Collaborative Atorvastatin Diabetes Study (CARDS) - Lipids Online

Collaborative Atorvastatin Diabetes Study (CARDS) 

Commentary by Harold Bays, MD, FACP 


Introduction 

According to the World Health Organization, approximately 200 million people worldwide currently have 

type 2 diabetes mellitus, a prevalence that has been predicted to increase to 366 million by 2030. 

Atherosclerotic coronary heart disease (CHD) is the most common cause of morbidity and mortality in 

patients with type 2 diabetes. Among diabetic patients, atherosclerosis accounts for about 80% of all 

mortality; three-quarters of these deaths are due to CHD, and one-quarter are due to cerebral or peripheral 

vascular disease. Diabetes mellitus is associated with a 2- to 4-fold increased risk of CHD, as well as an 

increased risk of dying after a myocardial infarction (MI) compared with patients without diabetes. In 

addition, there is a sizable increase in out-of-hospital mortality or sudden death even after the first MI. 

Given this CHD risk burden, the National Cholesterol Education Program (NCEP) Adult Treatment Panel 

(ATP) III has emphasized that patients with diabetes should be regarded as having CHD risk equivalent to 

that of patients with known CHD. Similarly, European guidelines on cardiovascular disease prevention 

note that the risk of developing an MI is the same for diabetic patients as it is for nondiabetic patients with 

a prior MI. Therefore, the same aggressive lipid treatment goals should be applied to both diabetic and 

CHD patients, even if the former have no evidence of existing CHD. While organizations such as the 

American Diabetes Association have suggested widespread statin use in virtually all patients with type 2 

diabetes, the clinical trial evidence suggesting the effectiveness and safety of lipid lowering for primary 

prevention in diabetes patients with lower levels of LDL-C has not been clear. 

Collaborative Atorvastatin Diabetes 

Study (CARDS) 

Patient Population 

• Type 2 diabetes mellitus 

• Men and women 40–75 

years of age 

• Primary C HD and stroke 

prevention 

• LDL-C ≤160 mg/dL 

(≤4.14 mmol/L) 

• TG ≤600 mg/dL 

(≤6.78 mmol/L) 

• ≥1 additional RF 

– HTN (or on HTN 

treatment) 

– Retinopathy 

– Albuminuria 

– Current smoking 

2838 

patients 

Atorvastatin 10 mg 

(n=1428) 

4-year follow-up 

Double-blind blind placebo 

(n=1410) 

• Primary endpoint: time to first 

major CV event (CHD death, nonfatal 

MI, unstable angina, resuscitated 

cardiac arrest, coronary 

revascularization, stroke 

• Secondary endpoints: total 

mortality, any CV endpoint, lipids, 

and lipoproteins 

Colhoun HM et al. Lancet 2004;364:685-696. 

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Baylor College of Medicine, Houston, Texas Page 1 of 5



CARDS: Patient Baseline Characteristics 

Age 

Mean (SD) years 

70 

Placebo 

(n = 1410) 

61.8 (8.0) 

529 (38%) 

708 (50%) 

173 (12%) 

Women 

453 (32%) 

White ethnicity 

1326 (94%) 

BMI 

Mean (SD), kg/m 2 28.8 (3.5) 

Obese (BMI >30 kg/m 2 ) 538 (38%) 

Atorvastatin 

(n = 1428) 

61.5 (8.3) 

558 (39%) 

703 (49%) 

167 (12%) 

456 (32%) 

1350 (95%) 

28.7 (3.6) 

515 (36%) 


Reprinted with permission from Elsevier. 

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Key Points 

The Collaborative Atorvastatin Diabetes Study (CARDS) was a multicenter, randomized, placebocontrolled, 

4-year, double-blind trial of atorvastatin 10 mg/day that was the first to evaluate statin therapy 

prospectively and specifically in patients with type 2 diabetes. Study participants were patients aged 40–75 

years with type 2 diabetes, low-density lipoprotein cholesterol (LDL-C) concentration 160 mg/dL or less, 

fasting triglycerides 600 mg/dL or less, and at least one additional risk factor (hypertension, retinopathy, 

microalbuminuria or macroalbuminuria, or current smoking) but no history of CHD, cerebrovascular 

accident, or severe peripheral vascular disease. Randomization was completed in June 2001. Follow-up was 

initially planned to be endpoint driven, concluding after the occurrence of 304 primary endpoints. 

However, as a result of a significant benefit demonstrated by atorvastatin at an interim analysis, the 

independent steering committee of CARDS stopped the trial earlier than planned, after 149 primary 

endpoints. 

Of 4053 subjects screened, 3249 (80%) entered baseline assessment, and 2838 (70%) were randomized; 

1410 subjects were allocated placebo (1398 [99.1%] of whom completed follow-up) and1428 to 

atorvastatin 10 mg/day (1421 [99.5%] of whom completed follow-up). The median time of follow-up was 

3.9 years. Baseline characteristics were similar between treatment groups. During the course of the study, 

some placebo group subjects were administered nonstudy statin. The percentage of patients taking at least 

one lipid-lowering drug (including atorvastatin) in the atorvastatin group was 90%, 87%, 86%, and 78% at 

years 1, 2, 3, and 4, respectively, with an average of 85% atorvastatin use over the duration of the study. 

The percentage of patients taking at least one lipid-lowering drug in the placebo group was 2%, 7%, 12%, 

and 15% at years 1, 2, 3, and 4, respectively, with an average of 9% nonstudy drug use over the duration of 

the study. 

The group treated with atorvastatin 10 mg/day had an average 26% (54 mg/dL) reduction in total 

cholesterol and 40% (46 mg/dL) reduction in LDL-C. The average reduction in triglyceride levels was 

19%, with a 1% increase in HDL-C levels compared with placebo. 

The relative risk reduction in the primary endpoint of first acute CHD event (MI including silent infarction, 

unstable angina, acute CHD death, resuscitated cardiac arrest), coronary revascularization procedures, or 





stroke (fatal or nonfatal) was significantly reduced by 37% with atorvastatin 10 mg/day compared with 

placebo (P=0.001). Stroke was significantly reduced by 48% (P=0.016) and all-cause mortality was 

reduced by 27% (P=0.059). The reduction in CHD, stroke, and mortality endpoints with atorvastatin may 

have been understated because (1) some of the placebo group received nonstudy statin treatment and (2) the 

trial was stopped 2 years early for ethical reasons. Had the trial been allowed to continue, the differences in 

CHD and stroke outcomes between treatment groups may have been greater. 

There was no difference in the overall frequency of adverse events or serious adverse events between the 

treatment groups. No cases of rhabdomyolysis were reported. One case of myopathy was reported in each 

group. Myalgia was reported in 72 and 61 patients in the placebo and atorvastatin groups, respectively. The 

number of patients who discontinued study drug because of muscle-related events was 9 in the placebo 

group and 7 in the atorvastatin group. 

CARDS: Patient Baseline Lipids 

Total cholesterol (mg/dL) 

(mmol/L) 

LDL cholesterol (mg/dL) 

(mmol/L) 

HDL cholesterol (mg/dL) 

(mmol/L) 

Placebo 

(n = 1410) 

Mean (SD) 

207 (32) 

5.35 (0.82) 

117 (27) 

3.02 (0.70) 

55 (13) 

1.42 (0.34) 


(n = 1428) 

Mean (SD) 

207 (32) 

5.36 (0.83) 

118 (28) 

3.04 (0.72) 

54 (12) 

1.39 (0.32) 

Triglycerides* (mg/dL) 

(mmol/L) 

148 (104–212) 

1.67 (1.17–2.40) 

150 (106–212) 

1.70 (1.20–2.40) 

*Median (interquartile range) 



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CARDS: Lipid Levels by Treatment 

Total Cholesterol (mg/dL) 

Average difference 26%, 

54 mg/dL; P



CARDS: Effect of Atorvastatin on the Primary 

Endpoint: Major CV Events Including Stroke 

Cumulative Hazard, (%) 

Placebo 


15 

10 

5 

Relative Risk Reduction 37% (95% CI, 17–52) 

P = 0.001 

Placebo 

127 events 

0 

0 1 2 3 4 

Years 

1410 

1428 

1351 

1392 



1306 

1361 

1022 

1074 


83 events 

651 

694 

4.75 

305 

328 

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CARDS: Adverse and Serious Adverse Events 

Type of Event 

Serious adverse event 

possibly associated 

with study drug 

Discontinued for AE 

Rhabdomyolysis 

Myopathy AE report 

CPK ≥10 × ULN 

ALT ≥3 × ULN 

AST ≥3 × ULN 

Patients (%) with Event 

Placebo 

(n = 1410) 

20 (1.1%) 

145 (10%) 

0 

1 (0.1%) 

10 (0.7%) 

14 (1%) 

4 (0.3%) 

Atorvastatin 10 mg 

(n = 1428) 

19 (1.1%) 

122 (9%) 

0 

1 (0.1%) 

2 (0.1%) 

17 (1%) 

6 (0.4%) 


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Implications and Clinical Relevance 

CARDS showed that in patients with type 2 diabetes mellitus with lower LDL-C levels, atorvastatin 10 mg 

daily was safe, well tolerated, and significantly efficacious in reducing the risk of first CHD events. 

CARDS supports recommendations such as that made by the American Diabetes Association that patients 

with type 2 diabetes mellitus should be considered as candidates for statin treatment—even at lower LDL-C 

levels. Subgroup analysis revealed that irrespective of whether the baseline LDL-C was at or above, or 

below the median of 120 mg/dL, atorvastatin patients in both subgroups had similar relative risk reductions 

of 37–38% for the primary endpoint. 

Previous support for the benefits of statin therapy in diabetes patients had been derived from the 

extrapolation of data from primary and secondary CHD prevention trials that included nondiabetic 

populations. Because CARDS was the first study to evaluate statin therapy prospectively and specifically 

in patients with type 2 diabetes mellitus, and because it was one of the few primary prevention trials 





conducted, CARDS significantly adds to the data from post hoc analyses of other clinical trials that have 

shown efficacy in reducing CHD events in patients with type 2 diabetes mellitus with lipid-altering drugs. 

Primary Prevention Trials of Lipid-Altering 

Therapy Including Patients with Diabetes 

Trial 

Diabetic,* 

n 

Total N 

in 

Study 

Lipid-Altering 

Drug, mg/d 

CHD* Risk vs 

Placebo in Diabetic 

Patients, % 

CARDS † 

2,838 

2,838 

Atorvastatin 10 

–37 (p=.001) 

AFCAPS 

155 

6,605 

Lovastatin 20–40 ‡ 

–44 (NS) 

HPS § 

2,912 

7,150 

Simvastatin 40 

–33 (p=.0003) 

ASCOT 

2,532 

10,305 

Atorvastatin 10 

–16 (NS) 

PROSPER 

623 

5,804 

Pravastatin 40 

+27 (NS) 

HHS 

135 

4,081 

Gemfibrozil 1200 

–68 (NS) 

* By history 

† Prospective trial in diabetic subjects; others are subgroup analyse s 

‡ Mean 30 mg/d 

§ Type 1 or 2 diabetes 

Bays H et al. Future Cardiology 2005;1:39-59. 59. | Colhoun HM et al. Lancet 2004;364:685-696. 696. | 

Downs JR et al. JAMA 1998;279:1615-1622. 1622. | HPS Collaborative Group. Lancet 2003;361:2005- 

2016. | Sever PS et al. Lancet 2003;361:1149-1158. 1158. | S hepherd J et al. Lancet 2002;360:1623- 

1630. | Koskinen P et al. Diabetes Care 1992;15:820-825. 825. 

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Secondary Prevention Trials of Lipid-Altering 

Therapy Including Patients with Diabetes 

Total N 

Trial 

Diabetic, 

n 

in 

Study 

4S 

Reanalysis 

202† 

483‡ 

4,444 

CARE 

586† 4,159 

LIPID 1,077‡ 9,014 

LIPS § 

202† 1,677 

HPS § 3,051† 13,386 

4D 

1,255† 1,255 

VA-HIT 769‡ 2,351 

DAIS || 418† 418 

*Includes stroke in 4D and VA-HIT 

†By history 

‡By history or glucose ≥126 mg/dL 

CHD* Risk vs 

Lipid-A ltering Placebo in Diabetic 

Drug, mg/d 

Patients, % 

Simvastatin 20–40 –55 (p=.002) 

–42 (p=.001) 

Pravastatin 40 –25 (p=.05) 

Pravastatin 40 –19 (NS) 

Fluvastatin 80 –47 (p=.04) 

Simvastatin 40 –18 (p=.002) 

Atorvastatin 20 –8 (NS) 

Gemfibrozil 1,200 –32 (p=.004) 

Fenofibrate 200 –23 (NS) 

§ Type 1 or 2 diabetes 

Prospective trial in diabetic subjects; others 

are subgroup analyses 

|| Angiographic study 

Bays H et al. Future C ar diology 2005;1:39-59. 59. | Pyör älä K et al. Dia betes Car e 1997;20:614- 620. | Ha ffne r SM 

et al. Arch I ntern Med 1999; 159: 2661-2667. 2667. | Goldberg RB et al. Circ ulati on 1998;98:2513-2519. 2519. | KeechA et 

al. Di abetes Care 2003;26:2713-2721. 2721. | Serruys PWJ C et al. JAMA 2002;287:3215-3222. 3222. | HPS C ollabor ative 

Gro up. Lancet 2003;361:2005-2016. 2016. | Wanner C. Presented at AS N annual meeting, 2004. | Rubins HB et al. 

Arch Intern Med 2002;162:2597-2604. 2604. | DAIS Investigators. Lancet 2001;357:905-910. 910. 

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Collaborative Atorvastatin Diabetes Study (CARDS) - Lipids Online

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