Triglyceride and highdensity lipoprotein intervention

Unlike the plethora of trial evidence of CHD risk reduction with statins, the evidence from drugs to decrease triglycerides or increase HDL cholesterol is sparse. A meta-analysis of 17 observational studies suggested a significant relationship of triglycerides with CHD, even after adjustment for HDL cholesterol, especially in women [33]. In the 4S trial, in post hoc analyses, patients who had the lipid triad (elevated LDL, elevated triglyceride, decreased HDL cholesterol) had the highest event rates in the placebo arm and the greatest risk reduction with simvastatin [34]. Despite a mechanistic plausibility of increased risk with these lipid abnormalities in patients who had metabolic syndrome and diabetes, few long-term randomized trials have been completed (Table 2).

In the Helsinki Heart Study, a primary prevention trial, a small subgroup of 135 patients who had diabetes achieved a 68%, but nonsignificant, decrease in CHD events with gemfibrozil over 5 years [35]. In the St. Mary's Ealing North-wick Park Diabetes Cardiovascular Prevention Study, which included 164 patients who had type 2 diabetes, intervention with bezafibrate resulted in no significant difference in the primary end point of carotid lesions that were detected by ultrasound; however, there were 60% fewer total coronary events over a period of 3 years (P < 0.01) [36]. In the Diabetes Atherosclerosis Intervention Study (DAIS), an angiographic regression trial, 418 patients who had type 2 diabetes and evidence of CHD on angiography were treated with fenofibrate or placebo over at least 3 years [37]. The group that received fenofibrate

Table 2

Major cardiovascular trial results with fibrates in patients who have type 2 diabetes

Table 2

Major cardiovascular trial results with fibrates in patients who have type 2 diabetes

Trial

Drug

Primary end points

Total subjects/ diabetics

CHD at baseline

Outcome

P value

HHS

Gemfibrozil

Cardiac events/deaths

4081/135

No

CHD reduction: 68%

NS

SENDCAP

Bezafibrate

Carotid ultrasound

164/164

No

No difference3

-

DAIS

Fenofibrate

Coronary stenosis

418/418

48%

Reduced lesion progression

0.02

on angiography

VA-HIT

Gemfibrozil

Fatal/nonfatal MI

2531/627

Yes

CHD reduction: 24%

<0.05

Abbreviations: DAIS, Diabetes Atherosclerosis Intervention Study; HHS, Helsinki Heart Study; SENDCAP, St. Mary's Ealing Northwick Park Diabetes Cardiovascular Prevention Study ;VA-HIT, Veterans Administration -HDL Intervention Trial.

Abbreviations: DAIS, Diabetes Atherosclerosis Intervention Study; HHS, Helsinki Heart Study; SENDCAP, St. Mary's Ealing Northwick Park Diabetes Cardiovascular Prevention Study ;VA-HIT, Veterans Administration -HDL Intervention Trial.

showed significantly slower progression of disease and a trend toward fewer clinical end points (38 versus 50) in this small trial.

The largest, randomized clinical trial of fibrate therapy in patients who had diabetes was the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) [38]. In this trial, 2531 men who had CHD were recruited who had LDL cholesterol of up to 140 mg/dL; HDL cholesterol that was less than 40 mg/dL, and triglycerides that were up to 300 mg/dL at baseline. Of these, 627 had type 2 diabetes and an additional 363 had evidence for insulin resistance [39]. Treatment with gemfibrozil for a median duration of 5.1 years resulted in 24% risk reduction in the combined outcome of CHD death, MI, and stroke, despite no change in LDL cholesterol; HDL cholesterol increased by 6% and triglyceride levels decreased by 30%. The diabetic subgroup had a greater reduction in the combined end points (32%) compared with the nondiabetics (18%), although these differences were not statistically significant (Fig. 2)

[39]. Subsequent analyses from the VA-HIT revealed that the outcomes were not explained by the change in triglycerides and were explained only partially by the increase in HDL cholesterol

[40]. The 5-year event rates were correlated highly with insulin resistance [41], with or without diabetes. The event reduction was significantly greater in those who had insulin resistance and was independent of the HDL cholesterol or triglyceride levels, before or after treatment [41]. These analyses suggest the possibility that other antiatherogenic effects of fibrates that are mediated by a variety of mechanisms (eg, PPAR-a agonism, anti-inflammatory effects on vessel wall, fibrinolysis) may contribute to the event reductions that were seen in the VA-HIT.

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