Experts' Perspective: Top News from ADA 2023

Each year, the scientific sessions of the American Diabetes Association (ADA) represent the foremost opportunity to showcase the latest information and clinical data in the management of diabetes and metabolic illness. The 83rd Scientific Sessions of the ADA (ADA 2023) were no different, with late breaking trials, oral presentations, and posters offering a glimpse, and sometimes a deep dive, into practice-changing studies.

This year’s meeting included more than 270 late breaking pieces of data and showcased clinical trial results from a multitude of phase 2 and phase 3 trials. Among these late breakers and clinical trials were SURMOUNT-2 and CLEAR Outcomes as well as data from trials examining novel therapies, including orforglipron and retatrutide.

SURMOUNT-2, which examined use of tirzepatide in patients with type 2 diabetes and obesity or overweight, concluded the least-squares mean change in body weight at week 72 with tirzepatide 10 mg and 15 mg was -12.8% (SE, 0.6) and -14.7% (SE, 0.5), respectively, compared to -3.2% (SE, 0.5) with placebo therapy, which correlated with an estimated treatment differences relative to placebo of -9.6 percentage points (95% CI, –11.1 to -8.1) with tirzepatide 10 mg and -11.6 percentage points (-13.0 to -10.1) with tirzepatide 15 mg (all P < .0001).

A subgroup analysis of a primary prevention cohort from CLEAR Outcomes, which included 4206 of the 13,970 included in the overall trial, results indicated use of bempedoic acid was associated with a 30% reduction in relative risk of a primary endpoint event in adjusted analyses during a median follow-up of 39.9 months (aHR, 0.70; 95% CI, 0.55-0.89; P = .002).

Incretin-based therapies stole the opening night of the meeting, which was held from June 23-26, 2023, with new data on novel therapies such as the oral, non-peptide GLP-1 receptor agonist orforglipron. In a pair of phase 2 trials presented at ADA 2023, results indicated use of the agent was associated with a mean reduction in body weight up to 14.7% and mean reduction in HbA1c with up to 2.1% at 26 weeks. Meanwhile, the final day of the meeting was headlined by results from a pair of phase 2 trials examining use of retatrutide in patients with overweight or obesity and with type 2 diabetes, respectively. The weight management trial reported body weight reductions of up to 24.2% at the end of the 48-week treatment period and the type 2 diabetes trial purported mean HbA1c reductions of -2.02% at 48 weeks with no reports of severe hypoglycemia.

As part of their coverage of ADA 2023, the editorial team of HCPLive Endocrinology has compiled responses to the question “What is the biggest news from ADA 2023?” from half a dozen interview guests during their time on-site at the meeting. To best capture the perspective across the spectrum of the diabetes care team and career-level. Our list of respondents includes Bob Gabbay, MD, PhD, chief scientific and medical officer for the ADA, Juan Frias, MD, medical director and principal investigator of Velocity Clinical Research, Yehuda Handelsman, MD, medical director and principal investigator of The Metabolic Institute of America, Viral Shah, MD, aassociate professor of tssociate professor of pediatrics at the Barbara Davis Center at the University of Caof Colorado, Rahul Aggarwal, MD, cardiology fellow at Birgham and Women's Hospital fellow in medicine at Birgham and Women's Hospital, and Ward Fickweiler, MD, fellow in ophthalmology at the Joslin Diabetes Center, Their responses can be found below.

^{(L to R) Bob Gabbay, MD, PhD; Juan Frias, MD; Yehuda Handelsman, MD; Viral Shah, MD; Rahul Aggarwal, MD; and Ward Fickweiler, MD
Credit: LinkedIn; Velocity Clinical Trials; Endocrine Society; Colorado University; LinkedIn; LinkedIn}

Top News at ADA 2023

Gabbay: I think, you know, the pace of innovation in so many different arenas, whether that is the explosion of new treatments for obesity or elsewhere, but what I think is important to highlight is what is happening in the startup world. It's a really dynamic area where there are solutions for people with diabetes. And I think bringing that into the fold is also going to be exciting because when we think about technology 5 years from now, there will be major players in managing diabetes in a variety of different ways. It's just getting on the tribe's radar that comes here, and I think you'll see a lot more of that as well.

Frias: I think, and I'm kind of biased because this is my area of research, it's the incretin-based therapies, these unimolecular multiagonists, like cagrilintide with semaglutide, combining medications with mechanisms of action that are complementary or within one single molecule, stimulating receptors that are complementary and may be synergistic. We are seeing the beginning of being able to achieve weight loss that is nearing metabolic surgery and, in those patients with diabetes, almost normalizing glucose. When we look at SURMOUNT-2, we see that over 50% of the patients achieved an HbA1c of less than 5.7%. So, this is not a brief answer, but I think it's all about the incretins and the combinations with other gut hormones or nutrient-stimulated hormones.

Handelsman: The thing that is most interesting is all the new incretin peptides, especially the ones that they're going to try to administer orally. We are now seeing all those peptides that we previously thought couldn't be taken orally, and there's already one on the market. So, we are looking at GLP-1 receptor agonists taken orally by different companies, and we're also looking at an oral PCSK9.But other companies are also entering this space. (At ADA), there was a nonpeptide GLP-1 receptor agonist, which is quite exciting.

This is still in very early development, but there was also a triagonist from Eli Lilly and Company that was being investigated for weight loss and diabetes. They are moving from the dual peptide approach and now going for the triple peptide. They also presented some data on weight loss in diabetes with just tirzepatide, which didn't provide any new information compared to what we already knew. I believe we have seen slightly less data on heart failure and CKD this year, but more on obesity. There was an interesting late-breaker presentation that came from the CLEAR Outcomes trial, focusing on a subpopulation of primary prevention.

Shah: There are so many things happening at this meeting, and I must disclose that I'm actually a planning committee member for the diabetes technology section of ADA 2023. I would say the focus on several topics, such as the role of timing range and where we are heading in that regard. We had the FDA present their perspective on time in range clinical trials, and we also had patients sharing their perspectives. Additionally, there was a session on continuous glucose monitoring (CGM) in people with type 2 diabetes.

In type 1 diabetes, it is widely acknowledged and agreed upon that CGM is now the standard of care. In type 2 diabetes patients on insulin therapy, again, we recognize it as standard of care. However, there is some uncertainty regarding the use of CGM in people on non-insulin therapy or individuals who do not have diabetes but are at risk of developing it. So, there were wonderful sessions addressing these topics. We also had a session specifically focusing on automated insulin delivery systems, discussing their applications in specific situations and addressing the challenges associated with their use.

Aggarwal: I'm incredibly excited about the oral GLP-1 receptor agonists. These are once daily pills for weight loss and I think the whole spectrum of GLP-1 receptor agonists will really change the landscape of obesity treatment. It's wonderful to see that there's a pill option, because, as I've seen in my clinics, certain patients prefer the injectable option, but some patients don't want to be on an injectable medication. I think having the oral option will really allow us to better treat patients with obesity.

Fickweiler: I think that there's a lot of interesting into research into early stages of diabetic retinopathy and I think that is what we really need. I think that we can treat advanced stages of retinopathy effectively, but for patients, clinicians, and also researchers, it's very important to develop effective treatments for early diabetic retinopathy. For example, there is a symposium of The Mary Tyler Moore Initiative this afternoon I'm very much looking forward to because this is a collaboration between researchers, which I really think is needed to tackle this problem and to develop new therapies. I think this effort of The Mary Tyler Moore Initiative might lead to new treatments in people with diabetes and, especially in early stages of diabetic retinopathy, not only the possibility of new treatments, but also more effective algorithms for detection or ways of predicting who is going to progress to advanced stages of diabetic retinopathy.

References:

1. Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet. Published 2023 June 24.
2. Nissen SE, Menon V, Nicholls SJ, et al. Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients. JAMA. Published online June 24, 2023. doi:10.1001/jama.2023.9696
3. Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity [published online ahead of print, 2023 Jun 23]. N Engl J Med. 2023;10.1056/NEJMoa2302392. doi:10.1056/NEJMoa2302392
4. Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study [Published: June 23, 2023]. The Lancet. DOI: 10.1016/S0140-6736(23)01302-8
5. Rosenstock J, Frias JP, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. Published online June 26, 2023. doi:10.1016/S0140-6736(23)01053-X
6. Jastreboff AM, Kaplan LM, Frias JP, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. The New England Journal of Medicine. Published online June 26, 2023. doi:10.1056/NEJMoa2301972