Archive for month: April, 2024

A recent study published in the Journal of the American College of Cardiology highlighted the increased risk of heart disease associated with higher Lipoprotein(a) or Lp(a) levels in a large, multi-ethnic U.S. cohort. The study utilized data from five major U.S. prospective studies that provided significant insights into the genetic risk factors which contributes to atherosclerotic cardiovascular disease (ASCVD).

The research analyzed data from the Multi-Ethnic Study of Atherosclerosis (MESA), the Coronary Artery Risk Development in Young Adults (CARDIA), the Jackson Heart Study (JHS), the Framingham Heart Study-Offspring (FHS-OS) and the Atherosclerosis Risk In Communities (ARIC) study. These studies included a diverse group of 27,756 participants aged between 20 to 79 years without any previous cardiovascular incidents of which 55% were women and 35.6% were identified as Black. The participants were tracked for an average of 21.1 years, during which their Lp(a) levels were closely monitored. Lp(a) levels were categorized based on cohort-specific percentiles, the association between these levels and the incidence of ASCVD events was analyzed using multivariable Cox regression.

The results from this study indicated a clear correlation between higher Lp(a) levels and an increased risk of ASCVD. The participants with Lp(a) levels in the highest percentile (≥90th) experienced a 46% higher risk of cardiovascular events when compared to them with levels below the 50th percentile. This risk appeared consistent across various demographics which included sex and ethnicity. However, the impact of high Lp(a) levels was particularly more pronounced in individuals with diabetes with the risk increased to 92% for the individuals in the highest Lp(a) percentile.

The elevated Lp(a) levels were linked to specific outcomes such as myocardial infarction, revascularization, stroke and coronary heart disease death. Also, the study found no significant association between high Lp(a) levels and overall mortality rates. These findings underline the importance of Lp(a) as a potent genetic risk factor for ASCVD in patients with diabetes which highlights the need for targeted strategies to manage and potentially reduce this risk in the vulnerable populations. The comprehensive analysis of this study reinforces the pivotal role of genetic factors in cardiovascular health and paves the way for future research and treatment approaches that are tailored to individual genetic profiles.

Reference:

Wong, N. D., Fan, W., Hu, X., Ballantyne, C., Hoodgeveen, R. C., Tsai, M. Y., Browne, A., & Budoff, M. J. (2024). Lipoprotein(a) and Long-Term Cardiovascular Risk in a Multi-Ethnic Pooled Prospective Cohort. In Journal of the American College of Cardiology (Vol. 83, Issue 16, pp. 1511–1525). Elsevier BV. https://doi.org/10.1016/j.jacc.2024.02.031

A recent study published in the Diabetes, Obesity and Metabolism journal found promising outcomes of the probiotic strain Lactiplantibacillus plantarum OLL2712 in improving glycemic control among adults with prediabetes and prevents the onset of type 2 diabetes. Prediabetes is a condition characterized by slightly increased blood glucose levels which is a significant global health concern due to its high risk of progressing to type 2 diabetes. Addressing this condition early on is crucial in the fight against the diabetes epidemic.

This study was conducted over a period of 12 weeks, with an additional 8-week follow-up to illuminate the path for integrating dietary interventions in prediabetes management. The study included a total of 148 adults who were diagnosed with prediabetes and looked into the impacts of consuming yogurt enriched with the heat-treated OLL2712 cells when compared to a placebo.

The participants were meticulously selected by ensuring a diverse group with glycated hemoglobin (HbA1c) levels that ranged from 5.6% to 6.4% and aged between 20 and 64 years. They were randomly assigned to two groups where one received conventional yogurt and the other group received yogurt containing over 5 × 10^9 OLL2712 cells daily. The primary metric for assessing the efficacy of intervention through the covariance analyzed the change in HbA1c levels at the 12th and 16th weeks.

The study unveiled that while both groups expressed a significant reduction in HbA1c and glycoalbumin levels at the 12-week mark, this improvement persisted only in the OLL2712 group by the 16th week. At weeks 12 and 16, the decrease in HbA1c levels was significantly more pronounced in the OLL2712 group when compared to the placebo that showed the potential of this strain in enhancing the glycemic control. However, by the 20th week following the discontinuation of the yogurt consumption, no significant differences were noticed between the two groups which underscore the need for continuous intake of the probiotic to maintain its beneficial effects.

These findings suggests that daily ingestion of OLL2712-enriched yogurt could play a vital role in preventing the deterioration of glycemic control in the individuals with prediabetes. Overall, the outcomes of this study highlights the potential of yogurt in contributing to glycemic regulation and could pave the way for future dietary recommendations and interventions for the early stages of diabetes

Reference:

Toshimitsu, T., Gotou, A., Sashihara, T., Hojo, K., Hachimura, S., Shioya, N., Iwama, Y., Irie, J., & Ichihara, Y. (2024). Ingesting probiotic yogurt containing Lactiplantibacillus plantarum OLL2712 improves glycaemic control in adults with prediabetes in a randomized, double‐blind, placebo‐controlled trial. In Diabetes, Obesity and Metabolism. Wiley. https://doi.org/10.1111/dom.15534

Obesity is a prevalent health concern, and effective weight loss interventions are crucial. However, sustaining weight loss over the long term poses significant challenges. Pragmatic and scalable interventions are needed to address this issue, especially in primary care settings where patients often seek guidance for weight management. A recent clinical trial aimed to evaluate the long-term effectiveness of an automated, online, behavioral obesity treatment program in primary care and to compare different weight loss maintenance approaches.

In a discovery that could hasten treatment for patients with multiple sclerosis (MS), UC San Francisco scientists have discovered a harbinger in the blood of some people who later went on to develop the disease. 

In about 1 in 10 cases of MS, the body begins producing a distinctive set of antibodies against its own proteins years before symptoms emerge. These autoantibodies appear to bind to both human cells and common pathogens, possibly explaining the immune attacks on the brain and spinal cord that are the hallmark of MS.

The findings were published in Nature Medicine.

MS can lead to a devastating loss of motor control, although new treatments can slow the progress of the disease and, for example, preserve a patient’s ability to walk. The scientists hope the autoantibodies they have discovered will one day be detected with a simple blood test, giving patients a head start on receiving treatment.

“Over the last few decades, there’s been a move in the field to treat MS earlier and more aggressively with newer, more potent therapies,” said UCSF neurologist Michael Wilson, MD, a senior author of the paper. “A diagnostic result like this makes such early intervention more likely, giving patients hope for a better life.”

Linking infections with autoimmune disease

Autoimmune diseases like MS are believed to result, in part, from rare immune reactions to common infections.

In 2014, Wilson joined forces with Joe DeRisi, PhD, president of the Chan Zuckerberg Biohub SF and a senior author of the paper, to develop better tools for unmasking the culprits behind autoimmune disease. They took a technique in which viruses are engineered to display bits of proteins like flags on their surface, called phage display immunoprecipitation sequencing (PhIP-Seq), and further optimized it to screen human blood for autoantibodies.

PhIP-Seq detects autoantibodies against more than 10,000 human proteins, enough to investigate nearly any autoimmune disease. In 2019, they successfully used it to discover a rare autoimmune disease that seemed to arise from testicular cancer.

MS affects more than 900,000 people in the US. Its early symptoms, like dizziness, spasms, and fatigue, can resemble other conditions, and diagnosis requires careful analysis of brain MRI scans.

The phage display system, the scientists reasoned, could reveal the autoantibodies behind the immune attacks of MS and create new opportunities to understand and treat the disease.

The project was spearheaded by first co-authors Colin Zamecnik, PhD, a postdoctoral researcher in DeRisi’s and Wilson’s labs; and Gavin Sowa, MD, MS, former UCSF medical student and now internal medicine resident at Northwestern University.

They partnered with Mitch Wallin, MD, MPH, from the University of Maryland and a senior author of the paper, to search for autoantibodies in the blood of people with MS. These samples were obtained from the U.S. Department of Defense Serum Repository, which stores blood taken from armed service members when they apply to join the military.

The group analyzed blood from 250 MS patients collected after their diagnosis, plus samples taken five or more years earlier when they joined the military. The researchers also looked at comparable blood samples from 250 healthy veterans.

Between the large number of subjects and the before-and-after timing of the samples, it was “a phenomenal cohort of individuals to look at to see how this kind of autoimmunity develops over the course of clinical onset of this disease,” said Zamecnik.

A consistent signature of MS 

Using a mere one-thousandth of a milliliter of blood from each time point, the scientists thought they would see a jump in autoantibodies as the first symptoms of MS appeared.

Instead, they found that 10% of the MS patients had a striking abundance of autoantibodies years before their diagnosis. 

The dozen or so autoantibodies all stuck to a chemical pattern that resembled one found in common viruses, including Epstein-Barr Virus (EBV), which infects more than 85% of all people, yet has been flagged in previous studies as a contributing cause for MS.

Years before diagnosis, this subset of MS patients had other signs of an immune war in the brain. Ahmed Abdelhak, MD, co-author of the paper and a postdoctoral researcher in the UCSF laboratory of Ari Green, MD, found that patients with these autoantibodies had elevated levels of neurofilament light (Nfl), a protein that gets released as neurons break down.

Perhaps, the researchers speculated, the immune system was mistaking friendly human proteins for some viral foe, leading to a lifetime of MS.

“When we analyze healthy people using our technology, everybody looks unique, with their own fingerprint of immunological experience, like a snowflake,” DeRisi said. “It’s when the immunological signature of a person looks like someone else, and they stop looking like snowflakes that we begin to suspect something is wrong, and that’s what we found in these MS patients.”

A test to speed patients toward the right therapies

To confirm their findings, the team analyzed blood samples from patients in the UCSF ORIGINS study. These patients all had neurological symptoms and many, but not all, went on to be diagnosed with MS.

Once again, 10% of the patients in the ORIGINS study who were diagnosed with MS had the same autoantibody pattern. The pattern was 100% predictive of an MS diagnosis. Across both the Department of Defense group and the ORIGINS group, every patient with this autoantibody pattern had MS.

“Diagnosis is not always straightforward for MS, because we haven’t had disease specific biomarkers,” Wilson said. “We’re excited to have anything that can give more diagnostic certainty earlier on, to have a concrete discussion about whether to start treatment for each patient.”

Many questions remain about MS, ranging from what’s instigating the immune response in some MS patients to how the disease develops in the other 90% of patients. But the researchers believe they now have a definitive sign that MS is brewing.

“Imagine if we could diagnose MS before some patients reach the clinic,” said Stephen Hauser, MD, director of the UCSF Weill Institute for Neurosciences and a senior author of the paper. “It enhances our chances of moving from suppression to cure.” 

Reference:

Zamecnik, C.R., Sowa, G.M., Abdelhak, A. et al. An autoantibody signature predictive for multiple sclerosis. Nat Med (2024). https://doi.org/10.1038/s41591-024-02938-3.

Combination treatments with two or more blood pressure drugs can significantly reduce blood pressure in patients taking ibrutinib, according to a new study published in Blood Advances.

Targeted drugs such as ibrutinib have improved outcomes for patients with cancers of the lymphatic system, but patients treated with ibrutinib and other drugs in its class often develop new or worsening high blood pressure (or hypertension or HTN). Few studies have examined how best to treat this potentially serious side effect, nor do any formal guidelines exist to steer doctors toward the most effective treatments.

“To our knowledge, this is the first and only study to examine how to optimally treat high blood pressure in patients receiving ibrutinib,” said Mazyar Shadman, MD, MPH, of Fred Hutchinson Cancer Center and the University of Washington School of Medicine, and the study’s senior author. “Our findings strongly suggest that aggressive treatment with certain combinations of antihypertensive medications can achieve significantly reduced blood pressures in this patient population.”

The researchers found that different drug combinations may be more effective depending on whether patients had high blood pressure before starting treatment with ibrutinib or developed high blood pressure while taking the drug.

Ibrutinib, which has been on the market since 2013, was the first drug in its class, known as Bruton tyrosine kinase inhibitors (BTKis), to receive U.S. Food and Drug Administration (FDA) approval to treat patients with mantle cell lymphoma, chronic lymphocytic leukemia, and certain other lymphoid cancers. “Several studies have shown that BTKis can cause patients to develop new or worsening high blood pressure,” said Laura Samples, MD, also of Fred Hutchinson Cancer Center and the University of Washington School of Medicine, and the study’s first author.

“One study found this to be the case in over 78% of patients treated with ibrutinib over a median of 30 months,” Dr. Samples said. “Uncontrolled high blood pressure, or hypertension, can lead to major adverse cardiovascular events, such as heart attack, heart failure, and stroke.”

For this study, Drs. Samples, Shadman, and their colleagues examined the medical records of 196 patients who were concurrently treated with a BTKi and one or more antihypertensive medication for at least three months between 2014 and 2018 at one of 14 medical centers in the United States. Nearly 93% of the study’s participants identified as Caucasian, with an average age of 67 years. Approximately 71% were male, while 29% were female. The patients were separated into two groups: those who were taking at least one antihypertensive medication before starting treatment with a BTKi (the prior-HTN group; 118 patients) and those who began taking one or more antihypertensive medications while being treated with a BTKi (the group that developed new onset high blood pressure after starting treatment; 78 patients).

The researchers categorized antihypertensive medications into four groups: ACE inhibitors and angiotensin receptor blockers (ARBs), beta blockers, calcium channel blockers, and hydrochlorothiazide. The study’s primary outcome was the effectiveness of antihypertensive treatment as assessed by the average reduction in mean arterial pressure (MAP), the average pressure in a patient’s arteries during one heartbeat cycle.

Results showed that patients in the prior-HTN group who took beta blockers along with hydrochlorothiazide achieved statistically significant average reductions in MAP of about five mmHg (unit of measurement for blood pressure). Patients in the de novo HTN group who took ACE inhibitors or ARBs along with hydrochlorothiazide achieved similar reductions in MAP. Approximately 15% of patients in both groups taking beta blockers and hydrochlorothiazide reached what researchers classified as a normal blood pressure range (120/80 or lower).

“Our results reinforce that – in this patient population as in patients with hypertension in general – you need to treat with multiple drugs to achieve successful blood pressure control,” said Dr. Samples.

The study findings do not shed any light on why certain combination regimens were more effective than others or why different combination regimens were most effective in patients with pre-existing and new-onset hypertension, Dr. Shadman added. “But we now have some data that other researchers can analyze to perhaps find answers to these questions,” he said.

A limitation of the study is that it is retrospective – that is, it looked back at patients’ medical records to determine how they were treated and what the outcomes were. “Large prospective studies are needed to develop formal guidelines on the most effective antihypertensive regimens in patients taking BTKis,” Dr. Samples said.

Secondly, patients’ blood pressure was measured only during clinic visits. Studies have shown that blood pressure measurements taken in doctors’ offices or other clinical settings can produce varying results. “Future studies should, if possible, measure patients’ blood pressure using wearable devices that measure blood pressure over a 24-hour period,” Dr. Shadman said.

Finally, nearly 90% of patients in the study were taking ibrutinib. The rest were treated with acalabrutinib or other, newer BTKi’s such as zanubrutinib, which received its initial FDA approval in 2019. Data for the study came from a period when ibrutinib was still more common than its second-generation counterparts. “Studies suggest that patients taking these newer agents still face an increased risk of major adverse cardiovascular events, although the risk may be lower than that of ibrutinib,” Dr. Samples said.

“Given that increased blood pressure is a “class effect” of treatment with BTKis, both doctors and patients need to be aware of this risk and patients’ blood pressure should be monitored regularly so that treatment can begin immediately when an increase is detected,” Dr. Samples said.