“DIABESITOLOGY”: A Call to Action for Novel Clinical Trial Designs in the Golden Era of GLP-1 Axis Medications

“DIABESITOLOGY”: A Call to Action for Novel Clinical Trial Designs in the Golden Era of GLP-1 Axis Medications

Jamie P. Dwyer, MD

(Source from LinkedIn): Associate Dean for Clinical Research, Professor of Medicine, and Director of the Utah DCC, PI of the Collaborative Study Group, Co-Founder of Corventum, Biorasi Scientific Advisory Board Member

A Golden Age for Obesity Drugs

The clinical treatment of obesity has radically changed in only the past few years. GLP-1 (Glucagon-like peptide-1) medications were initially developed in 2005, to help people with Type 2 diabetes control their blood sugar levels. Over time, researchers found that GLP-1 agonists also acted to decrease appetite and promote weight loss by suppressing urges to eat. This led to further studies on the use of GLP-1 agonists as weight loss medications. Today, the FDA has approved the use of semaglutide and high-dose liraglutide to help treat obesity.1 (tirzepatide/Mounjaro is approved as well) That approval has opened the door to a Golden Era of original weight loss drugs that work along the GLP-1 axis.

Nephrologist Dr. Jamie Dwyer, Professor of Medicine at the Data Coordinating Center and Clinical and Translational Research Institute at the University of Utah, and Biorasi Scientific Advisory Board Member, shared his belief that these drugs will go far beyond mere weight loss. “The single most important thing about these drugs, is they shut off appetite in the brain,” Dr. Dwyer said.

“We are now recognizing that GLP-1 type drugs reprogram the way your brain seeks reward from pleasurable interactions, like food. But there is so much more to be studied. These medications are being shown to reduce cravings for tobacco, alcohol, and even more addictive substances. Drugs operating on the GLP-1 axis are rife with potential.

“If there are 130 of these drugs under development…and say 50 percent of them fail, that is still 65 drugs that could enter phase three trials. I think that we are opening the door to an era of obesity related interventions and connections that hasn’t happened before. We are going to have so much clinical trial data that comes from these drugs, that the data being collected is ‘going to be obese’.”

Making Connections

In a recent lecture at Vanderbilt University School of Medicine, Dr. Dwyer spoke about cardiovascular clinical trials and the opportunity of detecting kidney progression events embedded within them. He also applied that linkage to an example of clinical trials for GLP-1 axis therapies like semaglutide.

“There’s a history of this, where the outcomes originally were hypothesis generating. We would look at various early biomarkers and surrogate outcomes and generate a hypothesis. And then from that hypothesis, a pivotal clinical trial could be launched at a later date. “The SUSTAIN program with semaglutide combined data from many trials and revealed a signal that the kidney was being protected. It was really just a hypothesis, but that is what triggered the launch of the FLOW clinical trial.”

The 2019 FLOW clinical trial investigated the effects of a GLP-1 agonist semaglutide, on kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD):

• The trial was a randomized, double-blind, parallel-group, placebo-controlled trial with 3,533 subjects with type 2 diabetes and CKD across 28 countries at 400 investigator sites.
• Participants received injectable semaglutide 1.0 mg or a placebo in addition to standard care.
• The results: The semaglutide demonstrated a 24 percent reduction in kidney disease progression and mortality compared to the placebo and a secondary end point also showed superiority over the placebo for other kidney-related outcomes. 2,3

“The FLOW trial, after the SUSTAIN program, applied the notion that you do a series of studies, develop a hypothesis, and then decide whether or not you want to tackle another indication,” said Dr. Dwyer. “But there is another method that is becoming increasingly in vogue – that scientists utilize novel clinical trial designs to estimate the totality of benefit for a drug. In that way, one study will answer multiple questions simultaneously. This is something that I think is seriously taking off, particularly in area of kidney medicine. Kidney issues and the cardiovascular risk factors associated with patients that have kidney disease can be studied together. You can enrich a trial design with kidney patients and get cardiovascular outcomes.”

“DIABESITOLOGY”

Dr. Dwyer believes so strongly in the inter-relatability of risk factors, that he has coined his own idiom for this new era of study. “We are now entering an era of studies in ‘Diabesitology,’ where I think we’re going to see clinical trials for multidimensional states of disease: The study of diabetes, obesity, metabolic disease, heart failure, cardiovascular and kidney disease.”

Instead of studying an individual disease state, the notion of diabesitology explores a multidimensional state of disease. There are currently over 100 interventions in development for obesity right now. With the many drugs that work along various weight loss axes, the extensions of the pathophysiology of how semaglutide works to cause weight loss can now be explored.

Dr. Dwyer illustrated the logic of his point by posing the question – “Do drugs that reduce obesity, prevent you from having a car accident?”

“Maybe there is a correlation. These drugs seem to work along so many different axes, that we find ourselves with data demonstrating reduction in all-cause mortality and other unique outcomes. For example, semaglutide was recently demonstrated to reduce the symptoms of sleep apnea.”

There is emerging substantiation that GLP-1 axis medications may help alleviate symptoms of sleep apnea. Obesity is a primary risk factor for obstructive sleep apnea (OSA), and weight reduction has been shown to improve sleep apnea symptoms. Therefore, semaglutide may help reduce sleep apnea symptoms primarily through weight loss, but there is also additional evidence surfacing that suggests that there are sleep benefits from semaglutide that are independent of weight loss. 4

“So given that result, could drugs like semaglutide reduce the risk of something as outrageous as a car accident?” he asked. “If you lose enough weight, you may have less daytime sleepiness from your sleep apnea, and in that case, you may be less likely to fall asleep at the wheel. That in turn may lead to a reduction in the total number of car accidents, and thus a reduction in the number of deaths due to automobile accidents. The trials may never demonstrate this, but it’s an intriguing hypothesis.”

Dr. Dwyer uses the example of GLP-1 drugs like semaglutide as a launching point to encourage students and colleagues to meditate on new ways to test for kidney disease and prevent kidney progression

embedded within other studies. “These drugs work across so many different axes related to obesity, but we should be expanding our thinking to include studying some of these drugs for other indications as well.”

“These are the first versions of these types of drugs. So on the one hand, we may hail them as revolutionary, and on the other hand, 30 years from now, we may look back and say, well, those were rusty needles, you know, those were not optimal therapies and that as we iterate on them and study them, we’ll find ways to reduce side effects, improve adherence, get people to be able to tolerate them better. When you take one molecule and have it tackle more than one thing, you can get a panoply of benefit.”

A Call to Action for Access

“I’m a clinical trialist, and I am always thinking in terms of the way we can apply these ideas to study designs, to answer new questions.” said Dr. Dwyer. “Clinical trials are unique places that offer safer care delivery and define how medicines are applied. If you follow what was done in the clinical trial, you are much more likely to replicate the results clinically,” he added.

Dr. Dwyer feels that large-scale growth in studies along the GLP-1 axis lies in the multi-level of applications for these compounds.

“Multiple drugs, multiple trials, multiple indications,” said Dr. Dwyer. “In order to investigate this many compounds, we should have trials with mechanisms in place to evaluate many of these interventions simultaneously across a broad range of outcomes. I feel that innovation in drug development is going to spur the use of novel clinical trial designs and conduct for the benefit of all.”

With any revolutionary therapy that captures the imaginations of the public, there will be obstacles surrounding access to these therapies. In a recent L.A. Times article, “‘Miracle’ weight-loss drugs could have reduced health disparities,” Dr. Lauren Eberly, a cardiologist and health services researcher at the University of Pennsylvania is quoted as saying, “These patients have a higher burden of disease, and they’re less likely to get the medicine that can save their lives. I feel like if a group of patients has a disproportionate burden, they should have increased access to these medicines.” 5 There is a plethora of reasons why access for some may be limited, but the primary driver is cost.

Dr. Dwyer notes the answer to these disparities can be found in novel clinical trial design. Novel clinical trials apply a more innovative approach to the clinical trial process. They aim to improve the efficiency and effectiveness of traditional trial methodologies by incorporating advanced statistical methods and leveraging innovative technologies. Goals of these types of trials are to enhance the quality and applicability of the trial results and potentially answer numerous questions across a single trial. 6

Dr. Dwyer sees a future where collaboration and novel approaches will be the key to more efficient designs and lead to more access for all patients.

“I think we could see a platform trial where trialists study various drugs by dropping them into single continuously running trial. Platforms like this can speed development of interventions and reduce cost.”

Sources:

1 “FDA Approves First Treatment to Reduce Risk of Serious Heart Problems Specifically in Adults with Obesity or Overweight.” March 8, 2024, U.S Food & Drug Administration.

2 Novo Nordisk Global. (2024, March 5). Novo Nordisk A/S: Semaglutide 1.0 mg demonstrates 24% reduction in the risk of kidney disease-related events in people with type 2 diabetes and chronic kidney disease in the FLOW trial [Press Release] https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir- materials/news-details.html?id=167028

3 “Novo Nordisk’s semaglutide cuts kidney disease progression in trial.” March 6, 2024, Clinical Trials Arena.

4 Kahn, Jeff. “Does Ozempic Help Sleep Apnea? What We Know So Far.” February 13, 2024, Rise.

5 Kaplan, Karen. “’Miracle’ weight-loss drugs could have reduced health disparities. Instead they got worse.” April 15, 2024, Los Angeles Times.

6 Sessler, Daniel I., et al. “Novel Clinical Trial Designs to Improve the Efficiency of Research.” January 2020, Anesthesiology.