What is Insulin Resistance?

Insulin resistance is a condition in which the body’s cells become less responsive to the effects of insulin, a hormone produced by the beta cells in the pancreas. Insulin is central for regulating blood sugar (glucose) levels, facilitating the uptake of glucose by cells for energy.

Leqvio, a Revolutionary Cholesterol Medication

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the United States and worldwide. In the US alone, a person dies from cardiovascular-related causes every 33 seconds. Therefore, it is crucial to develop new therapies that aim to reduce the risk of cardiovascular disease.

New FDA approval: fish oil (vascepa) for cardiovascular risk reduction

Vascepa is a form of omega-3 fish oil named icosapent ethyl. It was first approved by the FDA in 2012 for the treatment of severe hypertriglyceridemia, as defined by blood triglyceride levels >500 mg/dL.

The FDA has now added a second indication for Vascepa. It can be utilized in patients with established cardiovascular disease or in those who have diabetes plus two or more other risk factors (e.g., hypertension, hypercholesterolemia, smoking, kidney dysfunction) for cardiovascular disorder. Before treatment, patients must also have baseline triglyceride measures >150 mg/dL.

This significant approval comes after reviewing the results of REDUCE-IT, a landmark randomized clinical trial published in NEJM, January 2019. REDUCE-IT confirmed significant cardiovascular outcome reduction of 25% in patients receiving icosapent ethyl when added to statin therapy.

I anticipate widespread use of the fish oil, icosapent ethyl, especially in patients with diabetes, who, by its nature of insulin resistance, frequently have both the increased risk of ASCVD and high triglycerides. Clinicians should be aware of possible induction or worsening of atrial fibrillation, atrial flutter, and bleeding with Vascepa, particularly in the predisposed individuals.


FDA warning: biotin interferes with heart test

The FDA has now released a new warning against biotin interference with troponin, an essential heart blood test. Biotin or vitamin B7 is a water-soluble molecule found in many over-the-counter supplements such as multivitamins, prenatal, and in those that are meant to improve or protect the health of hair, skin, and nail.

Vitamin B7 is a central catalyst in many laboratory tests, especially those measuring troponin and thyroid hormone levels. When patients take high doses of biotin, especially >30 micrograms daily, it has the potential to underestimate the blood troponin concentration. Troponin measurements are critical in identifying adults with heart disease and particularly those having an acute event such as heart attack or myocardial infarction.

High doses of biotin intake, up to 300 mg daily, have been documented in patients with multiple sclerosis. These extraordinary doses may translate up to 1,200 ng/mL blood concentrations. Biotin has a short half-life of about two hours. It may be reasonable to suspend vitamin B7 intake for two to three days before undergoing any laboratory testing that incorporates biotin-analyte technology.

Patients, physicians, and laboratory personnel should be aware of possible interference of oral biotin with blood troponin and thyroid hormone testing, particularly in decisive clinical circumstances. A grave example would be a biotin user who presents clinically with a heart attack, and yet troponin measurements appear to be normal. Non-elevated troponin can lead to missed diagnosis and life-saving intervention.


Diabetes medication, Farxiga, crosses over into the cardiology world

SGLT-2 inhibitors first came into the market in 2013. FDA approved farxiga in January 2014. SGLT-2 inhibitors, as a class, have consistently shown to reduce cardiac outcomes in patients with type 2 diabetes, who also have clinical or subclinical heart failure.

The New England Journal of Medicine published the results of DAPA-HF, a major randomized clinical trial, in September 2019. Investigators evaluated the potential heart benefits of farxiga in patients without diabetes. A group of 5000 adults with heart failure stages 2–4 and an ejection fraction of <40% were randomized to receive farxiga or placebo. Participants were followed and analyzed at 18 months.

During this relatively short interval, farxiga improved the following outcomes significantly: 25% reduction in the primary endpoint (worsening of heart failure ± cardiovascular death), 30% reduction in worsening of heart failure, 18% reduction in cardiovascular death and a 17% reduction in mortality from any cause.

Surprisingly, these benefits were similar between patients with and without diabetes, indicating that the mechanism of heart failure protection of the SGLT-2 inhibitor is independent of hyperglycemia. The rates of adverse events were similar among adults receiving farxiga or a placebo.

DAPA-HF trial adds strong evidence for the use of SGLT-2 inhibitors in heart failure management, independent of diabetes status. I anticipate more extensive use of these medications by the cardiologists. It is fascinating to see how a class of drugs designed and utilized initially for diabetes is crossing over into the cardiology world.


More bad news for Niacin

The New England Journal of Medicine first published the results of the HPS2-THRIVE randomized clinical trial in 2014. Niacin addition to statin therapy did not improve cardiovascular outcomes. Instead, the trial found an increased rate of adverse events.

Last month, Clinical Therapeutics published a detailed analysis of the trial’s adverse events. Authors found that niacin addition significantly increased the risk of new-onset diabetes, worsening of diabetes, severe bleeding, and serious infections by about 30%, 55%, 40%, and 20% respectively.

The above adverse outcomes were more pronounced in the first year after the start of niacin. The infection rate was an exception, which stayed elevated throughout the trial. Investigators followed and analyzed a group of 25,000 patients with high baseline risk for the vascular disease over four years.

Based on HPS2-THRIVE data, it is difficult to justify the clinical use of niacin from the cardiovascular standpoint.


Heart strain in adults with diabetes

Technology is rapidly advancing in detecting subclinical heart disease at a much earlier stage. Global heart strain, better known as Left Ventricular Global Longitudinal Strain (LV-GLS) is such an example. It utilizes speckle tracking imaging of transthoracic echocardiography.

LV-GLS identifies left ventricular dysfunction at its embryo before the ejection fraction has declined, a definition of heart failure. Investigators have tested it in a variety of heart anomalies, including ischemic, atherosclerotic, viral, hypertrophic, and dilated myopathies.

Authors applied LV-GLS technology to adults with type 2 diabetes. Retrospectively, they followed about 400 diabetes patients for six years and documented their all-cause mortality.

The article defined abnormal global heart strain when LV-GLS measurement was greater than two positive standard deviations (>-17%). All-cause mortality was significantly higher, by 2.8-fold, in adults with abnormal LV-GLS versus those with normal LV-GLS.

Prospective research would need to validate these results in outcome-driven interventional randomized clinical trials. I anticipate positive results and wide-spread use of LV-GLS technology in the future.

Fortunately, we have SGLT-2 inhibitors as a unique class of medication that could potentially treat and manage patients with diabetes and abnormal heart strain.


Oral semaglutide demonstrates cardiovascular safety

FDA approved subcutaneous semaglutide (ozempic) in December 2017. Clinical trials and experience have shown that semaglutide helps with A1c lowering and weight loss. Additionally, SUSTAIN 6 trial proved its cardiovascular safety.

The current study PIONEER 6, published in the New England Journal of Medicine, addresses the cardiovascular safety of oral semaglutide in diabetes patients at “high risk” for adverse ASCVD events. Age greater than 50 with established cardiovascular disease or chronic kidney disease, or age greater than 60 with CVD risk factors defined the “high risk” status in study participants.

A group of 3200 adults was randomized to receive oral semaglutide or placebo. Patients’ mean age was 66 years. Investigators followed subjects for about 16 months. Final analysis revealed that participants receiving oral semaglutide experienced 20% less major adverse cardiovascular events (MACE) than placebo counterparts. Lower rates of CV death and death from any cause seem to be the main drivers of the reduced primary endpoint.

Although MACE occurred less frequently in the semaglutide group, the trial was designed to evaluate non-inferiority (safety) and not superiority (benefits). These findings are reassuring towards a positive FDA approval for the oral semaglutide. Such an endorsement would place the first oral GLP-1 agonist on the market.


2019 Endocrine Society Guidelines on Metabolic Risk

Endocrine Society recently published new guidelines on metabolic risk. Metabolic risk is characterized similarly to metabolic syndrome (syndrome X) but with the name change to emphasize action rather than description. Presence of three or more of the following entities defines high metabolic risk: high blood pressure, high glucose, high triglycerides, low HDLc, and increased waist circumference.

Although guidelines are similar to those of other national association such as ACC/AHA, ADA, AACE, and NLA; they introduce or emphasize the following elements:

  • Should measure waist circumference routinely.
  • Include A1c in the definition of metabolic risk (vs. fasting glucose only). 
  • Be more aggressive in using statin therapy for primary prevention. 
  • Can add fenofibrate rather than ezetimibe if triglycerides are above 200 mg/dL and HDLc is low.

These guidelines are essential as they further raise awareness of the real cardiovascular and diabetes risk associated with metabolic syndrome, and more importantly encouraging providers to act upon it.

I anticipate elaboration and incorporation of the above critical changes in other national guidelines.  Prevention, always first.


High natural testosterone production in men is associated with blood clots and heart disease

Analysis of two major Mendelian randomization studies revealed that endogenous testosterone production in men is positively correlated with blood clots, heart attack, and heart failure. Data from at least 200,000 participants were included in the analysis. A proposed mechanism for such a risk is the testosterone conversion into estrogen, in turn contributing to thromboembolism. Testosterone can also increase platelet aggregation via the thromboxane A2 pathway.

Data from these “natural experiments” overall follow the observed increased risk of deep venous thrombosis and heart disease in men who are over-supplemented with exogenous testosterone. On the contrary, low Testosterone levels are also associated with visceral adiposity, low muscle mass, and insulin resistance.  From a cardiovascular perspective, future clinical research is needed to identify the balancing point of how much or little testosterone men should have.