Pharmacologic Prevention of Microvascular and Macrovascular Complications in Diabetes Mellitus

Implications of the Results of Recent Clinical Trials in Type 2 Diabetes

Nikhil Tandon; Mohammed K. Ali; K.M. Venkat Narayan

Disclosures

Am J Cardiovasc Drugs. 2012;12(1):7-22. 

In This Article

4. Lipid Lowering

There are two aspects of lipid lowering that have been addressed in various clinical trials – benefits accrued with the primary target being LDL cholesterol, and benefits with additionally targeting triglyceride (very low-density lipoprotein cholesterol) levels. Dyslipidemia is a significant independent predictor of coronary heart disease events and mortality in individuals with diabetes.[48] Statins have been the drugs of choice for lipid lowering and have resulted in 27–40% reduction in LDL-cholesterol levels with a concomitant 25–42% reduction in CV events and mortality.[49,50]

A recent meta-analysis performed by the Cholesterol Treatment Trialists' (CTT) Collaboration evaluated the cholesterol-lowering efficacy of statins among 18 686 people with diabetes (21.7% of all participants) in 14 trials.[51] Each mmol/L reduction in LDL cholesterol level was associated with: 9% reduction in all-cause mortality, 13% reduction in vascular mortality, 21% reduction in major vascular events, 22% reduction in MI or coronary death, 25% reduction in coronary revascularization, and 21% reduction in stroke. Equally important was the fact that these benefits were observed in patients with diabetes irrespective of whether there was a prior history of vascular disease. The consensus based on existing studies targeting lowering of LDL cholesterol is that all patients with diabetes at sufficiently high vascular risk should be treated with statins irrespective of initial cholesterol levels.

However, several studies reported a significant residual CV risk despite the use of statin therapy, with event rates exceeding 20% at 10 years.[52–55] This residual risk was amplified in the diabetic subpopulation of these studies, with event rates ranging from 31% to 58% over 10 years. This led to investigations of whether patients with diabetes who are characterized by high triglyceride and low HDL levels will experience additional benefit in terms of macrovascular outcomes from the addition of a fibric acid derivative. The decision to use a fibric acid derivative and not niacin was based on previous trial evidence reporting benefits of fibric acid derivatives in populations with an over-representation of people with diabetes.[55,56] Hence, the final design of the lipid-lowering component of ACCORD involved all participants, irrespective of the presence of hypertriglyceridemia, receiving up to 40 mg/day of simvastatin (to achieve an LDL cholesterol target level of <100 mg/dL) and either fenofibrate (160 mg/day) or placebo.[57]

Combination lipid-lowering therapy did not result in any benefit with regard to either the primary outcome, which was a composite of first occurrence of non-fatal MI, non-fatal stroke, or death from CV causes, or any secondary outcome.[57] While the results did not support the routine use of a combination of statins and a fibric acid derivative in high-risk patients with type 2 diabetes, pre-specified subgroup analysis did suggest a possible benefit for patients with both a high baseline triglyceride level and a low baseline HDL cholesterol level. Intriguingly, only 17% of participants in the ACCORD lipid study had both low HDL cholesterol and high triglyceride levels at baseline, unlike some clinical practices where a much higher proportion of subjects carry such a lipid profile.

The probable benefit observed in patients with significant elevation of triglyceride levels and low HDL cholesterol levels is consistent with a post hoc subgroup analysis of three of the four major trials of fibric acid derivatives, namely the Helsinki Heart Study, Bezafibrate Infarction Prevention trial, and the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial.[58–60] A recent meta-analysis analyzing the effect of fibric acid derivatives on CV outcomes noted greater effect sizes in studies reporting a higher triglyceride level at baseline.[61] These data support current practices of adding on fibric acid derivatives to statins in patients who have significant elevations of triglyceride levels.

The ACCORD Eye Study has also reported that combination therapy for dyslipidemia retards the progression of retinopathy (OR 0.60; 95% CI 0.42, 0.87; p = 0.006).[26]

4.1 Conclusions

Aggressive lowering of LDL cholesterol levels using statins is accepted routine clinical practice. The observation of a significant residual CV risk despite lowered LDL-cholesterol levels raises the question about probable additional benefit of adding fibric acid derivatives. Currently available data clearly indicates that 'routine' therapy with fibric acid derivatives is unlikely to be of benefit, although 'tailored' therapy with fibric acid derivatives in individuals with elevated triglyceride levels is likely to be beneficial.

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