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New incretins poised to improve clinical care and cardiometabolic outcomes


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Sean Wharton, MD, PharmD
Sean Wharton, MD, PharmD, FRCPC

The next wave of incretin therapies is moving into clinical practice.

“The game has changed,” said Sean Wharton, MD, PharmD, FRCPC, Adjunct Professor of Medicine, McMaster University and York University, Toronto, Canada. “Effective obesity management is here, and it will significantly impact type 2 diabetes. Semaglutide opened the door, and there is much more to come.”

Dr. Wharton was a panelist for The Next Wave of Incretin Therapeutics—How May They Impact Care? on Monday, June 6, which examined approaches that could help utilization of incretins. These agents have the potential to dramatically improve A1C, cardiometabolic measures, obesity, and possibly even induce type 2 diabetes remission in some people. But only if providers actually prescribe them and patients take them.

The session was livestreamed and can be viewed on-demand by registered meeting participants at If you haven’t registered for the 82nd Scientific Sessions, register today to access the valuable meeting content.

The first glucagon-like peptide-1 (GLP-1) receptor agonist was approved by the U.S. Food and Drug Administration in 2005, and uptake has been stalled at about 5% of type 2 diabetes patients since at least 2013.

Carol H. Wysham, MD
Carol H. Wysham, MD

“There is some serious therapeutic inertia at play, and it is not just GLP-1s,” said Carol H. Wysham, MD, Clinical Professor of Medicine, University of Washington. “Type 2 diabetes patients remain in poor glycemic control for more than seven years before intensification of treatment.”

Repeated studies have shown that up-titrating GLP-1 receptor agonist dosing improves glycemic outcomes compared to lower dosing and has an even greater impact on weight, Dr. Wysham noted.

“We need to look at what patients value in diabetes management,” Dr. Wysham explained. “Surveys tell us patients are not willing to pay for additional A1C control, but they are willing to pay for weight loss and willing to pay even more to avoid weight gain. We need to change the conversation around diabetes management. Let’s talk more about what matters to patients: weight gain, complications, longer life.”

The recent approval of the first co-agonist to GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), tirzepatide, is already changing the conversation and the type 2 diabetes paradigm. Type 2 diabetes management has long been gluco-centric, aimed at reducing A1C ≤7%, explained Julie A. Lovshin, MD, PhD, FRCPC, Assistant Professor of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Canada.

GLP-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors added a second, cardio-centric pillar, aimed at reducing cardiovascular events.

Julie A. Lovshin, MD, PhD
Julie A. Lovshin, MD, PhD, FRCPC

Tirzepatide added a third, weight- or adipo-centric pillar, aimed at reducing adiposopathy, ectopic fat that accumulates around the liver, muscle, and intraperitoneal organs.

“Even with the addition of cardiorenal therapies, the SGLT2 and GLP-1 agents, we are just not getting our patients to target,” Dr. Lovshin said. “One way to improve management is to develop more effective agents.”

The SURPASS trial series that led to the approval of tirzepatide showed significantly more participants reaching A1C targets compared to placebo, insulin, or GLP-1 alone; more time in range; greater weight loss; and greater reduction in adipose volume without increasing the risk for major adverse cardiovascular events (MACE). Cardiovascular risk reduction trials are ongoing.

“There are unanswered questions about neuroprotection, renoprotection, and benefits to bone resorption and NASH (nonalcoholic steatohepatitis),” Dr. Lovshin said. “Co-agonists can impact the weight- and gluco-centric pillars, and I am cautiously optimistic it will impact the cardiovascular pillar of type 2 diabetes management.”

High-dose semaglutide also impacts all three pillars, especially weight. The Semaglutide Treatment Effect in People with Obesity (STEP) trial series using the 2.4 mg dose shows weight loss up to 32% with no indication of weight regain over two years.

Lee-Shing Chang, MD
Lee-Shing Chang, MD

“This is the first time we have seen this kind of weight loss in a non-surgical trial,” Dr. Wharton said. “There is a loss of fat mass and an increase in muscle mass. This is an indication of what we will see in complications, which are driven by white adipose tissue.”

Obesity is pandemic. Ninety percent of individuals with type 2 diabetes are obese, 85% of those with fatty liver disease and 77% of those with sleep apnea. Weight management treats the root problem of all three, Dr. Wharton noted, but lifestyle modification does not and cannot work long term for most people.

The hypothalamus, mesolimbic, and frontal lobes of the brain interact to drive obesity with neurochemicals and hormones that promote hunger and weight gain. Diet and exercise can bring short-term weight loss, but in the long term, these counter regulatory effects win the battle, Dr. Wharton said.

Semaglutide changes the odds by modifying the hunger response, he explained. People who are less hungry eat less, lose weight, and keep it off.

The key is getting the next wave of incretin therapies to patients.

“We know there is a huge burden of cardiovascular disease in type 2 diabetes,” said Lee-Shing Chang, MD, Endocrinologist at Brigham and Women’s Hospital and Instructor of Medicine, Harvard Medical School. “The good news is that we have increasing numbers of tools to reduce MACE.”

Based on inclusion and exclusion criteria for GLP-1 trials, up to 50% of individuals with type 2 diabetes are eligible for incretin therapy based on cardiovascular and/or renal risk factors alone. Cost, insurance barriers, and lack of knowledge about GLP-1 benefits all impede uptake, he explained. Multiple models have been developed to help remove or reduce these and other barriers to utilization.

“We need a new paradigm that includes primary care, diabetes specialists, and cardiology,” he said. “Type 2 diabetes patients who see cardiologists is a particularly high-yield area to focus on. I am optimistic about what lies ahead in terms of collaboration for our patients.”