Top 10 Clinical Studies of 2021
Top 10 Clinical Studies of 2021
Every week, we identify the top trending clinical topic, based on increased interest from medical professionals. We then compile the latest studies and findings that most likely drove interest and present them as a brief report, along with an infographic detailing the most relevant clinical information.
From game-changing drugs to surprising health concerns and the ongoing pandemic, here are this year's most popular trending clinical topics and the key studies associated with them.
Top 10 Clinical Studies of 2021
Clinical Trend #10: Borderline Personality Disorder
In early October, a study showing that omega-3 fatty acids may be a promising add-on therapy helped make borderline personality disorder (BPD) the top trending clinical topic. A meta-analysis of four randomized controlled trials published this summer found that adjunctive omega-3 fatty polyunsaturated fatty acids (PUFAs) were beneficial in reducing key BPD symptoms. The four studies had a total of 137 patients. Omega-3 fatty acids were used as monotherapy in one study. In the others, they were used as add-on therapy to other agents, such as antidepressants, benzodiazepines, and/or valproic acid. None of the studies included patients who were taking antipsychotics. The omega-3 fatty acids were derived from marine rather than plant sources.
Top 10 Clinical Studies of 2021
Clinical Trend #9: Vitamin D
In mid-November, studies on colorectal cancer and all-cause mortality resulted in the week's top trending clinical topic. An observational study found that women who consume higher levels of vitamin D — particularly from dietary sources — have a reduced risk of developing early-onset colorectal cancer. The study included 94,205 women (aged 25-42 years) who were followed between 1991 and 2015. Women who consumed the highest average total vitamin D (450 IU per day) demonstrated the most significantly reduced risk compared with those consuming < 300 IU per day. Associations between vitamin D levels and colorectal cancer have been documented over the years and are the subject of 10 recently completed or ongoing clinical trials. Few studies, however, have focused on early colorectal cancer and vitamin D intake.
Severe vitamin D deficiency has been linked to poor bone and muscle health, calcium absorption, immunity, and heart function, as well as colon, blood, and bowel cancers. This is in line with a prospective, population-based study of men which found that lower concentrations of vitamin D were associated with increase in all-cause mortality. The research concluded that assessment of free 25-hydroxyvitamin D offers little added benefit to the current standard of total 25(OH)D, the major circulating form of vitamin D, because deficiencies in each are associated with a similar risk. The men were between 40 and 79 years of age and had a mean follow-up of 12.3 years. During that time, about a quarter (23.5%) of them died. After adjustment for key confounders, including body mass index, smoking, alcohol consumption, kidney function, number of comorbidities at baseline, and other factors, men with a total 25(OH)D level < 20 µg/L had a significantly increased risk for mortality compared with those who had normal levels of vitamin D, defined as > 30 µg/L (hazard ratio, 2.03; P < .001).
Top 10 Clinical Studies of 2021
Clinical Trend #8: Semaglutide
In early July, news about a drug that has been called a "game changer" for the medical management of obesity resulted in a top trending clinical topic. In June, the US Food and Drug Administration (FDA) approved a 2.4-mg/week subcutaneous dose of the glucagonlike peptide-1 (GLP-1) receptor agonist semaglutide (Wegovy) for weight loss. Specifically, the drug format and dosage was approved as an adjunct to lifestyle modifications in adults with obesity (body mass index ≥ 30 kg/m2) or who are overweight (≥ 27 kg/m2) with at least one weight-related comorbidity.
A phase 1 study found that use of semaglutide (2.4 mg) with an investigational agent, cagrilintide, resulted in greater weight loss than semaglutide alone and was well tolerated. The research was presented at the online 28th European Congress on Obesity (ECO 2021) meeting by Lone Enebo, PhD, and was simultaneously published in The Lancet.
In an accompanying commentary, Sara Becerril, PhD candidate, and Gema Frühbeck, MD, stated: "Approved pharmacological treatment options [for overweight and obesity] are scarce and do not satisfactorily bridge the gap in efficacy between lifestyle behavioral changes and bariatric surgery to attain sustained long-term results." However, they emphasized: "Because the study was designed for safety, the weight loss outcomes need to be analyzed with caution. No lifestyle intervention was prescribed to produce weight loss...Moreover, the protocol was amended to include the highest cagrilintide dose, which might have been data driven."
Not all findings were positive for semaglutide. A study found that tirzepatide, a novel "twincretin" agent, was superior to 1-mg semaglutide treatments in patients with type 2 diabetes. SURPASS-2 compared three different tirzepatide doses delivered once weekly by subcutaneous injection against a 1-mg weekly, subcutaneous dose of semaglutide in 1879 adults. Patients on each of the three tirzepatide doses — 5 mg, 10 mg, or 15 mg once weekly — showed dose-dependent reductions in A1c that were significantly superior to those seen with semaglutide. Weight reduction was a key secondary endpoint; each of the three tirzepatide doses produced significant incremental loss beyond what semaglutide produced.
Top 10 Clinical Studies of 2021
Clinical Trend #7: STI Guidelines
Interest in new guidelines resulted in the top trending clinical topic for late September. For the first time since 2015, the Centers for Disease Control and Prevention (CDC) updated its guidance for the screening, testing, and treatment of sexually transmitted infections (STIs). The comprehensive recommendations contain a multitude of changes. In addition to updated treatment approaches, the guidelines contain information on rectal and oral tests used to diagnose chlamydia and gonorrhea, two-step testing for diagnosing genital herpes simplex virus, and expanded risk factors for syphilis testing in pregnancy.
The guidelines come at a critical time. According to the World Health Organization, more than 1 million STIs are acquired every day worldwide. In the United States, annual cases have risen 6 years in a row. A CDC report released in April showed 129,813 cases of syphilis in 2019, up 74% since 2015. Almost 2000 cases of congenital syphilis were reported, up 279% since 2015, and 128 infants died. The report also noted 1.8 million cases of chlamydia in 2019, a jump of 19% in 4 years, and a 56% increase in gonorrhea in that time period, to a total of 616,392 cases. Experts hope that the new guidelines will help reduce the impact and stem the tide of the STI wave.
Top 10 Clinical Studies of 2021
Clinical Trend #6: Obesity and COVID
Results of a large CDC study regarding COVID-19 severity and obesity resulted in a top trending clinical topic in late March.
The CDC study of nearly 150,000 adult patients hospitalized with COVID-19 suggests that the risk for more severe disease dramatically increases with higher body mass index (BMI). More than half (50.8%) of the patients included had obesity. The lowest risks for adverse outcomes were found in those with a BMI on the border between healthy and overweight, from 23.7 to 25.9 kg/m2. The risk for ICU admission jumped from 6% in those with a BMI of 40-44.9 to 16% in those with a BMI of 45 or higher.
Experts say that the data show a dose-response relationship with obesity. For example, the risk of being hospitalized was 7% higher for adults with a BMI of 30-34.9 and climbed 33% higher for those with a BMI of at least 45. Of note, being underweight was also associated with elevated risk for hospitalization. Patients with COVID-19 who had a BMI of less than 18.5 had a 20% higher risk for admission, compared with those in the healthy BMI range. Most concerning is that the risk for death spiked from 8% higher for those with a BMI of 30-34.9 to 61% higher for those with a BMI of 45 or higher.
Top 10 Clinical Studies of 2021
Clinical Trend #5: Coffee
A study on coffee intake among individuals with cardiovascular conditions resulted in a top trending clinical topic for mid-May. Using a large epidemiologic database, researchers recently determined that coffee drinking habits are largely driven by cardiovascular health. The study used a strategy called Mendelian randomization, which allows genetic information, such as variants that reflect higher blood pressures and heart rate, to provide evidence for a causal association. Participants with cardiovascular symptoms were "more likely to drink less caffeinated coffee and to be nonhabitual or decaffeinated coffee drinkers compared with those who did not report related symptoms," according to the authors.
The findings indicate that human bodies regulate behavior in ways that may go unnoticed. Researchers say the study also shows how other observational studies may create a false impression of health benefits linked to coffee consumption. Essentially, because those with certain conditions appear to naturally avoid caffeinated coffee, investigations of habitual coffee drinkers would then include fewer people who have those conditions, potentially causing a misleading health association.
Top 10 Clinical Studies of 2021
Clinical Trend #4: Stress Damage
Scientific confirmation of a long-held theory, as well as new research into an association with Alzheimer's disease, helped put stress in the spotlight, resulting in a top trending topic in late July.
Although gray hair is often jokingly referred to as "stress highlights," the connection between personal pressure and pigment changes has been difficult to prove, until now. Researchers measured color loss in single strands of human hair from volunteers who kept diaries to document the weekly levels of stress they experienced. Using high-resolution scanners, the team captured images of hair fragments so tiny that they represented 1 hour's growth. When hair color changed, the team saw variations in 300 proteins. This allowed them to develop a mathematical model to predict what may happen to hair over time and identify a point when those changes are reversible.
A separate review of human and animal epidemiologic studies found that long-term stress, along with genetic factors, may contribute to the development of Alzheimer's disease. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which regulates bodily levels of cortisol in response. Increased cortisol levels are frequently observed in patients with Alzheimer's disease and "make a major contribution to the disease process," the authors wrote. Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer's disease and how genetic variants affect neurodegeneration. Ultimately, understanding how stress contributes to the disease's development may lead to the identification of therapeutic targets.
Stress that leads to burnout was a problem for physicians long before the pandemic began. Experts continue to emphasize the need for doctors to incorporate self-care and wellness into their routines moving forward. The importance of protecting mental well-being in healthcare professionals is more evident than ever. However, the damage that stress can do is not limited to mental health, as is evident by the studies that resulted in this week's top trending clinical topic.
Top 10 Clinical Studies of 2021
Clinical Trend #3: Alcohol
New studies on the health impacts of alcohol consumption released at a time when drinking is on the rise resulted in the top trending clinical topic for early June. One of the largest studies on alcohol and brain health ever undertaken found that consuming any amount of alcohol is associated with poorer brain health. The study, which has not yet been peer reviewed, included more than 25,000 adults: 691 never-drinkers, 617 former drinkers, and 24,069 current drinkers. After adjusting for all known potential confounders, a higher volume of alcohol consumed per week was associated with less gray matter in nearly all brain areas. Widespread negative associations were also found between drinking alcohol and all measures of white matter integrity that were assessed. Regarding interpretation of the results, experts caution that the extent to which minor reductions in brain volume is significantly harmful remains unclear.
In news regarding heart health, even one drink was found to increase the likelihood that an episode of atrial fibrillation (AF) will occur within a few hours; the more alcohol consumed, the higher the risk. The study showed that consuming any alcoholic beverage was associated with more than twofold greater odds of an AF event in the subsequent 4 hours, and having two or more drinks was linked to more than a threefold higher risk. Although the highest risk was observed within the first 3-4 hours after drinking, the effects lasted nearly 9 hours.
Another study by the same investigators provides some biologic plausibility. It demonstrated that patients with AF who drank alcohol had a substantial reduction in the pulmonary vein atrial effective refractory period, which would probably render their atria more prone to fibrillate. Studies have also shown that advising drinkers with AF to abstain from alcohol results in fewer AF episodes.
Top 10 Clinical Studies of 2021
Clinical Trend #2: Single-Dose Vaccination
The runner-up for most popular clinical trend is from early March. As vaccination efforts ramped up worldwide, interest in single-dose administrations increased. Data submitted to the FDA about the efficacy of a single dose of the Pfizer/BioNTech vaccine, along with previous findings about a single Moderna vaccine dose, garnered much attention. A letter regarding the Pfizer vaccine, published in The New England Journal of Medicine, stated that "the administration of a second dose within 1 month after the first, as recommended, provides little added benefit in the short term, while high-risk persons who could have received a first dose with that vaccine supply are left completely unprotected." Correspondence published in The Lancet that includes data from Israel showed that one dose of the Pfizer vaccine was associated with 85% protection against symptomatic COVID-19 in an adjusted analysis of more than 9000 healthcare workers.
At a February 19 White House press briefing, Anthony Fauci, MD, announced that the United States would indeed stick to a two-dose strategy for both the Pfizer and Moderna vaccines. "And the reason is, even though you can get a fair degree of protection after a single dose, it clearly is not durable," he said. "We know that the durability is not as much as the durability that you would get with the boost." Fauci and other experts argue that more data are needed before diverting from the regimen that was tested in clinical trials.
Top 10 Clinical Studies of 2021
Clinical Trend #1: Colon Cancer
The top trending clinical topic of 2021 was prompted by a study from the summer that suggested a potentially concerning risk factor. Findings presented at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2021 indicated that exposure to antibiotics may be associated with the development of colon (but not rectal) cancer. The nested case-control study used primary care data from Scotland, including almost 8000 cases of colorectal cancer (CRC) and over 30,000 healthy controls. Any antibiotic use was associated with an adjusted odds ratio of colon cancer of 1.49 (P = .018) in patients younger than 50 years compared with 1.09 (P = .029) in those aged 50 years and older.
Commenting for ESMO, Alberto Sobrero, MD, PhD, said that it is too early to conclude that antibiotics are a causative factor, stating, "We need to understand more about the possible role of the microbiome in bowel cancer before we consider the impact of antibiotics on the intestinal flora." He reiterated that the findings are a reminder that "antibiotics should not be given unless they are really needed, and we cannot exclude the possibility that unnecessary use of antibiotics may be exposing people to an increased risk of cancer."
A better-known risk factor in the development of CRC, the consumption of red meat, is now even better understood. A new study potentially identified the mechanistic link associated with the increased risk. Researchers identified an alkylating mutational signature that indicates DNA damage in normal and cancerous colon tissue. This mutational signature significantly correlated with high red meat consumption prior to CRC diagnosis but not with increased intake of poultry or fish or with other lifestyle aspects. Furthermore, patients with tumors that had the highest levels of alkylating damage had a 47% greater risk of dying of CRC than patients with lower levels.
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