N.G. Boeck

With the new generation of anti-obesity medications such as Wegovy and Zepbound, adherence is key, as patients must remember to take them weekly. However, a new medication taken less frequently may offer similar results.

In a Phase II clinical trial, researchers found maridebart cafraglutide (MariTide) was effective at reducing weight in patients with obesity with just once-monthly doses. And this was true for patients with or without type 2 diabetes.

, professor of medicine (endocrinology) at Yale School of Medicine and director of the 

, served as the principal investigator for the Phase II trial evaluating the safety and efficacy of MariTide.

MariTide works by targeting the action of two hormones: glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both hormones are involved in the regulation of blood sugar and, importantly, they target the brain mechanisms associated with obesity.

Like several approved treatments, MariTide works at the receptor for GLP-1, activating it by mimicking the natural hormone. Uniquely, MariTide also blocks the action of GIP at its receptor. This dual action is thought to both help the body regulate blood sugar and treat obesity.

The trial included two groups of patients: 465 people with obesity (defined as a body mass index of over 30 or over 27 with an obesity-related disease) and 127 with both obesity and type 2 diabetes. During the year-long trial, study participants received MariTide in various dosages at a frequency of once per month or once every other month.

Overall, the study showed that the obesity-only cohort lost up to an average of 20% of their body weight, while the obesity-diabetes cohort lost up to an average of 17% of their body weight. Hemoglobin A1c, a measure of blood glucose levels, decreased up to an average of 2.2% in the patients with diabetes.

The fact that both cohorts of patients—those with and without type 2 diabetes—lost weight at similar rates was a surprise to Jastreboff and her colleagues.

“This was an intriguing finding,” says Jastreboff. “Usually with the medications in this class, we observe less weight reduction in patients with obesity and type 2 diabetes than in those who have obesity alone. In this study, the discrepancy between participants with and without diabetes was not as large as we usually observe.”

Patients enrolled in the study reported mostly mild to moderate side effects including nausea, vomiting, constipation, and diarrhea consistent with other medications in this class. A more gradual increase in dosage, tested in several groups in the obesity-only cohort, was associated with fewer gastrointestinal side effects.

Clinical trials are conducted in four phases. A Phase I trial assesses how the body interacts with the drug and evaluates safety in a small number of participants, while a Phase II trial assesses safety, tolerability, and efficacy in a few hundred participants. A Phase III trial expands the number of participants to a large group to assess whether the new treatment leads to better outcomes, monitoring side effects while evaluating efficacy, and a Phase IV trial, conducted after a medication has been approved by the U.S. Food and Drug Administration, assesses long-term outcomes, risks, and benefits.

The promise of these drugs is immense, as obesity is both a chronic disease and a leading cause of death and disability in the United States. Currently, about 42% of adult Americans are classified as having obesity, according to the U.S. Centers for Disease Control and Prevention. Of the 38 million Americans with diabetes, 

90% are also classified as overweight or having obesity.

Left untreated, diabetes leads to high levels of blood sugar, which can cause heart disease, nerve damage, and kidney disease, among other risks. These health risks underscore the promise of the emerging generation of medications that can have a significant impact on improving health.

Jastreboff says that while more research is needed to understand the underlying mechanisms by which MariTide might be helping patients with and without diabetes lose weight at similar rates, the Phase II trial results are promising. The ability for patients to require less-frequent dosing of the medications could lead to improved adherence to treatments and better overall health outcomes.

Currently, Jastreboff and her colleagues are conducting the Phase III study assessing once-monthly MariTide dosages in the MARITIME-1 trial at Y-Weight.

If you are interested in taking part in this or other clinical trials investigating novel anti-obesity medications, please email Yweight@yale.edu.

The research reported in this news article was supported by

Articles

A new anti-obesity medication, maridebart cafraglutide (MariTide), shows promise in reducing weight with once-monthly doses, offering a potential advantage over weekly treatments like Wegovy and Zepbound. In a Phase II trial, MariTide demonstrated significant weight loss in patients with obesity, both with and without type 2 diabetes, by targeting GLP-1 and GIP hormones. The trial revealed similar weight loss rates in both patient cohorts, a surprising finding. Mild to moderate side effects were reported, and further research is ongoing to explore the drug's mechanisms and efficacy.

Cafraglutide was effective with less frequent dosing than currently available medications that target GLP-1.

Once-Monthly Obesity Medication Shows Promise for Those With and Without Type 2 Diabetes

It’s widely recognized that our health is determined by more than our genetics. Socioeconomic factors, physical activity, nutrition, substance use, and even job stress are among the many other factors that play a role. Now, Yale researchers, led by 

 associate professor of surgery (general, trauma, and surgical critical care) at Yale School of Medicine (YSM), recently published two studies that identify populations of older Americans that could be at greater risk for earlier death or disability based on where they live.

The researchers created new composite indices to identify populations of Americans 65 years of age and older whose overall health could be affected by specific state- and county-level conditions. These indices—the geriatric index of state-level health policy contextual disadvantage (called the “GERi-State” index) and the geriatric index of county-level multi-dimensional contextual disadvantage (the “GERi-County” index)—consider measurements such as tobacco taxes and the number of older adults living below the poverty line at the state level, and median household income and physician density at the county level, to assess health risks for older Americans.

The researchers found that older Americans in the lowest 20% of both the state and county-level indices were at significantly higher risk for mortality. Older Americans in the lowest 20% of the county-level index were more susceptible to several types of age-related health conditions, including frailty, probable dementia, and disability, meaning the inability to perform tasks associated with daily living, such as getting out of bed and getting dressed. Their findings were published in 

Journal of the American Geriatrics Society

Our research shows that these geographic factors appear to be vitally important in assessing health risks in this population. These two studies are just the start of trying to understand the crossroads of older Americans, disadvantage, and health, including major surgery.
Robert D. Becher, MD

Becher, a surgeon by training, explains that his interest in geriatric health outcomes based on geography came about because of the differences he saw in post-surgical outcomes among his older patients. He notes that while 

one in every seven older Americans will need major surgery

 at some point in the years ahead, in his own practice he observed that some patients experienced significantly better recovery than others. That led him to ask deeper questions about what kinds of factors affect older Americans’ overall health outcomes.

“One of the most consistent findings in the medical literature is that place matters,” he explains. “The social, economic, environmental, and policy contexts at different geographic levels create complex structural conditions in daily life that are fundamental determinants of health outcomes, rather than just mediators.”

Becher’s goal is to understand why different populations of older adults have different outcomes after major surgery, which could ultimately lead to better health outcomes, systems, practices, and policies that improve care for all older people in the United States.

Creating single indices that measured state- and county-level factors that could contribute to health differences, Becher reasoned, would help inform health policy at the state and county levels aimed toward improving the health of older adults.

, Becher and his research team, used, in part, the World Health Organization’s socio-ecological framework to help determine which factors to use in their composite indices. The framework is a theoretical model that describes the many measurable factors that shape health and health outcomes across societies.

The research team included co-senior author 

 Humana Foundation Professor of Medicine (Geriatrics) at YSM and professor of epidemiology (chronic diseases) at Yale School of Public Health (YSPH); 

 assistant professor of sociology in the Faculty of Arts and Sciences, of biostatistics at YSPH, and of global affairs; 

 assistant professor of biostatistics at YSPH; and 

, a postdoctoral associate in the Department of Internal Medicine at YSM.

For their indices, the researchers focused on factors that could potentially be modified at the state and county levels through legislation, for example, or improvements in health policy. They focused on variables that could be measured in all 50 U.S. states for which historical data existed for the period from 2006 to 2019. For example, state-level variables included preventable hospital stays, which are highly correlated with health care accessibility and quality; county-level variables include physician density, which predicts a local population’s ability to access preventive care as well as care for chronic conditions. States and counties were considered socially disadvantaged if they scored in the lowest 20% of the GERi-State and/or the GERi-County indices.

Using these criteria, the researchers classified 10 of 50 U.S. states and 627 of 3,132 counties as “disadvantaged.” The disadvantaged states were generally concentrated in the American South in both timeframes studied. Disadvantaged counties were more widely spread out, mostly located in the American South, as well as the southwest and western portions of the United States.

From there, the researchers looked at death rates in the 65-and-older population of each state and county being studied, focusing on community-living older adults—those who were able to participate in the life of their community, as opposed to being treated in a nursing home. The researchers examined whether the disadvantaged states and counties showed statistically significant higher rates of death in this older population.

 the same team of researchers, along with YSM biostatistician 

 examined rates of frailty, probable dementia, and disability, in disadvantaged vs. non-disadvantaged counties.

Geography affects health at both the state and county level

The researchers found that mortality rates were consistently higher in both disadvantaged counties and disadvantaged states for two time periods, 2010-2015 and 2014-2019. For these time periods (used to test the robustness of the indices over different time periods), disadvantaged states showed an 11% and a 14% increased risk of premature mortality, respectively. Disadvantaged counties showed a 10% increased risk of premature mortality in both time periods.

In the second study, the researchers found that among 7,499 study participants in the 65-and-older age range, the five-year incidence rates for all health conditions measured—frailty, dementia, and disability—were significantly higher in the disadvantaged versus non-disadvantaged counties.

Becher hopes that these studies will help highlight the importance of geography when considering the health and well-being of older Americans.

“Our research shows that these geographic factors appear to be vitally important in assessing health risks in this population,” Becher says. “These two studies are just the start of trying to understand the crossroads of older Americans, disadvantage, and health, including major surgery.”

The research reported in this news article was supported by Yale Claude D. Pepper Older Americans Independence Center (award P30AG021342), the National Institute on Aging (award U01AG032947), the National Institute on Minority Health and Health Disparities (award R01MD017298), and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Yale researchers have developed indices to assess health risks for older Americans based on geographic factors, identifying populations at higher risk for mortality and age-related conditions. The GERi-State and GERi-County indices evaluate state- and county-level conditions, such as tobacco taxes and physician density, to determine health disadvantages. Findings indicate that older adults in disadvantaged areas face increased risks of mortality, frailty, dementia, and disability. These studies underscore the significance of geographic factors in health outcomes and aim to inform policies to improve care for older populations.

Yale researchers reveal how geographic factors impact health risks for older Americans, highlighting disparities in mortality and disability rates.