Lipids

A future of high triglycerides

A future of high triglycerides

Familial chylomicronemia syndrome is rare. Its prevalence is about 1 in 1 million. It is characterized by defective or deficient lipoprotein lipase (LPL) enzyme, severely high triglycerides, and recurrent pancreatitis. Apoprotein C3 antagonizes LPL activity leading to hypertriglyceridemia. Much effort has been done to target Apo C3 pharmacologically. Now we have an anti-sense inhibitor to the hepatic Apo C3 mRNA, called volanesorsen.

This phase 3, double-blind randomized clinical trial shows that volanesorsen lowers both Apo C3 and triglycerides remarkably.  Apo C3 is decreased by 25.7 mg/dL and triglycerides by about 1700 mg/dL (Δ80% reduction). Low platelet count and injection site reactions were seen more commonly with volanesorsen than placebo.  Although the study was designed to evaluate changes in triglyceride levels, clinical outcomes (pancreatitis) are also expected to improve.

Study findings are of major importance as it provides us with another tool and pathway of lowering elevated triglycerides. Hypertriglyceridemia, commonly found in patients with metabolic syndrome, is a well-established independent risk factor for cardiovascular events. I anticipate that the antisense inhibitor technology will also be tested in patients with metabolic syndrome, insulin resistance, prediabetes, and diabetes; as these conditions are far more prevalent than familial chylomicronemia syndrome.

GT

2019 NLA scientific statement: Lp(a) - key points

2019 NLA scientific statement: Lp(a) - key points

The various large meta-analysis, Mendelian randomizations, and prospective population-based studies have found the Lipoprotein (a) to be an independent risk factor for atherosclerosis, aortic valve stenosis, and thrombosis. Lp(a) test is considered to be high when its value is >50 mg/dL or >100 nmol/L. These measures correspond to the top 20th percentile of the general population.

Currently, there are no approved specific therapies for Lp(a). The NLA does not recommend the use of Niacin, HRT (hormonal replacement therapy) or Lomitapide (microsomal triglyceride transfer protein inhibitor). Recent trials such as FOURIER and ODYSSEY have shown that addition of PCSK9 inhibitors to Statin therapy can lower Lp(a) by 30%.

However, various guidelines including 2018 AHA/ACC and 2019 NLA scientific statement recommend the use of PCSK9 inhibitors only in the context of uncontrolled LDLc/non-HDLc in patients at high-risk or very-high-risk for ASCVD events.

GT

Lipoprotein(a) is an independent ASCVD risk

Lipoprotein(a) is an independent ASCVD risk

Blood Lipoprotein(a) measurements are genetically determined.  Lifestyle, physical activity or dietary habits do not change its levels.  Epidemiologically, Lp(a) has been found to be an independent risk factor for poor ASCVD outcomes.  Lp(a) is a promoter of atherosclerosis, thrombosis and aortic valve stenosis.

In this meta-analysis of 7 statin-outcome randomized clinical trials, authors showed that baseline and on-statin treatment Lp(a) levels correlated positively and linearly with ASCVD events: the higher the Lp(a) measurements, the higher the cardiovascular outcomes.

Development of specific drug therapies in reducing Lp(a) are needed.  These therapies would then be tested in outcome driven ASCVD clinical trials.

GT

New drug development for hypercholesterolemia

New drug development for hypercholesterolemia

The study shows that bempedoic acid, when added to statin therapy, reduces LDLc levels further. Bempedoic acid is an inhibitor of ATP citrate lyase, an important enzyme of cholesterol and fatty acid synthesis.

A group of 2300 patients with either established cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) were followed for about 12 months.  Baseline LDLc was 103 mg/dL.  Mean LDLc reduction with bempedoic acid was about 20 mg/dL.

These results are meaningful as it is well-established that the lower the LDLc the lower the ASCVD outcomes.  No increased adverse events were seen with the ATP Citrate lyase inhibitor compared to placebo.

GT

ACLY variants vs. cardiovascular outcomes

ACLY variants vs. cardiovascular outcomes

ATP citrate lyase is a key enzyme in cholesterol and fatty acid biosynthesis. It helps convert citrate to Acetyl CoA, the precursor to endogenous lipid genesis. Recent studies have shown that pharmacological inhibition of ATP citrate lyase causes a 30% reduction in LDLc, 50% reduction when combined with ezetimibe, and an extra 20% LDLc lowering when added to statin therapy.

This major Mendelian randomization study revealed that genetic variants in the ACLY gene led to similar clinical and biochemical outcomes as HMGCR variants. This provides a theoretical basis that medical inhibition of ATP citrate lyase could have similar cardiovascular benefits as statin therapies.

Mendelian randomization is considered nature’s randomized “clinical trial”. About 800,000 participants were included and analyzed.

GT

Addition of PCSK9 inhibitor Alirocumab further lowers CVD events.

Addition of PCSK9 inhibitor Alirocumab further lowers CVD events.

In ODYSSEY trial, the addition of PCSK9 inhibitor, Alirocumab to high-intensity statin further reduced cardiovascular events by 15% in patients with very-high baseline CVD risk (prior ACS) and elevated atherogenic cholesterol particles. Atherogenicity was defined by LDLc ≥70 mg/dL, non-HDLc ≥100 mg/dL, or Apo B ≥80 mg/dL.

About 19,000 patients with acute coronary syndrome 1-12 months prior to study initiation were followed for 3 years. The study target was final LDLc between 25-50 mg/dL. Similar to FOURIER 2017 results, ODYSSEY 2018 adds more evidence to the notion “the lower the LDLc, the lower ASCVD events”

GT

Vascepa (fish oil) reduces ischemic cardiovascular events in high risk patients

Vascepa (fish oil) reduces ischemic cardiovascular events in high risk patients

The current study is of a major clinical significance as it shows that EPA lowers ischemic cardiovascular events by 25% in high rick CVD patients who are already receiving statin therapy. The EPA treated patients, however, experienced more hospitalizations for atrial fibrillation and a higher propensity for serious bleeding than placebo. Findings are remarkable as they come from a major randomized clinical trial (REDUCE IT). About 8,000 patients were followed for 5 years.

This outcome data is in accordance with established observation and notion that hypertriglyceridemia is an independent risk factor for cardiovascular disease, mainly via increased inflammation and concentration of the non-HDL cholesterol. Prior clinical studies have also shown that EPA lowers non-HDL cholesterol more than DHA.

Omega-3s, EPA and DHA, are two key ingredients of fish oil. A stable and pure form of EPA has been FDA approved for very high serum triglyceride >500 mg/dL since 2012. It is marketed under the brand-name vascepa. Lovaza, a mixture of EPA and DHA, has also been approved by FDA since 2004 for severe hypertriglyceridemia.

I anticipate that in the future NLA, ACC/AHA, AACE and ADA guidelines will reflect and incorporate the current findings of REDUCE IT.

GT

Lipoprotein(a), Familial Hypercholesterolemia and CVD

Lipoprotein(a), Familial Hypercholesterolemia and CVD

Familial hypercholesterolemia (FH) has a high prevalence of cardiovascular morbidity and mortality, due to the lifelong cumulative exposure of high serum cholesterol levels.

The study finds that only a minority of patients are capable of achieving LDLc targets set by the European guidelines. About 25% of FH patients reach LDLc ≤100 mg/dL and only 8% of very high-risk CVD patients reach LDLc ≤70 mg/dL.

Importantly, those with high Lp(a) experienced twice as much CHD events than those with low Lp(a) levels. Specific drug development toward Lp(a) would be a breakthrough in helping patients with familial hypercholesterolemia.

A group of 714 FH adults were followed for about 11 years.

GT

2018 Cholesterol Guidelines: Diabetes Mellitus

2018 Cholesterol Guidelines: Diabetes Mellitus

For diabetes patients, practical recommendations would be:

  • Start moderate-intensity statin therapy if:

    • Young — age 20-39 with microvascular complications or long-standing DM.

    • Older— age 40-75 without major risk factors.

  • Start high-intensity statin ± ezetimibe if the following factors are present with the goal of reducing LDLc ≥50%:

    • Multiple risk factors

    • ASCVD 10YR ≥20%

  • For adults >75, clinician-patient discussion is needed if statin were to be started or continued.

GT

2018 Cholesterol Guidelines: Severe Hypercholesterolemia

2018 Cholesterol Guidelines: Severe Hypercholesterolemia

An approximate solidifying recommendation is:

  • For patients with severe hypercholesterolemia defined by baseline LDLc ≥190 mg/dL; target LDLc is <100 mg/dL. To achieve this target, patients could receive the following medications in the following order: max statin ± ezetimibe ± BAS ± PCSK9 inhibitor.

    • If baseline TGs >300 mg/dL, do not use BAS

    • If baseline LDLc is very high, >220 (+30) mg/dL, then target LDLc could be <130 (+30) mg/dL

GT

Familial Hypercholesterolemia and CVD risk factors

Familial Hypercholesterolemia and CVD risk factors

Genetic inability to clear LDL-particles leads to familial hypercholesterolemia. Persistent high serum LDLc and total-cholesterol are major cumulative risk factors for premature cardiovascular disease.

The article identifies other independent risk factors contributing to CVD in these patients. Such factors are male sex, smoking, hypertension, diabetes, elevated Lp(a), and family history of CVD.

Obviously, the modifiable contributors; hypertension, smoking and diabetes need to be managed aggressively.

GT

Statins improve diabetic retinopathy?

Statins improve diabetic retinopathy?

This major observational study suggests that statins reduce the risk of diabetic neuropathy, diabetic foot ulcers, and more importantly the risk of diabetic retinopathy. Risk reduction ranges from 10% to 45%. This could be due to statin-induced decreased microvascular inflammation. About 38,000 patients were followed for 7.5 years.

GT

2018 Cholesterol Guidelines: Secondary ASCVD Prevention

2018 Cholesterol Guidelines: Secondary ASCVD Prevention

Although current guidelines are an honest attempt in reflecting complex medical evidence from clinical trials, they may not be very practical or user-friendly to general practitioners.

A simplified but reasonable approach to lipid management for secondary ASCVD prevention would be:

  • Patients with established clinical ASCVD should achieve LDL-cholesterol <70 mg/dL by using statins ± ezetimibe ± PCSK9 inhibitors.

GT

LCAT, key to HDL particle formation

LCAT, key to HDL particle formation

Lecithin-Cholesterol Acyl Transferase (LCAT) is a critical enzyme in the cholesterol metabolism. It helps transport cholesterol from the periphery, including diseased coronary arteries, back to the liver via formation of mature HDL particles (“good cholesterol”).

LCAT deficiency due to genetic mutations is rare. It leads to a profound low HDLc <10 mg/dL, in turn causing corneal opacities, target cell hemolytic anemia, and renal failure. Treatment is mainly supportive.

Authors have identified an acquired immune-mediated form of LCAT deficiency. It is the 7th case worldwide. It lead to nephrotic syndrome, but the patient responded well to the anti-inflammatory agent, prednisolone.

Although these are rare illnesses, they help us understand lipid physiology deeper, and more importantly to provide quick and effective treatment.

GT

Certified Lipidologist

Certified Lipidologist

I am pleased to announce that, as of October 2018, I am a certified clinical lipidologist, accredited by the American Board of Clinical Lipidology (ABCL). The role of the lipidologist is to diagnose, treat, and manage patients with elevated cholesterol or triglyceride levels. Currently, there are approximately 700 certified lipidologists in the U.S.

Dyslipidemia is a major public health concern. Elevated cholesterol levels, particularly what’s called the “bad” cholesterol (LDLc) or non-HDL cholesterol are major risk factors for atherosclerotic cardiovascular disease leading to heart attack and stroke. World Health Organization estimates that globally, 45% of people have elevated total cholesterol.

Dyslipidemia could be monogenic, polygenic or due to comorbidities such as metabolic syndrome, insulin resistance, diabetes mellitus, chronic kidney disease, nephrotic syndrome, weight gain, lack of exercise, or use of other medications.

According to ABCL, I am 1 of 3 physicians in the U.S. who is certified in all three specialties; endocrinology/diabetes, hypertension and dyslipidemia. This allows me to provide comprehensive and detailed care to endocrine patients, particularly those with diabetes.

GT

2018 Cholesterol Guidelines: Key Points

2018 Cholesterol Guidelines: Key Points

Cardiovascular disease is the leading cause of death in the United States. Cholesterol anomaly, or dyslipidemia, is a major contributor to atherosclerosis morbidity and mortality. Multi-society new cholesterol guidelines were recently published. They were contributed and endorsed by ACC, AHA, ADA, and NLA, among other national associations. You can find below the key recommendations published in the journal of Circulation, November 2018.

GT

Leptin improves brain insulin resistance

Leptin improves brain insulin resistance

Leptin deficiency leads to weight gain, obesity, and insulin resistance. Leptin replacement in the form of metreleptin has been approved by the FDA for congenital or acquired generalized lipodystrophy. The current analysis reveals that metreleptin also improves central insulin sensitivity primarily via hypothalamus and to a lesser extent prefrontal cortex.

GT

Review of 2018 ADA guidelines: dyslipidemia in the context of diabetes

Review of 2018 ADA guidelines: dyslipidemia in the context of diabetes

ADA recommendations are released each January. Below is a succinct ACP review of guidelines in screening, treatment goals, lifestyle intervention, and drug approach to dyslipidemia in the setting of diabetes mellitus. LDL-cholesterol is still a main target. Charts depict indications and doses of statins, the mainstay therapy to diabetic lipid disorders.

GT

Benefits of zetia + zocor are enhanced in patients with diabetes

Benefits of zetia + zocor are enhanced in patients with diabetes

About 18,000 participants with acute coronary syndrome and LDL 50-125 received either zetia plus zocor, or zocor alone. After seven years of follow up, authors found that addition of zetia improved cardiovascular outcomes more in patients with diabetes then those without diabetes. Findings are consistent with the notion that diabetics are at higher baseline CVD risk.

GT