Evidence from lipid lowering trials in diabetes

Low-density lipoprotein lowering

Given the heterogeneity of lipoprotein and the complexity of lipoprotein metabolism in patients who have diabetes, the optimal approach for lipid management remains to be determined. Over the past 10 years, a variety of randomized, controlled trials with hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) established the efficacy of these LDL-lowering agents in reducing cardiovascular outcomes. In four of these large trials (Scandinavian Simvastatin Survival Study [4S], Cholesterol and Recurrent Events [CARE], Long-term Intervention with Pravastatin in Ischemic Disease [LIPID], and Air Force/Texas Coronary Atherosclerosis Prevention Study [AF-CAPS/TexCAPS]), subgroup analyses revealed similar coronary artery disease risk reductions in smaller numbers of diabetic patients compared with the general population. (Table 1) [15-21]. The most recent and largest trial (more than 20,000 subjects) was the Heart Protection Study (HPS) which randomized 5963 patients who had diabetes [22,23]. Of these, approximately 2000 had preexisting CHD; 1000 had other occlusive vascular disease (including cerebrovascular disease), and 3000 had no evidence of CHD or other vascular disease. Noteworthy observations in this 5-year trial in patients who had diabetes were (Fig. 1):

The proportional reductions in clinical CVD events with simvastatin, 40 mg, daily were approximately 25% in each of the categories based on age, gender, obesity, duration of diabetes, degree of control by hemoglobin A, C, and lipid parameters at baseline.

The benefits in the 2592 patients who were older than 65 years were similar to those that were seen in the 3371 patients who were younger than 65 years. This was in contrast to the results in the Pravastatin in Elderly Individuals at Risk of Vascular Disease Trial which was performed in an elderly population (aged 70-82 years at baseline) in which the diabetic subgroup (n = 390) did not achieve a reduction in the major CVD end points over a mean follow-up of 3.2 years [24].

The risk reduction in 2426 subjects who had baseline LDL that was less than 116 mg/dL (3mM) was 27%, similar to those whose LDL was greater than 116 mg/dL (20%).

Among patients who received placebo, the 5-year rates of first major vascular event ranged from 13% in those who had diabetes alone to 36% in those who had diabetes and vascular disease. This supports the concept that the absolute risk of CVD is determined mainly by underlying pre-existing disease, rather than lipid levels.

Table 1

Major CHD event reductions in long-term trials with HMG-CoA reductase inhibitors (Statins)

Table 1

Major CHD event reductions in long-term trials with HMG-CoA reductase inhibitors (Statins)

Trail

(mg/dL)*

Overall patient population

Diabetes sub-group

reduction (%)

P

n

Risk-reduction (%)

P

Primary prevention

AFCAPS/TexCAPS

Lovastatin

156

6605

37

<0.001

155

43

NS

HPS

Simvastatin

124

7150

25

<0.0001

3982

26

<0.0001

CARDS

Atorvastatin

118

2838

37

0.001

ALLHAT-LLT**

Pravastatin

146

10,355

9

NS

3638

11

NS

ASCOT-LLA

Atorvastatin

132

19,342

36

0.0005

2532

16

NS

Secondary prevention

4S

Simvastatin

188

4444

34

<0.0001

202

55

0.002

4S (ADA criteria)

Simvastatin

187

483

42

0.001

CARE

Pravastatin

139

4159

23

<0.001

586

25

0.05

LIPID

Pravastatin

150

9014

24

<0.001

782

19

NS

HPS

Simvastatin

124

13,386

24

<0.0001

1981

15

<0.05

Abbreviations: AFCAPS/TexCAPS, Airforce/Texas Coronary Atherosclerosis Prevention Study; HPS, Heart Protection Study; CARDS, Collaborative Atorvastatin Diabetes Study; ALLHAT-LLT, Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial-Lipid Lowering Trial-Lipid Lowering Treatment; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease. * Approximate means.

** 155 of the cohort had pre-existing CHD; LDL data obtained in 5-10% of cohort.

Abbreviations: AFCAPS/TexCAPS, Airforce/Texas Coronary Atherosclerosis Prevention Study; HPS, Heart Protection Study; CARDS, Collaborative Atorvastatin Diabetes Study; ALLHAT-LLT, Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial-Lipid Lowering Trial-Lipid Lowering Treatment; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol and Recurrent Events; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease. * Approximate means.

** 155 of the cohort had pre-existing CHD; LDL data obtained in 5-10% of cohort.

Six hundred and fifteen patients had type 1 diabetes. The mean risk reduction was similar to that in the entire cohort.

In addition to these trials, a recently completed secondary prevention trial, the Greek Atorvastatin and Coronary Heart Disease Evaluation study (GREACE), was designed to target LDL cholesterol with atorvastatin, (10-80 mg/d) [25]. The target level of LDL cholesterol (<100 mg/dL) was reached in 95% of patients (compared with 3% of those who were given "usual" medical care). Of the 1600 patients in this study, 313 had diabetes. There was a 51% and 58% reduction in the major coronary end points in total and diabetes subgroup, respectively, during this 3-year trial.

In two primary prevention trials, statin therapy was evaluated in populations who had high risk, based on hypertension. In the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm Trial, 2531 of 10,305 patients had diabetes [26]. Atorvastatin, 10 mg/d for 3.3 years resulted in a 36% reduction in nonfatal MI and fatal CHD; however, the difference in the diabetic subgroup was not significant. This could be due to the small number of events in this trial over the shorter length of the study. Similarly, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the lack of benefit from pravastatin, 40 mg, in the trial group of 10,355 or the diabetic subgroup of 3638 subjects is less surprising [27]. In this study, the cholesterol level that was achieved was only 9% less than in subjects who were given placebo, mainly as a result of the nonstudy use of statin in the control group.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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