Diabetes Core Update – May 2025

Podcast Date: April 28, 2025
Hosts: Dr. Neil Skolnik & Dr. John J. Russell
Guests: Dr. Steven Nissen, Dr. Muthu Vaduganathan, Dr. Darren McGuire

Overview

This episode of Diabetes Core Update dives into recent, clinically impactful studies in diabetes, heart, and kidney care. The hosts and guest experts explore new research on lipoprotein(a) lowering, the links between diabetes and anemia, the pooled safety and efficacy data for finerenone in diabetic patients, and two pivotal papers on GLP-1 receptor agonists—highlighting both injectables and oral agents—focusing on cardiovascular, renal, and mortality outcomes. Each segment analyzes what these findings mean for real-world clinical practice.

Key Discussion Points & Insights

1. Long-Duration siRNA Targeting Lipoprotein(a): The ALPACA Trial

Guest: Dr. Steven Nissen
Source: NEJM

Why Lp(a) Matters (02:03–03:16)

• Lipoprotein(a) [Lp(a)] is a genetic lipid particle linked to atherosclerosis and aortic stenosis, with up to 20% global prevalence.
• Testing is rarely done (“only 13.9% had a lipoprotein A drawn”), mainly because traditional interventions (diet, statins) don’t impact its levels.

Quote:
“It’s not being tested even though the testing is inexpensive because people have felt there’s no treatment…that is in the process of changing.”
— Dr. Steven Nissen [03:16]

ALPACA Trial Methods & Results (03:46–07:08)

• Lepodiserin, a small interfering RNA (siRNA) agent, was studied in a phase 2 trial with 320 patients (all with Lp(a) >175 nmol/L; normal <75).
• Participants received 400mg doses subcutaneously, at baseline and six months.
• Results:
  • 93.9% time-averaged reduction in Lp(a) out to 180 days.
  • With a second dose, reductions hit 95%, many participants to undetectable levels.
  • Safety: Only mild, transient injection site reactions (12% at highest dose); no serious treatment-related adverse events.

Quote:
"Levels of lipoprotein A were near to zero... without substantial adverse effects."
— Dr. Steven Nissen [07:08]

Phase 3, Population Impact, and Diabetes Link (07:39–10:03)

• Phase 3 started before phase 2 ended; unique for including primary prevention patients.
• 12,500 patients enrolled to assess both primary and secondary prevention.
• Lowering Lp(a) must show clinical outcome benefits before FDA can approve.
• Diabetes Amplifies Risk:
  • Combination of diabetes and elevated Lp(a) is especially risky for cardiovascular outcomes.

Quote:
“The combination of diabetes and an elevated lipoprotein A is particularly bad for outcomes... additive effect for cardiovascular events.”
— Dr. Steven Nissen [09:33]

2. Diabetes and Anemia: Evidence from NHANES & UK Biobank

Summary by Hosts
Source: Diabetes Care

Study Design & Findings (10:44–12:25)

• Assessed over 9,000 NHANES and ~400,000 UK Biobank participants (ages 40–69).
• Result: Diabetes doubled to quadrupled the odds of anemia, and over 14 years, hazard ratios for various anemias in diabetics were:
  • Iron Deficiency: 3-fold increased risk
  • Anemia of Chronic Disease: 3-fold
  • Vitamin B12 Deficiency: Almost 5-fold

“The adjusted odds of study participants with diagnosed diabetes also having anemia was two- to four-fold higher than those with normal glycemia.”
— Dr. Neil Skolnik [11:35]

Clinical Implications (12:25–14:51)

• Suggests CBC may need to be standard in diabetes management, to check for anemia routinely.
• Factors to Consider:
  • Kidney disease highly related to anemia in diabetes.
  • B12 deficiency risk increases with metformin use.
  • Iron deficiency anemia can falsely elevate A1C. Hemolytic anemia can lower A1C.

“The point that I think is worth thinking about is…how much should we be dampening or modifying our A1C based on hemoglobin...”
— Dr. John Russell [13:12]

3. Efficacy and Safety of Finerenone in Type 2 Diabetes: Pooled Analysis

Guest: Dr. Muthu Vaduganathan
Source: Diabetes Care

Finerenone Overview & Rationale (15:26–16:40)

• Finerenone: Non-steroidal mineralocorticoid receptor antagonist; now shown safe and effective in chronic kidney disease (CKD) and heart failure (Fine Arts/HF trials).
• This analysis pooled data from three phase 3 trials, focusing on ~15,000 with type 2 diabetes.

Results & Key Insights (16:48–19:35)

• Consistency: Benefits seen regardless of concurrent diabetes medication (insulin, metformin, GLP-1s, SGLT2is), and across A1C levels.
• Benefits: Reduced heart failure hospitalizations, slowed CKD progression, reduced all-cause mortality.

“The treatment effects of finerenone were entirely consistent, irrespective of background use of these therapies…can really be layered or added alongside existing regimens in a safe and effective way.”
— Dr. Muthu Vaduganathan [18:41]

• Additive Effect: Works effectively on top of SGLT2 inhibitors and GLP-1 receptor agonists.
• Supports Integrated Guidelines: Findings support new, “cardio-kidney-metabolic” approach in future guidelines.

“These data…may influence multiple guidelines including emerging cardio-kidney-metabolic guidelines.”
— Dr. Muthu Vaduganathan [21:20]

4. Oral Semaglutide & Cardiovascular/ Renal Outcomes: Two Major Studies

Guest: Dr. Darren McGuire
Sources: NEJM & Diabetes Care

Oral Semaglutide CVOT (23:46–24:34)

• Nearly 10,000 patients with T2D + atherosclerotic CVD and/or kidney disease randomized to daily oral semaglutide vs placebo.
• Primary Outcome (CV death, MI, stroke):
  • 14% relative risk reduction (statistically significant), matching what is seen with GLP-1 injectables.

“We showed a 14% relative risk reduction, statistically significant…oral option for patients.”
— Dr. Darren McGuire [24:10]

Systematic Review & Meta-Analysis of GLP-1s (25:00–25:42)

• 14% risk reduction for MACE matches precisely with injectables (“needle didn’t move” with addition of oral agent data).
• Robust benefits for both oral and injectable routes.

Number Needed to Treat (NNT) & Comparative Efficacy (26:00–28:07)

• NNT: 50 patients treated for 3 years prevents 1 major CV event—comparable to aspirin, statins.
• Most patients will stay on these therapies long-term, so true benefit may be greater over time.

“This is squarely in the context of aspirin for secondary prevention, moderate dose statins, good blood pressure control…puts us right in step.”
— Dr. Darren McGuire [26:44]

• GLP-1s unlike statins offer added kidney protection, weight loss, and potentially heart failure benefits.

Clinical Take-Home (29:27–30:02)

• For eligible patients unwilling/unable to use injectables, oral semaglutide offers equal CV and renal protection.

“If you can get your patient to take the injection, I’d choose that every time. But…we now have an oral option and it maps right on the efficacy of the outcomes.”
— Dr. Darren McGuire [29:38]

Notable Quotes & Memorable Moments

• On Lp(a) and Testing:
  "The idea of not testing for LP because currently we can’t do anything about it makes as much sense as not asking about family history."
  — Dr. Neil Skolnik [03:16]

• On Interpreting A1C with Anemia:
  “Iron deficiency anemias might falsely elevate people’s A1Cs.”
  — Dr. John Russell [13:44]

• On Finerenone’s Broad Utility:
  “Finerenone can really be layered or added alongside existing regimens in a safe and effective way.”
  — Dr. Muthu Vaduganathan [18:41]

• On GLP-1s and Expanding Roles:
  “These are not endocrinology drugs… They’re cardiovascular risk-reducing medications.”
  — Dr. Darren McGuire [28:07]

Timestamps for Key Segments

• Lp(a) & ALPACA Trial: 02:03–10:35
• Diabetes & Anemia (NHANES, UK Biobank): 10:44–14:51
• Finerenone in T2D Pooled Analysis: 15:26–22:06
• Oral Semaglutide CVOT & GLP-1 Meta-Analysis: 23:34–30:02

Clinical Application

• Lp(a) Screening: Expect future shifts in primary care and risk stratification; new therapies may dramatically reduce a major population risk factor, especially relevant in diabetes.
• Anemia Monitoring: Consider routine CBC in diabetes management, screen for B12 deficiency with metformin use, and interpret A1C considering possible anemia.
• CKD/Heart Failure in T2D: Finerenone is a safe, additive therapy across the cardiorenal metabolic spectrum, regardless of background diabetes medications.
• GLP-1s for CV, Renal Protection: Both injectables and oral semaglutide now have robust data for reducing CV and renal events. Oral options broaden patient accessibility.

For additional article links and detailed references, visit www.diabetesjournals.org.