This article is a transcript of a monthly podcast hosted by Neil Skolnik, MD, that covers the most practice-changing articles from the last month. Listen to the streaming version on Univadis.
Neil Skolnik, MD: Hello, I’m Dr. Neil Skolnik, Professor of Family and Community Medicine at Sidney Kimmel Medical College, Thomas Jefferson University, and Associate Director of the Family Medicine Residency Program at Abington Jefferson Health. We have an excellent issue this month addressing important clinical questions.
Empagliflozin May Benefit Patients With T2D With Fatty Liver Disease
An important question for those of us in primary care is what to do with patients who have diabetes and nonalcoholic fatty liver disease. To look at this question, we're going to review an article from Diabetes Care on the effect of empagliflozin on liver fat in patients with type 2 diabetes (T2D) and nonalcoholic fatty liver disease.
The authors of this study looked at 50 patients with T2D and nonalcoholic fatty liver disease. The patients were randomly assigned to either the empagliflozin group, which received standard treatment for their T2D plus empagliflozin, or the control group, which received standard treatment without empagliflozin. The researchers then measured change in liver fat, using MRI-derived proton density fat fraction.
What they found was that empagliflozin was significantly better at reducing liver fat. In fact, it decreased liver fat over just 20 weeks by 4% with a P value
Why is this important? Well, remember that the current population prevalence for nonalcoholic fatty liver disease in the United States is 20%, due to the increase in obesity over the last 20 years. But patients with T2D, when studied, showed up to a 70% prevalence of nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease is important. Remember, there's nonalcoholic fatty liver which does not show evidence of inflammation, but can lead to NASH (nonalcoholic steatohepatitis), which shows evidence of inflammation. And remember, NASH can in turn lead to cirrhosis and actually has become the most common cause of a need for liver transplant.
So looking for ways to both prevent and treat nonalcoholic fatty liver disease is important. Clearly, the most effective treatment is lifestyle modification when it's able to be achieved. Weight loss decreases the amount of fat in the liver, but many people are not able to successfully lose weight, so medications are being evaluated as an option. And really, none of them have proven to reliably work. The TZDs, which are also used to treat diabetes, show some evidence of efficacy at decreasing fat in the liver, but really nothing to date has demonstrated efficacy. So this is pretty exciting if larger studies also show that empagliflozin can decrease the amount of fat in the liver. So, we await those larger studies to decide what to do.
Cardio Fitness in Midlife May Help Prevent Later Depression
An important clinical question is, How important is it to exercise and to advise our patients to exercise? The answer: very important. One aspect of this was looked at recently in an article titled "Association of Midlife Cardiorespiratory Fitness With Incident Depression and Cardiovascular Death After Depression in Later Life," published in JAMA Psychiatry.
The authors here looked at a retrospective cohort study at a single center and examined >17,000 participants, 80% of whom were men, with a mean age of 50 years. Fitness was estimated from results of treadmill exercise testing. What they found was that a high level of fitness in midlife was associated with a 16% lower risk of depression compared to those who had a low level of fitness. A high fitness level was also associated with a 61% lower risk of death due to cardiovascular disease without depression, and almost that great a decrease in cardiovascular disease in individuals who did develop depression.
But what does this mean to us? It's very clear from a lot of robust data sets that lifestyle, nutrition, and exercise matter. This study reinforces that exercise is important. We know that exercise decreases the risk of many cancers, particularly breast cancer and colon cancer. It decreases the risk of developing diabetes. It decreases the risk of developing heart disease and dying of heart disease.
This study also shows, and supports other data suggesting, that exercise decreases the risk of developing depression. And, for those who develop depression, it actually decreases the risk of developing cardiovascular disease and dying from cardiovascular disease.
What's the importance of this study to those of us in primary care? It’s a reminder to redouble our efforts at primary prevention using diet and exercise to really not just decrease disease but also to improve the health of our patients and help them prevent serious diseases, including diabetes, cardiovascular disease, and, as this study shows, depression.
Indacaterol/glycopyrronium Prevents COPD Deterioration in FLAME
An important clinical question in primary care over the last 2-3 years is what should be the primary therapy for patients with severe COPD. The current study, titled "Indacaterol/glycopyrronium Versus Salmeterol/fluticasone in the Prevention of Clinically Important Deterioration in COPD: A Sub-analysis From the FLAME Study," published in Respiratory Research, helps address this question.
Essentially, the authors found, in a very large study, that indacaterol/glycopyrronium significantly delayed the time to clinically important deterioration by 28% with a very significant P value and reduced the incidence of clinically important deterioration vs salmeterol/fluticasone. Additionally, that same result was found in all patient subgroups.
Why is this important? Well, until recently, ICS/LABA therapy (an inhaled steroid and a long-acting beta agonist) was considered the unquestioned approach to moderate to severe COPD. Then a number of studies, including the FLAME trial, were published showing better bronchodilator effect with dual bronchodilator therapy, a LAMA/LABA (a long-acting muscarinic antagonist and a LABA), than with an inhaled steroid/LABA therapy.
The FLAME trial also showed better bronchodilation and fewer exacerbations with dual bronchodilator therapy than with ICS/LABAs. In addition, studies showed that patients who received an inhaled steroid had a higher incidence of pneumonia. This led the GOLD guidelines, a year ago in the fall of 2017, to recommend LAMA/LABA dual bronchodilator therapy as first-line treatment for patients with moderate to severe COPD.
This current post hoc analysis of the FLAME trial, using clinically important deteriorations, again shows the benefit of LAMA/LABAs over ICS/LABAs. Remember, though, that the recent IMPACT trial compared triple therapy (an ICS/LABA and a LAMA) to dual bronchodilator therapy and showed a 25% decrease in moderate to severe exacerbations, as well as a 34% decrease in severe exacerbations leading to hospitalizations.
So, what do we do with all that information? I think we really let the people who analyze the data carefully guide us with their recommendations. So the current GOLD guidelines say that for patients with moderate to severe COPD, the primary therapy is dual bronchodilator therapy (a LABA/LAMA) and then, for patients who are continuing to have exacerbations, add an inhaled corticosteroid.
Whether or not the IMPACT study changes those recommendations over the coming year is to be determined. And we'll see what the GOLD guidelines say when they come out late this year. But for now, we'll stay with the current guidelines. And the FLAME study, in particular, this subanalysis looking at clinically important deteriorations, clearly shows that for patients with moderate to severe COPD, dual bronchodilator therapy shows a favorable decrease in clinically important deteriorations and exacerbations when compared to an ICS/LABA.
Opioid-Related US Deaths Rose 345% Between 2001 and 2016
An important issue that all of us have been dealing with over the last few years is opioid-related mortality, diversion, and abuse. The article we’re going to review, "The Burden of Opioid-Related Mortality in the United States," published in JAMA Network Open, looks at part of this issue.
The authors used a serial cross-sectional design to look at different time point estimates of deaths from opioid-related causes in the United States from 2001 to 2016. They looked at opioid-related deaths, which were defined as those in which a prescription or illicit opioid contributed substantially to an individual’s cause of death, as determined by death certificates.
Between 2001 and 2016, the number of opioid-related deaths in the United States increased by 345%, going from 9489 to 42,245 deaths per year. Men accounted for two-thirds of these deaths, and the burden was highest among adults aged 24-35 years. In that age group, 20% of all deaths were attributed to opioid-related causes.
This is a tough issue, and clearly an issue we've been grappling with over the last 10 years. Essentially, what this study says is that there are currently >100 deaths daily from opioids. And fortunately, we're learning a lot more about opioids now than we used to know. We're learning how dangerous they are. We're learning from a recent study published in JAMA this past March that very simply, for chronic pain, opioids don't work better than nonopioids.
We're also learning that the rate of long-term use is often related to how long we have patients on opioids to begin with. For instance, in 1 study recently, 6% of patients who used opioids for 1-6 days were on opioids a year later. But for individuals who were prescribed opioids for >8 days, the number of users at 1 year rose from 6% to 13%. Among individuals whose first episode of use was longer than 30 days, a third were on opioids a year later.
So, what do we do with this information? It is critical that we decrease our use of opioids. We want to have limits on first prescriptions. We always want to check our state registries, which are now available. We should also have an increased awareness of this both with regard to our own prescribing habits and in terms of educating patients, which will hopefully help combat this epidemic.
USPSTF Issues Osteoporosis Screening Recommendations
An important question for those of us in primary care is who and when to screen for osteoporosis. We'll now review the new US Preventive Service Task Force (USPSTF) recommendations on screening for osteoporosis, which gives us guidance.
Essentially, the USPSTF recommends screening for osteoporosis with bone measurement testing, most commonly a dual-energy X-ray absorptiometry (DXA) scan, to prevent osteoporotic fractures in women 65 years and older. They also recommend using a DXA scan in postmenopausal women younger than 65 years who are at increased risk of osteoporosis, that is, a risk that is equivalent to that of a 65-year-old woman but without specific risk factors, and to determine that risk using a formal clinical risk assessment tool. They also state that there is inconclusive evidence as to whether or not screening should be done for men.
These are important recommendations because >2 million osteoporotic fractures occur every year in the United States. Most of those fractures occur among women. Compression fractures are the most common of those fractures, and they're very painful. Hip fractures, which are less common but also occur frequently, lead to loss of independence and actually have a 30% 1-year mortality. We know that drug therapy reduces the risk of fracture in postmenopausal women with osteoporosis. Therefore, it's important to screen appropriate individuals.
How do we decide which individuals younger than 65 years to screen? Well, we want to think about risk factors. If someone has a parental history of hip fracture, if they smoke, if they have excessive alcohol consumption or low body weight or are quite sedentary, then we want to think about doing a formal risk assessment. The most commonly used risk assessment tool is the FRAX risk score. If their risk is greater than that of 65-year-old white woman without major risk factors, then we should do a DXA scan.
What's the issue with men, though? Because men account for 29% of osteoporotic fractures in the United States, and they actually have a higher fracture-related morbidity and mortality rate than women. Each year, there are about 80,000 men in the United States who have a hip fracture. Well, it turns out that for men, hip fracture does not increase substantially (i.e., to the same extent as women >65 years) until men are about 80 years of age. And very simply, the USPSTF did not recommend screening because there aren't good studies on the effect of treatment in men.
So, what does this mean? Well, we ought to be screening for osteoporosis using a DXA scan in women >65 years of age and in younger women who are at higher risk. In men, the effect of screening is unclear, and so the USPSTF says that the evidence is inconclusive.
The other thing is, it's important to remember primary prevention. We talked about another article looking at exercise and decreasing cardiovascular disease and depression. And it's important to remember that exercise also is good for bone density. And we should be recommending good diet and good exercise as well, as a form of prevention.
Listen to the streaming version on Univadis.
Neil Skolnik, MD, is Professor of Family and Community Medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, and Associate Director of the Family Medicine Residency Program at Abington Jefferson Health, also in Pennsylvania.