NLA 2025: Practical Strategies for Identifying the Right Patient for Incretin Therapy

The use of incretin-based therapies has rapidly expanded in recent years, driven by advances in understanding their mechanisms, efficacy across multiple metabolic outcomes, and broadening indications. Pharmacists play a pivotal role in translating this evolving science into clinical practice, helping to optimize patient outcomes through appropriate patient selection, counseling, and management of these therapies.¹

At the 2025 National Lipid Association (NLA) Scientific Sessions, Layla Abushamat, MD, MPH, DABOM, assistant professor in the Section of Cardiovascular Research at Baylor College of Medicine in Houston, Texas, provided a review of incretin biology, the expanding therapeutic indications of glucagon-like peptide-1 (GLP-1) and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) receptor agonists, and practical considerations for identifying patients who may benefit from these therapies.¹

Mechanisms of Action and Therapeutic Potential

A microscopic view of a GLP-1 molecule. Image Credit: © Tameem - stock.adobe.com

Incretins, such as GLP-1 and GIP, are gut-derived hormones secreted postprandially. GLP-1 is secreted by L-cells in the ileum and colon in response to food intake, and GIP is secreted by K cells in the duodenum and jejunum. These hormones augment insulin secretion in a glucose-dependent manner, inhibit glucagon release, slow gastric emptying, and promote satiety through central nervous system effects.¹

However, the endogenous half-life of these hormones is limited (approximately 2 minutes) due to rapid degradation by the enzyme dipeptidyl peptidase-4. Pharmacologic therapies have harnessed these pathways by developing receptor agonists with extended half-lives and enhanced efficacy, including GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists.¹

Indications and Expanding Populations for Incretin Therapy

Data from clinical trials demonstrate the potent efficacy of incretin-based therapies in lowering glycated hemoglobin (A1c) and promoting weight loss. For example, semaglutide (Ozempic, Wegovy; Novo Nordisk), a GLP-1 receptor agonist, and tirzepatide (Mounjaro, Zepbound; Eli Lilly), a dual GLP-1/GIP receptor agonist, achieve A1c reductions of up to 2%, compared to approximately 1% with earlier agents such as liraglutide (Victoza, Saxenda; Novo Nordisk), which is also a GLP-1 receptor agonist.¹

Abushamat highlighted a key shift occurred in the American Diabetes Association (ADA) standards of care, which now recommend GLP-1 receptor agonists as a first-line injectable therapy in uncontrolled type 2 diabetes before the initiation of insulin.¹

“These [therapies] are so effective that our ADA standards of care now actually suggest GLP-1 and GLP-1–based therapies to be the first-line injection therapy for people who have very uncontrolled diabetes, so you should actually consider them prior to starting insulin in these patients,” Abushamat said during the NLA presentation.¹

Notably, the SELECT trial (NCT03574597), a randomized, double-blind, placebo-controlled cardiovascular outcomes trial of semaglutide 2.4 mg once weekly, enrolled 17,604 adults aged 45 and older with overweight/obesity and established cardiovascular disease (CVD), excluding diabetes. SELECT demonstrated a 20% relative risk reduction in major adverse cardiovascular events (MACE), underscoring the potential of GLP-1 receptor agonists to extend benefits beyond glucose and weight control.^1,2

Additionally, although weight loss outcomes with incretin therapies vary across agents, newer agents such as investigational retatrutide (LY3437943; Eli Lilly and Company) have demonstrated weight reductions comparable to bariatric surgery.¹

A surgery being conducted. Image Credit: © Vadim - stock.adobe.com

“With lifestyle intervention, our most effective therapy is actually bariatric surgery,” Abushamat said. “One hundred percent of people lose weight with bariatric surgery, and also 100% of people lose weight with endoscopic intervention as well, which is a newer option… But we do have several new therapies that are being investigated, and you can see some of these therapies achieve levels that we typically have only seen before with bariatric surgery, such as retatrutide, which is our triple agonist.”¹

Current FDA-approved indications for incretin therapies are broadening. All GLP-1 receptor agonists are indicated for type 2 diabetes. Liraglutide, dulaglutide (Trulicity; Eli Lilly), and semaglutide have additional approval for patients with type 2 diabetes and established atherosclerotic CVD (ASCVD). For overweight and obesity management, liraglutide, semaglutide, and tirzepatide are approved; semaglutide is also specifically indicated for obesity with ASCVD, while tirzepatide holds an additional indication for obesity with obstructive sleep apnea. Emerging research points to potential future indications, including for metabolic dysfunction-associated steatotic liver disease, heart failure with preserved ejection fraction, and chronic kidney disease.¹

According to analysis of National Health and Nutrition Examination Survey using 2015 to 2020 data scaled to the 2020 US census, more than half of US adults—approximately 140 million individuals—meet eligibility criteria for incretin therapy based on current indications. This highlights the public health significance of optimizing patient selection in therapy initiation, engagement, and monitoring, according to Abushamat.¹

Defining Obesity Beyond BMI

Abushamat emphasized that body mass index (BMI)–based definitions of overweight and obesity, though standard in clinical trials and regulatory approvals, are imperfect. BMI cutoffs (≥27 kg/m² for overweight with comorbidities, ≥30 kg/m² for obesity) are based on mortality and cardiometabolic risk associations in predominantly White populations and may not accurately reflect risk in diverse racial and ethnic groups.¹

“A BMI of over 30 would be obese, and that accounts for about 42% of Americans. But these are population-based definitions. They do vary by age, sex, race and ethnicity, and so they may not be ideal for every individual patient when they come in front of you, but anti-obesity medications were studied under these definitions, and so a BMI of greater than or equal to 27 with a weight related co-morbidity is an indication for therapy, as well as a BMI of greater than or equal to 30. But as I mentioned, it's not an ideal measurement,” Abushamat said. “Particularly I really want to stress that cutoffs are developed from observational studies that were mostly done in White or European populations based on the association of BMI to mortality as well as cardiometabolic outcomes.”¹

Abushamat explained that when looking at cutoffs based on race and ethnicity, the changes are actually drastic.¹

“The BMI cutoff of 30 is based on when someone has a higher risk for diabetes in a White population, but for South Asians, that same amount would really be at a BMI of around 23 or 24. So really, these cutoffs should probably be adapted, not only by sex and age, but also by race and ethnicity,” Abushamat said. “Now the NLA, along with Obesity Medicine Association, did put out a joint expert review last year acknowledging this definition of obesity [should be] more than just adipocyte hypertrophy and increased adipose tissue accumulation, but also adiposopathy, or that it leads to local and systemic insulin resistance, and we see adiposopathic dyslipidemia that leads to lipid abnormalities that we typically see in our patients with overweight and obesity.”¹

Abushamat noted that additional measures should be considered as a measurement of overweight, obesity, and adiposopathy, such as waist circumference, waist-to-hip ratio, or body composition assessments (eg, dual-energy X-ray absorptiometry or magnetic resonance imaging) when evaluating patients. However, Abushamat acknowledge there are practical limitations of these methods in routine clinical practice.¹

Ultimately, Abushamat recommended a shift from BMI-centric to complication-centric prescribing that focuses on obesity as an adiposity-based chronic disease (ABCD) characterized by dysfunctional adipose tissue, inflammatory mediators, and hormonal dysregulation.¹

“BMI is not great, and really one of the first steps is acknowledging that obesity is a chronic disease, just like hypertension, diabetes, and hyperlipidemia. We really should be thinking of this from the perspective of managing different stimuli, as well as hormones, and that it's an ABCD. So, we [should] not only focus on the amount of adiposity, but also its function. What hormones are put out by the adipose tissue, what inflammatory markers are present, as well as distribution, so that it's both a fatty mass disease as well as a sick fat disease,” Abushamat said.¹

A shift away from BMI to ABCD evaluation may help reduce weight stigma and support more equitable, patient-centered care, Abushamat explained.¹

“[This strategy] helps with reducing weight stigma. I mentioned the stigma relating to obesity is so high, and there's a lot of internalized weight bias among patients with obesity,” Abushamat said. “Shifting away from a BMI-centric approach to more of a complication-centric approach [helps to] focus on obesity-related complications for patients, and there's a lot of evidence for doing so.”¹

Patient Selection Considerations

While incretin therapies offer significant benefits, their use requires thoughtful counseling on tolerability and adverse effects (AEs). Gastrointestinal AEs (eg, nausea, diarrhea, constipation) are common, affecting 40% to 70% of patients, but are typically transient and manageable with slower dose titration, dietary modifications, hydration, and supportive measures such as ginger chews or teas.¹

Additionally, GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Caution is also warranted in patients with a history of gallbladder disease or pancreatitis.¹

Incretin therapies may also affect the absorption of oral medications such as warfarin, thyroid hormone, and oral contraceptives, according to Abushamat. Counseling should reinforce the importance of adherence to dosing schedules—particularly resuming at a lower dose if therapy is interrupted for more than 14 days—and holding therapy for 7 days prior to surgery to reduce anesthesia-related risks.¹

Clinical Considerations

There are many potential barriers to accessing incretin therapies for patients, according to Abushamat. There has been a chronic long-term medication supply issue with these therapies, and there are also challenges for patients related to cost and insurance coverage.¹

“I know there were a lot of supply issues, and that led to them being on the short supply list, and kind of the proliferation of compounding pharmacy use of these medications,” Abushamat said.¹

Additionally of note, patients can have variable responses with incretin therapies. “Not everyone necessarily benefits from a GLP-1 and may have better benefit with other therapies,” Abushamat said.¹

The prevalence of discontinuation of incretin therapies is also an important clinical consideration, according to Abushamat.¹

“Thirty-six point five percent of patients do discontinue these therapies within a year, and when you look at those with obesity, 50% discontinue, and a lot of that has to do with the fact that they get less coverage of these therapies under insurance,” Abushamat said. “We have a long way to go when it comes to cost, coverage, adherence, as well as demand and supply, so it's an active discussion I think that we all need to have as a medical community.”¹

Conclusion

Considerations related to patients’ ability to obtain, tolerate, and adhere to incretin therapy is what is really important when it comes to patient selection for these medications, Abushamat explained.¹

“I am excited about the future of these medications. But we have a long way to go with improving access and affordability and reducing stigma towards obesity,” Abushamat said. “There are exciting data for pharmacogenetics as well as increasing options [become available], hopefully in the near future, and this reduction in variable response may lead to greater benefit for the majority of our patients.”¹

REFERENCES

1. Abushamat L. Incretin Therapy: Who is the right candidate? NLA Scientific Sessions; Miami, Florida; May 29-June 1.

2. Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT). Clinicaltrials.gov. Updated August 30, 2024. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT03574597