Diana Isaacs, PharmD, BCPS, BCACP, BC-ADM, CDCES

With topline data announced in August and the full study released at the 

American Heart Association Scientific Sessions 2023

, the results of the SELECT trial serve as the signal for a new age in 

Results of the trial, which enrolled more than 17,000 patients with 

 and preexisting cardiovascular disease, indicate use of semaglutide 2.4 mg (Wegovy) was associated with a 20% reduction in risk of cardiovascular events relative to placebo therapy. Coming less than 3 years after semaglutide 2.4 mg received a historic indication from the US Food and Drug Administration as the first agent approved for chronic weight management in adults with general obesity or overweight since 2014, results of the double-blind, randomized, placebo-controlled, event-driven superiority trial provide evidence the cardiovascular protective benefits of extend beyond patients with type 2 diabetes.

“Our findings expand the opportunity to treat patients who have overweight or obesity and existing heart disease without Type 1 or Type 2 diabetes, and we have a chance to significantly reduce their risk of a secondary cardiovascular event including death,” said principal investigator A. Michael Lincoff, MD, vice chairman for research of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine and an interventional cardiologist in the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic.

The largest and longest trial of semaglutide in adults without type 1 or type 2 diabetes, the trial’s primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Inclusion criteria required patients to be 45 years of age or older, have no history of type 1 or type 2 diabetes, have a BMI of 27 kg/m2 or greater, and established cardiovascular disease, which was defined as previous myocardial infarction, previous stroke, or symptomatic peripheral arterial disease.

Analysis of the primary outcome suggested an event occurred among 6.5% of the semaglutide group and 8.0% of the placebo group (HR, 0.80; 95% Confidence interval [CI], 0.72 to 0.90; 

 <.001). Further analysis indicated the mean change in body weight observed in the trial was –9.39% with semaglutide and –0.88% with placebo (estimated treatment difference, –8.51 percentage points; 95% CI, –8.75 to –8.27). When assessing secondary endpoints, results detailed nonsignificant trends towards benefit for cardiovascular death (HR, 0.85; 95% CI, 0.71 to 1.01; 

=.07), heart failure hospitalization or urgent medical visit (HR, 0.82; 95% CI, 0.71 to 0.96), all-cause mortality (HR, 0.81; 95% CI, 0.71 to 0.93), an HbA1c of 6.5% or greater (HR, 0.27; 95% CI, 0.24 to 0.31).

To celebrate the ushering in of this new era and discuss what it means for the future of care, hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, sat down to record a special edition episode of 

Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives

In the episode, Isaacs and Bellini take a deep dive into the study’s results, including secondary endpoints, and what it means for the care of patients with overweight or obesity and preexisting cardiovascular disease in real-world settings.

Hosts take a deep dive into the SELECT trial and what it means for patients with overweight/obesity and preexisting cardiovascular disease. 

Diabetes Dialogue: SELECT Trial Proves CV Benefit of Semaglutide 2.4 mg (Wegovy)

Lincoff AM, Brown-Frandsen K, Calhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. 

AHA Newsroom. Major CVD event risk cut by 20% in adults without diabetes, with overweight or obesity. American Heart Association. Accessed November 11, 2023.

https://newsroom.heart.org/news/major-cvd-event-risk-cut-by-20-in-adults-without-diabetes-with-overweight-or-obesity

Articles

In this episode, hosts take a deep dive into the study’s results, including secondary endpoints, and what it means for the care of patients with overweight or obesity and preexisting cardiovascular disease in real-world settings.

Diabetes Dialogue: SELECT Proves Semaglutide 2.4 mg CV Benefit at AHA 2023

Diabetes Dialogue: Automated Insulin Delivery News in October 2023

Although those in the diabetes community has witnessed an avalanche of advances in management in recent decades, few have held the same promise, and captivated clinicians in the same fashion as automated insulin delivery systems.

 hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, discuss recent news in the world of automated insulin delivery. Hosts also spend time sharing perspective on the impact of the recent US Food and Drug Administration clearance of the Omnipod 5 App for iPhone.

See below for a brief overview of the studies discussed in this episode.

Presented at the 2023 European Association for the Study of Diabetes (EASD) Meeting and simultaneously published in the 

, the AiDapt study was an open-label, multicenter, randomized, controlled trial comparing automated hybrid closed-loop insulin delivery against continuing standard intensive insulin therapy, with both groups using continuous glucose monitoring, in pregnant women. The trial randomized 124 participants, with a mean age of 31.1 (Standard Deviation [SD], 5.3) years and a mean baseline HbA1c of 7.7% (SD, 1.2%).

Upon analysis, results suggested the mean percentage of time in the target range of 63 to 140 mg/dL was 68.2% (SD, 10.5) in the closed-loop group and 55.6% (SD, 12.5) in the standard-care group (mean adjusted difference, 10.5 percentage points; 95% Confidence Interval [CI], 7.0 to 14.0; 

< .001). Investigators noted no unanticipated safety problems occurred during pregnancy with use of closed-lop therapy and no differences were observed between groups with regard to number of preterm births, birth weight, neonatal complications, or admissions to the neonatal intensive care unit.

The second study discussed by Isaacs and Bellini, which was also presented at EASD 2023, examined the effects of automated insulin delivery with the MiniMed 780G on ability to achieve time in tighter range using real-world data uploaded from August 2020 to December 2022 by de-identified users. In the study, time in tighter range was described as 70 to 140 mg/dL.

Investigators used univariate and multivariable models to identify glycemic metrics, demographics and system characteristics associated with increased time in tighter range post-AHCL initiation, and associated with increased time in range post-AHCL initiation. Results of the study, which included 15,348 individuals, indicated users of the MiniMed 780G system on achieved a time in tighter range of 48.9%, with this figure growing to 56.1% when recommended settings were used.

Relevant disclosures for Dr. Isaacs include Eli Lilly and Company, Novo Nordisk, Sanofi, Abbott Diabetes Care, Dexcom, Medtronic, and others. Relevant disclosures for Dr. Bellini include Abbott Diabetes Care, MannKind, Provention Bio, and others.

Lee TTM, Collett C, Bergford S, et al. Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes. 

. 2023;389(17):1566-1578. doi:10.1056/NEJMoa2303911

Medtronic real-world evidence demonstrates consistent results of the MiniMedTM 780g regardless of demographic or cultural differences. Medtronic News. October 5, 2023. Accessed November 1, 2023. https://news.medtronic.com/2023-10-05-Medtronic-real-world-evidence-demonstrates-consistent-results-of-the-MiniMed-TM-780G-regardless-of-demographic-or-cultural-differences.

In this episode, hosts discuss the FDA clearance of the Omnipod 5 App for iPhones and a pair of studies examining use of automated insulin delivery systems.

 is a more prominent topic of discussion among healthcare providers now than ever before in history. Due in part to rising prevalence of obesity and its impact on health systems, but also as a result of advances in therapies, with these advances centered around the GLP-1 receptor agonists and combination agents.

During early October, the community was offered further insight into the potential of one of these agents, tirzepatide (Mounjaro) in the form of trial results from SURMOUNT-3 and SURMOUNT-4, which were presented at ObesityWeek and the European Association for the Study of Diabetes Annual Meeting, respectively.

SURMOUNT-3 was designed to assess the effects of tirzepatide relative to placebo therapy following a lead-in period where patients were exposed to an intensive lifestyle intervention. A double-blind, placebo-controlled trial, participants were randomized in a 1:1 ratio to tirzepatide or placebo therapy for 72 weeks following the 12-week lead-in period.

In the treatment efficacy estimand, results indicated use of tirzepatide was associated with an additional 21.1% mean weight loss following the lead-in period compared to a 3.3% increase in body weight among the placebo group 3.3% with placebo (estimated treatment difference [ETD], −24.5 percentage points; 95% Confidence Interval [CI], −26.1 to −22.8; 

 < .001). Analysis of the treatment regimen estimated suggested the mean change in body weight at week 72 was −18.4% with tirzepatide and 2.5% with placebo (ETD, −20.8 percentage points; 95% CI, −23.2 to −18.5; 

Additional analysis suggested the percentage of participants achieving additional weight reduction of 5% or greater was met in 87.5% of the tirzepatide group compared to 16.5% of the placebo group achieving this threshold (odds ratio, 34.6; 95% CI 19.2 to 62.6; 

SURMOUNT-4 was designed to assess the effect of tirzepatide discontinuation on body weight reduction in people with overweight or obesity relative to continued therapy. With this in mind, patients were randomized to tirzepatide or placebo therapy for 52 weeks after a 36-week open-label tirzepatide lead-in period. The primary endpoint of the trial was the mean percent change in body weight from week 36 to week 88.

At the end of the 36-week lead-in period, study participants achieved a mean weight loss of 21.1%. Upon analysis of the primary endpoint, results suggested use of tirzepatide was associated with a superior mean percent change in body weight relative to placebo. In contrast, those randomized to placebo experienced a mean weight regain of 14.8% at 88 weeks (Placebo-adjusted net change: -21.4%). The tirzepatide group achieved a mean body weight reduction of 26.0% during the trial.

 hosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, discuss the results of these studies and how it might help inform use of tirzepatide if approved by the US Food and Drug Administration for chronic weight management.

Wadden TA, Chao AM, Machineni S, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial [published online ahead of print, 2023 Oct 15]. 

. 2023;10.1038/s41591-023-02597-w. doi:10.1038/s41591-023-02597-w

Tirzepatide demonstrated significant and superior weight loss compared to placebo in two pivotal studies. Eli Lilly and Company. July 27, 2023. Accessed October 26, 2023. https://investor.lilly.com/news-releases/news-release-details/tirzepatide-demonstrated-significant-and-superior-weight-loss

In this episode, hosts discuss the results of SURMOUNT-3 and SURMOUNT-4 as well as how it might help inform use of tirzepatide if approved by the US Food and Drug Administration for chronic weight management. 

Diabetes Dialogue: SURMOUNT-3 and -4 Inform Use of Tirzepatide in Obesity

Less than a year after receiving approval as the first therapy in US Food and Drug Administration history for delaying the onset of 

, teplizumab (Tzield) is once again making headlines with the results of the PROTECT trial.

Results of the trial, which assessed the effects of teplizumab in patients with newly diagnosed type 1 diabetes, suggested use of the agent was associated with a significant reduction in the decrease in mean C-peptide levels, a marker of beta-cell function, at 78 weeks relative to those who received placebo therapy.

“These new results build on the findings from multiple studies across different stages of the disease process, further supporting TZIELD’s potential to modulate the progression of [type 1 diabetes],” said Kevan Herold, MD, the C.N.H. Long Professor of Immunobiology and of Medicine at Yale School of Medicine, in a statement from Sanofi.

The FDA approval of teplizumab for delaying the onset of stage 3 type 1 diabetes in adults and pediatric patients 8 years and older who currently have stage 2 type 1 diabetes on November 17, 2022 ushered in a new era of diabetes management. This approval was based on results from the TN-10 trial.

PROTECT trial was a phase 3, randomized, placebo-controlled trial aimed at assessing the effect of teplizumab use in people with stage 3 type 1 diabetes. With this in mind, the trial enrolled patients and randomized them in a 2:1 ratio to teplizumab or matching placebo for 2, 12-day courses. Investigators pointed out randomization was stratified according to the peak C-peptide level and age.

In addition to achieving its primary endpoint of a significantly less decrease in mean C-peptide levels following a 4-hour mixed-meal tolerance test (difference in least-squares means of 0.13 pmol/mL; 95% CI, 0.09 to 0.17; P<0.001). the trial also provided insight into the effects using multiple secondary outcomes of interest:

HbA1c was rapidly controlled in both groups and did not differ between groups through week 78.

Time in range favored teplizumab, but failed to reach statistical significance (4.71 percentage points; 95% CI, -1.72 to 11.15).

Estimated mean daily insulin doses were 0.46 units and 0.59 units per kilogram per day for the teplizumab and placebo groups, respectively (difference, 0.13 units per kilogram per day; 95% CI, –0.28 to 0.02).

Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, spotlight the data in the latest episode of 

Ramos EL, Dayan CM, Chatenoud L, et al. Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes [published online ahead of print, 2023 Oct 18]. 

. 2023;10.1056/NEJMoa2308743. doi:10.1056/NEJMoa2308743

Press release: TZIELD® Phase 3 data presented at Ispad shows potential to slow the progression of stage 3 type 1 diabetes in newly diagnosed children and adolescents; full data simultaneously published in the NEJM. Sanofi. October 25, 2023. Accessed October 18, 2023. https://www.sanofi.com/en/media-room/press-releases/2023/2023-10-18-08-45-00-2762096.

In this episode, hosts discuss data from the PROTECT trial, which examined the effects of teplizumab on beta-cell function in patients with newly diagnosed type 1 diabetes.