Diabetes Core Update – November 2025 Episode Summary

Podcast: Diabetes Core Update
Release Date: November 4, 2025
Hosts: Dr. Neil Skolnik & Dr. John J. Russell
Special Guest: Dr. J. Rao
Main Theme: Latest clinically relevant research articles from ADA journals and New England Journal of Medicine on diabetes, with a special focus this month on kidney disease, GLP-1 advances (including new oral therapies), dementia risk, and updates in obesity treatment.

Episode Overview

This episode delivers an in-depth review of five recently published research articles relevant to diabetes practice, examining new data on kidney and cardiovascular outcomes, novel oral GLP-1 receptor agonists, dementia risk in type 1 diabetes, and recent progress in obesity therapies. The discussion is tailored for practicing clinicians looking to apply the latest evidence to patient care, with insightful clinical context provided by the hosts and guest expert.

Key Discussion Points & Insights

1. Semaglutide & Mineralocorticoid Receptor Antagonist (MRA) Use in Type 2 Diabetes and CKD

Article: Diabetes Care – FLOW Trial Secondary Analysis
Timestamps: [00:02] – [03:48]

• Purpose: Explores whether the beneficial effects of semaglutide in chronic kidney disease (CKD) differ based on baseline MRA use (mainly spironolactone).
• Study Design:
  • Participants with T2D and CKD randomized to weekly semaglutide 1mg vs. placebo.
  • Primary outcome: composite of ≥50% eGFR reduction, kidney failure, or death from kidney/CV causes.
• Results:
  • Semaglutide reduced primary kidney outcomes by 49% with baseline MRA use and 21% without.
  • No heterogeneity in reduction of major adverse cardiac events (MACE) or all-cause mortality between groups.
  • Albuminuria reduced by 15% (MRA users) and 33% (non-users) at 104 weeks. Similar slowing of eGFR decline.

Key Takeaways:

• Semaglutide’s kidney and cardiac benefits are preserved regardless of MRA use.
• Spironolactone as MRA wasn’t widely embraced, possibly due to hyperkalemia concerns, but evidence suggests these may be overestimated.
• Quote (Russell, [03:48]):

  "Spironolactone never really got the embrace it should have… probably is not as big a worry as people can have [re: hyperkalemia]."

2. Oral GLP-1 Receptor Agonist "Orforglipron" – Effects in Early Type 2 Diabetes & Obesity

Articles: New England Journal of Medicine – Two Trials
Guest Expert: Dr. J. Rao
Timestamps: [05:27] – [13:35]

A. Orforglipron in Early Type 2 Diabetes

• Study Design: Phase 3, diet-managed T2D patients, randomized to three different doses vs. placebo.
• Results:
  • HbA1c reduction of 1.25–1.5% at 40 weeks (vs. 0.5% with placebo).
  • Notable weight loss.

B. Orforglipron in Obesity (Non-Diabetics)

• Study Design: Randomized, double-blind, >1 year, adjunct to diet & activity.
• Results:
  • 7.5–10% weight loss depending on dose (vs. 2% placebo) at 72 weeks.
  • Improvements in BP, triglycerides, cholesterol.
• Side Effects:
  • Mainly GI (nausea); led to some discontinuations but no surprises.

Clinical Implications:

• Provides a true oral, small-molecule GLP-1 option with less “finickiness” than current oral peptides (e.g., semaglutide).
• Expected to be more convenient for patients averse to injections.
• Potential "game changer" if oral administration requirements are less strict.
• Quote (C, Dr. Rao, [12:20]):

  "It has to be taken in a certain way on an empty stomach...that becomes really hard for patients. And I’m hoping this [orforglipron] will be a little bit easier."

3. Dementia Risk in People with Type 1 Diabetes

Article: Diabetes Care – Swedish Nationwide Cohort Study
Timestamps: [13:37] – [15:28]

• Study: Over 43,000 Swedish T1D patients, matched to 217,000+ controls.
• 13–20 Years Follow-Up:
  • All-cause dementia incidence: 1.2% (T1D) vs. 0.9% (controls).
  • Increased risk (hazard ratios): 2.02 (all-cause), 1.38 (Alzheimer’s), 3.73 (vascular), 1.87 (non-Alz/non-vasc).
  • Key risk factors: lower education, being single, high systolic BP, higher HbA1c, prior stroke/TIA, cardiovascular disease, longer diabetes duration.

Clinical Pearls:

• Dementia should be discussed as a downstream complication of T1D, much like nephropathy and retinopathy.
• Modifiable risk factors: HbA1c and systolic BP.
• Quote (Skolnik, [15:28]):

  “Dementia…can be thought of as a downstream complication of diabetes and one of those things that we talk to people about as a reason to try and have tight control.”

4. Impact of GLP-1 Use on Albuminuria Reduction with Finerenone + Empagliflozin in T2D & CKD

Article: Diabetes Care – CONFIDENCE Trial Subanalysis
Timestamps: [15:28] – [19:06]

• Purpose: Does prior GLP-1 use affect albuminuria reduction and safety when adding finerenone (non-steroidal MRA) + empagliflozin?
• Results:
  • Albuminuria reduction similar in those with (+51%) and without (+50%) baseline GLP-1.
  • Hyperkalemia incidence and eGFR changes consistent across both groups.
• Clinical Implication:
  • Using GLP-1 does not diminish additive benefit of MRA + SGLT2i combo in reducing albuminuria.
  • Quote (Russell, [19:06]):

    “Does this kind of peanut butter and jelly combination…present or absent GLP-1…screw up that synergy? And it really doesn’t seem to.”

5. Oral Semaglutide 25mg for Obesity – Efficacy & Quality of Life

Article: New England Journal of Medicine
Timestamps: [19:06] – [26:47]

• Study: 71-week double-blind RCT, non-diabetic obese participants, 2:1 randomization to semaglutide 25mg vs. placebo.
• Results:
  • Mean weight loss: 13.6% (semaglutide) vs. 2.2% (placebo), difference 11.4%.
  • 1/3 achieved ≥20% weight loss; improvements in physical function.
  • GI side effects: 74% (semaglutide) vs. 42% (placebo).
• Recent Regulatory Developments:
  • FDA application submitted for obesity treatment.
  • 14mg dose (for diabetes) approved for cardiovascular risk reduction based on SOUL trial (14% MACE reduction).
  • 25mg application includes reducing MACE in patients with obesity, referencing SELECT trial (20% MACE reduction over 3 years).

Clinical Perspective:

• Oral semaglutide (25mg) is approaching efficacy seen with subcutaneous formulations for weight loss.
• Anticipated arrival of one or two oral GLP-1 options over the next 1–2 years for obesity.
• Quote (Skolnik, [23:06]):

  “Looks like we may have an oral effective option for treatment of obesity and that would be very welcome.”

Notable Quotes & Memorable Moments

• On MRA Use:
  “Spironolactone never really got the embrace it should have… probably is not as big a worry as people can have.”
  — Dr. John Russell ([03:48])

• On Oral GLP-1 Advantages:
  “I’m hoping that this will be a little bit easier because it’s a smaller molecule and doesn’t maybe have that sort of regimented approach when you’re taking it.”
  — Dr. J. Rao ([12:20])

• On Dementia as a Complication:
  “Dementia…can be thought of as a downstream complication of diabetes and one of those things that we talk to people about as a reason to try and have tight control.”
  — Dr. Neil Skolnik ([15:28])

• On Additive Effects in Albuminuria Reduction:
  “Does this kind of peanut butter and jelly combination…present or absent GLP-1…screw up that synergy? And it really doesn’t seem to.”
  — Dr. John Russell ([19:06])

• On Oral Semaglutide for Obesity:
  “Looks like we may have an oral effective option for treatment of obesity and that would be very welcome.”
  — Dr. Neil Skolnik ([23:06])

Timestamps for Key Segments

• Semaglutide & MRA in CKD: [00:02] – [03:48]
• Orforglipron in Early T2D & Obesity (with Dr. J. Rao): [05:27] – [13:35]
• Dementia Risk in Type 1 Diabetes: [13:37] – [15:28]
• GLP-1 + MRA/SGLT2i Effects on Albuminuria (CONFIDENCE): [15:28] – [19:06]
• Oral Semaglutide 25mg for Obesity: [19:06] – [26:47]

Closing Note

Podcast Update:
The show will be rebranded as Diabetes, Obesity, and Cardiometabolic Update (DOC Update) to better reflect its expanding focus on the full spectrum of cardiometabolic diseases.

For article links and more resources, visit: www.diabetesjournals.org

Listen to the next episode for more on diabetes, obesity, and cardiometabolic research!