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............................................................................................................................................................................. performed before many of the modern treatment options were available.276278

8.3.4 Adverse effects and interactions Gastrointestinal (GI) adverse effects (most commonly flatulence, constipation, dyspepsia, and nausea) are often present with these drugs, even at low doses, which limits their practical use. These adverse effects can be attenuated by beginning treatment at low doses and ingesting ample fluid with the drug. The dose should be increased gradually. Reduced absorption of fat-soluble vitamins has been reported. Furthermore, these drugs may increase circulating TG levels in certain patients. Bile acid sequestrants have major drug interactions with several commonly prescribed drugs, and must therefore be administered either 4 h before or 1 h after other drugs. Colesevelam is better tolerated and has fewer interactions with other drugs, and can be taken together with statins and several other drugs.279

8.4 Proprotein convertase subtilisin/kexin

type 9 inhibitors 8.4.1 Mechanism of action Recently, a new class of drugs, PCSK9 inhibitors, has become available that targets a protein (PCSK9) involved in the control of the LDLR.280 Elevated concentration or function of this protein in plasma reduces LDLR expression by promoting, upon binding, LDLR lysosomal catabolism and a subsequent increase in plasma LDL concentrations, while lower concentration or function of PCSK9 is related to lower plasma LDL-C levels.281 Therapeutic strategies have been developed mainly using mAbs; the mechanism of action relates to the reduction of the plasma level of PCSK9, which in turn is not available to bind the LDLR. Since this interaction triggers the intracellular degradation of the LDLR, lower levels of circulating PCSK9 will result in increased expression of LDLRs at the cell surface and therefore in a reduction of circulating LDL-C levels.281 Currently, the only approved PCSK9 inhibitors are two fully human mAbs, alirocumab and evolocumab. Statin treatment increases circulating PCSK9 serum levels,282 and thus the best effect of these mAbs has been demonstrated in combination with statins.

8.4.2 Effects on lipids 8.4.2.1 Low-density lipoprotein cholesterol. In clinical trials, alirocumab and evolocumab—either alone or in combination with statins, and/or other lipid-lowering therapies—have been shown to significantly reduce LDL-C levels on average by 60%, depending on dose. The efficacy appears to be largely independent of any background therapy. In combination with high-intensity or maximally tolerated statins, alirocumab and evolocumab reduced LDL-C by 4673% more than placebo, and by 30% more than ezetimibe. Among patients in whom statins cannot be prescribed, PCSK9 inhibition reduced LDL-C when administered in combination with ezetimibe.283 Both alirocumab and evolocumab have also been shown to effectively lower LDL-C levels in patients who are at high CV risk, including those with DM.284 Given the mechanism of action, these drugs are effective at reducing LDL-C in all patients capable of expressing LDLR in the liver. Therefore, this pharmacological approach is effective in the vast majority of patients, including those with HeFH and, albeit to a lower level, those with HoFH with residual LDLR expression. Receptordeficient HoFH responds poorly to the therapy.285

8.4.2.2 Triglycerides and high-density lipoprotein cholesterol. These highly efficacious LDL-lowering agents also lower TG levels, and increase those of HDL-C and ApoA-I as a function of the dosing regimen. In phase II trials, evolocumab lowered TG levels by 26%, and raised HDL-C and ApoA-I by 9 and 4%, respectively; similar findings have been reported for alirocumab.286,287 However, the TG effect must be confirmed in populations with higher starting plasma TG levels.

8.4.2.3 Lipoprotein(a). In contrast to statins, inhibiting PCSK9 with mAbs also reduces Lp(a) plasma levels. Pooled results of phase II trials have shown that treatment leads to an Lp(a) reduction of about 3040%.288,289 While recent investigations have attempted to unravel the mechanism, it remains unclear. However, it appears to be distinct from that of statins, which also enhance LDLR function but do not lower circulating Lp(a) levels in humans. The relative contribution of this effect to the reduction of risk remains to be addressed in appropriately designed studies.

8.4.3 Effect on cardiovascular morbidity and mortality Early preliminary data from phase III trials suggests a reduction of CV events in line with the LDL-C reduction achieved.286,290,291 Recently, two major studies were completed: the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and the Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY Outcomes) trials.119,120 The designs of the trials were similar with regard to the settings of secondary prevention and background therapy; however, the populations enrolled had either stable CHD, peripheral arterial disease (PAD), or stroke; or a recent (median 2.6 months) ACS, respectively. The relative benefit ranged from 1520% reductions in the risk of the primary endpoints. Both studies had relatively short follow-up periods and the evidence from statin trials indicates that the clinical benefits of LDL-lowering may only emerge after about 1 year,51 so these trials may have underestimated the potential impact of longer-term treatment.120,290 In the FOURIER trial,119 27 564 patients with atherosclerotic CVD, and LDL-C levels of 1.8 mmol/L (70 mg/dL) or higher who were receiving statin therapy, were randomly assigned to receive evolocumab or placebo. Allocation to evolocumab reduced median LDL-C from 2.38 mmol/L (92 mg/dL) at baseline to a mean of 0.78 mmol/L (30 mg/dL) at 48 weeks. After a median follow-up of 2.2 years, evolocumab treatment significantly reduced the risk of the primary endpoint (composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) by 15% [hazard ratio (HR) 0.85, 95% CI 0.790.92]. An analysis of the time to benefit also showed that there was a lower benefit in the first year than in subsequent years, consistent with the effects of statins observed within the CTT meta-analysis.268 In the FOURIER trial, allocation to evolocumab did not reduce the risk of CV mortality (HR 1.05, 95% CI 0.881.25) or all-cause mortality. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026