C10: Lipid modifying agents
Lipid modifying agents lower the levels of cholesterol and other fats (lipids) in the blood. The group is divided into single-agent products (C10A) and fixed combinations (C10B).
How do lipid modifying agents work?
Statins (C10AA) have their own page: HMG CoA reductase inhibitors.
Fibrates (C10AB), such as fenofibrate (C10AB05), activate the peroxisome proliferator-activated receptor alpha (PPARα). They lower the production of very low-density lipoprotein (VLDL), and increase the breakdown of triglyceride-rich particles by lipoprotein lipase. They lower plasma triglycerides substantially and raise high-density lipoprotein (HDL) cholesterol, and usually lower low-density lipoprotein (LDL) cholesterol moderately [1].
Bile acid sequestrants (C10AC), such as colestyramine (C10AC01), bind bile acids in the gut and divert them from their recycling between the gut and the liver (the enterohepatic circulation). The liver then makes more bile acids from cholesterol, and plasma LDL cholesterol falls [2].
Ezetimibe (C10AX09) inhibits the uptake of dietary and biliary cholesterol from the intestine [3].
PCSK9 inhibitors act on proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that raises plasma LDL cholesterol by reducing the number of LDL receptors on liver cells. Evolocumab (C10AX13) is a monoclonal antibody that binds PCSK9. At lower concentrations, it is eliminated mainly through saturable binding to PCSK9, which makes its pharmacokinetics nonlinear [4]. Inclisiran (C10AX16) is a small interfering RNA (siRNA) that is taken up into liver cells and directs the breakdown of the messenger RNA for PCSK9, so less PCSK9 is made. More LDL receptors are then recycled to the surface of liver cells, and more LDL cholesterol is taken up from the blood. Inclisiran is undetectable in plasma by 48 hours after the recommended dose, yet in healthy volunteers a single dose of 300 mg or more kept PCSK9 and LDL cholesterol lowered for 6 months [5].
Bempedoic acid (C10AX15) inhibits ATP citrate lyase [6].
Efficacy
LDL cholesterol is a prognostic factor for cardiovascular risk. Whether it is also a valid surrogate for cardiovascular outcomes, at the level of the trial, is debated. For statins, the size of the LDL cholesterol reduction predicted the effect on outcomes poorly across trials; see the statin page [7].
LDL cholesterol is a continuous measurement, and its fall lags behind that of PCSK9: evolocumab suppresses PCSK9 within 4 hours, but at steady state LDL cholesterol is lowest about 1 week after a dose given every 2 weeks [4]. An indirect response model, in which the drug inhibits or stimulates the production or loss of the response, accounts for such delays [8]. Because inclisiran leaves the plasma long before its effect ends, its dose-related LDL cholesterol lowering was described with a kinetic-pharmacodynamic (K-PD) model that included an effect compartment representing the liver [9].
Added to statin therapy, evolocumab lowered LDL cholesterol by 59% relative to placebo at 48 weeks, and the hazard ratio for the primary composite cardiovascular endpoint, a time-to-event measure, was 0.85 [10]. In patients unable or unwilling to take statins because of adverse effects, bempedoic acid lowered LDL cholesterol after 6 months by 21 percentage points more than placebo, and the hazard ratio for major adverse cardiovascular events was 0.87 [6].
Safety
The muscle toxicity of statins, and the drug interactions and genotypes that raise its risk, are described on the statin page.
Fibrates are generally well tolerated, and indigestion (dyspepsia) and abdominal pain are their most common adverse effects. They carry a small risk of gallstones (cholelithiasis). Combined with a statin, they increase the incidence of muscle inflammation (myositis) and muscle breakdown (rhabdomyolysis) [11].
Bile acid sequestrants are not absorbed from the gut, so they have no systemic drug interactions, but they can interfere with the absorption of some drugs taken with them [2]. Colestyramine lowers the bioavailability of ezetimibe, so the two should be given several hours apart [3].
In the FOURIER outcome trial, adverse events with evolocumab did not differ significantly from placebo, including new-onset diabetes and effects on memory and thinking (neurocognitive events). Injection-site reactions were the exception, at 2.1% vs 1.6% [10].
In the CLEAR Outcomes trial, gout (3.1% vs 2.1%) and gallstones (2.2% vs 1.2%) were more common with bempedoic acid than with placebo. So were small increases in serum creatinine, uric acid and liver enzymes [6].