Nonstatin Low-Density Lipoprotein-Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council

Hegele RA, Gidding SS, Ginsberg HN et al.
Arterioscler Thromb Vasc Biol. 2015 Sep 16. pii: ATVBAHA.115.306442

Statins play an undisputed role in cardiovascular disease (CVD) prevention and halting atherogenesis. Their LDL-lowering effect is central to these benefits, but other benefits may also include improving endothelial function, anticoagulant, antioxidant and anti-inflammatory effects, and inhibiting cell proliferation, among other effects. Since elevated LDL levels adversely affect these effects, it is unclear whether these represent LDL-independent, pleiotropic effects, or simply consequences of the LDL-lowering. Considering the central role of LDL-lowering to CVD reduction, nonstatin-based LDL-lowering is also expected to provide CV benefit. This review considers the mechanisms of all nonstatin LDL-lowering therapies.
 Classical epidemiological and observational studies have confirmed the centrality of LDL-c in predicting CVD risk. Furthermore, functional studies suggest that quantitative and qualitative abnormalities of LDL are involved in atherogenesis.
Atherosclerosis begins early in life and lipids measured in youth better predict subclinical atherosclerosis at middle age than risk factors assessed in middle age. Thus, when atherosclerosis prevention is started later in life, in addition to risk factors, existing atherosclerotic disease should be addressed.
Human genetic evidence also underscore LDL’s role in atherosclerosis. In the single gene disorder familial hypercholesterolaemia (FH), livelong exposure to elevated LDL leads to early atherosclerosis. Mendelian randomisation studies into DNA polymorphisms associated with modest effects on LDL also suggest a causative role. Genetic variants at the PCSK9, HMGCR and NPC1L1 loci predict coronary heart disease (CHD) risk. A causal relationship is harder to identify for variants at other genetic loci, because they also affect other variables. CHD risk reductions seen with genetic variants are larger than with a similar degree of LDL lowering obtained in short-term statin randomised clinical trials (RCTs), presumably because genetic effects are present from birth.

Conventional nonstatins and CVD risk

Ezetimibe blocks intestinal sterol absorption, thereby lowering LDL-c. In the IMPROVE-IT trial, a CV event reduction was seen with treatment with ezetimibe plus simvastatin, which was proportional to the incremental LDL lowering as compared with simvastatin monotherapy. Also the larger regression of coronary artery plaque volume seen with ezetimibe plus atorvastatin vs. atorvastatin monotherapy points in the direction of a direct role for LDL-c in atherosclerotic CVD.

Bile acid sequestrants divert bile acids from the enterohepatic circulation, thereby depleting the liver of bile. Bile synthesis from cholesterol is then upregulated. Due to depletion of the intrahepatic cholesterol pool, LDL receptor  (LDLR) activity is upregulated, which decreases LDL-c levels. CHD event reduction in the Coronary Primary Prevention Trial was proportional to the degree of LDL-lowering.

Niacin lowers LDL and triglycerides and increases HDL. As monotherapy, niacin has been shown to reduce recurrent myocardial infarction, mortality and atherosclerotic progression. Addition of niacin to statins did not show a CV benefit in patients with pre-existing CVD and well-controlled LDL (AIM-HIGH and HPS2-THRIVE). These results refute the hypothesis that HDL directly protects against atherosclerosis.

Fibrates lower triglycerides and increase HDL levels, which could be of use in dyslipidaemias associated with metabolic disease with or without type 2 diabetes (T2DM). Outcome trials with fibrate monotherapy have yielded both positive and negative results. Addition of fenofibrate to stable background simvastatin had no effect on CVD endpoints in the ACCORD trial. Subgroup analyses in individuals in the upper tertiles of triglyceride and HDL levels suggested a benefit in this group.

Newer nonstatin agents

- the original document gives more detailed results for each of the agents-
PCSK9 inhibitors effectively lower LDL-c by preventing degradation of the LDLR. Monoclonal antibodies (mABs) directed at PCSK9 give robust lowering of LDL-c, as well as of other lipid parameters, such as Lp(a). Preliminary data suggest a CVD event reduction when using PCSK9 mABs over 1-1,5 years, but large and longer outcome trials are ongoing. PCSK9 mABs may already be an option for high-risk patients who would benefit from additional LDL-lowering.
In the United States, the antisense oligonucleotide directed at apoB mRNA mipomersen is available for use in homozygous FH (HoFH). It lowers LDL-c, apoB and Lp(a) in an LDLR-independent manner. Discontinuation rates in RCTs have been high, and concerns exist about hepatotoxicity. Larger and longer studies will need to establish the usefulness of mipomersen.

Inhibition of microsomal triglyceride transfer protein(MTP) by lomitapide reduces synthesis of apoB-containing lipoproteins independently of LDLR. It has been shown to lower LDL-c by 35-50% in HoFH and is approved by EMA and FDA in addition to diet and drug therapy. Its effect on liver function (elevated liver enzymes and steatosis) is a source of concern and requires monitoring.

Inhibiting cholesteryl ester transfer protein (CETP) was hypothesised to reduce CV events by raising HDL-c and lowering apoB-containing lipoproteins. Two CETP-inhibitors, dalcetrapib and torcetrapib, have failed to show CV benefit in outcomes trials, due to increased CV events and mortality, possibly due to off-target effects on blood pressure, and futility, respectively. Two other CETP-inhibitors, anacetrapib and evacetrapib, are still under investigation: they show substantial HDL-raising and LDL-lowering effects, without apparent off-target effects.

A small molecule called bempedoic acid (previously known as ETC-1002) inhibits fatty acid and cholesterol synthesis. In short-term phase 2 trials it was shown to lower LDL by 25 and 43% in patients with hypercholesterolaemia and T2DM, respectively. Longer and larger phase 3 studies will need to evaluate the durability and safety of this new type of drug.

Remaining unanswered questions

Are there better alternatives to LDL cholesterol as measures of atherogenicity?
Despite its undisputed reputation as agent provocateur, chief epidemiological analyte and treatment target in CV disease, measuring LDL has its limitations. Direct measurement is labour intensive or methods are incompletely validated. Indirect measurement requires a relatively long period of fasting and it does not completely capture the total burden of atherogenic particles.
ApoB and non-HDL cholesterol have been proposed to be alternative measures to quantify atherogenic lipoproteins, and both have been described to have superior predictive value over LDL-c. Because of this and the fact that they can be measured from nonfasting samples, several guidelines now (also) recommend these measures for risk assessment and monitoring treatment effect.

What is the role of LDL treatment in children?
Concerning LDL-lowering therapy in childhood, guidelines focus on FH or children with elevated LDL in combination with diabetes or other risk factors. Statins are first choice treatment, with recommended treatment goals attempting to balance treatment effect and risk of long-term side-effects. RCTs of LDL-lowering therapies have mostly been limited to children with FH. It is to date unclear at which age lipid-lowering treatment should be initiated for optimal benefit, when plaque development is most likely to start. In children who are unable to achieve satisfactory LDL-lowering with statins (HoFH or severe HeFH), lipoprotein apheresis can be added. Studies on the paediatric safety and efficacy of new agents are warranted.

What is the role of monitoring subclinical atherosclerosis?
Although the presence of subclinical atherosclerosis improves risk classification, the role of monitoring subclinical markers in clinical practice has not been established. In conditions like FH with elevated lifetime risk, it could be informative to assess baseline risk and as a surrogate or treatment response.

Can LDL cholesterol be too low?
Now that therapies are available that can lower lipid levels to VLDL, monitoring some adverse effects becomes relevant. For instance, patients with heterozygous familial hypobetalipoproteinaemia, with lifetime LDL-c < 0.78 mmol/L, may develop liver disease. Fatty liver was also reported in patients with ANGPTL3 mutations who have similarly low LDL-c levels. The FDA has called for neurocognitive assessment in ongoing PCSK9 mAb RCTs, after patients receiving evolocumab in the open-label OSLER study reported amnesia (1%) and memory or mental impairment (1%), unrelated to achieved LDL-c levels. Also patients randomised to rosuvastatin who achieved LDL-c <0.78 mmol/L have been described to have higher rates of diabetes, haematuria, hepatobiliary disorders and insomnia. Long-term follow-up will need to better establish the risk profile of very low LDL-c.

Does diabetes mellitus risk with statins extend to nonstatins?
Studies have revealed that statins increase the risk of developing T2DM in prediabetic individuals. The underlying mechanism has not yet been identified, and it can be questioned whether it is the statin per se, cholesterol synthesis, or LDLR function that plays a causative role. Fewer people (100-150) need to be treated with a statin to prevent 1 CVD event than to cause a new case of diabetes (>500), emphasising the importance of risk-benefit considerations. Similar risks have not yet been reported with nonstatins, except for niacin.

Can newer nonstatins regress lesions?
In statin RCTs, atherosclerosis regression continued as LDL-c dropped until 0.39 mmol/L. Combination therapy with maximally tolerated statins, ezetimibe and the novel agents may therefore have large effects on atherosclerosis stabilisation and regression. Long-term follow-up of the ongoing CVD outcomes trials of new agents may also reveal a legacy effect of plaque stabilisation and regression in high-risk patients, like the persistently reduced CVD risk seen in statin-treated patients. It might be that aggressive LDL-c lowering suffices for a few years, after which maintenance therapy with maximally tolerated statin therapy is adequate to suppress new plaque formation. Also animal data suggest that early, aggressive LDL-c lowering may reset the vascular aging clock.

Targets or no targets?
The 2013 AHA/ACC guidelines eliminated lipid targets, and recommended to base treatment decisions on CVD risk instead. Comparison of no targets based on the ACC/AHA guidelines with using LDL-c thresholds based on the updated ATP III guidelines suggested that the ACC/AHA guidelines more accurately identify increased risk of CVD and subclinical CHD, in particular in intermediate-risk individuals. The concept of targets will need to be discussed anew when the results of the outcome studies with novel agents are available.

Conclusions

The direct causal role of LDL-c in atherogenesis is compelling based on biological, genetic, epidemiological and clinical trial evidence. Statins have the largest RCT evidence base supporting their CV benefit. Until recently the relative importance of LDL-c lowering vs other pleiotropic effects of statins in this benefit was disputed. Recent evidence of CVD event reduction with various nonstatin agents, also involving LDL-c and LDLR biology, challenge the importance of statins’ other pleiotropic effects. In the near future, the longer term RCT data of PCSK9 inhibitors may provide definitive support to this growing body of evidence.  Algorithms on when to add PCSK9 inhibitors for CVD event reduction will also become clear. And the optimal timing of initiating treatment deserves attention, so that event rate reductions predicted from Mendelian randomisation studies can be achieved in most.

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