The field of family medicine is constantly evolving, making it challenging for the interprofessional healthcare team to stay up to date with recent developments. This article covers key advancements in the field that may have important implications for clinical practice.

HEARING LOSS TIED TO MORE FATIGUE IN MIDDLE AND OLDER AGE

Hearing loss is a common condition that becomes more frequent and severe with increasing age. In the United States, it is most prevalent among adults aged over 70 years and is thought to affect around two-thirds of this population.^[1] People with hearing loss may be likely to experience fatigue as a result of their condition.^[2] Fatigue is described as a feeling of exhaustion and is related to reduced cognitive performance and quality of life.

A new study sought to explore the relationship between hearing loss and fatigue.^[2] Researchers at Johns Hopkins University, Baltimore, examined NHANES data from 2015 to 2016 and 2017 to 2018, including findings on more than 3000 participants aged 40 and older. Based on the audiometry subset of NHANES data, hearing loss was associated with a higher frequency of fatigue – even after adjustment for demographics, comorbidities, and lifestyle variables such as smoking, alcohol, and body mass index, in a nationally representative sample of adults in middle and older age.

Like many stressful chronic conditions, hearing loss appears to foster fatigue, according to an analysis of National Health and Nutrition Examination Study data published in JAMA Otolaryngology – Head & Neck Surgery.

"We wanted to get away from small clinical data and take a look at the population level to see if hearing loss was related to fatigue and, further perhaps, to cognitive decline," said coauthor Nicholas S. Reed, AuD, PhD, an assistant professor of epidemiology at Johns Hopkins University, Baltimore, in an interview. "We found people with hearing loss had twice the risk of reporting fatigue nearly every day vs those not reporting fatigue." This cross-sectional study provides needed population-based evidence from a nationally representative sample, according to Dr. Reed and associates, who have been researching the possible connection between age-related hearing loss, physical activity levels, and cognitive decline.

Study details

The 3031 age-eligible participants had a mean age of 58 years; 48% were male, and 10% were Black. Some hearing loss was reported by 24%. They responded to the following question: "Over the last 2 weeks, how often have you been bothered by feeling tired or having little energy?" Response categories were "not at all," "several days," "more than half the days," and "nearly every day." Those with hearing loss were more likely to report fatigue for more than half the days (relative risk ratio [RRR], 2.16; 95% CI: 1.27, 3.67) and nearly every day (RRR, 2.05; 95% CI: 1.16, 3.65), compared with not having fatigue. Additional adjustment for comorbidities and depressive symptoms showed similar results.

Hearing loss was defined as > 25 decibels hearing level (dB HL) vs normal hearing of ≤ 25 dB HL, and continuously by every 10 dB HL poorer. Each 10-dB HL of audiometric hearing loss was associated with a higher likelihood of reporting fatigue nearly every day (RRR, 1.24; 95% CI: 1.04, 1.47), but not for more than half the days. The association tended to be stronger in younger, non-Hispanic White, and female participants, but statistical testing did not support differential associations by age, sex, race, or ethnicity.

While some might intuitively expect hearing loss to cause noticeably more fatigue in middle-aged people who may be straining to hear during hours in the daily workplace or at home, Dr Reed said older people probably feel more hearing-related fatigue owing to age and comorbidities. "And higher physical activity levels of middle-aged adults can be protective."

Dr Reed advised primary care clinicians to be sure to ask about fatigue and hearing status during wellness exams and take appropriate steps to diagnose and correct hearing problems. "Make sure hearing is part of the health equation because hearing loss can be part of the culprit. And it's very possible that hearing loss is also contributing to cognitive decline." Dr Reed's group will soon release data on a clinical trial on hearing loss and cognitive decline.

The authors called for studies incorporating fatigue assessments in order to clarify how hearing loss might contribute to physical and mental fatigue and how it could be associated with downstream outcomes such as fatigue-related physical impairment.

GLOBAL BURDEN OF BRAIN DISORDERS SURPASSES CVD, CANCER

The Global Burden of Disease (GBD) study is an ongoing effort, directed by the Institute for Health Metrics and Evaluation (IHME), to determine the scale at which major medical conditions occur. The study is designed to capture prevalence of these diseases in a standardized way, to enable comparisons over time.^[4]

In a new secondary analysis of the GBD study, brain disorders, including mental illness, neurologic conditions, and stroke, were found to account for more than 16% of all health loss worldwide — more than either cardiovascular disease or cancer — at huge cost to healthcare systems and society.^[2]

"The burden of brain conditions will increase as populations continue to grow and age," said study presenter Shayla Smith, MPH, an epidemiologist at the IHME, the University of Washington, Seattle, Washington. "By 2050, more than 50 million people will be aged 65 to 79," she explained, adding that the COVID-19 pandemic "has also influenced the prevalence of mental disorders globally, as people were forced to isolate and social networks broke down."

Other factors related to brain disorders, she noted, include education level, obesity, and smoking. "There's still research to be done on what is the most effective way to maintain brain health, but some literature suggests a healthy brain can be achieved through a healthy lifestyle of managing conditions such as high blood pressure and diabetes, limiting alcohol consumption and smoking, prioritizing sleep, eating healthy, and staying physically and mentally active," said Smith.

The findings were presented at the Congress of the European Academy of Neurology (EAN) 2023.

An "Ambitious Exercise"

In an interview, co-investigator Xaviera Steele, also from the IHME, stated that the institute was established at the University of Washington in 2007 with the aim of "standardizing the measurement of health outcomes around the world and for all health conditions." A central part of that is the GBD study, "which is a very ambitious exercise in descriptive epidemiology in an effort to systematically quantify health loss" due to disease, injury, and risk factors over time, stratified by country, region, age, and sex.

In addition, researchers are mapping and projecting trends over the next century and are estimating disease expenditure by country, by type of expense, and by condition "to derive a healthcare access and quality score for each health system in the world," Steele said. They are also estimating exposure to risk factors, how those risk factors contribute to health burden, and associated health outcomes by race and ethnicity to reflect the "disparities that we know are very prevalent in countries such as the United States." From that work, Steele said that brain health and related conditions "do emerge as one of the more pressing challenges of the 21st century."

Increase in Dementia, Mental Health Conditions

The data, which were gathered from 200,000 sources by the IHME, indicate that the number of individuals aged ≥ 65 years will increase by 350% by 2100. Steele underlined that "policy action will be needed to help families, who will struggle to provide high-quality care for their loved ones with dementia at a reasonable cost."

The IHME calculates that in Europe, healthcare spending on Alzheimer's will increase by 226% between 2015 and 2040.

Turning to other conditions, Steele showed that since 1990, the number of individuals living with anxiety in the European region has increased by 14%, while the number living with depressive disorders has gone up by 13%. Worldwide, the figures are even starker. Depression is estimated to affect 300 million people across the globe, which represents a 71% increase since 1990. The number of strokes increased by 95% over the same period.

To estimate the toll caused by brain conditions, including neurologic disorders, mental disorders, cerebrovascular disease, brain cancer, brain injuries, and select infectious conditions, the researchers calculated disability-adjusted life years (DALYs).

This, Smith explained in her presentation, "captures the morbidity and mortality associated with brain conditions" and is adjusted for patient location, age, and sex.

The investigators found that globally, brain conditions accounted for more than 15% of all health loss in 2021, at 406 DALYs. More than the 206 million DALYs were associated with cancer, and the 402 million were linked to cardiovascular disease.

This health loss is associated with a $1.22 trillion loss in income for people living with health disorders worldwide and accounts for $1.14 trillion in direct healthcare costs.

The burden of mental disorders, neurologic conditions, and stroke is expected to increase dramatically between now and 2050, said Smith, who noted that health loss linked to brain conditions is higher in younger patients.

Worrying Increase in Stroke

Jurgita Valaikiene, MD, PhD, Center of Neurology, Clinic of Neurology and Neurosurgery, Vilnius University Faculty of Medicine, Vilnius, Lithuania, who chaired the session, was taken aback by the findings, particularly by the worldwide increase in stroke cases.

"I work in stroke," she told Medscape Medical News, and "we spend a lot of time on the diagnosis of stroke" and its prevention. "We try to be faster, to catch asymptomatic stenosis in the neck or head, and to apply the best medical treatment to avoid a stroke. But despite that, the numbers are increasing. I understand the population is getting older... but still it's a huge number."

Valaikiene pointed out that stroke is not necessarily a condition of aging, insofar as increasing age "is not related directly to stenosis in the neck. "For example, we can have healthier vessels in older age and unhealthy vessels, with high-grade stenosis, in someone aged 30 or 40 years. There are a lot of risk factors, such as smoking, physical activity, and so on. It depends on the individual," she added.

DEBATE: INITIAL COMBINATION THERAPY FOR TYPE 2 DIABETES?

Type 2 diabetes is a chronic disease that affects more than 37 million people in the United States, and in 2014, It was estimated to impact 422 million people globally.^[5,6] Type 2 diabetes is a progressive disorder, and there is often a need to intensify therapy over time to control glycemia.^[7]

This raises the question: should pharmacologic treatment of type 2 diabetes start with combination therapy or metformin monotherapy, adding other agents over time? This question was debated at the recent American Diabetes Association 83rd Scientific Sessions by 2 well-known clinician-researchers in the diabetes world.

Ralph A. DeFronzo, MD, argued for combination therapy at the time of diagnosis, and David M. Nathan, MD, countered that sequential therapy is a better way to go.

"The Ominous Octet": Addressing Multiple Underlying Defects

Of course, DeFronzo said, the right agents must be selected. "The drugs we're going to use as combination at a minimum have to correct the underlying insulin resistance and beta-cell failure, or we are not going to be successful."

In addition, he said, these drugs should also provide protection against cardiovascular, kidney, and fatty liver disease, because "[managing] diabetes is more than just controlling the glucose."

Recent US data suggest that half of people with diabetes have an A1c above 7%, and a quarter remain above 8%.^[8] "We're not really doing a very good job in terms of glycemic control," said DeFronzo, chief of the diabetes division at University of Texas Health, San Antonio.

One reason for this failure, he said, is the complex pathophysiology of type 2 diabetes represented by 8 major defects, what he called the "ominous octet": decreased pancreatic insulin secretion, gut incretin effects, glucose uptake in the muscle, increased lipolysis, glucose reabsorption in the kidney, hepatic glucose production, increased glucagon secretion, and neurotransmitter dysfunction.

"There are eight problems, so you're going to need multiple drugs in combination...not ones that just lower the A1c."

And, DeFronzo said, these drugs "must be started early in the natural history of type 2 diabetes if progressive beta-cell failure is to be prevented." He pointed to the United Kingdom Prospective Diabetes Study (UKPDS), in which the sulfonylurea glyburide was used first, followed by metformin.^[9] With each drug, the A1c decreased initially but then rose within 3 years. By 15 years, 65% of participants were taking insulin.

More recently, the GRADE study examined the effects of adding four different glucose-lowering agents (glimepiride, sitagliptin, liraglutide, or insulin glargine) in people who hadn't achieved target A1c with metformin.^[10] "So, by definition, drug number one failed," he observed. During the study, all participants showed an initial A1c drop, followed by progressive failure, "again...showing that stepwise therapy doesn't work."

All patients with type 2 diabetes at his center are treated using the "DeFronzo algorithm" consisting of three drug classes: a glucagon-like peptide-1 (GLP-1) agonist, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, and pioglitazone, as each of them targets more than one of the "ominous octet" defects. "The drugs that clearly do not work on a long-term basis are metformin and sulfonylureas," he emphasized.

Several studies demonstrate the efficacy of combination therapy, he said. In one, DURATION 8, the combination of exenatide and dapagliflozin was superior to either agent individually in lowering A1c, cardiovascular events, and all-cause mortality over 2 years.^[11]

And in the 5-year VERIFY study, early combination therapy with vildagliptin plus metformin proved superior in A1c-lowering to starting patients on metformin and adding vildagliptin later.^[12,13]

DeFronzo's own study, EDICT, in people with new-onset type 2 diabetes, compared the initial combination of metformin, pioglitazone, and exenatide with conventional sequential add-on therapy with metformin, glipizide, and insulin glargine.^[14] The primary endpoint — the difference in the proportion of patients with A1c less than 6.5% — was 70% vs 29% with combination compared to sequential therapy, a difference "as robust as you can be going against the stepwise approach" at P < .00001, he said. The combination therapy virtually normalized both insulin sensitivity and beta-cell function, whereas the conventional therapy did neither.

Also from DeFronzo's group, in the Qatar study, which compared exenatide plus pioglitazone with basal-bolus insulin in people with about 10 years' duration of type 2 diabetes and A1c above 7.5% taking sulfonylurea plus metformin, the combination therapy produced an A1c of 6.2% vs 7.1% with insulin.^[15]

DeFronzo pointed to new language added to the ADA Standards of Medical Care in Diabetes in 2022.^[16]

While still endorsing stepwise therapy, the document also says that "there are data to support initial combination therapy for more rapid attainment of glycemic targets and longer durability of glycemic effect." The two references cited are EDICT and VERIFY. "Finally, the American Diabetes Association has gotten the message," he concluded.

Sequential Therapy: Far More Data, Lower Cost

Nathan began by pointing out that the ADA Standards of Care continues to advise use of metformin as first-line therapy for type 2 diabetes "because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost."

He emphasized that he was not arguing "against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications." But Nathan pointed out, those patients are not the majority with type 2 diabetes.

He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it "enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs."

Second, traditional sequential therapy allows for assessment of side effects from individual drugs. "With DeFronzo's algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won't know which drug it is...If they get an allergic reaction, you won't know which medication it is," observed Nathan, who is director of the Clinical Research Center and the Diabetes Center at Massachusetts General Hospital, Boston.

Moreover, he said, traditional sequential therapy "promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that."

Further, sequential therapy is "parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most." And, there are "lots of data" supporting traditional sequential therapy and relatively little for initial combination therapy.

Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy vs monotherapy, but only three that examined combination vs sequential therapy.

"Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice," he said.

Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%. "So, looking over time is very important," Nathan cautioned. "We really have to be careful...Six months is barely enough time to see A1c equilibrate...You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful."

Nathan acknowledged to DeFronzo that the latter's EDICT study was "well conducted" and "long enough," and that the researchers did examine monotherapy vs sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy vs 68% for conventional treatment. "That's a bit problematic," Nathan noted.

At 2 years, the "trivial" difference in A1c was 6.5% with conventional therapy vs 6.0% with triple therapy. "This is all on the very flat complications curve with regard to A1c," he observed. Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.

However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States that difference comes to an additional cost per year of about $22 billion, Nathan calculated.

"Although current sequential therapy leaves much to be desired...initial combination therapy has generally only been tested for brief, clinically insufficient periods. And therefore, I think sequential therapy is still what is called for," he concluded. "Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care."

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