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ADA Report June 23-26 2023

• Obesity Takes The Great Center Stage At The Diabetes Meeting

Obesity management will take center stage at this year's 4-day American Diabetes Association (ADA) 83rd Scientific Sessions, a game-changer, being held in San Diego, June 23-26, which is shorter by a day than prior meetings. This year 20% digital and 80% physical at the meeting, totally 14 000 participants.

Of five major clinical trials to be presented, four involve obesity management and three evaluate incretin drugs specifically.

These results will be reported more efficiently than in years past, as all symposia have been trimmed from 2 hours down to 90 minutes.

Also new in 2023 will be an opening keynote address, on Friday morning, by former National Institutes of Health (NIH) Director Francis Collins, MD, PhD, now a White House science advisor, an "innovation challenge" Saturday afternoon, and a plethora of debates scattered throughout the 4 days, totaling 17 in all. The debates will involve more audience interaction than in the past, complete with real-time polling.

"We've tried to be less didactic and more engaging. It's all geared towards a better educational experience," ADA Vice President, Research & Science Marlon Pragnell, PhD, told Medscape Medical News.

Indeed, Robert A. Gabbay, MD, PhD, agreed: "I think this will be a really exciting meeting with a lot of great content delivered in a more innovative way."

And much of that content will address obesity. "The really big theme, not just in the Scientific Sessions, but in the field in general, is obesity. There will be several really exciting presentations in that realm. I think there will be a lot of interest," noted Gabbay, who is ADA chief science & medical officer.

Obesity Management: Incretins, Surgery, and Lifestyle

On Friday afternoon, complete results of the 79-week randomized phase 3 SURMOUNT-2 trial of the twincretin tirzepatide (Mounjaro, Eli Lilly) for treating obesity or overweight in people with type 2 diabetes will be presented.

Top-line results for SURMOUNT-2 were released in April 2023, showing that tirzepatide achieved its primary weight-loss endpoints and key secondary endpoints, including A1c reduction.

The drug, a dual glucagon-like peptide-1 (GLP-1) agonist and glucose-dependent insulinotropic polypeptide (GIP) agonist, was approved by the US Food and Drug Administration (FDA) in 2022 for type 2 diabetes and is already being used off-label to treat obesity.

Previously, the results of SURMOUNT-1 had shown "unprecedented" weight loss with tirzepatide in people with obesity but without diabetes.

During the SURMOUNT-2 presentation, "We'll get a lot more information. There was some top-line suggestion that the weight loss wasn't as potent in people with diabetes as in those without, which is what we often see. But they'll drill down into the data...The dual agonist does seem to have added benefit," Gabbay commented.

Pragnell noted, "I suspect there will be some dramatic weight loss in type 2 diabetes as well."

On Sunday afternoon, data from two phase 3 trials of the oral formulation of the GLP-1 agonist semaglutide (Rybelsus, Novo Nordisk) will be presented.

OASIS 1 is a 68-week trial of weight loss in people with type 2 diabetes and overweight or obesity given once-daily 50-mg oral semaglutide, while PIONEER PLUS investigates different daily doses of oral semaglutide as a glucose-lowering agent in type 2 diabetes, with weight loss as a secondary endpoint.

"The key thing here is getting from injectable to oral," Pragnell told Medscape Medical News. "The ideal drug is something you can take as a tablet...A lot of work is going into incretin-like drugs with oral bioavailability...You want a drug with the most convenience for people so you get the best adherence."

The FDA approved the once-weekly subcutaneously injectable form of semaglutide for type 2 diabetes as Ozempic in 2017, oral semaglutide(Rybelsus) for type 2 diabetes in 2019, and once-weekly subcutaneous injectable semaglutide for obesity in adults as Wegovy in 2021. Wegovy was also approved for obesity for those aged 12 and over in the United States in 2022.

On Monday afternoon, phase 2 trial data will be presented for Lilly's novel GIP/GLP-1/glucagon receptor "triagonist," retatrutide, for treating obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD).

Results of a previous small 12-week, phase 1 study suggested that the triple agonist (then called LY3437943), might provide even more weight loss than currently approved incretin agents in people with type 2 diabetes.

"People are still learning about what incretins are doing. When you combine them it's interesting to see empirically how they work...Each has a different role and function. In combination, they may be additive or work differently...It's a very exciting area," Pragnell said.

Fittingly, this year's Banting Medal for Scientific Achievement will be awarded to Matthias H. Tschöp, MD, the German scientist whose pioneering work in gut hormones led to the development of the incretin drugs.He'll deliver the keynote Banting lecture on Sunday morning.

The fourth major piece of obesity research, the Alliance of Randomized Trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) is a consortium of four studies designed to compare long-term efficacy and safety of surgery versus medical/lifestyle therapy on type 2 diabetes control and clinical outcomes.

Gabbay commented, "Bariatric surgery has been around a long time. It's quite effective and underutilized, given how big the problem is. t's going to be tough to beat bariatric surgery. Future studies will compare it with tirzepatide and other newer medications."

Cardiovascular Healthcare Delivery, DCCT Update

On Monday afternoon, results will be presented from COORDINATE on the effectiveness of a novel clinic-level educational intervention to improve the management of patients with type 2 diabetes and cardiovascular disease.

"It will be interesting. Improving care is not just creating new drugs but also improving how practices perform and how care is provided. ADA has disseminated the Standards of Care, and it's so important to see research on how best to implement that,"

Pragnell observed.

It's then the turn of type 1 diabetes to take the spotlight, in a special symposium that will provide new data on the impact of the landmark Diabetes Control and Complications Trial (DCCT) and its ongoing observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, 40 years after DCCT's launch.

At a similar symposium held at the ADA meeting in 2013 to commemorate 30 years of DCCT, dramatic reductions in diabetes complications in participants with type 1 diabetes — achieved with intensive glycemic control — were still being seen.

Debates, With Audience Involvement

Type 1 diabetes management will also be addressed in at least three of the 17 planned debates, including one on Friday evening on do-it-yourself devices versus commercial closed-loop systems (artificial pancreas); technology versus immunomodulation on Saturday afternoon; and beta-cell replacement versus artificial pancreas on Monday afternoon.

Two debates will cover pregnancy-related topics, including use of low-carb diets and use of metformin during pregnancy in women with type 2 diabetes, both on Saturday.

Other hot-button debate topics will address initiation of combination therapy for type 2 diabetes on Friday morning, low-carb diets on Friday evening, and a "dual incretin duel" on Sunday afternoon.

Each debate speaker will give just a short argument, followed by back-and-forth and discussion involving the audience. With most debates, the audience will be polled at the beginning and at the end to see how many minds were changed.

"They're really interesting topics. We've tried to choose them so there's real debate, not a lopsided one where there's obviously just one side," Pragnell said.

Gabbay noted: "We realized we've been doing the same format since the 1980s. It hadn't changed that much. We really want to engage people more. What makes it special to go to a meeting versus reading the paper? It's an opportunity to interact, go back and forth, to have discussion."

Press release from ADA San Diego

• Triple Agonist Retatrutide Hits New Weight-Loss Highs

ADA Report

New designer molecules that target weight loss via multiple mechanisms continue to raise the bar of how many pounds people with overweight or obesity can lose.

Retatrutide (Eli Lilly), an investigational agent that combines agonism to three key hormones that influence eating and metabolism into a single molecule, safely produced weight loss at levels never seen before in a pair of phase 2 studies that together randomized more than 600 people with overweight or obesity, with or without type 2 diabetes.

Among 338 randomized people with overweight or obesity and no type 2 diabetes, 48 weeks of treatment with retatrutide at a 12-mg dose given by weekly subcutaneous injection (the highest dose tested) safely produced an average 24% drop from baseline bodyweight.

Among 281 randomized people with overweight or obesity and type 2 diabetes, the same dose of retatrutide produced a nearly 17% cut in weight from baseline after 36 weeks of treatment.

Never Before Seen Weight Loss

Dr Ania M. Jastreboff

"I have never seen weight loss at this level" after nearly 1 year of treatment, said Ania M. Jastreboff, MD, PhD, who led the obesity study, during a press briefing here at the American Diabetes Association (ADA) 83rd Scientific Sessions.

The average weight loss by study participants taking high-dose retatrutide in the two studies "is really impressive, way beyond my wildest dreams," commented Carel le Roux, MBChB, PhD, an obesity and diabetes researcher at University College Dublin, Ireland, who was not involved with the retatrutide studies.

And Robert Gabbay, MD, chief scientific and medical officer of the ADA, called the results "stunning," and added,

-"we are now witnessing the first triple-hormone combination being highly effective for not only weight loss but liver disease and diabetes."

A prespecified subgroup analysis of the obesity study showed that at both 8-mg and 12-mg weekly doses, 24 weeks of retatrutide produced complete resolution of excess liver fat (hepatic steatosis) in about 80% of the people eligible for the analysis (those with at least 10% of their liver volume as fat at study entry); that figure increased to about 90% of people on these doses after 48 weeks, Lee M. Kaplan, MD, reported during a separate presentation at the meeting.

"When you add glucagon activity," one of the three agonist actions of retatrutide, "liver-fat clearance goes up tremendously," said Kaplan, who is director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

-"To my knowledge, no mono-agonist of the glucagon-like peptide-1 (GLP-1) receptor such as semaglutide or liraglutide produces more than 50% clearance of liver fat," added Kaplan.

The separate, randomized study of people with type 2 diabetes showed that in addition to producing an unprecedented average level of weight loss at the highest retatrutide dose, the agent also produced an average reduction from baseline levels of A1c of about 2 percentage points, an efficacy roughly comparable to maximum doses of the most potent GLP-1 mono-agonist semaglutide (Ozempic, Novo Nordisk), as well as by tirzepatide (Mounjaro, Eli Lilly), a dual agonist for the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors.

-"No other medication has shown an average 17% reduction from baseline bodyweight after 36 weeks in people with type 2 diabetes," commented Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, who presented the results from the type 2 diabetes study of retatrutide.

For the obesity study, people with a body mass index (BMI) of 27-50 kg/m²and no diabetes were randomized to placebo or any of four retatrutide target dosages using specified dose-escalation protocols. Participants were an average of 48 years old, and by design, 52% were men. The study sought to enroll roughly equal numbers of men and women. Average BMI at study entry was 37 kg/m².

Weight loss levels after 24 and 48 weeks of retatrutide treatment followed a clear dose-related pattern. Weight loss averaged about 2% among the 70 controls who received placebo.

26% Without Diabetes Lost ≥ 30% of Bodyweight

Every person who escalated to receive the 8-mg or 12-mg weekly dose of retatrutide lost at least 5% of their bodyweight after 48 weeks, 83% of those taking the 12-mg dose lost at least 15%, 63% of those on the 12-mg dose lost at least 20%, and 26% of those on the highest dose lost at least 30% of their starting bodyweight, reported Jastreboff, director of the Yale Obesity Research Center of Yale University in New Haven, Connecticut.

The highest dose was also associated with an average 40% relative reduction in triglyceride levels from baseline and an average 22% relative drop in low-density lipoprotein cholesterol levels.

The results were simultaneously published online in the New England Journal of Medicine.

The incidence of serious adverse events with retatrutide was low, similar to the rate in those who received placebo, and showed no dose relationship.

The most common adverse events were gastrointestinal, in as many as 16% of those on the highest dose; these were mild to moderate in severity and usually occurred during dose escalation. In general, adverse events were comparable to what is seen with a GLP-1 agonist or the dual agonist tirzepatide, Jastreboff said.

HbA1c Normalization in 26% at the Highest Dose

A similar safety pattern occurred in the study of people with type 2 diabetes, which randomized people with an average A1c of 8.3% and an average BMI of 35.0 kg/m². After 36 weeks of treatment, the 12-mg weekly dose of retatrutide led to normalization of A1c < 5.7% in 27% of people and A1c ≤ 6.5% in 77%.

"The number of people we were able to revert to a normal A1c was impressive," said Rosenstock. These results were simultaneously published online in The Lancet.

The additional findings on liver-fat mobilization in people without diabetes enrolled in the obesity study are notable because no agent currently has labeling from the US Food and Drug Administration for the indication of reducing excess liver fat, said Kaplan.

The researchers measured liver fat at baseline and then during treatment using MRI.

-"With the level of fat clearance from the liver that we see with retatrutide it is highly likely that we'll also see improvements in liver fibrosis" in retatrutide-treated patients, Kaplan predicted.

Next up for retatrutide is testing in pivotal trials, including the TRIUMPH-3 trial

https://clinicaltrials.gov/study/NCT05882045?term=retatrutide&rank=1

has plans to enroll about 1800 people with severe obesity and cardiovascular disease, with findings expected toward the end of 2025.

The retatrutide studies are sponsored by Eli Lilly. Jastreboff, Rosenstock, Kaplan, and Le Roux have reported financial relationships with Eli Lilly as well as other companies.

ADA Scientific Sessions. Session CT-1.5-SY26. Presented June 26, 2023.

Lancet. Published online June 26, 2023. Full Text

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01053-X/fulltext

N Engl J Med. Published online June 26, 2023. Full Text

https://www.nejm.org/doi/full/10.1056/NEJMoa2301972

• OASIS and PIONEER PLUS Support High-Dose Oral Semaglutide

ADA Report

SAN DIEGO – Higher doses of oral semaglutide than the 14-mg/day dose that is currently approved for type 2 diabetes may be additional options for patients with prediabetes or diabetes and obesity, according to the results of two new Phase 3 clinical trials.

The two trials, OASIS

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01185-6/fulltext

in patients with overweight or obesity without diabetes and PIONEER PLUS

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01127-3/fulltext

in patients with inadequately controlled type 2 diabetes, were presented here at the American Diabetes Association (ADA) 83rd Scientific Sessions and simultaneously published in The Lancet.

Filip K. Knop, MD, PhD, University of Copenhagen, Denmark, presented highlights of the OASIS-1 results, and Vanita R. Aroda, MD, Brigham and Women's Hospital and Harvard University, Boston, Massachusetts, presented key findings of PIONEER PLUS, during a press briefing prior to the ADA session.

OASIS-1 showed that "oral semaglutide 50 mg may represent an effective option for the treatment of obesity, particularly in patients who prefer oral administration," Knop summarized.

And "the PIONEER PLUS trial showed superior glycemic control and body-weight loss and improvement in cardiometabolic risk factors, with higher doses of once-daily oral semaglutide (25 mg and 50 mg) compared with the currently highest approved 14-mg dose," said Aroda.

Session Chair Marion Pragnell, PhD, vice president of research & science at ADA, told Medscape Medical News there is a need for multiple treatment options, as different patients respond differently to individual drugs.

The oral dose of semaglutide has to be higher than that approved for subcutaneous injection as Ozempic or Wegovy due to bioavailability, but small molecule research is advancing such that in future lower doses of oral drugs may have the same effect as the current lower subcutaneous doses of the drug.

The oral version of semaglutide (Rybelsus) was approved in the US for type 2 diabetes in doses of 7 mg or 14 mg per day in 2019; it has not been approved for use in obesity.

Knop remarked that in his clinical practice, about 25% of patients with type 2 diabetes prefer daily oral semaglutide and the rest prefer weekly injected semaglutide.

-"Having an oral formulation of semaglutide in addition to the subcutaneous, or injectable, formula available will allow people who struggle to lose weight with diet and physical activity alone to take this effective medication in a way that best suits them," he added.

Participants in OASIS and PIONEER PLUS were instructed to take the once-daily study drug tablet in the morning, in the fasting state, with up to half a glass of water (120 mL) at least 30 minutes before intake of any other food, beverage, or oral medication.

Sean Wharton, MD, PharmD, the assigned discussant and last speaker in the packed room at the ADA session where the results were revealed, said:

-"OASIS 1 and PIONEER PLUS introduce the world to a medication that is oral, relatively easy to administer, scalable, and effective, with a similar magnitude of efficacy as injectable semaglutide," a 15% weight loss at 52 weeks.

Wharton is an assistant professor at the University of Toronto, Ontario, Canada, and lead author of the 2020 Canadian obesity guidelines. He was not involved with either trial.

OASIS: 50-mg Daily Pill in Adults With Overweight or Obesity

Knop and colleagues say that, to their knowledge, OASIS is "the first trial to assess the bodyweight-lowering effect of an oral GLP-1 agonist semaglutide 50 mg taken once per day in adults with overweight or obesity, without type 2 diabetes."

The 50-mg dose induced clinically meaningful reductions in bodyweight, with accompanying improvements in cardiometabolic risk factors, consistent with results reported for subcutaneous semaglutide 2.4 mg once weekly Wegovy in a similar population.

As an adjunct to diet and physical activity, oral semaglutide 50 mg led to a mean bodyweight reduction of 15.1% compared with 2.4% in the placebo group, and greater percentages of participants reaching bodyweight reduction targets of at least 5%, 10%, 15%, and 20%

Body-weight reductions were accompanied by significant improvements in cardiometabolic risk factors compared with placebo.

"These results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist," they conclude.

PIONEER PLUS: Inadequately Controlled Type 2 Diabetes

Reporting the PIONEER PLUS data, Aroda and colleagues say: "For people with inadequately controlled type 2 diabetes on a stable dose of one to three oral glucose-lowering drugs, higher doses (25 mg and 50 mg) of once-daily oral semaglutide provided more effective glycemic control and greater bodyweight loss than 14-mg semaglutide, without additional safety concerns."

PIONEER PLUS is the first study to indicate that these bigger doses of semaglutide might provide a highly effective oral option to improve both glycemic control and weight loss in type 2 diabetes.

"This trial provides compelling evidence that the availability of a wider range of doses of oral semaglutide will allow for individualized dosing to the desired effect, and the ability to intensify treatment as needed," said Aroda.

- "We are hopeful that these results encourage earlier effective management of type 2 diabetes and allow for broader management in the primary care setting."

In an accompanying editorial, Christina H. Sherrill, PharmD, and Andrew Y. Hwang, PharmD, write: "This expansion in dosing titration might provide clinicians with more opportunities to obtain the maximum efficacy of this oral GLP-1 agonist."

But additional investigations "to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular riskreduction" are needed, say Sherrill, High Point University, North Carolina, and Hwang, Massachusetts College of Pharmacy and Health Sciences University, Boston.

Such investigations "would further elucidate the place in therapy of high-dose oral semaglutide," they conclude.

Aroda and colleagues agree: "Future real-world studies will be needed to investigate the clinical impact of the availability of higher doses of oral semaglutide."

Where Would Oral Semaglutide Fit in Clinical Practice?

During his discussion, Wharton said the current "landscape" includes rapid weight management medication development ("like whiplash"), high demand, lack of availability of injectables, and a "Hollywood phenomenon," where people take these medications off-label to lose a few pounds.

"Oral semaglutide 25 mg and 50 mg are effective," he summarized. The magnitude of mean weight loss in these trials (15%) is the same with the oral medication as for 2.4 mg subcutaneous semaglutide. For both formulations, a third of patients lose over 20% of their initial weight.

Wharton pointed out that injectable GLP-1 receptor agonists are unavailable to many people in the world with obesity. Meanwhile, the three countries that have launched injectable semaglutide 2.4 mg (Wegovy) — Norway, Denmark, and the United States — are among the richest in the world.

A pill might have a larger global reach and increase access to care. Semaglutide 50 mg may be a long-term solution for obesity, with reduced associated comorbidities, he said

What is striking about these trials is that "the company was able to produce a sensational molecule that many people did not think would have such a significant impact," Wharton told Medscape Medical News.

-"For those who can afford it, who can take it," he said, "it has a very nice place in overall therapy to give additional options that are similar in efficacy. I also believe it is possible we have the chance of getting equity in getting newer meds to other people."

The trials were funded by Novo Nordisk.

ADA 2023 Scientific Sessions. Presented June 24, 2023.

Lancet. Published online June 25, 2023. OASIS Study, PIONEER PLUS Study, Editorial

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01233-3/fulltext

• SURMOUNT-2: Tirzepatide Rings Up Major Weight Loss in Type 2 Diabetes

ADA Report SAN DIEGO — Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial,

https://clinicaltrials.gov/study/NCT04657003?term=surmount-2%20and%20tirzepatide&rank=1

a finding that will likely lead to US Food and Drug Administration (FDA) approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent — a "twincretin" that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor — had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

https://www.nejm.org/doi/full/10.1056/NEJMoa2206038

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

"We anticipate that tirzepatide will be [FDA] approved for weight loss later this year," said W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, during a press briefing here at the American Diabetes Association (ADA) 83rd Scientific Sessions.

Tirzepatide "Fills the Gap"

Tirzepatide "fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better," Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial.

HTTPS://WWW.THELANCET.COM/JOURNALS/LANCET/ARTICLE/PIIS0140-6736(21)00213-0/FULLTEXT

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

"If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss" compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. Although cross-trial comparisons of different medications often have uncertain reliability.

"The data suggest an incremental effect from tirzepatide" compared with the GLP-1 agonists now approved for weight loss, commented Marlon Pragnell, PhD, vice president, Research & Science, ADA, who was not involved in the tirzepatide studies.

This is a "step forward for treating people with obesity and type 2 diabetes; it's a very promising treatment option," Pragnell said in an interview.

Tirzepatide the "Most Effective Agent"

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings "confirm that tirzepatide is the most effective agent currently on the [US] market to help achieve the two coprimary goals for patients with type 2 diabetes — weight loss and glycemic control — while also having favorable effects on cardiovascular risk factors," said Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Lingvay offered as evidence the performance of tirzepatide's main rival for weight loss semaglutide Wegovy, delivered at the 2.4 mg/week subcutaneous injected dose approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

"It's fair to say that tirzepatide has an edge," despite the limitations of cross-trial comparisons, Lingvay said in an interview.

But she also acknowledged that superior weight loss efficacy takes a back seat in US practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive.

Affordability and Access Will Remain a "Big Problem"

Garvey too cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

-"These medications are very expensive — more than $1000 a dose — and this cost limits access which is]a big problem," Garvey noted. US healthcare payers "do not want to open the gates [to expensive treatments] for a disorder that's as common as obesity."

"Access and affordability are always an issue for these medications," agreed Janet Brown-Friday, RN, president, Health Care & Education, ADA, who also had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5%, again after 72 weeks.

In-Trial Weight Loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline "will prevent a broad array of complications," Garvey noted.

The results were simulatenously published online in The Lancet.

Glucose Control Without Severe Hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was "amazing," Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a "big reduction in fasting insulin levels," which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Garvey said.

Lancet.

Published online June 23, 2023. Full Text

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01200-X/fulltext

ADA Scientific Sessions. Session CT-1.5-SY40. Presented June 23, 2023.

From www.medscape.com

• ADA Report: Screen All With Type 2 Diabetes for Fatty Liver Disease

SAN DIEGO — The American Diabetes Association (ADA) now advises universal screening of people with type 2 diabetes and prediabetes for fatty liver disease and provides new recommendations for management in those with the condition, or who are at risk for it.

Liver disease affects up to 70% of people with type 2 diabetes, and is common in people with prediabetes, and in those with type 1 diabetes who also have obesity. Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease in people with diabetes. It can lead to cirrhosis and liver cancer and is associated with an increased risk for cardiovascular disease and death. The condition includes non-alcoholic steatohepatitis (NASH).

"The ADA has recognized that this has become a big problem for their patients because NASH is becoming the number one cause of cirrhosis in people with type 2 diabetes and the number one cause of liver transplantation in the US, so we have to do something about it," Kenneth Cusi, MD, who presented a summary of the new guidance here at the ADA's annual Scientific Sessions, told Medscape.

The new ADA guidance was published June 24 as a mid-year update to the ADA's Standards of Care in Diabetes—2023 in the section on "Comprehensive Medical Evaluation and Assessment of Comorbidities."

Asked to comment, Atlanta endocrinologist Scott Isaacs, MD, said "It is wonderful to see that the ADA has recognized NAFLD…as the hepatic complication of type 2 diabetes and has updated the Standards of Care reflecting the current knowledge and evidence of this ubiquitous and often silent disease."

The new ADA guidance aligns with those of other professional societies, including the American Association for the Study of Liver Diseases (AASLD),

https://www.medscape.com/viewarticle/985482

the American Gastroenterological Society, and the American Association of Clinical Endocrinology (AACE).

Isaacs, who chaired the AACE guidance writing panel, noted, "The ADA update essentially repeats the same guidance in the AACE and AASLD documents. It is excellent to see this type of alignment of guidance among the major organizations."

FIB-4: Easy Calculation in the EHR

The ADA now advises screening all adults with type 2 diabetes or prediabetes, particularly those with obesity or cardiometabolic risk factors or established cardiovascular disease — even those with normal liver enzyme levels. People with type 1 diabetes who have obesity and/or cardiovascular risk factors are also to be screened for NAFLD.

The recommended screening tool is the fibrosis-4 index (FIB-4), a calculation that includes the patient’s age, liver enzyme levels, and platelet counts. A score of 1.3 or higher is considered high risk for clinically significant fibrosis, and above 2.6 is very high-risk.

Cusi noted,

-"The reason we advise using the FIB-4…instead of liver enzymes as ADA advised in the past, is that now we know that 70% of people with type 2 diabetes have steatosis already and about one in five have fibrosis, but if you go by liver enzymes you will miss most of them. Liver enzymes are ineffective as a screening tool."

The FIB-4 is "a simple tool we already have in our electronic health records (EHR) but we’re just simply not using it," noted Cusi, chief of endocrinology, diabetes, and metabolism at the University of Florida, Gainesville.

Indeed, Isaacs said, "The FIB-4 is a simple…great screening test because it is essentially free." But he cautioned that it has some limitations.

"It is a good test for ruling out advanced liver disease but can have false positives and false negatives. The FIB-4 cutoffs need to be adjusted for persons over 65 years old and is not to be used for persons under 30 years old."

Isaacs also pointed out that, while the calculation can be done from a website, "even this adds time to a clinician’s busy day. Ideally, the FIB-4 should be automatically calculated in the EHR or on the lab report, similar to the [estimated glomerular filtration rate] calculation [for kidney function] and flagged if greater than 1.3."

The ADA update also provides guidance on follow-up for patients flagged with the FIB-4, including when referral to a gastroenterologist or hepatologist is appropriate.

Treatment: Lifestyle Modification Plus GLP-1 Agonists or Pioglitazone

Lifestyle modification is recommended for all adults with diabetes or prediabetes and NAFLD, particularly those with overweight or obesity.

In addition, the ADA now advises consideration of a using a glucagon-like peptide 1 (GLP-1) agonist with demonstrated benefits in NAFLD as adjunctive therapy to lifestyle interventions for weight loss in those with type 2 diabetes, particularly with overweight/obesity.

And for those with biopsy-proven NASH or who are identified with clinically significant liver fibrosis using non-invasive tests, either a GLP-1 agonist or pioglitazone are the "preferred treatments."

However, insulin is the preferred treatment for hyperglycemia in adults with type 2 diabetes who have decompensated cirrhosis.

Isaacs commented,

-"Pioglitazone has so many benefits and a few known risks…it is an underused medication. It is very inexpensive. Pioglitazone should be considered as a first line treatment for patients with type 2 diabetes and NAFLD."

The ADA update also advises statin therapy for people with type 2 diabetes and NAFLD, given their increased cardiovascular risk. However, statins are not recommended for people with decompensated cirrhosis because of limited safety and efficacy data.

Cusi noted that he has been advocating for fatty liver screening in people with type 2 diabetes for over a decade.

"Doctors have already been adopting it, but ADA as an organization in diabetes care has a big impact. I dreamed many years ago that the day would come when we would screen all people with type 2 diabetes, and that day is today."

Update to ADA's Standards of Care. Published June 24, 2023 and presented at the ADA Scientific Sessions.

https://diabetesjournals.org/care/issue/46/Supplement_1

• ADA Report

Kids With Type 2 Diabetes Face Dire Complications as Young Adults

SAN DIEGO — Children with type 2 diabetes face a strikingly high complication rate as they age into young adulthood, with an 80% incidence of at least one vascular complication during up to 15 years of follow-up, show findings from the TODAY prospective, longitudinal study of 699 US children newly diagnosed with type 2 diabetes.

Arterial stiffness and worsened cardiac function often appear in these children within 2-5 years of diagnosis and seem driven in part by the development of hypertension and worsening A1c levels, said Rachelle G. Gandica, MD, at the American Diabetes Association (ADA) 83rd Scientific Sessions.

Indeed, an A1c > 6.2% at study entry generally predicts these children will fail treatment and is a red flag, said Gandica. "I teach fellows this all the time, that if a child's A1c is above 6.2% they will fail, and you have to watch for that," she noted.

The results from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) https://clinicaltrials.gov/study/NCT00081328

study showed, for example, an overall cardiovascular event rate of 3.7/1000 patient-years in a population that had just reached an average age of 26 years old, with type 2 diabetes diagnosed for an average of more than 13 years.

During follow-up, there were six cases of congestive heart failure, four myocardial infarctions, four strokes, and three cases of coronary artery disease in the cohort. Hypertension ballooned from a prevalence of 19% at study entry to 68% by the end of follow-up.

Gandica called these and other findings "sobering details" that document the toll type 2 diabetes takes on children, who averaged 14 years old at the time they entered the study — when their diabetes had been diagnosed for an average of about 8 months — and then underwent an average 12.6 years of follow-up.

Investigators also found:

After more than 12 years of type 2 diabetes, 49% of the cohort had developed diabetic retinopathy, with 3.5% having macular edema.
Kidney damage (diabetic nephropathy) affected 8% of the cohort at entry, and then increased to a prevalence of 55% after up to 14 years of follow-up.
Among the 452 girls who entered the study, 141 (31%) later became pregnant, with a total of 260 pregnancies. A quarter of the pregnancies resulted in preterm deliveries (43% went to term), 25% resulted in miscarriage or fetal demise, with the remaining 8% having elective terminations or unknown outcomes.
Complications in neonates were common, including hypoglycemia (29%), respiratory disorder (19%), and cardiac issues (10%).

Dire Prognosis a Reason to Aggressively Treat These Patients

It has become apparent from this and other studies in youth with type 2 diabetes that the difference in outcomes between youth and adults is stark and could indicate that type 2 diabetes in childhood or adolescence likely has a different underlying pathology and natural history, with a more aggressive disease course.

The dire prognosis is therefore a reason to aggressively treat these patients with antidiabetic medications from drug classes with proven cardiovascular disease protection, specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, said Gandica, a pediatric endocrinologist at Columbia University Medical Center in New York City.

"It's fair to say we now more aggressively use [these agents] in children," she said in an interview, and noted the very recent approval, just last week, by the US Food and Drug Administration of the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) for children as young as 10 years, as reported by Medscape Medical News.

https://www.medscape.com/viewarticle/993480

"I look forward to prescribing empagliflozin to children with type 2 diabetes to lower their blood pressure and get additional cardiovascular disease benefits," Gandica said.

Other newer type 2 diabetes medications approved for US children in the past few years include the once-weekly injectable GLP-1 agonist exenatide extended release (Bydureon/Bydureon BCise, AstraZeneca) for children with type 2 diabetes aged 10 and older, in 2021, and the daily injectable GLP-1 agonist liraglutide (Victoza, Novo Nordisk) in 2019.

A1c Spike Heralds Treatment Failure: "Watch for That"

TODAY enrolled 699 children with type 2 diabetes for an average of 8 months since diagnosis at 16 US sites starting in 2004. The protocol began with a run-in phase of up to 6 months, when participating children came off any pre-existing antidiabetes medications and then began a metformin-only regimen to bring A1c below 8.0%. If achieved, patients were eligible to continue to randomization.

Participants were randomized to one of three treatment groups: metformin alone, metformin plus lifestyle interventions, or metformin plus rosiglitazone (Avandia, GSK). The primary endpoint was the incidence of treatment failure, defined as A1c that rose back above 8.0% for at least 6 months or persistent metabolic decompensation during initial follow-up, for an average of just under 4 years.

The results showed that only metformin plus rosiglitazone significantly surpassed metformin alone for preventing treatment failure, reported in 2012in the New England Journal of Medicine.

More recent reports on findings from longer-term follow-up have appeared in several journals, including the cardiovascular disease results, reported in 2021 also in the New England Journal of Medicine.

Another key finding from TODAY is the importance of A1c as a risk marker for impending treatment failure. Study findings show that an A1c of 6.2% or higher when children entered the study best predicted loss of glycemic control during follow-up. Also, a rise in A1c of at least 0.5 percentage points was significantly associated with loss of glycemic control within the following 3-6 months.

That's an important message for clinicians, Gandica concluded.

TODAY and TODAY2 received no commercial funding. Gandica has reported no relevant financial relationships.

ADA Scientific Sessions. Session CT-1.5-SY25. Presented June 24, 2023