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March 4th, 2016

GOOD HEARTS, BAD GENES

THE STORY

Triglycerides are back in the spotlight this week, as investigators look for new drug targets to knock out heart disease.

THE BASICS

Eat a handful of French fries and you'll send fat towards your intestines. Fats are digested to triglycerides, which leave the small intestine within chylomicrons and ultimately find their way to circulating blood. The enzyme lipoprotein lipase (LPL), present in muscle and adipose tissue, metabolizes triglycerides as they cycle through the bloodstream within lipoproteins. High serum triglyceride levels have long been associated with increased risk of heart disease. 

THE GENOME

Fresh off the press is ANGPTL4, the gene that encodes the protein angiopoietin-like 4. The protein inhibits LPL and increases serum triglycerides. Investigators looked at over 40,000 human genomes and found that the roughly 2% of people with inactivating mutations of ANGPTL4 had lower triglyceride levels and a lower risk of heart disease. Separate investigators looked at known carriers of an inactive gene variant of ANGPTL4, and found similar results. These investigators also tested angiopoietin-like 4 protein inhibitors in mice and monkeys, and found that they reduced serum triglyceride levels.
NEJM

SOUNDS FAMILIAR

Researchers have looked at serum triglyceride levels frequently over the years. In 2014, investigators found that loss-of-function mutations to APOC3, a gene encoding an important protein within triglyceride carrying particles, were associated with lower serum triglyceride levels and a decreased incidence of ischemic vascular disease. A phase 2 study in 2015 showed that RNA inhibition of APOC3 reduced serum triglyceride levels in patients with dyslipidemia.

THE TAKEAWAY

Congrats to ANGPTL4, the week's most obvious drug target. An increasing repertoire of gene targets and new therapies brings the goal of curbing atherosclerosis before patients hit the cath lab a bit further within reach.

SAY IT ON ROUNDS

WHEN YOU WANT LESS PRICKLY INTERACTIONS WITH YOUR PATIENTS

Combining diabetes injections could be a good start. The injectable GLP-1 receptor agonist liraglutide (Victoza) increases insulin secretion and promotes weight loss. A phase 3 RCT demonstrated that a combination formulation of liraglutide and degludec, an ultra-long acting insulin that produces less hypoglycemia than other basal insulins, was non-inferior to escalating doses of insulin glargine in lowering hemoglobin A1c levels. Those on the combo regimen saw an overall reduction in A1c of about 0.6%, as well as more weight loss and less hypoglycemia. Victoza and degludec (Tresiba) are individually expensive, so joint formulations are unlikely to come at a discount. 
JAMA

WHEN MARCH SNOWFALL GIVES YOU A NORDIC CHILL

Like the US, Finland has struggled with high mortality from cardiac disease. But a population based observational study that began in 1972 showed an 82% reduction in cardiovascular mortality among participants, mostly attributable to a decrease in smoking, high cholesterol, and hypertension. Even if your patients are far from Finnish, the study hammers home the need to toss cigarettes and get blood pressure and cholesterol under control. 
BMJ

WHEN YOU PRETEND TO KNOW STUFF ABOUT DERMATOLOGY

For cutaneous abscesses, simple drainage is the gold-standard treatment when signs of systemic infection are absent. An RCT examining the use of I&D plus placebo or Bactrim for cutaneous abscesses in 5 emergency departments found a small improvement (7%) in cure rate in the Bactrim group. Those treated with antibiotics had fewer new infections and were less likely to infect household members. Remember: a lot of people are allergic to Bactrim, and adverse reactions include the rare but serious Stevens-Johnson syndrome.
NEJM

WHEN A NEW PATIENT HAS ATTACHMENT ISSUES

Take a deep breath, and remember that Staph Aureus is pretty sticky, too. A study of 143 arthroplasties showed that prosthetic joint infections came mostly from community, rather than nosocomial, staph infections. Multiple joint prostheses were strongly associated with increased risk of infection.
Am J Med

BRUSH UP

TO DIAGNOSE HIV INFECTION

Screen for HIV with the HIV-1 ab ELISA and confirm with Western blot testing. Pooled HIV RNA tests can detect acute HIV 2 weeks after infection, though the ELISA may lag behind. Most newly infected persons experience acute retroviral syndrome, characterized by fever, sore throat, swollen glands, rash, and myalgia. The syndrome is difficult to diagnose, since all of the symptoms are non-specific. 

WHAT'S THE EVIDENCE

For early initiation of antiretroviral (ARV) therapy?  In the 2000s ARV initiation was often deferred until HIV patients developed AIDS, especially in low resource settings like Sub-Saharan Africa. START, a 2015 multinational RCT, demonstrated 50% reduced morbidity and mortality with early initiation of ARVs. Patients had lower cardiovascular disease, end stage renal and liver disease, and non-AIDS defining cancer. Federal guidelines now call for initiation of ARVs regardless of CD4 count, and give the recommendation an A1 grade. 

ADA DIABETES GUIDELINES FOR 2016

Are largely similar to 2015. Major changes to the American Diabetes Association document include a recommendation that all adults over age 45 undergo diabetes screening, regardless of weight.  Here's a synopsis of the guidelines and a summary of changes.

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