WHOLE BODY BENEFITS OF GLP-1 MEDICATIONS

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From Medscape Medical News

Carolyn Crist

October 28, 2024

The potential of glucagon-like peptide 1 (GLP-1) receptor agonists continues

to grow more promising as new studies identify benefits beyond glucose

control and weight loss.

With hundreds of studies underway or recently completed on

ClinicalTrials.gov, the signals are becoming clearer: GLP-1 medications

appear to boost patient outcomes across the body, leading to improvements

in cardiovascular (CV), gastric, hepatic, and renal values. GLP-1 drugs also

seem to be linked to mental and psychological changes, with researchers

finding positive shifts in addictive and compulsive behaviors.

Beyond the current popular options — semaglutide (Ozempic/Wegovy) and

tirzepatide (Mounjaro/Zepbound) — newer options may prove to be even

more effective for weight loss and systemic improvements. While

semaglutide mimics the GLP-1 hormone to regulate blood sugar, appetite,

and digestion, tirzepatide acts as a dual receptor agonist of both GLP-1 and

glucose-dependent insulinotropic polypeptide (GIP), often leading to greater

weight loss.

Next-generation drugs (such as Eli Lilly’s retatrutide) will operate as triple

agonists, targeting GLP-1, GIP, and glucagon receptors and potentially

offering even better results. Today’s phase 3 clinical trials could set the

scene for new options to be available in 2025 and 2026.

Andres Acosta, MD

“More pharmaceutical companies are jumping into the research pipeline, and

the GLP-1 era is going to be like the era of statins,” said Andres Acosta, MD,

associate professor of medicine at Mayo Clinic and principal investigator of

Mayo’s Precision Medicine for Obesity Laboratory in Rochester, Minnesota.

Acosta spoke about the potential of GLP-1 use in clinical gastroenterology

practice at Digestive Disease Week in May.

“In the next 3 years, we’re going to learn more about how the gut signals to

the brain through intestinal hormones, and we’ll see more molecular targets

such as GLP-1, GIP, glucagon, insulin, amylin, leptin, and so on — we’ll have

peptides targeting each receptor,” he said. “Who’s going to win? Retatrutide

seems to be taking the lead so far, but we’re waiting to see the data on what

delivers the best weight loss and improvement for comorbidities.”

Here's a look at the latest research and promising results:

Heart Health

After trying to address diabetes and obesity, GLP-1 studies have focused on

CV risks and events. The SELECT trial found semaglutide consistently

reduced major adverse CV events by about 20% among patients with prior

CV disease and overweight or obesity. The drop was observed for CV-related

death, nonfatal myocardial infarction, and nonfatal stroke. The STEP-Heart

Failure With Preserved Ejection Fraction (HFpEF) trial also found multiple

improvements among patients with obesity-related HFpEF.

In addition, GLP-1 mechanisms appear to have direct effects on blood

vessels, blood pressure, and lipids, which can further influence CV-related

risks and events, according to 2024 analyses of SELECT trial data.

Darren McGuire, MD

“We continue to discover new effects in expanded populations for these

medications, with not only favorable effects on CV risk, weight, and glycemic

control, but also lipid profiles and blood pressure,” said Darren McGuire, MD,

professor in the Department of Internal Medicine and chair of Cardiovascular

Science at the University of Texas Southwestern Medical Center in Dallas.

McGuire and colleagues wrote about the SELECT trial and recent data

analyses in July in Nature Medicine and what the results could mean for

clinicians.

“The biggest unknown is how we might afford their use on the societal level,

especially for the weight loss indication,” he told Medscape Medical News.

“And how soon we might start them for such — such as adolescence. It

would also be great to explore early use in patients characterized as a

primary prevention population to see if we can inflect CV risk over a longer

time horizon.”

Renal Health

After heart-related outcomes, researchers have looked at GLP-1 use and

kidney function. The FLOW trial found semaglutide prevented major kidney

disease, CV events, and death in patients with chronic kidney disease (CKD)

and type 2 diabetes.

In particular, patients who took semaglutide had a 24% lower risk for a

major kidney event, such as kidney failure onset, dialysis, or transplantation,

as well as death from kidney- or CV-related causes. The risk for death from

any cause was also 20% lower.

“GLP-1/GIP can be viewed as agents that holistically reduce the totality of

risks in cardiovascular-kidney-metabolic syndrome,” said Katherine Tuttle,

MD, executive director for research at Providence Inland Northwest Health

and professor of medicine in nephrology and kidney research at the

University of Washington, Seattle. Tuttle is a FLOW co-investigator.

“Semaglutide is a foundational therapy proven to save kidneys, hearts, and

lives in persons with type 2 diabetes and CKD,” she said. “Ongoing studies of

semaglutide — and other GLP-1/GIP agents — will further elucidate safety

and efficacy across the drug class for CKD in persons without diabetes and in

type 1 diabetes.”

Hepatic Health

Scientists are beginning to note the emerging role of anti-obesity drugs in

liver function as well. In a September analysis published in JAMA Internal

Medicine, GLP-1 use was associated with a statistically significant reduction

in the risk for progression to cirrhosis among patients with metabolic

dysfunction–associated steatotic liver disease, or fatty liver disease

Other studies have shown reduced risks for hepatocellular carcinoma, liver

transplant, and liver-related death as well.

“Choose any organ you like, and obesity is a major contributor to its most

important disease,” Acosta said. “The GLP-1 era is exciting, and we don’t

need to hide it. These medications are changing the conversation about

obesity.”

Bone Health

Beyond the benefits to organs, GLP-1 options may be able to help

musculoskeletal conditions, too. The STEP 9 trial found semaglutide

improved knee pain and physical function in people with knee osteoarthritis

(OA). Although weight loss can certainly reduce knee pain, researchers are

also investigating whether GLP-1 drugs act specifically on joints through

metabolic changes.

“These drugs potentially offer game-changing impact in the field of

osteoarthritis where there are currently no disease-modifying treatments

and conventional analgesia is either contraindicated or inadequate,” said Co-

author Tonia Vincent, MBBS, a professor of musculoskeletal biology and an

honorary rheumatologist at the Kennedy Institute of Rheumatology at

Oxford University, Oxford, England.

“However, there is still much we do not understand about these drugs and

the effects they have on normal functioning of musculoskeletal tissues,” she

said. “We know that weight loss is one of the few things that really works for

OA symptoms and disease progression, but we also need to ensure that this

is balanced by enhanced nutritional support.”

Mental Health

Studies worldwide have looked more closely at behavioral and psychological

outcomes linked to GLP-1 use. So far, researchers have found declines in

addictive behaviors, such as heavy drinking, smoking, opioid use, gambling,

and shopping, as well as lower risks for suicidal thoughts or suicide

attempts.

Based on functional MRI studies, GLP-1 drugs appear to decrease the

activation of brain reward centers, which can reduce addictive behaviors. In

addition, psychological benefits could stem from weight loss or other

reasons, scientists in Israel wrote in an October article on suicidal ideation or

attempts in adolescents with obesity in JAMA Pediatrics.

“While the weight loss associated with GLP-1 treatment may indeed improve

body image and overall mental health, other potential mechanisms could

also be at play,” said Co-author Liya Kerem, MD, a pediatric endocrinologist

at Hadassah University Medical Center in Jerusalem, Israel.

“These may include effects on neuro-inflammation and neural pathways

related to reward and food addiction,” she said. “However, these remain

preliminary, and further research is necessary to explore these pathways in

depth and establish any direct connections.”

Full-Body Health

Additional GLP-1 associations are emerging weekly, it seems, with positive

results seen for inflammation, sleep health, and Alzheimer’s disease (EVOKE

trial).

In the SURMOUNT-OSA trial, for instance, tirzepatide reduced symptoms of

obstructive sleep apnea and improved sleep-related outcomes reported by

patients. Based on SELECT trial data, semaglutide led to a 38% reduction in

the inflammatory marker high-sensitivity C-reactive protein, even in patients

who didn’t lose much weight.

Current trials recruiting patients are looking at the effects of semaglutide or

tirzepatide on breast cancer risk factors, psoriatic arthritis, and polycystic

ovary syndrome.

Phase 1 trials are beginning to study GLP-1 safety and tolerability in younger

ages, including children aged between 6 and 11 years with

obesity and adolescents aged between 12 and 17 years with weight-related

comorbidities, and a phase 4 study will soon conclude in older adults aged

over 65 years.

“While not indicated for such, in observational analyses these medications

are associated with improvement in cognitive decline, increased success for

tobacco and alcohol reduction or cessation, improved biomarkers of

metabolic-associated fatty liver disease, etc.,” McGuire said. “And as next-

generation agents continue to hold promise to augment even further the

weight loss achieved, it really seems like a lot of work yet to be done.”

McGuire reported research support for clinical trials leadership from

Boehringer Ingelheim, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly

USA, and CSL Behring, as well as honoraria for consultancy from Lilly USA,

Pfizer, Boehringer Ingelheim, Lexicon, Novo Nordisk, Applied Therapeutics,

Altimmune, CSL Behring, Bayer, Intercept, and NewAmsterdam Pharma.

Kerem reported receiving personal fees from Novo Nordisk for three invited

lectures on childhood obesity given in Israel.