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.
