Statins vs Fibrates in Dyslipidemia

Charles P. Vega, MD


August 18, 2023

I recently posted a case about a 58-year old woman with multiple medical problems including obesity, hypertension, chronic kidney disease, and dyslipidemia. With a total cholesterol of 170 mg/dL (low-density lipoprotein cholesterol [LDL-C] level of 97 mg/dL; high-density lipoprotein cholesterol [HDL-C] level of 35 mg/dL) and triglycerides of 198 mg/dL, I asked what readers would recommend to manage this patient's lipid profile.

There was some variability in the answers to the question, and I hope the discussion of lipid therapy helps to enhance your practice.

I also want to be sure to address a couple pertinent issues in lipid management:

  1. How safe are statins over time?

  2. What role do fibrates play in cardiovascular prevention?

Many patients receive statins for more than one decade, putting them at risk for potential long-term adverse events associated with statin therapy. These effects have been hypothesized to include everything from hemorrhage to incident diabetes to cognitive dysfunction. A review by Mach and colleagues, which appeared in the July 14, 2018 issue of European Heart Journal, addressed these concerns.

Diabetes risk. Diabetes stands out as a proven albeit rare complication of chronic statin therapy; however, the risk for incident diabetes associated with statin therapy should be taken in the context of the cardiovascular benefits of statin drugs.

The overall effect of statins on the risk for incident diabetes is a relative increase of about 9%. Statins are more likely to be associated with a higher risk for diabetes among patients with more metabolic risk factors, such as prediabetes and obesity. But statins remain more effective vs placebo in the prevention of cardiovascular events even among adults who develop incident diabetes on statin therapy. Mach and colleagues cite a meta-analysis that found that statins could prevent about three-and-a-half cardiovascular events for every incident case of diabetes associated with these medications.

Cognitive function risk. There is no convincing evidence that statin therapy has a negative effect on cognitive function or the risks for Alzheimer's or Parkinson's disease. Again, statins probably improve cognitive function on a population level by preventing stroke. Though a mild increase in transaminase levels may occur in 0.5%-2.0% of patients taking a statin, these events are not clinically significant. Statin therapy is safe in the setting of nonalcoholic fatty liver disease, and routine monitoring of liver enzymes during statin therapy is discouraged.

Hemorrhagic stroke risk. One randomized, placebo-controlled trial of atorvastatin 80 mg among patients with a history of cerebrovascular disease demonstrated a higher risk for hemorrhagic stroke in the atorvastatin group. However, a subsequent analysis of clinical study data from nearly 250,000 patients failed to find a significant signal for statins in promoting hemorrhagic stroke. Any risk for hemorrhagic stroke associated with statins needs to be balanced with the 26% relative reduction in ischemic stroke per mmol/L reduction in LDL-C that these drugs afford.

Fibrate or No Fibrate?

Returning to our patient with multiple cardiovascular risk factors, it seems clear that she has much to gain and little to lose from moving up to a higher-intensity statin. Should we also consider combining her statin with a fibrate to reduce her risk for cardiovascular disease even further? The short answer is no.

Hope has been raised that fibrate therapy in the right patient group could drive down the risk for cardiovascular events. Data from the ACCORDION study, which enrolled adults with type 2 diabetes and other risk factors for cardiovascular disease, suggested that the presence of both diabetes and hypertriglyceridemia could represent an opportunity for fibrates to make an impact on cardiovascular outcomes.

The publication of the PROMINENT trial has essentially rejected the idea that fibrate therapy can improve cardiovascular outcomes. The PROMINENT trial included 10,497 patients with type 2 diabetes who were receiving moderate- or high-intensity statin therapy, had mild to moderate hypertriglyceridemia, and low HDL-C levels. The trial included adults with or without previous cardiovascular events. The primary efficacy endpoint of PROMINENT was the composite of nonfatal myocardial infarction (MI), nonfatal ischemic stroke, coronary revascularization, and cardiovascular death.

Patients meeting eligibility were randomly assigned to receive either pemafibrate 0.2 mg twice daily or matching placebo. Nearly three quarters of the study cohort were men, and more than 85% were White. Over 95% of participants received statin therapy.

Compared with placebo, pemafibrate led to reductions in triglyceride levels, very low-density-lipoprotein cholesterol, remnant cholesterol, and apolipoprotein C-III, whereas total cholesterol, HDL-C, LDL-C, and apolipoprotein B levels increased slightly. Despite changes in lipid parameters, the risk for the primary composite endpoint over a median of 3.4 years in the pemafibrate group was no different from placebo, and none of the individual components of the endpoints trended significantly. Pemafibrate was not more effective than was placebo for the primary outcome regardless of age, sex, or previous cardiovascular disease.

Overall, we should be maximizing the value of statins and treat to target for LDL-C lowering, with more intense statins for patients with a high risk for cardiovascular events. Fibrates still have a role in reducing very elevated levels of triglycerides among patients who are at risk for pancreatitis, but they should not be routinely applied for cardiovascular prevention.

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