A. LDL

The atherogenic risk of a lipoprotein is related to its size. LDL particles, and more particularly the small and dense LDL particles, are more likely to penetrate the endothelium and initiate atherosclerosis than VLDL particles. For a given LDL cholesterol level, small LDL particles or a high number of LDL particles (LDL-p) are more atherogenic than large or less numerous LDL particles, because they lead to more endothe- lial penetration and injury.⁷ In fact, cholesterol is only a portion of any given liproprotein (LDL, HDL, or VLDL), which also contains proteins (Apo B), triglycerides, and phospholipids. In patients with low LDL who continue to have recurrent events, a high number of small LDL particles is suspected, and is indirectly reflected by a low HDL level and high triglyceride, VLDL, and non-HDL cholesterol levels. LDL-p has not been studied independently at a large scale, and thus this measurement is not routinely performed, especially in primary prevention. Apo B is the protein found in all atherogenic particles, such as LDL, VLDL, and Lp(a). Apo B levels correlate with the number of LDL particles and may predict cardiovascular outcomes as well as or better than LDL, especially in patients with low LDL levels. Apo A is the central pro- tein of HDL, and low Apo A levels may be associated with impaired outcomes.

B. Non-HDL cholesterol

Non-HDL cholesterol = total cholesterol – HDL = LDL + VLDL + VLDL remnants. It is a strong predictor of adverse outcomes and should be targeted to <100 mg/dl in the high-risk categories (along with LDL<70 mg/dl). The targeting of non-HDL is particularly relevant in patients with high TGs (and thus high VLDL), whose atherogenic particles and risk may not be fully represented by LDL. While LDL calculation may not be possible in patients with TG>300 mg/dl, it remains possible and important to calculate and target non-HDL.

C. HDL

HDL scavenges “bad” cholesterol from the endothelium and lipid-laden macrophages (cholesterol efflux), then empties it onto VLDL through the cholesteryl ester transfer protein (CETP). VLDL is then taken up by the liver and eliminated in the bile (reverse transport mecha- nism). A spontaneously high HDL is protective against CAD as it indicates that “bad” cholesterol has been scavenged and will be eliminated through the CETP enzyme. Drugs that increase HDL by inhibiting CETP may saturate HDL and inhibit its capacity to scavenge cholesterol (dysfunctional HDL). This may paradoxically increase cardiovascular events.¹⁵ In fact, the HDL process is complex, and a pharmacological increase in HDL may not improve outcomes. Niacin increases HDL but also the efficacy of the scavenging effect by reducing VLDL, and reduces atherogenic lipoproteins, which explains the possible improvement of outcomes with niacin.

Furthermore, HDL may cease to predict cardiovascular outcomes in patients receiving statin who have an adequately controlled LDL (substudies of JUPITER and CETP inhibitor trials).^15–17

D. Triglycerides (TGs)

TGs, when >500 mg/dl, warrant therapy because of the marked risk of pancreatitis. TGs are associated with some increase in the risk of cardiovascular events, through their association with a high level of atherogenic lipoproteins, rather than a direct TG effect. In fact, a high TG level is associated with high levels of VLDL and VLDL remnants; large VLDLs may not be atherogenic, but the smaller VLDLs and their remnants are small enough to penetrate the endothelium. A high VLDL precludes cholesterol elimination from HDL, which affects the efficacy of HDL scavenging. Thus, a high TG level reflects a high level of atherogenic lipoproteins, and primarily mandates a calculation of non-HDL cholesterol and a reduction of non-HDL cholesterol rather than TG per se.

A. Statins

Statins inhibit HMG-CoA reductase, the enzyme that synthesizes intracellular cholesterol. This leads to an increase in LDL receptors and LDL uptake by cells. Statins lower LDL by 30–60%, TG by 15–25%, and increase HDL by 5–10%. Statins are the best agents for lowering non-HDL cholesterol as well.

1. The most potent statins are rosuvastatin (5–40 mg/day) and atorvastatin (10–80 mg) (LDL ↓ 40–60%), followed by simvastatin 10–40 mg (LDL ↓ 35–45%) and pravastatin (LDL ↓ 30%). Rosuvastatin is the most effective statin for raising HDL, while atorvastatin is the most effective statin for reducing TGs.
   
2. Doubling the statin dose lowers LDL by 6% more, but is associated with a more significant increase in myopathy.
   
3. Increasing the dose of atorvastatin to 80 mg reduces LDL by 60% vs. 40% reduction with a dose of 10 mg.
   
4. Dosing:
   
   
   
   1. In high-risk patients with established vascular disease, high statin doses proven to be the best in clinical trials are used (atorvastatin 40–80 mg; rosuvastatin 20–40 mg). These doses reduce LDL by ≥50% and are particularly important in ACS, where statins may directly stabilize active plaques.
      
   2. If the patient is a lower-risk patient, or if there is a concern about side effects (e.g., elderly patients >75, renal failure, or possibility of drug interactions), use a moderate-intensity statin dose, which reduces LDL by 30–50% (simvastatin 20 mg, atorvastatin 10 mg, pitavastatin 1–4 mg, pravastatin 40 mg). Ezetimibe may be added for further LDL reduction.
      
   3. Low-intensity statin is only tried in patients with statin intolerance.

B. Ezetimibe

Ezetimibe inhibits cholesterol absorption and reduces LDL by ~20% even in patients already receiving a statin. It also reduces non-HDL cholesterol. In the IMPROVE-IT trial, patients with a recent ACS (mainly MI) and a baseline LDL of 95 mg/dl were randomized to simvastatin 40 mg vs. simvastatin 40 mg + ezetimibe. The statin group achieved LDL of 69 mg/dl, while the combined group achieved LDL of 53 mg/dl, which translated into a 10% reduction of MI, and 20% reduction of stroke. Lower LDL was better in this high-risk ACS population, even when a non-statin drug was added.⁸

C. Anti-PCSK9 antibodies (alirocumab, evolocumab)

PCSK9 is an enzyme that destroys LDL receptors. Blocking this enzyme increases LDL receptors and dramatically reduces LDL by over 50% even in patients already receiving a statin (“double negative effect on LDL receptor”). Genetic studies have shown that individuals with loss of function of the PCSK9 gene have low LDL and cardiovascular events. This led to the development of fully human, monoclonal antibodies inhibiting PCSK9. These drugs are administered subcutaneously, once every 2 weeks. They have been associated with a reduction of cardiovascular events in 2 groups of patients and are approved in those 2 groups:

• Patients with established cardiovascular disease whose LDL remains >70 mg/dl with statin (FOURIER and ODYSSEY OUTCOMES trials, mean LDL 90 mg/dl).^9,10 Cardiovascular events are reduced by ~15%, including mortality in ACS, but the benefit is more striking in patients whose baseline LDL is>100 mg/dl or those who do not tolerate any statin (risk reduction >25%).¹⁰
  
• Patients with familial hypercholesterolemia whose LDL remains >100 mg/dl (especially 130 mg/dl) with statin therapy.

D. Bile acid sequestrants (cholestyramine, colestipol)

These agents reduce bile acid reabsorption, which reduces the cholesterol available to synthesize LDL (LDL ↓ 15–30% but TG may ↑). These agents raise TG and are avoided if TG >300 mg/dl.

E. Nutrients high in phytosterols (plant sterols)

Phytosterols decrease cholesterol absorption and reduce LDL by ~10%. A high intake of fibers also lowers cholesterol absorption.

A. Niacin

Niacin reduces fat degradation in the adipose tissue, which reduces the release of free fatty acids in the circulation, reducing VLDL synthesis. The reduction in VLDL indirectly improves the HDL scavenging mechanism, which raises HDL and reduces LDL. Thus, niacin raises HDL 15–25%, lowers TG 20–25% (at high doses, ~2000 mg), and lowers LDL 10–15%. Niacin is the best available agent for raising HDL. It also improves the quality of LDL cholesterol, increasing the size and reducing the number of LDL particles. Niacin doses >2000 mg are better avoided because of the risk of increasing glucose levels.

Niacin was the first lipid-lowering drug to show a reduction in MI and total mortality in the Coronary Drug Project (secondary preven- tion trial of patients with prior MI).²¹ However, in a contemporary trial of CAD patients already receiving statin with well-controlled LDL levels and mildly reduced HDL levels (~35 mg/dl), niacin did not provide additional benefit (AIM-HIGH trial).¹¹ It may still have a role in patients with CAD and markedly abnormal TG or HDL.²²

B. Fibrates

Fibrates increase lipoprotein lipase activity, which degrades VLDL into VLDL remnants and buoyant LDLs that are readily taken up by the liver. Fibrates also have other effects, such as reducing VLDL synthesis in the liver and increasing Apo A1 synthesis (HDL protein). Thus, fibrates lower TG 20–50%, increase HDL 10–20%, ± lower LDL 10–15% (especially fenofibrate).

Fibrates are the most effective agents in lowering TGs. However, gemfibrozil may raise LDL in patients with severely increased TGs (by converting some VLDL into LDL). In the Helsinki and VA-HIT studies, patients with low HDL and without CAD (Helsinki study) or with CAD (VA-HIT study) derived a reduction in MI and stroke with gemfibrozil.^23,24 However, these patients were not receiving statin therapy, and no reduction in mortality was seen. Routine fenofibrate therapy failed to show a benefit in diabetic patients receiving statin therapy, most of whom did not have a CAD history (ACCORD); this result may not extend to patients with prior CAD or severely abnormal HDL or triglycerides, wherein a trend toward benefit was seen.¹¹

Fibrates, when used in renal failure or in combination with statins, are associated with an increased risk of myositis of 1%. If a decision is made to provide a combination therapy in statin-treated patients who continue to have a markedly reduced HDL or a high TG, niacin or fenofibrate is generally the preferred agent. Gemfibrozil is best avoided in combination with a statin;¹¹ fenofibrate is a safer fibrate in patients who require combined therapy with a statin.²⁵

C. Omega-3 fatty acids

Omega-3 fatty acids reduce TG by ~30–40%, through reduction of the hepatic synthesis of TG and activation of the lipoprotein lipase. In the GISSI-Prevenzione trial of patients with recent MI (≤3 months), omega-3 fatty acids (1 gram/d) reduced the risk of cardiovascular events, likely via an improvement of endothelial function and oxidative stress.²⁶ In the GISSI-HF trial of HFrEF, omega-3 fatty acids reduced mortality.²⁷

Yet, omega-3 fatty acids have not been beneficial in most primary or secondary prevention trials.²⁸ This may be due to the low dose of omega-3 used in those trials and to the fact that these formulations contain both EPA and DHA acids (DHA is less likely to be beneficial). Depending on the formulation, 1 gram of fish oil only contains ~350–800 mg of omega-3 fatty acids; ≥1 gram of omega-3 (>>1 gram of fish oil) is likely required for benefit. One large trial, REDUCE-IT, used a purified EPA, icosapent ethyl (2 g twice daily), on top of statin in patients with CAD or diabetes and triglycerides>135 mg/dl, and showed a 25% reduction of cardiovascular events and 20% reduction of cardiovascular mortality.²⁹

D. Tight glycemic control

Tight glycemic control is one of the most effective means of achieving the TG/HDL goal in diabetic patients.

E. Lifestyle modification

Diet and exercise are indicated in all patients. These are moderately effective in reducing LDL (usually a 20% reduction, possibly more with a stricter diet). The most effective diets are the Mediterranean diet (fruits, vegetables, whole grains, fish, nuts, and olive oil), the vegan diet, and a diet switch from saturated to monounsaturated fat (olive oil).

Lifestyle modification, particularly the reduction of simple and refined sugars, is quite effective in reducing TG and raising HDL, more so than it is effective in reducing LDL.

Smoking cessation raises HDL. Mild alcohol consumption (1 drink/day) raises HDL and may improve cardiovascular outcomes but should be avoided if TG >200 mg/dl.

A. Diagnosis

Three of five criteria are needed for the diagnosis (AHA):³⁰

1. Obesity (male: waist >40 inches; female: waist >35 inches). Lower cut-points are used in Asian populations.
   
2. TG level >150 mg/dl
   
3. HDL <40 mg/dl in men, <50 mg/dl in women
   
4. HTN >130/80 mmHg
   
5. Fasting blood glucose >100 mg/dl

B. Treatment

1. Diet, exercise, and weight loss.
   
2. HTN: ACE-I/ARB may reduce glucose levels and lower the risk of diabetes.^30,31
   
3. Glucose intolerance and risk of diabetes: metformin is effective in decreasing the risk of diabetes in pre-diabetic patients. However, therapeutic lifestyle changes are the most effective means of reducing this risk. Semaglutide, a GLP-1 agonist, given at a once weekly SQ dose higher than the diabetic dose, dramatically reduces weight by ~15% and improves the metabolic profile.32
   
4. Statin therapy is indicated in most of these patients, based on their 10-year cardiovascular risk.

A. Statin therapy

All diabetic patients older than 40 years of age derive a reduction of cardiovascular events, stroke and mortality with statin therapy, even in the absence of established CAD and regardless of LDL levels (even if <100 mg/dl) (HPS and CARDS trials).^33,34 Not infrequently, patients with diabetes have low yet atherogenic levels of LDL.

B. SGLT-2 inhibitors (gliflozins) and GLP-1 receptor agonists (“-glutides”) are recommended after initial metformin therapy

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors inhibit glucose and Na reabsorption in the proximal tubule. In randomized trials of patients with or without cardiac disease, they consistently and strikingly reduced HF events (by ~35–40%). They also reduced mortality of patients with diabetes and cardiovascular disease (EMPA-REG trial with empagliflozin, mainly CAD at baseline, 32% relative risk reduction);³⁵ and patients with HFrEF with or without diabetes (DAPA-HF trial with dapagliflozin).³⁶ They do not clearly reduce MI.

Glucagon-like peptide 1 (GLP1) is normally a gut hormone secreted during eating, as a response to oral glucose; it works on the pancreas to increase insulin and reduce glucagon secretion; it also slows gastric emptying and causes satiety (brain effect). GLP-1 receptor agonists mimic GLP-1 and are mostly administered subcutaneously. In randomized trials that predominantly recruited patients with cardiovascular disease, they reduced cardiovascular events, mainly MI (liraglutide, dulaglutide, and semaglutide, which is the only GLP-1 agonist also available orally).^37,38 In LEADERS trial, liraglutide reduced mortality by 15%.

SGLT-2 inhibitors mainly reduce HF events (+/- mortality), while GLP-1 agonists mainly reduce MI events. Both attenuate long-term severe renal deterioration (by ~40% and ~20%, respectively), and reduce weight, BP, TGs and VLDL.

Even without diabetes, SGLT-2 inhibitors dramatically reduce HF hospitalizations in HFrEF (DAPA-HF), and dramatically reduce the risk of renal deterioration by 40% in CKD patients with GFR 25–75 ml/min (DAPA-CKD).

Distinguish those agents from dipeptidyl peptidase-4 inhibitors (gliptins). The latter are oral drugs that inhibit the degradation of GLP-1 but are less effective than GLP-1 agonists for glycemic control and mostly have a neutral cardiovascular effect.

A. Markedly elevated LDL (>190 mg/dl) suggests familial hypercholesterolemia

In this case, the LDL receptor is underproduced or dysfunctional.

B. Markedly elevated TG level (>500 mg/dl) suggests familial hypertriglyceridemia

C. Consider secondary causes of dyslipidemia in the proper setting

Hypothyroidism (↑ LDL), nephrotic syndrome (↑ LDL), uremia (↑ TG), alcohol abuse (↑ TG), and medications: β-blockers (↑ TG, ↓ HDL), thiazides (↑ LDL), contraceptive pills (↑ TG).

A. Statins

Adverse effects:

1. Myopathy. Muscle symptoms with or without elevated CK are reported in up to 10–15% of real-world, registry patients, and usually occur within 4–6 weeks of statin initiation (<12 weeks, median of 1 month).⁴² Statin toxicity may manifest as cramping, heaviness, or weakness, particularly with exertion. Myopathy is typically bilateral and involves large muscle groups. Active patients, especially athletes, are more likely to manifest muscular symptoms. Myopathy may be related to pharmacokinetics (high dose or drug interactions) or to an underlying metabolic disorder that is unveiled by statin therapy.⁴³ The latter patients typically cannot tolerate any statin. Three degrees of muscular effects occur with statin:⁴⁴
   
   
   
   1. Myalgia: muscular symptoms without CK elevation
      
   2. Myositis: muscular symptoms with CK elevation
      
   3. Rhabdomyolysis: muscular symptoms with CK elevation over 10× upper limit of normal. It is often accompanied by acute renal failure. Rhabdomyolysis occurs in <0.1% of patients.
   
   

   Many patients with mild muscle aches have improvement of symptoms within 2 weeks of continued use, and thus immediate discontinuation may not be warranted. CK elevation 3–10× normal without significant symptoms does not warrant discontinuation either.^42,43 Statin is discontinued if CK >10× normal or the patient experiences severe muscle aches. Muscle aches usually disappear within a few days to 2 weeks of discontinuation. The persistence of symptoms longer than 2 weeks after discontinuation implies that they are not related to statin; the original statin may be resumed. If the patient has severe muscle aches or myositis without rhabdomyolysis, he may tolerate another statin, which should be started once symptoms resolve. Based on PRIMO study, fluvastatin XL has the least muscle toxicity, followed by pravastatin. ⁴², Some data suggest pitavastatin is one of the safest statins.^45,46 Among the potent statins, rosuvastatin may be the safest, especially when administered at a low dose, such as 5 mg, on alternate days.⁴³

   
   

   The risk of myositis increases with age; renal failure; combined therapy with fibrate (~1%) and, less so, niacin; and combined therapy with CYP450 inhibitors (diltiazem, amiodarone, macrolides, HIV protease inhibitors, azole, grapefruit juice).