Tag: Cardiovascular Disease

Bariatric surgery more effective in controlling hypertension rates in obese patients

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Bariatric surgery is more effective in controlling hypertension rates, or high blood pressure, in people with obesity and uncontrolled high blood pressure compared to blood pressure medication alone, according to a study published today in the Journal of the American College of Cardiology. People who underwent bariatric surgery had lower BMI and were on fewer medications after five years while maintaining normal blood pressure levels than those who only used antihypertensive medications.

According to the CDC, the U.S. obesity and hypertension rates in adults are 41.9% and 45.4%, respectively. Obesity is a known risk factor for cardiovascular disease and a major contributor to high blood pressure, which can make a person more susceptible to heart attack, stroke and heart failure, among other risks.

In clinical practice, obesity is an overlooked condition. As a consequence, there is a frequent failure in approaching obesity as a crucial step for mitigating the risk of important cardiovascular risk factors including hypertension.”

Carlos Aurelio Schiavon, MD, FACS, lead author of the study and a surgeon specializing in bariatric surgery at Heart Hospital (hcor) and BP Hospital in Sao Paulo

Researchers in this study looked at the impact of treating obesity to lower high blood pressure. While there are new medications to treat obesity, long-term adherence to medication can be challenging. This study looks at bariatric surgery as a better long-term solution to control obesity and, as a result, high blood pressure.

The GATEWAY trial included 100 people (76% of which were female) who had a body mass index (BMI) of around 36.9Kg/m². All participants had hypertension and were using at least two medications. People with previous cardiovascular events and poorly controlled Type 2 diabetes were excluded. Subjects were assigned to either Roux-en-Y gastric bypass with medical therapy or medial therapy alone and the primary outcome was reduction of at least 30% antihypertensive medications while maintaining blood pressure levels less than 140/90 mmHg at five years.

At five years, BMI was 28.01 Kg/m²for those who received bariatric surgery and 36.40 Kg/m²for those on medical therapy alone. People who had bariatric surgery had an 80.7% reduction in the number of medications they were taking compared to a 13.7% reduction in those only using medical therapy. Hypertension remission, defined as controlled blood pressure without medications, was 46.9% in those who underwent bariatric surgery compared to 2.4% in those on medical therapy alone.

“Our results underscore the importance of approaching obesity in reducing hypertension rates,” Schiavon said.

Limitations of the study include that it was a single-center, open-label study with a small sample size and there was loss of follow up in some patients.

In an accompanying editorial comment, Michael Hall, MD, MSc, professor and chair of the Department of Medicine at the University of Mississippi Medical Center, said the study provides important long-term data on the benefits of gastric bypass on weight loss and blood pressure control, but questions remain.

“Further studies assessing the threshold for bariatric surgery in people with obesity, optimal timing of bariatric surgery in obese people with cardiometabolic diseases, type of bariatric surgery and comparative studies of obesity pharmacotherapies and bariatric surgery are needed to clarify the optimal treatment pathways for this common and growing disease,” he said.

Source:

American College of Cardiology

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February 6, 2024
New weight loss drug may be an effective strategy for preventing or treating high blood pressure
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The new weight loss medication tirzepatide significantly lowered the systolic blood pressure (the top number in a blood pressure reading) for nearly 500 adults with obesity who took the medication for about eight months, according to new research published today in Hypertension, an American Heart Association journal.

Systolic blood pressure, or the top number in the blood pressure reading, is a stronger predictor for cardiovascular death than diastolic, or bottom number, blood pressure. According to the American Heart Association’s 2024 Heart Disease and Stroke Statistics, more than 122 million adults in the United States, or 47% of adults have hypertension, and nearly 42% of adults have obesity.

Tirzepatide works by mimicking two metabolic hormones in the body: it acts as a glucagon-like peptide-1 (GLP-1) receptor agonist and also as a glucose dependent insulinotropic polypeptide (GIP) receptor agonist. These hormones stimulate insulin secretion and sensitivity after a person eats. Together, they have been found so far to help regulate the body’s blood sugar levels, slow down digestion and reduce appetite, which makes a person feel more full and eat less, leading to weight loss. In contrast, semaglutide has only the GLP-1 hormone; it does not contain a GIP receptor agonist.

In 2022, the Food and Drug Administration approved tirzepatide for prescription as a treatment for Type 2 diabetes. In late 2023, the FDA also approved it for chronic weight management for people with obesity (body mass index of 30 kg/m² or higher) or overweight (body mass index of 27-29 kg/m²) and at least one weight-related health condition, such as high blood pressure, Type 2 diabetes or high cholesterol.

“Our findings indicate treating obesity with the weight loss medication tirzepatide may be an effective strategy for preventing or treating high blood pressure,” said lead study author James A. de Lemos, M.D., FAHA, the Kern Wildenthal, M.D., Ph.D., distinguished chair of cardiology and a professor of medicine at UT Southwestern Medical Center in Dallas. “Although tirzepatide has been studied as a weight loss medication, the blood pressure reduction in our patients in this study was impressive. While it is not known if the impact on blood pressure was due to the medication or the participants’ weight loss, the lower blood pressure measures seen with tirzepatide rivaled what is seen for many hypertension medications.”

The current research was a planned sub-study including 600 of the participants from the SURMOUNT-1 weight loss study to determine if there was an effect on blood pressure. The sub-study was designed to assess the effects of tirzepatide on blood pressure levels as measured by 24-hour ambulatory blood pressure monitoring in people with obesity but without Type 2 diabetes.

Participants received either a placebo or a dose of tirzepatide in one of three strengths (5 mg, 10 mg or 15 mg). About one-third of participants reported they had high blood pressure at the beginning of the study and were taking one or more hypertension medications. When the sub-study began, all of the participants had blood pressure levels that were less than 140/90 mm Hg, and if they used blood pressure medications, they were required to have been taking their blood pressure medications for at least three months. The sub-study included participants who had hypertension and who had normal blood pressure.

The study was conducted from December 2019 to April 2022, and the participant results after 36 weeks of taking tirzepatide indicate:
- For participants taking 5 mg of tirzepatide, there was an average reduction in systolic blood pressure of 7.4 mm Hg.
- For participants taking 10 mg of tirzepatide, there was an average reduction in systolic blood pressure of 10.6 mmHg.
- For participants taking 15 mg of tirzepatide, there was an average reduction in systolic blood pressure of 8.0 mm Hg.
- The blood-pressure lowering effects of tirzepatide were evident in blood pressure measures taken during both the day and night. Nighttime systolic blood pressure is a stronger predictor for cardiovascular death and all-cause death than daytime blood pressure readings.
The reductions in systolic blood pressure were consistent across subgroups of participants in the study who were categorized by additional factors, including age, sex, body mass index and hypertension-related risk factors.

Study background and details:
- SURMOUNT-1 was a randomized study on the effect of increasing doses of tirzepatide on weight loss. It found that in participants with overweight or obesity (body mass index (BMI) ≥27 kg/m²), once-weekly injections of 5 mg, 10 mg or 15 mg of tirzepatide led to mean weight reductions of 15%, 19.5% and 20.9%, respectively, compared to placebo.
- The sub-study included 600 adults from SURMOUNT-1: 155 participants received placebo; 145 were taking tirzepatide 5 mg; 152 were taking tirzepatide 10 mg; and 148 were taking tirzepatide 15 mg.
- Blood pressure measurements were available and analyzed for 494 participants who valid ambulatory blood pressure monitoring data at the beginning of the study and at week 36.
- Only the study participants with at least 70% valid readings on ambulatory monitoring and a minimum of 20 daytime and seven nighttime readings were included in the data analyses. This was 494 out of 600 initial participants.
- 69% of study participants self-identified as female, and 31% self-identified as male. 66.8% self-identified as white adults, 11.8% self-identified as Black adults and 25% self-identified as Hispanic ethnicity.
- The average age of the participants was 45.5 years, and their average BMI was 37.4 kg/m², which meets the criteria for obesity (obesity is BMI≥30). People with obesity have an increased risk of high blood pressure, heart disease, stroke and Type 2 diabetes, as well as other health conditions.
- Ambulatory blood pressure monitoring used in this study included blood pressure measurements every 30 minutes during the day and every hour at night, providing a more comprehensive assessment of blood pressure than in office or daily home blood pressure measurements. For ambulatory blood pressure monitoring, study participants wore a blood pressure monitoring device for a 24- to 27-hour period that measured blood pressure throughout waking and sleeping hours. Ambulatory blood pressure monitoring was conducted when participants first began taking tirzepatide at the start of the study and after 36 weeks of being enrolled in the study.
The 2017 ACC/AHA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults classifies hypertension, or high blood pressure, as having top and bottom blood pressure measures greater than or equal to 130/80 mm Hg.

Study limitations include that it was only conducted in a subset of the original 2,539 SURMOUNT-1 participants; the ambulatory blood pressure monitoring was only measured at two points in the study -; baseline and at 36 weeks; and measurements were only taken once per hour at night to minimize the burden on study participants. In addition, changes in food intake and 24-hour urine sodium excretion were not assessed, meaning the contribution of dietary modifications including salt intake or other changes that may help to reduce blood pressure are unknown and cannot be estimated.

“Overall, these data are encouraging that novel weight-loss medications are effective at reducing body weight and they are also effective at improving many of the cardiometabolic complications of obesity including hypertension, Type 2 diabetes and dyslipidemia, among others. While the impact of each of these beneficial effects is individually important, many of these obesity-related complications act synergistically to increase the risk of cardiovascular disease. Thus, strategies that mitigate multiple obesity-related complications may reduce the risk of cardiovascular events,” said Michael E. Hall, M.D., M.S., FAHA, chair of the writing group for the Association’s 2021 scientific statement on weight-loss strategies for prevention and treatment of hypertension and chair of the department of medicine at the University of Mississippi Medical Center in Jackson, Mississippi.

Additional studies will be necessary to determine the long-term impact on cardiovascular events such as heart attack and heart failure. Also, studies are needed to investigate what happens to blood pressure when medications like tirzepatide are discontinued – does the blood pressure rebound and go back up, or does it remain lowered?”

Michael E. Hall, M.D., M.S., FAHA, chair of the writing group

Co-authors and disclosures are listed in the manuscript. The study was funded by Eli Lilly and Company, the manufacturer of tirzepatide.

Source:

American Heart Association

Journal reference:

de Lemos, J. A., et al. (2024) Tirzepatide Reduces 24-Hour Ambulatory Blood Pressure in Adults With Body Mass Index ≥27 kg/m2: SURMOUNT-1 Ambulatory Blood Pressure Monitoring Substudy. Hypertension. doi.org/10.1161/HYPERTENSIONAHA.123.22022.
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February 5, 2024
Over 80% of semaglutide users achieve significant weight loss after 12 months, study finds

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In a recent study published in the International Journal of Obesity, researchers assessed the effectiveness of semaglutide dosages between 0.25 and 2.4 mg in overweight or obese people for up to one year.

Specifically, they assessed whether its use was safe and improved weight loss, metabolic, and comorbidity outcomes, including 10-year atherosclerotic cardiovascular disease [ASCVD] risk.

Study: Weight loss and cardiovascular disease risk outcomes of semaglutide: a one-year multicentered study. Image Credit: myskin/Shutterstock.com

Background

Obesity affects around 650 million adults globally, which has increased the burden of associated comorbidities, resulting in substantial morbidity and mortality.

Anti-obesity medications (AOMs) in conjunction with lifestyle modifications have consistently shown superior weight loss outcomes than lifestyle-targeted interventions alone.

For instance, randomized clinical trials (RCTs) on semaglutide, a Food and Drug Administration (FDA)-approved AOM, have shown superior weight loss outcomes for semaglutide than other AOMs.

Yet, only some real-world studies have assessed outcomes of semaglutide use over more than six months, limiting its clinical use.

About the study

The present retrospective study was conducted across all Mayo Clinic Hospitals in Florida, Minnesota, and Arizona in the US among patients with BMI ≥ 27 kg/m² who were prescribed weekly subcutaneous semaglutide injections between January 1, 2021, and January 15, 2023, for weight loss.

They obtained their metabolic, clinical, and laboratory data at baseline, three, six, nine-, and 12-month follow-ups. The prescribed doses of semaglutide were 0.25, 0.5, 1, 1.7, 2, or 2.4 mg.

In-person and virtual visits and physician-patient communication through electronic medical records (EMR) enabled data collection within 30 days of these time points.

Data collected was weight using calibrated scales, laboratory results for fasting blood glucose [FBG], lipid panel, glycosylated hemoglobin [HbA1c], blood pressure [BP] readings, and liver function tests [LFTs].

The team also assessed all obesity comorbidities, type-2 diabetes mellitus (T2DM), CVD, dyslipidemia, gastroesophageal reflux disease (GERD), non-alcoholic fatty liver disease (NAFLD), and obstructive sleep apnea (OSA), depression/anxiety, and their medications taken at baseline and last follow-up.

In addition, they documented side effects associated with semaglutide use and the number of visits with bariatric psychologists/dietitians.

This study’s primary endpoint was total body weight loss percentage (TBWL%) 12 months after the semaglutide start date.

Secondary endpoints were the percentage of patients attaining ≥5, 10, 15, and 20% weight loss and improvements in metabolic, cardiovascular, and comorbidities after 12 months of follow-up.

The statistical analyses involved a matched paired t-test to analyze the primary endpoint.

In addition, the team used a multivariate logistic regression model to determine weight loss post-bariatric psychologist/dietician visits accounting for T2DM status and setting the statistical significance of 2-sided P at <0.05.

Results

A total of 1,023 patients received semaglutide prescriptions for obesity. However, this analysis encompassed 304 patients, of which 73% were female and 93% were of White ethnicity.

The mean age of the included participants was 48.8 years, and they had a mean BMI of 40.9 kg/m2.

Patients achieved a TBWL of 5.7% at three, 9.7% at six, 12.7% at nine, and 13.4% at 12 months, with 22% of patients achieving weight loss of ≥20%.

At 12 months, patients without T2DM achieved a higher TBWL than patients without T2DM (16.9 vs. 9.9).

Likewise, patients on higher doses of semaglutide achieved a higher TBWL than patients taking lower doses at all time points.

Furthermore, patients with obesity experienced significant improvements in metabolic, lipid profile, blood pressure, liver function tests, and CVD outcomes.

Notably, 10-year ASCVD risk declined in patients with no history of CVD at one-year follow-up: 8.% to 6.7%.

Even though more than 50% of patients experienced side effects, mainly gastrointestinal symptoms, it required stopping semaglutide use or dose mitigation in only ~16% of the patients, showing that this drug is well-tolerated, which is crucial for chronic weight management.

Conclusions

Overall, semaglutide administration resulted in notable improvement in obesity, metabolic, and CVD risk outcomes among obese patients in a clinical setting.

Future trials should evaluate body weight changes over longer follow-up periods after stopping this medication.

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February 5, 2024
Xist lncRNA identified as key trigger in female-biased autoimmune diseases
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In a recent study published in the journal Cell, a team of scientists predominantly from Stanford University discovered that sex-biased autoimmunity, where females are more affected by autoimmune disorders than males, is primarily driven by the Xist ribonucleoprotein complex containing various autoantigenic components.

Study: Xist ribonucleoproteins promote female sex-biased autoimmunity. Image Credit: Kateryna Kon / Shutterstock

Background

After cancer and cardiovascular disease, autoimmune disorders are the most prevalent category of disease, with females having a four-fold higher incidence of autoimmune diseases than males. Sjögren’s disease has a 19 to one female to male prevalence, while the sex ratio of systemic lupus erythematosus patients is 9:1 for females to males. Furthermore, Klinefelter syndrome patients who have XXY sex chromosomes and are phenotypically male with hormonal patterns of a biological male also have the same risk of autoimmune disorders as females.

While the role of hormones has been extensively studied in relation to autoimmune disorders, research indicates that irrespective of hormone status and sex, X chromosome dosage seems to be one of the major drivers of autoimmune disease risk. Additionally, studies among identical twins indicate that the penetrance of autoimmune disease can also vary, suggesting that environmental factors can influence the genetic disposition to autoimmune disorders. X-linked genes such as toll-like receptor 7 (TLR7) have been thought to contribute to the development of some autoimmune disorders.

About the study

In the present study, the researchers used autoimmune-resistant and autoimmune-prone mouse models, C57BL/6J and SJL/J, respectively, to understand the role of X chromosome dosage compensation in determining the disproportionate risk of autoimmune diseases in females.

Since mammalian females have two copies of the X chromosomes as compared to mammalian males, who have an XY genotype, one of the two X chromosomes in females is epigenetically silenced for dosage compensation in every cell through a mechanism involving a 19-kb pair long non-coding ribonucleic acid (lncRNA) called Xist. Xist is not expressed in males, and only the inactive X chromosome transcribes this lncRNA in females.

Studies in embryonic stem cells from mice have shown that X chromosome inactivation is established when Xist forms a ribonucleoprotein complex with 81 binding proteins that are unique to this complex. Xist binds directly to 10 of these binding proteins through RNA-protein interactions, and to the remaining 71 indirectly through protein-protein interactions. Several of these binding proteins have previously been identified as autoantigens and are thought to activate innate immune system pathways through toll-like receptors.

Here, the researchers used non-silencing alleles of Xist that were inducible and introduced them into the autosomes of the autoimmune-resistant and autoimmune-prone mice strains. The induction of Xist ribonucleoprotein complex formation in male mice of a chemically induced systemic lupus erythematosus mouse model allowed this female-specific process to be observed in a male background.

RNA sequencing and ATAC-sequencing or assay of transposase-accessible chromatin by sequencing were used to assess changes in gene expression in splenic CD4+ T cells and potential transcription regulation alterations. Principal component analysis was also used to determine similarities between male mice expressing the induced Xist allele.

Serum samples from treated mice were also assessed for antigens against scleroderma and systemic lupus erythematosus. Additionally, serum samples obtained from human patients of systemic lupus erythematosus, dermatomyositis, and scleroderma were tested for reactivity against proteins from the Xist ribonucleoprotein complex.

Results

The results reported that the induction of transgenic expression of non-silenced Xist in male mice formed Xist ribonucleoprotein complexes and led to the production of autoantibodies. Male autoimmune-prone mice models of pristane-induced systemic lupus erythematosus showed multi-organ pathology that was more severe than that seen in the wild-type mice. Furthermore, the expression of Xist in the male mice had reprogrammed the chromatic states and the B and T cell populations to be more similar to those found in wild-type female mice.

The reactivity against multiple proteins from the Xist ribonucleoprotein complex was also found to be significant in the serum samples obtained from human systemic lupus erythematosus, dermatomyositis, and scleroderma patients.

The findings highlight the potential for using these Xist ribonucleoprotein complex-associated proteins as novel antigens for detecting and monitoring autoimmune diseases. The discovery of atypical B cell accumulation due to Xist ribonucleoprotein complex expression also provides a potential area of research for autoimmune disorder therapy.

Conclusions

Overall, the findings indicated that the Xist ribonucleoprotein complex selectively expressed in females and involved in X chromosome dosage compensation drives sex-biased autoimmunity. Patients with autoimmune conditions such as scleroderma and systemic lupus erythematosus have higher reactivity against proteins from the Xist ribonucleoprotein complex, highlighting the potential use of these proteins as antigens for screening and early detection of autoimmune disorders.
Journal reference:

Dou, D. R., Zhao, Y., Belk, J. A., Zhao, Y., Casey, K. M., Chen, D. C., Li, R., Yu, B., Srinivasan, S., Abe, B. T., Kraft, K., Hellström, C., Sjöberg, R., Chang, S., Feng, A., Goldman, D. W., Shah, A. A., Petri, M., Chung, L. S., & Fiorentino, D. F. (2024). Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell, 187(3), 733-749.e16, 10.1016/j.cell.2023.12.037, https://www.cell.com/cell/fulltext/S0092-8674(24)00002-3
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February 5, 2024
Moderate kimchi intake linked to lower obesity rates, study shows
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In a recent study published in the journal BMJ Open, researchers explored the relationship between kimchi consumption and obesity in South Korea.

Study: Association between kimchi consumption and obesity based on BMI and abdominal obesity in Korean adults: a cross-sectional analysis of the Health Examinees study. Image Credit: Nungning20/Shutterstock.com

Obesity is associated with nutritional, environmental, and lifestyle factors and is a significant risk factor for diabetes, chronic kidney disease, cardiovascular disease, and hyperlipidemia. Obesity prevalence in South Korea has increased steadily over the years. Meanwhile, the prevalence of abdominal obesity has also increased over time.

Increased obesity prevalence is associated with higher medical expenditure; thus, obesity prevention remains a public health priority. In Korea, kimchi is a traditional side dish low in calories but rich in vitamins, dietary fiber, polyphenols, and lactic acid bacteria. There are concerns about kimchi as one of the major contributors to sodium intake.

A 2019-20 survey revealed that daily sodium intake from kimchi was 500 mg (15% of total sodium intake). Studies have shown associations between increased sodium intake and a greater prevalence of hypertension and obesity. Nevertheless, consuming fermented vegetables and kimchi has been associated with lower body weight and improved total cholesterol and fasting blood glucose levels.

About the study

The present study explored the associations between kimchi consumption and obesity in South Korean adults. The researchers used data from a large, prospective, community-based cohort study, “Health Examinees” (HEXA). HEXA was part of a larger genome and epidemiology study examining genetic and environmental risk factors for chronic diseases in adults aged > 40.

Baseline assessments in the HEXA study were performed between 2004 and 2013. Participants were excluded if they had a history of cancer, cerebrovascular disease, diabetes, cardiovascular disease, hyperlipidemia, or hypertension. Those with an implausible energy intake and missing anthropometric data were also excluded.

A semi-quantitative food frequency questionnaire assessed dietary intake for the past year. Total kimchi included kkakdugi, dongchimi (watery kimchi), baechu kimchi (cabbage kimchi), and others, e.g., mustard green kimchi, lettuce kimchi, and green onion kimchi. Intake of sodium, potassium, macronutrients, and fiber was calculated. Obesity is having a body mass index (BMI) ≥ 25 kg/m².

Abdominal obesity was defined as having a waist circumference (WC) ≥ 90 cm for males and ≥ 85 cm for females. A questionnaire was administered to capture data on sociodemographics, smoking, disease history, menopause status, and physical activity.

Participants were stratified into groups based on kimchi intake. A multivariable logistic analysis estimated odds ratios and 95% confidence intervals of obesity by kimchi intake.

Findings

The study included 115,726 individuals aged 51.8, on average. Most participants (> 68%) were female. Obesity prevalence was 28.2% overall, 24.7% in females, and 36.1% in males. Individuals consuming five or more servings/day of total kimchi had increased weight and WC compared to those consuming less than one serving per day; they were also more likely to consume alcohol and be obese.

Males with ≥ five servings/day of total kimchi were younger, smokers, taller, and more physically active than those with less than one serving/day. By contrast, females consuming ≥ five servings per day were older, non-smokers, physically inactive, post-menopausal, shorter, and married compared to those consuming less than one serving a day.

Males consuming up to three servings of total kimchi daily had a lower obesity prevalence than those consuming less than one serving a day. Baechu kimchi consumption (≥ three servings/day) among males was significantly associated with a 10% reduced prevalence of obesity and abdominal obesity relative to those with less than one serving/day.

In females, two to three servings per day of baechu consumption was associated with about 8% lower obesity prevalence and 6% lower prevalence of abdominal obesity compared to those with less than one serving/day. Individuals consuming kkakdugi more than the median quantity had lower odds of having abdominal obesity compared to non-consumers.

Conclusions

Overall, the study illustrated an inverse association between total kimchi consumption (one to three servings per day) and obesity risk in males. In addition, males with a higher intake of baechu kimchi had a lower prevalence of abdominal obesity and obesity. Increased kkakdugi intake was associated with lower abdominal obesity prevalence in both males and females.

While consuming five or more servings of kimchi was associated with higher obesity prevalence, it was not statistically significant. Higher total kimchi intake was also associated with increased protein, carbohydrates, fat, sodium, cooked rice, and total energy intake. The study’s limitations include its cross-sectional design, which limits causal inference, and lack of generalizability to other populations.
Journal reference:

Jung H, Yun Y, Hong SW, et al. (2024). Association between kimchi consumption and obesity based on BMI and abdominal obesity in Korean adults: a cross-sectional analysis of the Health Examinees study. BMJ Open. doi: 10.1136/bmjopen-2023-076650. https://bmjopen.bmj.com/content/14/2/e076650
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February 4, 2024
Breakthrough obesity treatments on the horizon, rivaling surgery’s success

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In a recent study published in the International Journal of Obesity, researchers discussed the pipeline of obesity pharmacotherapies.

Obesity is a chronic disease affecting about 650 million individuals worldwide. It increases the risk of several metabolic complications, including cardiovascular disease and type 2 diabetes (T2D). Lifestyle interventions form the core of obesity management. Still, the average weight loss (WL) is ≤ 10%, even with the most intensive interventions.

Moreover, weight maintenance is challenging as weight regain occurs over time. While 5% to 10% WL is clinically beneficial, higher WL is required to improve or attain remission of obesity complications. Furthermore, bariatric surgery can offer up to 30% WL and longer-term weight maintenance; nevertheless, people may not opt for bariatric surgery due to perceived postoperative risks.

Understanding the role of entero-pancreatic hormones resulted in the development of glucagon-like peptide (GLP)-1 receptor agonists (RAs) for obesity and T2D treatment. Semaglutide is the latest GLP-1 RA approved for obesity, which can result in 15% to 17% mean WL. Nonetheless, a significant difference exists between WL achieved through obesity pharmacotherapies and bariatric surgery.

Further, current GLP-1 RAs for obesity are injectables, which some people may not consider. However, oral RAs are being developed to increase acceptance and adherence. Besides, a pipeline of pharmacotherapies based on entero-pancreatic hormones is being developed to enhance or complement GLP-1 RAs. In the present study, the authors discussed the pipeline of obesity pharmacotherapies.

Study: What is the pipeline for future medications for obesity? Image Credit: Suzanne Tucker / Shutterstock

GLP-1 RAs

Subcutaneous semaglutide (2.4 mg) and liraglutide (3 mg) have been approved for obesity management. A higher semaglutide dose (7.2 mg) is being evaluated in a phase 3 trial. Because people may be reluctant to use injectables, oral semaglutide has been introduced and approved for T2D, with the 14 mg dose improving hemoglobin A1c (HbA1c) levels and WL.

A phase 3 trial evaluated the efficacy and safety of a 50 mg oral dose of semaglutide in non-T2D obese subjects over 68 weeks. The trial revealed that semaglutide recipients achieved over 17% WL while placebo subjects attained < 2% WL. In a different trial on T2D subjects, the 50 mg semaglutide dose resulted in approximately 10% WL compared to 5.4% WL with the 14 mg dose.

Danuglipron is a non-peptide, G protein-based, oral GLP-1 RA. A phase 2b investigation among obese subjects showed that 40 mg to 200 mg doses of danuglipron resulted in over 11% WL after 32 weeks. Orforglipron is another non-peptide, oral GLP-1 RA, which is being evaluated for T2D and obesity management.

In obese subjects, 36-week orforglipron treatment led to WL of ≤ 14.7% and improvements in cardiometabolic risk factors. Likewise, in T2D patients, nearly half of the participants attained 10% or higher WL after a 26-week orforglipron treatment in a phase 2 trial. Currently, several phase 3 trials on orforglipron and oral semaglutide are underway for different populations.

GLP-1 glucagon like peptide-1, GIP glucose-dependent insulinotropic polypeptide, PYY peptide YY, *data mainly from animal studies.

Entero-pancreatic hormones and their combinations for obesity management

Multiple entero-pancreatic hormones are currently evaluated alone or in combination with GLP-1 RAs to augment or complement the effects of GLP-1 agonism on weight and metabolism. Jejunal K-cells secrete glucose-dependent insulinotropic peptide (GIP) in response to food intake. GIP stimulates insulin release and increases lipogenesis, glucagon secretion, and lipid buffering capacity.

Animal studies suggest an anorexigenic action of GIP receptor agonism. A phase 1 trial recently showed that repeated doses of long-acting GIP RA caused a modest WL in T2D subjects. Tirzepatide is an unimolecular subcutaneous dual (GIP and GLP-1) RA with comparable affinity to the GIP receptor but lower GLP-1 receptor affinity.

A phase 3 study investigated the efficacy and safety of tirzepatide for obesity, and it has now been approved for chronic weight management. Various trials are evaluating the effectiveness and safety of tirzepatide in ameliorating cardiometabolic complications. Further, several injectable or oral GIP/GLP-1 RAs are in the early phases of development.

Preliminary findings from rodent studies indicated a synergistic role of dual glucagon and GLP-1 agonism in reducing food intake. As such, numerous glucagon/GLP-1 co-agonists have been developed. Notwithstanding the promising results of glucagon/GLP-1 co-agonism in experimental studies, the efficacy and tolerability of the co-agonists have been heterogeneous in obese subjects.

A triple agonist targeting glucagon, GIP, and GLP-1 could result in superior WL and glycemic control than dual agonists. For instance, retatrutide is a triple agonist and has been shown to improve WL and glucose profile in preclinical models relative to tirzepatide through reduced calorie intake and elevated energy expenditure. A phase 2 study in non-T2D obese individuals reported dose-dependent WL following 48-week treatment with varying doses of retatrutide.

Concluding remarks

Taken together, a new era has commenced for obesity treatment where combinations of entero-pancreatic hormones can reach the WL efficacy of bariatric surgery. Besides tirzepatide, the dual agonist approved for chronic management, various dual and triple agonists are evaluated in phase 3 trials.

The multitude of obesity treatment options will enable tailored therapies based on individuals’ preferences, treatment responses, and comorbidities. Overall, obesity pharmacotherapies represent a rapidly growing field, and research on efficacy, safety, and cost-effectiveness will inform their place in therapeutic options for obesity and related complications.

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February 4, 2024
Exercise shapes our gut health, study finds
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In a recent study published in the journal EBioMedicine, a team of scientists investigated the association between physical activity levels and gut microbiota using accelerometer-based assessments of sedentary, moderate, and vigorous physical activity levels.

Study: Accelerometer-based physical activity is associated with the gut microbiota in 8416 individuals in SCAPIS. Image Credit: Zhanna Mendel / Shutterstock

Background

A growing body of evidence shows that optimal levels of physical activity lower the risk of type 2 diabetes, cardiovascular disease, and mental health conditions such as depression. Furthermore, sedentary habits involving activities that include extensive periods of sitting or lying down have been known to increase the risk of cardiovascular mortality and type 2 diabetes, and these risks can be lowered through high-intensity exercise. Recent studies have also shown that the positive effects of exercise on health might be mediated through gut microbiome changes.

Substantial research also indicates that the gut microbiome plays a significant role in developing various diseases and mental health problems. Apart from the interactions with the host in the gastrointestinal tract, the gut microbiota is also thought to produce neurotransmitters that can influence the immune system, central nervous system, and brain homeostasis through various neuronal pathways and the microbiota-gut-brain axis. Physical activity and resulting changes in circulation, enterohepatic movement of bile acids, intestinal permeability, and gut immunity can influence the gut microbiota.

About the study

In the present study, the researchers used data from a cardiopulmonary bioimage study from Sweden to determine if sedentary, moderate, and vigorous levels of physical activity were associated with gut microbiome changes. While quite a few previous studies have examined this association, most of them have used self-reported levels of physical activity, which is subject to bias. Furthermore, the authors believe that the taxonomic resolution of the gut microbes had been limited in these studies.

This study used data from a hip-worn accelerometer to obtain a more reliable and accurate measure of physical activity levels. Additionally, the use of deep shotgun metagenomics was thought to provide high-resolution taxonomic information about the gut microbial communities.

The participants in the study were required to answer a detailed questionnaire about health and medical history, diet, and lifestyle habits. They underwent a series of physical and clinical examinations such as lungs, coronary artery, and abdominal computed tomography (CT). Participants also provided fecal samples that were used for the gut microbiome analysis. An accelerometer was worn on the hip by all the participants for one week, at all hours except while involved in water-based activities or sleeping.

The data from the accelerometer was converted to counts per minute, which was then used to define sedentary, low, moderate, and vigorous levels of physical activity according to cut-offs validated from previous studies. Deoxyribonucleic acid (DNA) extraction was carried out for all the fecal samples, and the extracted DNA was then used to identify the metagenomic species.

Various indices of species diversity, such as the inverse Simpson index, Shannon diversity index, and species richness, were calculated to determine the alpha diversity. Additionally, the dissimilarity in the microbe composition between the samples was determined by calculating the beta diversity.

Results

The results showed that the association between sedentary habits or very low levels of physical activity and the abundance of various gut microbe species was converse to the association between moderate or vigorous physical activity levels and the abundance of gut microbiome species.

The abundance of Escherichia coli was found to be high in association with sedentary physical activity levels, while moderate physical activity levels were linked to a lower abundance of E. coli. The abundance of butyrate-producing bacteria such as those belonging to the Roseburia genus, and Faecalibacterium prausnitzii was high in individuals with moderate and vigorous physical activity levels.

Furthermore, differences were also observed in the abundance of species, such as Prevotella copri, between individuals with moderate physical activity levels and those in the vigorous physical activity group. The abundance of P. copri was higher in association with moderate levels of exercise, but vigorous exercise showed no association with P. copri abundance.

The functional potential of the gut microbiome was also found to differ in association with differing physical activity levels. Moderate levels of physical activity were found to be associated with higher acetate and butyrate synthesis. Vigorous exercise was found to be linked to higher propionate synthesis, and sedentary activity levels were associated with a lower capacity for carbohydrate degradation by the gut microbiota.

Conclusions

Overall, the findings suggested that physical activity levels were strongly linked to the abundance of specific gut microbes. Furthermore, the diversity and abundance of the gut microbiota, and subsequently its functional potential, changed according to different levels of physical activity. Sedentary habits and higher levels of physical activity exhibited converse associations with gut microbiome abundance and diversity.
Journal reference:

Baldanzi, G., Sayols-Baixeras, S., Ekblom-Bak, E., Ekblom, Ö., Dekkers, K. F., Hammar, U., Nguyen, D., Ahmad, S., Ericson, U., Arvidsson, D., Börjesson, M., Johanson, P. J., Gustav, S. J., Bergström, G., Lind, L., Engström, G., Ärnlöv, J., Kennedy, B., Orho-Melander, M., & Fall, T. (2024). Accelerometer-based physical activity is associated with the gut microbiota in 8416 individuals in SCAPIS. EBioMedicine, 100. DOI: 10.1016/j.ebiom.2024.104989, https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(24)00024-0/fulltext
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February 4, 2024
Machine learning could personalize diuretic treatment for patients with acute decompensated heart failure

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A recent study co-authored by Dr. Matthew Segar, a third-year cardiovascular disease fellow at The Texas Heart Institute and led by his research and residency mentor, University of Texas Southwestern Medical Center’s Dr. Ambarish Pandey, utilized a machine learning-based approach to identify, understand, and predict diuretic responsiveness in patients with acute decompensated heart failure (ADHF).

The study “A Phenomapping Tool and Clinical Score to Identify Low Diuretic Efficiency in Acute Decompensated Heart Failure,” published in the prestigious Journal of American College Cardiology Heart Failure (JACC Heart Failure), leverages decades of clinical and registry datasets funded by the National Institutes of Health and American Heart Association.

The researchers leveraged machine-learning-based approaches to develop a prediction tool called the BAN-ADHF score, which showed promising results in accurately predicting diuretic response. After validation in other clinical populations, implementing this tool could potentially lead to personalized strategies for effectively managing the congestion of patients hospitalized with ADHF.

There remains a lack of agreement among experts regarding the most effective approach to address diuretic resistance in patients with heart failure who are stable hemodynamically and have an excess volume of fluid. It is generally recommended to optimize the dosage of loop diuretics before considering combination therapy; however, there is no consensus on how much the dosage should be increased before introducing another diuretic.

“Inefficient diuretic response in hospitalized patients can hinder treatment progress and increase the risk of post-discharge rehospitalization and mortality. It’s crucial to identify individuals with low diuretic efficiency early on to tailor decongestion strategies and improve clinical outcomes,” according to Dr. Segar.

ADHF is a public health issue that is becoming increasingly concerning. The disease results in emergency room visits, hospital admissions, and associated high healthcare costs. ADHF is characterized by the body having too much fluid, which often requires hospitalization or changing a patient’s current treatment plan.

Today, a primary goal of treating ADHF is to relieve congestion using loop diuretic drugs. However, there is still uncertainty about the best dose of these agents to administer. Additionally, because of the heterogeneity of ADHF patients, a more personalized approach to predicting optimal dosing strategies is needed.”

Dr. Joseph G. Rogers, President and CEO of The Texas Heart Institute

In the study, researchers from institutions across the United States utilized machine learning (ML) algorithms to identify subgroups of patients with acute heart failure based on their responsiveness to diuretic therapy. Specifically, the researchers developed a diuretic efficiency phenomapping approach for patients with ADHF by using publicly available and deidentified data from several clinical trials and registries, including DOSE, ROSE-AHF, CARRESS-HF, ATHENA-HF, ESCAPE, and the American Heart Association Precision Medicine Platform Get with the Guidelines-HF (GWTG-HF) registry. This participant-level pooled data enabled the investigators to develop a phenomapping approach and diuretic efficiency score. The patients within each subgroup shared similar characteristics but were clinically distinct from other subgroups, particularly in their response to diuretic therapy. In addition to differences in their diuretic response, the patient subgroups also had meaningfully different clinical outcomes, highlighting the prognostic utility of the phenogrouping approach. The investigators subsequently developed and validated the BAN-ADHF score to predict the probability of being in the phenogroup with the least diuretic response.

“We know the BAN-ADHF score can accurately identify, characterize, and predict diuretic resistance among individuals with ADHF mathematically. Now we must take this medical knowledge and conduct a clinical study to evaluate whether implementing the BAN-ADHF score in our care protocols improves outcomes for patients hospitalized with acute decompensated heart failure,” shared Dr. Segar.

Notably, the work described in this study received recognition from the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI) as a winning solution to the NHLBI Big Data Analysis Challenge: Creating New Paradigms for Heart Failure Research. The challenge encouraged the development of novel, open-source disease models to define subgroups of heart failure and support further advancements in managing the disease. Additionally, Dr. Segar received the American Heart Association’s Samuel A. Levine Early Career Clinical Investigator Award for his role in developing the phenomapping tool and the diuretic resistance clinical risk score. As part of the honor, he presented his research on “Development and Validation of a Phenomapping Tool To Identify Patients With Diuretic Resistance in Acute Decompensated Heart Failure: A Multi-Cohort Analysis” at the American Heart Association’s 2022 Scientific Sessions.

Study collaborators included investigators from The Texas Heart Institute, Duke University School of Medicine, Cleveland Clinic, Houston Methodist DeBakey Heart and Vascular Center, University of Mississippi Medical Center, Baylor Scott and White Research Institute, St. Vincent Heart Center, The University of Texas Southwestern Medical Center, Ronald Reagan UCLA Medical Center, Institute for Precision Cardiovascular Medicine at the American Heart Association, Stony Brook University School of Medicine, Northwestern University School of Medicine, and University of Colorado.

Source:

Journal reference:

Segar, M. W., et al. (2023). A Phenomapping Tool and Clinical Score to Identify Low Diuretic Efficiency in Acute Decompensated Heart Failure. JACC: Heart Failure. doi.org/10.1016/j.jchf.2023.09.029.

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January 31, 2024