Are your patients taking their GLP-1s as prescribed?

Some patients on GLP-1s appear to be taking liberties with their dosing schedules, according to published case data and anecdotal evidence.

Current GLP-1 standards of care focus on once-weekly dosing, with doctor-recommended, supervised titration depending on outcomes and side effects. However, evidence is building that structured dose de-escalation (while still maintaining weight loss) might be an option for select patients.

“As an endocrinologist and obesity medicine physician, I’m really happy that these conversations are happening — first and foremost — because we are treating obesity as any other chronic disease,” Peminda Cabandugama, MD, director of digital obesity at the Cleveland Clinic in Cleveland and Obesity Society spokesperson, told Medscape Medical News.

“We’re talking about how to modify treatment — the same thing we do with other chronic diseases like diabetes and high blood pressure. Conversations about de-escalating treatment should not be shunned by any prescriber, whether or not they’re obesity medicine physicians or primary care physicians. This is a step in the right direction,” Cabandugama said.

From the Clinic to the Page

Mitch Biermann, MD, PhD, is an obesity medicine physician and scientist at Scripps Clinic in San Diego. He is also a co-author of a retrospective case series demonstrating how changing the GLP-1 dosing schedule might influence weight loss.

Biermann explained that taking GLP-1s less often is quite prevalent in his patients.

“A few patients came to me and told me that they were maintaining their weight, which I could see on my scales and body composition analyzer in the clinic that they were doing fantastically,” said Biermann. “After several patients either expressed upfront hesitancy about taking the medication every week for the rest of their lives (ie, they wouldn’t take it if there was no destination maintenance strategy) or had reached a good weight (and didn’t want to lose more) and expressed interest in tapering the medicine, I started recording it,” he said.

The result was a retrospective case series in 30 adults attending the Scripps Clinic prescribed semaglutide or tirzepatide (for type 2 diabetes, BMI ≥ 27 or ≥ 30 with at least one weight-related comorbidity) who had reached their weight loss plateau (< 5% variation over 3 months). Though 34 patients were offered de-escalation of their medication as part of clinical care (switching from once-weekly to every other week at their current dose), four opted to return to standard dosing due to weight regain.

The strategy “worked for roughly 88% of people, who maintained their weight. Statistically, they lost an additional 2% of their weight when they were taking the GLP-1 drugs every other week,” said Biermann.

He said that, in the overall sample, there were a few outliers, for example, six patients who changed the dosing frequency from 14 to 10 days (they couldn’t make it to 14 days because the food noise returned), one who went from 12 to 14 days, and five who spaced their doses further out to 3 weeks. One patient spaced out doses to every 5-6 weeks.

According to the chart data, patients initially reduced their BMI from roughly 30 to 25, and then further to a BMI of 24.6. Improvements in metabolic syndrome measures (eg, mean A1c, mean triglycerides, high-density lipoprotein, and blood pressure) were retained or slightly improved with the change in dosing frequency. Declines in prevalence of patients with any comorbidity were also observed.

Redefining ‘Nonadherence’

Researchers like Calvin Wu, MD, Brooklyn, New York-based endocrinologist and Sean Lawley, PhD, associate professor of math at The University of Utah in Salt Lake City, have been using real-world data and mathematical modeling to evaluate the degree to which agents such as semaglutide and tirzepatide are able to “forgive” changes in dosing frequency without causing patients to return to their former weight.

They’ve co-authored and published three papers (one in Obesity and two in Diabetes, Obesity and Metabolism) in which they found that GLP-1 efficacy was disproportional to dose size or dose frequency.

“What the mathematical modeling predicts, which I think is borne out by clinical experience, is that the reduction in body weight is not proportional to dosing size or frequency. We found that these drugs could be taken half as often but patients would still maintain 70%-75% of weight loss,” said Lawley.

Wu said that the modeling exercises (which, for semaglutide, relied on a recent pharmacokinetic [PK] and pharmacodynamic [PD] model, and for tirzepatide, a recent PK model and a reparameterized semaglutide PD to fit clinical data) emphasized how forgiving these medications can be.

The goal of the series of papers was to demonstrate not only that an altered GLP-1 dosing strategy can work for some patients but also that it can be translated into broader access, he said.

“By reducing frequency, you are reducing cost as well. So if you take one dose every 14 days instead of every 7, you can save that money and spend it elsewhere. Now we can think about helping twice as many people and potentially see 75% of the benefit at population scale,” said Wu.

There is a caveat, however.

Biermann emphasized that many of the people who were able to keep the weight off were exercising an average of an hour a day.

“When you exercise that much, your GLP-1 increases by something like 30% (which is tiny compared to what happens after bariatric surgery or drugs),” said Biermann.

“I think what it shows is that you don’t need that much excess GLP-1 to maintain weight loss than to lose weight initially. Exercise was the number one trait among people who kept it off.”

In the Clinic

Wu stressed the reduced dosing strategy is not for everyone.

“It’s about long-term benefits, really trying to work with the patient,” said Wu. “It’s about choosing the patients who are motivated, who’ve actually made the changes, and have seen them stick,” he said.

“What I want to convey is that there’s a gray zone with the GLP-1s; it’s not all or nothing,” said Wu.

The main goal, he noted, was that the strategy “needs to be personalized to the patient.”

“We taper other medicines based on clinical results, right?” said Biermann. “Patients instinctively want to taper medications, so if they express the desire, it’s fine for doctors to try.”

A key consideration is that alternate dosing strategies currently focus on frequency, not total dose, though that might also change in the future.

“I think that we are going to find that what the GLP-1s do best is reduce inflammation,” said Cabandugama. “One of the things researchers will have to look at is even if they titrate down the medications for weight loss, they might need a certain maintenance dose to address those other conditions,” he said.

“I tell my patients, if you have a history of heart attack, even when you get to your goal weight, I will keep you on the smallest therapeutic dose for maintenance and cardiac protection,” said Cabandugama.

“There are a lot of nuances that need to be taken into account,” he said.

Cabandugama, Lawley, and Wu reported having no relevant financial relationships. Biermann reported being a clinical site investigator for Eli Lilly and Company and Novo Nordisk and serving as a consultant to Icon Pharmaceuticals.

Liz Scherer is an independent health and medical journalist. She frequently writes about GLP-1s and obesity.