PJ, Holme IM, Kallend D, et al. dal-OUTCOMES Committees and Investigators. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158:896–901.View ArticlePubMedGoogle Scholar
  42. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. dal-OUTCOMES Investigators: Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med. 2012;367:2089–99.View ArticlePubMedGoogle Scholar
  43. Hanefeld M, Fischer S, Schmechel H, Rothe G, Schulze J, Dude H, et al. Diabetes Intervention Study. Multi-Intervention Trial in newly diagnosed NIDDM. Diabetes Care. 1991;14:308–17.View ArticlePubMedGoogle Scholar
  44. The FIELD Study Investigators. Fenofibrate intervention and event lowering in diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481]. Cardiovasc Diabetol. 2005;4:13.View ArticlePubMed CentralGoogle Scholar
  45. The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.View ArticleGoogle Scholar
  46. Scott R, O’Brien R, Fulcher G, Pardy C, D’Emden M, Tse D, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9795 individuals with type 2 diabetes and various components of the metabolic syndrome. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care. 2009;32:493–8.View ArticlePubMed CentralPubMedGoogle Scholar
  47. GISSI. Prevenzione Investigators (Gruppo Italiano per lo Studio della Soprovvivenza nell’Infarto Miocardico): Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? Ital Heart J. 2000;1:810–20.Google Scholar
  48. Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus “usual” care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18:220–8.View ArticlePubMedGoogle Scholar
  49. Athyros VG, Papageorgiou AA, Symeonidis AN, Didangelos TP, Pehlivanidis AN, Bouloukos VI, et al. Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus. A subgroup analysis of the GREACE Study. Angiology. 2003;54:679–90.View ArticlePubMedGoogle Scholar
  50. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583–92.View ArticlePubMedGoogle Scholar
  51. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237–45.View ArticlePubMedGoogle Scholar
  52. Koskinen P, Mänttäri M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinki Heart Study. Diabetes Care. 1992;15:820–5.View ArticlePubMedGoogle Scholar
  53. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.View ArticleGoogle Scholar
  54. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005–16.View ArticleGoogle Scholar
  55. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279–91.View ArticlePubMed CentralGoogle Scholar
  56. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, Tikkanen MJ, Holme I, et al. Design and baseline characteristics of the incremental decrease in end points through aggressive lipid lowering study. Am J Cardiol. 2004;94:720–4.View ArticlePubMedGoogle Scholar
  57. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomised controlled trial. JAMA. 2005;294:2437–45.View ArticlePubMedGoogle Scholar
  58. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al. ILLUMINATE Investigators: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–22.View ArticlePubMedGoogle Scholar
  59. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al. Japan EPA lipid intervention study (JELIS) Investigators: Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoint analysis. Lancet. 2007;369:1090–8.View ArticlePubMedGoogle Scholar
  60. Meade TW. The MRC General Practice Research Framework and Participating Vascular Clinics: Design and intermediate results of the Lower Extremity Arterial Disease Event Reduction (LEADER) trial of bezafibrate in men with lower extremity arterial disease. Curr Control Trials Cardiovasc Med. 2001;2:195–204.View ArticlePubMed CentralPubMedGoogle Scholar
  61. Meade T, Zuhrie R, Cook C. Cooper J on behalf of MRC General Practice Research Framework: Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ. 2002;325:1139.View ArticlePubMed CentralPubMedGoogle Scholar
  62. The Lipid Study Group. Design features and baseline characteristics of the LIPID (Long-Term Intervention With Pravastatin in Ischemic Disease) Study: a randomized trial in patients with previous acute myocardial infarction and/or unstable angina pectoris. Am J Cardiol. 1995;76:474–9.View ArticleGoogle Scholar
  63. The Lipid Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–57.View ArticleGoogle Scholar
  64. The Lipid Study Group. Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up. Lancet. 2002;359:1379–87.View ArticleGoogle Scholar
  65. Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. A randomized controlled trial. JAMA. 2002;287:3215–22.View ArticlePubMedGoogle Scholar
  66. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006;368:1155–63.View ArticlePubMedGoogle Scholar
  67. Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, et al. For the ORIGIN Trial Investigators. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012;367:309–18.View ArticlePubMedGoogle Scholar
  68. Bousser MG, Amarenco P, Chamorro A, Fisher M, Ford I, Fox KM, et al. PERFORM Study Investigators. Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial. Lancet. 2011;377:2013–22.View ArticlePubMedGoogle Scholar
  69. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997;336:153–62.View ArticleGoogle Scholar
  70. Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman SA, et al. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the Post Coronary Artery Bypass Graft Trial. Circulation. 2000;102:157–65.View ArticlePubMedGoogle Scholar
  71. Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, et al. PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–90.View ArticlePubMedGoogle Scholar
  72. Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A, The PROActive Study Group. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive). Diabetes Care. 2004;27:1647–53.View ArticlePubMedGoogle Scholar
  73. Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactice Study (PROspective pioglitAzone Clinical Trial In macro Vascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89.View ArticlePubMedGoogle Scholar
  74. Yoshii H, Onuma T, Yamazaki T, Watada H, Matsuhisa M, Matsumoto M, et al. Effects of pioglitazone on macrovascular events in patients with type 2 diabetes mellitus at high risk of stroke: the PROFIT-J study. J Atheroscler Thromb. 2014;21:563–73.PubMedGoogle Scholar
  75. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30.View ArticlePubMedGoogle Scholar
  76. Rischio and Prevenzione Investigators. Efficacy of n-3 polyunsaturated fatty acids and feasibility of optimizing preventive strategies in patients at high cardiovascular risk: rationale, design and baseline characteristics of the Rischio and Prevenzione study, a large randomised trial in general practice. Trials. 2010;11:68.View ArticleGoogle Scholar
  77. Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368:1800–8.View ArticleGoogle Scholar
  78. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection):a randomised placebo-controlled trial. Lancet. 2011;377:2181–92.View ArticlePubMed CentralPubMedGoogle Scholar
  79. White H, Held C, Stewart R, Watson D, Harrington R, Budaj A, et al. Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease. Am Heart J. 2010;160:655–61.View ArticlePubMedGoogle Scholar
  80. STABILITY Investigators, White HD, Held C, Stewart R, Tarka E, Brown R, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014;370:1702–11.View ArticleGoogle Scholar
  81. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effects of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91.View ArticlePubMedGoogle Scholar
  82. Waters DD, Guyton JR, Herrington DM, McGowan MP, Wenger NK, Shear C, et al. Treating to new targets (TNT) study: Does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit? Am J Cardiol. 2004;93:145–8.Google Scholar
  83. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425–35.View ArticlePubMedGoogle Scholar
  84. Shepherd J, Kastelein JJP, Bittner V, Deedwania P, Breazna A, Dobson S, et al. Effect on intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: The Treating to New Targets (TNT) Study. Clin J Am Soc Nephrol. 2007;2:1131–9.View ArticlePubMedGoogle Scholar
  85. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007;357:1301–10.View ArticlePubMedGoogle Scholar
  86. Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes. The Treating to New Targets (TNT) Study. Diabetes Care. 2006;29:1220–6.View ArticlePubMedGoogle Scholar
  87. The Veterans Administration Cooperative Study Group. The treatment of cerebrovascular disease with clofibrate. Final report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section. Stroke. 1973;4:684–93.View ArticleGoogle Scholar
  88. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipotrotein cholesterol. N Engl J Med. 1999;341:410–8.View ArticlePubMedGoogle Scholar
  89. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, et al. Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. JAMA. 2001;285:1585–91.View ArticlePubMedGoogle Scholar
  90. Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ, et al. Diabetes, plasma insulin, and cardiovascular disease. Subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med. 2002;162:2597–604.View ArticlePubMedGoogle Scholar
  91. Costa J, Borges M, David C, Vaz Carneiro A. Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ. 2006;332:1115–8.View ArticlePubMed CentralPubMedGoogle Scholar
  92. Ofstad AP, Gullestad L, Orvik E, Aakhus S, Endresen K, Ueland T, et al. Interleukin-6 and activin A are independently associated with cardiovascular events and mortality in type 2 diabetes: the prospective Asker and Bærum Cardiovascular Diabetes (ABCD) cohort study. Cardiovasc Diabetol. 2013;12:126.View ArticlePubMed CentralPubMedGoogle Scholar
  93. Jiao FF, Fung CS, Wong CK, Wan YF, Dai D, Kwok R, et al. Effects of the Multidisciplinary Risk Assessment and Management Program for Patients with Diabetes Mellitus (RAMP-DM) on biomedical outcomes, observed cardiovascular events and cardiovascular risks in primary care: a longitudinal comparative study. Cardiovasc Diabetol. 2014;13:127.View ArticlePubMed CentralPubMedGoogle Scholar
  94. Wang Y, Lammi-Keefe CJ, Hou L, Hu G. Impact of low-density lipoprotein cholesterol on cardiovascular outcomes in people with type 2 diabetes: a meta-analysis of prospective cohort studies. Diabetes Res Clin Pract. 2013;102:65–75.View ArticlePubMed CentralPubMedGoogle Scholar
  95. Rousan TA, Pappy RM, Chen AY, Roe MT, Saucedo JF. Impact of diabetes mellitus on clinical characteristics, management, and in-hospital outcomes in patients with acute myocardial infarction (from the NCDR). Am J Cardiol. 2014;114:1136–44.View ArticlePubMedGoogle Scholar
  96. Fatemi O, Yuriditsky E, Tsioufis C, Tsachris D, Morgan T, Basile J, et al. Impact of intensive glycemic control on the incidence of atrial fibrillation and associated cardiovascular outcomes in patients with type 2 diabetes mellitus (from the Action to Control Cardiovascular Risk in Diabetes Study). Am J Cardiol. 2014;114:1217–22.View ArticlePubMedGoogle Scholar
  97. Sarma S, Mentz RJ, Kwasny MJ, Fought AJ, Huffman M, Subacius H, et al. EVEREST investigators. Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure: findings from the EVEREST trial. Eur J Heart Fail. 2013;15:194–202.View ArticlePubMed CentralPubMedGoogle Scholar

Copyright

© Hermans et al.; licensee BioMed Central. 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement