Lipids

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.

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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.

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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.

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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.

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2017 ADA guidelines: dyslipidemia and diabetes

2017 ADA guidelines: dyslipidemia and diabetes

Below you can find ADA recommendations on screening, cardiovascular risks, and treatment of dyslipidemia in the context of diabetes. As always improve lifestyle choices first. If ASCVD likelihood is still high then add medications. Statins are first-line, either of moderate or high intensity. Statin selection would depend on age, CVD status, and contributing factors.

Statin plus PCSK9 inhibitor or statin plus zetia could be used in adults with residual ASCVD risk. Statin plus fenofibrate is no longer advised unless special circumstances are present; severe hypertriglyceridemia or in men with profound metabolic syndrome. Statin plus niacin is also not recommended due to stroke concerns.

For more details, ADA standards are listed below with a slightly modified wording for easier and succinct reading:

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New paradigm: how to treat diabetes in the context of cardiovascular illness

New paradigm: how to treat diabetes in the context of cardiovascular illness

Based on EMPAREG, LEADER, SUSTAIN, CANVAS and IRIS trials, authors propose a new treatment model for persons with type 2 diabetes and cardiovascular disease. The algorithm is listed below.

Metformin is still first-line therapy for those with A1c > 7.0%. SGLT2-inhibitors; jardiance or invokana should be prescribed next for adults with heart failure or cardiac atherosclerosis. However, patients with history of stroke or TIA should receive pioglitazone after metformin. GLP-1 agonists; victoza, saxenda or semaglutide are listed as third-line agents in this protocol.

The proposed paradigm is reasonable; however, cost, health insurance decree, side effects, added benefits, kidney function, route of administration, drug frequency and patient's preference also need to be considered.

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2017 NLA guidelines: PCSK9 inhibition and cholesterol

2017 NLA guidelines: PCSK9 inhibition and cholesterol

PCSK9 inhibitors are a relatively new class of medications. They lower atherogenic cholesterol and cardiovascular disease significantly. Although effective, cost limits their use to persons at high risk for CVD in spite of being optimally manged with statins (mainly crestor or lipitor).

National Lipid Association recently published the updated guidelines on the use of PCSK9 inhibitors in patients with residual CVD risk, very high LDL-cholesterol and those with intolerance to statin therapy. Recommendations are listed below with slightly modified wording for easier and succinct reading:

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Fish oil and cardiovascular mortality

Fish oil and cardiovascular mortality

Omega 3 fatty acids, mainly eicosapentaenoic and docosahexaenoic acids, seem to lower cardiac death by 8%. This meta-analysis includes 14 randomized clinical trials with a total of 72,000 subjects. 

Further benefits (13-29% death reduction) were seen in adults utilizing higher doses of omega 3 (> 1 gram per day) and in those with higher baseline cardiovascular risk; elevated triglycerides (>150 mg/dL), LDL-cholesterol (>130 mg/dL) and non-statin users.

Important to note that these results are to some degree in accordance with the recent Science Advisory from the American Heart Association published in March 2017, suggesting the use of omega three for secondary prevention of coronary heart disease, heart failure and sudden cardiac death.

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Coffee extends longevity

Coffee extends longevity

This major prospective study finds that coffee consumption reduces all cause mortality by 12% in men and 7% in women. About 500,000 participants were followed for 16 years.

More specifically, coffee intake seems to lower gastrointestinal death in men by 60%. In women however, the digestive, circulatory, and cerebrovascular disease mortality are reduced by 40%, 22% and 30% respectively, while raising the risk death by 30% from an ovarian cancer.

The study also uncovers the antiinflammatory effect of coffee on hepatic-insulin resistance axis, as documented by lower levels of AlkPhos, ALT, AST, GGT, CRP, Lp(a) and A1c in high consumers.

Unless side effects are present, coffee consumption promotes a good anti-inflammatory health.

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A massive trial on a new cholesterol medication: CETP inhibitor

A massive trial on a new cholesterol medication: CETP inhibitor

Cholesteryl ester transfer protein (CETP) is an important component of lipid metabolism. It helps exchange triglycerides and cholesterol between HDL and atherogenic particles (LDL, IDL and VLDL). Reduction or inhibition of CETP leads directly to both higher HDL-cholesterol and lower atherogenic particle concetrations. In principle, these lipid profile modifications are expected to reduce cardiovascular outcomes. 

To date, three CETP inhibitors (torcetrapib, dalcetrapib, evacetrapib) tested in clinical trials were either not effective in reducing CV outcomes or caused major adverse events. The current study published in NEJM September 2107 paints a different picture: anacetrapib 100 mg once daily lowered coronary events by 10% in patients with established CVD being treated with high intensity statin (atorvastatin/lipitor). Authors attribute these benefits primarily to non-HDL reduction of 17 mg/dL. Although HDL increased by 43 mg/dL, it is not considered causative or therapeutic.

Some unforeseen outcomes with anacetrapib were the subtle increase in systolic blood pressure of 0.7 mmHg, slight decrease in kidney function and lower incidence of new-onset type 2 diabetes. 

Study results are of major significance for several reasons. Some adults with very high baseline CVD risk (ex. prior myocardial infarction) still have residual chance for more coronary events even when receiving a high intensity statin such as atrovastatin or rosuvastatin. Thus an add-on medication like  anacetrapib could be useful. Importantly, results were derived from a massive amount of data involving ~30,000 participants over a 4 year period. Participants' baseline LDL-cholesterol (~60) and non-HDL-cholesterol (~90) were well controlled and balanced across study groups.

Given poor outcomes from other sister medications, I suspect more research is needed to fully elucidate the benefit/harm ratio for CETP inhibitors, and particularly for anacetrapib.

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Mounting evidence that troponin predicts CVD

Mounting evidence that troponin predicts CVD

A group of 3,300 male participants, randomized to receive pravastatin 40 mg or placebo, were followed for 5 years. Troponin I was measured at baseline and one year later. Authors found that troponin alone can anticipate coronary heart disease; and more importantly its levels were reduced by pravastatin, independently of the LDL lowering effect.

I anticipate troponin measurements to be clinically useful in the future in assessing CVD risk and response to therapy, like statins and PKSK9 inhibitors, especially in high risk individuals (diabetes, chronic kidney disease, prior MI, smoking, etc)

Take home message is nicely emphasized in the diagram below:

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Inflammation, lipids and atherosclerosis

Inflammation, lipids and atherosclerosis

CANTOS trial shows that specific inhibition of interleukin-1β leads to lower hsCRP levels and cardiovascular events in 1 and 4 years respectively. A group of 10,000 participants with established myocardial infarction and elevated hsCRP > 2 mg/L were randomized to receive canakinumab, a specific anti- IL1β monoclonal antibody, or placebo.

Cardiovascular benefits (17% event reduction) were seen with canakinumab 150 mg compared to control subjects, irrespective of lipid profile trends. Other significant clinical outcomes among patients receiving canakinumab were; more pseudo-membranous colitis (+233%), fatal infections and sepsis (+72%), leukopenia (+67%) and thrombocytopenia (+40%), but less fatal cancers (-30%), osteoarthritis (-28%) and gout (-53%); all consistent with the anti-inflammatory pathway of treatment.

The study supports the notion that vascular inflammation, in this case measured by IL1β-hsCRP axis, is a reversible contributor to atherosclerosis, independent of lipid measures. Participants' baseline LDL was 82 mg/dL, with no meaningful alterations during the course of the trial.

In the setting of unforeseen adverse events of pseudo-membranous colitis, fatal infections and sepsis, leukopenia and thrombocytopenia, I anticipate that more research would be needed to FDA approve canakinumab for secondary CVD prevention in adults with statin-residual atherosclerosis risk.

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A perspective on cholesterol management

A perspective on cholesterol management

The overarching goal is to derive maximum benefit from clinical care while maintaining alignment with each patient’s preferences and goals. The strongest treatment recommendations should be where the risk is highest, the evidence is robust, and the cost is affordable. The use of statins for higher-risk patients and the judicious use of other evidence-based options, partnership in decision making with patients, and wise reliance on healthful lifestyles provide the best hope of success in preventing the morbidity and mortality caused by cardiovascular disease.

JAMA Network

Thyroid-cholesterol axis in overweight children

Thyroid-cholesterol axis in overweight children

A group of 330 overweight or obese children, without thyroid anomalies, were followed for TSH, free T4 versus CVD identifiers; total cholesterol (TChol), LDL-cholesterol (LDL), triacylglycerol (TAG), and monocyte chemotactic protein 1 (MCP1).

Tests were measured before and after one year of lifestyle intervention, including weight loss. Study finds that TSH, but not free T4, correlates positively with CVD markers, suggesting direct involvement of TSH in lipoprotein metabolism.

It is speculated that TSH receptors, present in hepatocytes, are responsible for direct cholesterol synthesis and lower bile acid production under TSH stimulation. Future studies could address interventional outcomes of thyroid hormone on TSH and CVD risk factors.

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Lipids affected by sitting

Lipids affected by sitting

The study evaluates lipidome outcomes of interrupted versus continues sitting in patients with type 2 diabetes. A group of 21 individuals were analyzed at fasting and 7-hour postprandial for 338 lipid species using mass spectrometry. Sitting, interrupted by light-intensity walking and simple-resistance activity, produced favorable lipid profiles of anti-inflammation, antioxidants and platelet activation.

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Lipoprotein (a): sneaky and dangerous

Lipoprotein (a): sneaky and dangerous

Lipoprotein (a) is an independent risk factor for poor cardiovascular outcomes. Authors find that PCSK9-i lowers Lp(a) and LDL by 20% and 50% respectively. Lp(a) and LDL reduction are 60% concordant, suggesting that some Lipoprotein (a) improvement could be via non-LDL-receptor pathway. More research is needed as pharmacological options targeting Lp (a) are limited.

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Fat vs. water soluble statins 

Fat vs. water soluble statins 

This meta-analysis reveals that lipophilic and hydrophilic statins are similar in preventing cardiovascular outcomes. Safety profile is also alike among the two types. Although not clinically significant, the study finds that liver enzymes are more commonly elevated with fat-soluble statins (like simvastatin/zocor or atorvastatin/lipitor) then water-soluble ones (pravastatin/pravachol or rosuvastatin/crestor). Solubility characteristics should not be considered in choosing the right statin for cardiovascular prevention.

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A Rare Complication: LipoAtrophy from Insulin Use

A Rare Complication: LipoAtrophy from Insulin Use

Local fat-loss from insulin use is seen in a patient with type 2 diabetes. The side effect is formally labeled insulin-induced lipoatrophy. Cause could be immune related, as insulin antibodies were found to be very high in this case. Insulin switch or discontinuation is needed in such scenarios.

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Children, Lipodystrophy and Leptin

Children, Lipodystrophy and Leptin

Lipodystrophy (LD) could be familial or acquired, partial or generalized. This original NIH study shows that metreleptin, a leptin analog, can nicely improve LD metabolic anomalies; such as high glucose, triglycerides and liver enzymes. These benefits are expected to decrease long-term lipodystrophy complications in young individuals.

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