Richard Harris MD, PharmD, MBA (2025)

25/11/2025

Effect of Exogenous Ketones as an Adjunct to Low-Calorie Diet
on Metabolic Markers

https://doi.org/10.3390/nu17223582

Over two-thirds of US adults are classified as overweight or obese. Excess adiposity is causally linked to insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, fatty liver, and increased risk of early death. In trials of weight-loss interventions, lean tissue, aka fat-free mass (skeletal muscle, bone, organs, water), accounts for 20-30% of total weight loss. Therefore, the goal is to create body recomposition by decreasing fat mass while preserving lean mass/increasing muscle mass. Beta-hydroxybutyrate (BHB) may be muscle-preserving by modulating mTOR signaling and increasing anti-catabolic hormones such as IGF-1 and growth hormone. This study assessed the effects of exogenous BHG salts on body composition, metabolic rate, and other cardiometabolic biomarkers in obese and overweight adults following a hypocaloric diet (500-calorie deficit) over 8 weeks.

5g of BHB salt was compared to a placebo twice a day. There were no significant differences in cardiometabolic markers or resting metabolic rate between groups. Body mass decreased by -1kg in the placebo group and -3kg in the BHG group. Within-group changes showed statistically significant reductions in fat mass and the lean-to-fat mass ratio, whereas the placebo group showed no significant change. However, there was no statistically significant group-by-time interaction for either parameter.

Limitations: Short duration, used racemic BHB (a mix of active and inactive BHB), only 51 participants, excluded those with metabolic diseases, no measurement of plasma ketone levels

14/11/2025

Blood Pressure After Changes in Light-to-Moderate Alcohol Consumption in Women and Men

PMID: 41123524

Alcohol consumption appears to show a dose-response relationship with cardiovascular events, including new-onset hypertension. This study was a longitudinal study that assessed whether blood pressure improves with alcohol cessation and if initiation of alcohol use is associated with blood pressure changes in previous non-drinkers.

10g of alcohol was used as the reference value for one drink. A reduction of 10g of alcohol consumption was associated with a SBP reduction of 0.92 and a DBP reduction of 0.82. Cessation of 2-3 drinks per day reduced SBP by 2.35, cessation of 3-4 drinks reduced SBP by 4.56, and cessation of more than 4 drinks per day reduced SBP by 5.61. Reductions were similar for diastolic blood pressure, and when the results were stratified by s*x.

In the alcohol initiation cohort, every 10g increase in alcohol consumption was associated with an SBP increase of 0.78 and a DBP increase of 0.53. Initiation of 2-3 drinks per day increased SBP by 2.73, 3-4 drinks per day by 3.55, and more than four drinks per day by 4.35. Dose-dependent increase in DBP was also detected when non-drinkers initiated alcohol intake. When stratified by s*x, men showed a more significant increase in BP at low to moderate intake, while women showed a more pronounced BP increase at higher levels of alcohol intake.

When stratified by beverage type, similar decreases in SBP and DBP were observed across all beverage types. Also, the effects were stronger in individuals with preexisting hypertension compared to those without hypertension. While these numbers seem small, a reduction of SBP by two lowers stroke mortality by 10% and ischemic heart disease mortality by 7%.

Limitations: Japanese, not US, population; self-reported alcohol intake; excluded people under treatment for hypertension; participants' average blood pressure was healthy in both cohorts; median alcohol intake was low in both cohorts.

13/11/2025

The Mediterranean Diet for Irritable Bowel Syndrome A Randomized Clinical Trial

PMID: 41144975

IBS is a common disorder estimated to affect up to 10% of the population. Traditional dietary advice (TDA, healthy eating patterns) is first-line therapy with response rates of approximately 40%. Nonresponders are often escalated to other dietary strategies, like a low FODMAP diet. Recent evidence also supports the Mediterranean diet (MD) for IBS. This trial was a noninferiority study comparing an MD diet to TDA over 6 weeks.

In the primary analysis, 62% of the MD diet group achieved the primary endpoint (a 50-point reduction in IBS-SSS scores) compared with 42% of the TDA group. A superiority analysis showed a statistically significant improvement in symptoms with MD compared to TDA. Main improvements in symptoms were observed as early as 2 weeks in both groups. When examining individual components of IBS-SSS scores, MD improved abdominal pain more than TD, with statistical significance. MD also improved somatic and quality-of-life questionnaires, but these improvements did not differ significantly from those in the TDA group. The MD group saw a greater increase in fiber intake, folate, magnesium, and oligosaccharides.

Patients with severe IBS were more likely to experience a clinically significant improvement in symptoms. By IBS subtype (mixed, diarrhea, constipation), MD achieved better response rates than TD. Diet satisfaction and adherence were high in both groups.

11/11/2025

Greater adherence to healthful dietary patterns is associated with lower insomnia risk in the Women's Health Initiative observational study

PMID: 41065709

Chronic sleep deprivation is associated with adverse mental and physical health outcomes. There is evidence that dietary patterns are associated with changes in sleep. There are myriad plausible mechanisms for this, including increased fiber intake, melatonin & melatonin precursors, polyphenols, and modulation of the gut microbiota. This study examined the association of the DASH diet and a modified Mediterranean diet (aMed) on insomnia incidence in postmenopausal women from the WHI-OS cohort.

Among women without insomnia at baseline, relative to poor adherence to the DASH and aMED diets, good adherence was associated with a 7.5% and a 6.3% lower odds of developing insomnia at the 3-year follow-up, respectively. Each SD increase in baseline DASH and aMed scores was associated with a 4.1% and 3.8% lower risk of insomnia, respectively.
In the longitudinal analysis, those with good diet quality on the aMed and DASH had 8.5% and 6.3% lower odds of stable or new-onset insomnia over 3 years, respectively. When the DASH diet was analyzed by components, high intake of nuts and legumes was associated with a 5.7% lower odds for developing insomnia at the 3-year follow-up. Nuts and legumes are excellent dietary sources of fiber and tryptophan.

TLDR: Adherence to a Mediterranean and DASH dietary pattern was associated with reduced risk for developing insomnia as well as persistent insomnia over 3 years.

Limitations - single FFQ used at baseline, measurements done at baseline and then at 3 years, observational, not a representative demographic sample of the US population

07/11/2025

Physical activity as a modifiable risk factor in preclinical Alzheimer’s disease

PMID: 41184638

Currently, 14 modifiable risk factors are estimated to account for nearly half of AD cases. Previous research shows that higher step counts in adults with higher amyloid plaque burden were associated with slower cognitive decline. This study examined the association between pedometer-measured physical activity, AD neuroimaging by PET scan, and annual cognitive assessment over a maximum of 14 years.

Higher physical activity was associated with slower amyloid-related decline on the PACC5 scale and slower overall PACC5 decline. In the CDR-SOB cognitive testing, higher physical activity was associated with slower amyloid-related cognitive decline. In neuroimaging, higher physical activity was associated with a slower accumulation of tau proteins. In the dose-response analysis, individuals with elevated amyloid, even at low levels of physical activity (3k-5k steps per day), showed slower rates of tau accumulation and cognitive decline. These effects increased up to 7.5k steps per day. Those with elevated amyloid 3k to 5k and 4k to 7.5k steps per day were associated with 40% and 54% lower rates of cognitive decline on PACC5 scores and 34% and 45% lower rates on CDR-SOB scores compared to those who were inactive (less than 3k steps per day). Overall, these findings were independent of baseline or longitudinal amyloid burden. Higher physical activity was associated with lower tau accumulation in individuals with high amyloid burden, nearly fully mediating the PACC5 findings and partially mediating the CDR-SOB findings.

Limitations - small sample size, observational study, no information on duration/intensity/type of physical activity, not a representative sample of the US population

04/11/2025

Viral Infections and Risk of Cardiovascular Disease: Systematic Review and Meta-Analysis

PMID: 41160032

CVD is the leading cause of death worldwide. Viral infections lead to acute inflammatory responses, including increased clotting and blood vessel dysfunction, that could play a role in CVD deaths. COVID-19 infection has been shown to increase the risk of stroke and heart attack. This systematic review and meta-analysis of epidemiologic studies examined the risk of viral infections with CVD.

155 studies were included in the analysis, with most of them (105) being cohort studies. HIV infection was associated with a 65% higher risk of CVD. In cohort studies, COVID-19 infection was associated with an increased risk of CVD (82%), CHD (74%), and stroke (69%) up to a year later; however, there was high between-study heterogeneity. Influenza infection was associated with higher MI and stroke risk in the first month after infection. Hepatitis C infection was associated with a 39% higher risk of CVD. Herpes zoster was associated with an increased risk of CVD by 31% in cohort studies, with elevated risk persisting for up to 10 years in several of the cohort studies. In studies lasting longer than 5 years, there was an increased association with CHD and stroke. Two cohort studies showed that high-risk HPV infection was associated with increased CVD (25%).

31/10/2025

Prenatal Exposure to Fine Particulate Matter Components
and Autism Risk in Childhood

PMID: 41129149

PM2.5 is an air pollutant with established links to cardiovascular disease, dementia, and other poor health outcomes. Urban areas are particularly prone due to industrial waste and vehicle emissions. Preclinical studies suggest PM2.5 may influence ASD risk through epigenetic modifications, inflammation, gut microbiota dysbiosis, and oxidative stress, leading to structural and functional changes in the developing brain. This study was a retrospective study examining the association between prenatal and early-life exposure to PM2.5, sulfate, ammonium, and 03 (ozone) and ASD diagnosis.

The cohort included just over 2.1 million live births. 0.8% (19.5k children) were diagnosed with ASD before age 5, with 3.5x more boys than girls being diagnosed. Children with ASD were more likely to be born to mothers with underlying health conditions like asthma, diabetes, and hypertension, as well as be born into families with lower socioeconomic status. Prenatal PM2.5 exposure was associated with a 15% increased risk of ASD per 3.5 μg/m3 increase, which was no longer significant when adjusted for NH4 and S04 (two types of PM2.5 air pollutants). Prenatal NH4 exposure showed a 13% increased risk of ASD per 0.60 ug/m3 increase. In general, the effect sizes were larger during the second and third trimester and in urban compared to rural areas. In the first year of life, 03 exposure was associated with a 9% increased risk of ASD diagnosis. In the PM2.5 concentration analysis, ASD risk decreased at low concentrations, reaching a minimum around 5 μg/m3, then rose sharply above 10 μg/m3.

Limitations - Not US population, retrospective cohort design, air pollution information sourced from databases, heavy dependence on mathematical modeling

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30/10/2025

Handgrip Strength and Trajectories of Preclinical Obesity Progression: A Multistate Model Analysis Using the UK Biobank

PMID: 41092288

Recent evidence indicates that muscle strength and function may help protect against some of the metabolic dysfunction associated with excess adiposity. Declines in muscle strength and mass are associated with higher obesity-related cardiovascular and all-cause mortality. The Lancet published a consensus statement in 2025, adding preclinical (obesity without obesity-related dysfunction or disorders) and clinical obesity. This study investigated whether grip strength was associated with progression from preclinical to clinical obesity and with mortality risk in participants followed for an average of nearly 14 years.

In the fully adjusted model, each standard deviation increase in grip strength (11.6 kg) was associated with a 14% lower risk of conversion from preclinical to clinical obesity, an 8% lower risk of developing multiple obesity-related complications, and a 13% lower risk of progressing from multiple obesity related complications to all-cause death. When broken down into tertiles, the lowest tertile (less than 36.5 kg for men, 20.5 kg for women) compared with the highest tertile (greater than 44 kg for men, 26 kg for women), the risk reductions were 20%, 12%, and 23%, respectively. This association persisted in the sensitivity analysis done by biological s*x. When progression from double dysfunction to cardiovascular and cancer mortality was analyzed, each standard deviation increase in grip strength lowered the risk of death by 18% and 9% respectively. Another sensitivity analysis should result in a reduction in all 3 progression stages, with increased muscle-to-weight ratio measured by thigh MRI scans. Increased lean-to-weight ratio, assessed by DEXA, was associated with decreased risk in the first two progressions but not in the third.

28/10/2025

Short-term impact of tirzepatide on metabolic hypogonadism and body composition in patients with obesity: a controlled pilot study

PMID: 40604795

Metabolic hypogonadism is a condition in which low testosterone levels are associated with metabolic disorders often seen in obese or insulin-resistant men. Excess visceral fat leads to increased aromatization of testosterone into estradiol. Inflammatory mediators associated with obesity and insulin resistance may alter brain-testes signaling, reducing testosterone secretion. Testosterone itself plays a role in maintaining muscle mass, body fat distribution, and insulin sensitivity. TRT alone may not address the metabolic dysfunction in these patients. Tirzepatide (TZP) has been shown to improve obesity related metabolic dysfunction. This study evaluated the effects of TZP in men with obesity and metabolic hypogonadism.

Participants were split into three groups: TZP lifestyle (Group A), lifestyle only (Group B), and TRT + lifestyle (Group C). The lifestyle intervention included a Mediterranean-type diet with a 20% caloric deficit and 20 minutes of brisk walking per day. When comparing changes from baseline across groups, Group A showed greater decreases in body weight, BMI, waist circumference, and fat mass. Lean mass increased in Group A compared with Group B, but not in Group C. Group A also showed greater improvement in hormonal markers LH, FSH, and TT, with a decrease in estradiol.

Limitations - small sample size, significant baseline differences between groups, dose and route of TRT, short duration (2 months)

24/10/2025

A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD

PMID: 41057918

Emerging evidence is supporting insulin resistance as part of the pathologic process in Alzheimer's dementia (AD) even in invididuals without established diabetes. SGLT2is improve insulin sensitivity and vascular function, may also reduce oxidative stress and neuroinflammation, and improve neuronal plasticity and mitochondrial bioenergetics. In mouse models, SGLT2is reduces amyloid plaques, microhemorrhages, and brain inflammation while improving memory. Intranasal insulin (INI) provides direct access to the brain, with previous evidence supporting improved brain glucose utilization, improved cognition, reduced levels of inflammatory and AD biomarkers, and reduced white matter hyperintensities (adverse imaging changes).

This study evaluated the safety and efficacy of INI and empagliflozin (EMPA) alone and in combination in older adults with mild cognitive impairment (MCI) and early AD in a 4-week trial. Patients received INI 40 IU four times a day, EMPA 10 mg once daily, both agents, or placebo. In the primary analysis, there were no differences in treatment-related adverse events between the INI and non-INI groups, the EMPA and non-EMPA groups, or the combined groups compared with the individual groups and placebo. The events were rated as mild, with full recovery, and included nasal irritation and yeast infections, which were the most common.

For cognitive outcomes, the INI and combined groups improved their scores on the mPACC5. The EMPA group showed an increase in HDL. The INI-only group showed lower GFAP levels, and the EMPA-only group showed lower tau levels in the spinal fluid. Both agents influenced multiple immune and inflammatory markers.

23/10/2025

Open-Label Placebos as Adjunct for the Preventive Treatment of Migraine
A Randomized Clinical Trial

PMID: 41060655

Headaches are the third leading cause of disability, with migraine-type headaches estimated to affect 15% of the global population. Preventative treatment of migraines includes sleep, nutrition, exercise, and stress management/relaxation techniques. Previous trials have shown that placebo response rates for migraine sufferers are as high as 46% and a meta-analysis involving anti-CGRP therapy suggested the placebo effect may explain up to 66% of the therapeutic improvement. This study examined the effect of a 3-month open-label placebo (OLP) treatment plus usual care compared to usual care alone (TAU) on monthly headache days (MHD) and other secondary endpoints.

There was no statistically significant reduction in MHDs in the OLP vs TAU group (6 days vs 7 days, respectively). Both groups significantly reduced MHDs from the beginning to the end of the study by about 16%. There was a non-statistically significant reduction in rescue medication days in the OLP vs TAU group (4 days vs. 5 days). At 3 months, the OLP group reported significantly higher positive response rates; however, at 6 months, no difference was seen. Physical health scores on the SF-12 were significantly higher in the OLP group than in the TAU group, and this difference remained significant at 6 months. The OLP group showed significantly greater improvements in pain-related disability scores at 3 months, with these improvements persisting at 6 months. Of note, 40 of the 58 OLP participants received OLP as a standalone intervention without other preventive pharmacology.

Limitations - did not enroll enough patients, German population (limits generalizability), part of the placebo effect is thought to be due to the physician-patient relationship, which was minimized in this trial design (may underestimate OLP effects)

21/10/2025

Implications of a New Obesity Definition Among the All of Us Cohort

PMID: 41091468

A Lancet journal recently proposed incorporating anthropometrics and direct measures of body fat into the diagnostic criteria of obesity, given the shortcomings of BMI at the individual level. This new definition is based on the following criteria: 1. Elevated BMI + an elevated anthropometric measure (waist circumference, waist-to-hip ratio, waist-to-height ratio) or a BMI > 40. 2. 2 elevated anthropometric measures irrespective of BMI 3. excess body fat on DEXA or similar modalities. The new guidelines also distinguish clinical and preclinical obesity to differentiate individuals with and without obesity-associated organ dysfunction and/or physical limitations. This study applied the new definition to a large US-based cohort to determine the prevalence of preclinical and clinical obesity.

Over 300k individuals were included in this analysis. Under the old guidelines, the prevalence of obesity was just under 43%, which increased to 68.6% under the new guidelines. When broken down by s*x, a higher proportion of males had anthropometric-only obesity compared to females (32.5% vs 21.7%). Anthropometric-only obesity prevalence also increased with age, affecting nearly 27% of those 18 to 29 and almost 53% of those 70 or older. 22.3% of anthropometric-only obesity individuals had a BMI classified as normal or underweight (often referred to as "skinny-fat"). 36% of participants overall and nearly 53% of participants with obesity met the new clinical obesity definition. In a multivariate analysis, the odds of organ dysfunction were increased by 231% for those with BMI plus anthropometric obesity and by 76% for anthropometric-only obesity, compared to individuals without obesity.

In the longitudinal analysis, BMI plus anthropometric obesity had the greatest risk of diabetes (295%), cardiovascular disease (81%), and all-cause mortality (22%). Anthropometric obesity only increased diabetes risk by 112%, cardiovascular events by 55% and all-cause mortality by 20%.

Richard Harris MD, PharmD, MBA