Podcast Summary: Diabetes Core Update – Special Edition: CVOTs Part 2

Episode Date: November 19, 2025
Host: Dr. Neil Skolnick
Guest: Dr. Darren McGuire

Episode Overview

This special episode is the second in a two-part series focused on Cardiovascular Outcomes Trials (CVOTs) in the field of diabetes care. Dr. Neil Skolnick and guest Dr. Darren McGuire, a leading expert in cardiovascular science and diabetes trials, review the evolution, impact, controversies, and future directions of CVOTs. The discussion ranges from the initial rationale for these trials, groundbreaking findings, updated FDA regulations, to the methodological advancements exemplified by the Surpass CVOT.

Key Discussion Points & Insights

1. Setting the Stage: The Genesis of CVOTs

• Historical Background:
  • FDA began mandating CVOTs for new diabetes drugs in 2008 after concerns about cardiovascular safety (00:43).
  • Early trials focused on DPP4 inhibitors to establish cardiovascular safety rather than efficacy.
  • Many initial trials confirmed DPP4 inhibitors as "the perfect placebo" from a cardiovascular outcome perspective (05:44).

    "We proved over these four trials that the DPP4 inhibitors are the perfect placebo for cardiovascular outcomes."
    — Dr. McGuire [05:44]

2. Key Milestones: Breakthrough Efficacy Findings

• EMPA-REG OUTCOME Trial (2015):
  • Changed the field by demonstrating a 16% reduction in major adverse cardiovascular events (MACE) with empagliflozin, and a 30% reduction in heart failure risk (08:00).
  • Marked the shift from proving safety to demonstrating efficacy in CVOTs.

    "September 15th ... marked in history, we had the very first positive outcomes trial in the field of diabetes."
    — Dr. McGuire [05:45]

• Number Needed to Treat (NNT):
  • NNT was approximately 30, making the effect size clinically meaningful (09:34).

3. The Expansion and Impact of CVOTs

• Therapeutic Classes:
  • SGLT2 inhibitors and GLP-1 receptor agonists established as evidence-based treatments for reducing cardiovascular, heart failure, and renal risks.
• Treatment Paradigms:
  • Shift from a glucocentric model (focused on glucose control) to a more personalized, cardio-kidney-metabolic approach (12:34).

    "The ADA has now acknowledged with these comorbidities that metformin is no longer a first-line drug and it is at, at a minimum, a fourth-line drug."
    — Dr. McGuire [13:36]

• Guidelines & Standards of Care:
  • Recent ADA guidelines prioritize SGLT2 inhibitors or GLP-1 RAs over metformin for patients with significant CV, heart failure, or CKD risk (13:36).

4. FDA's 2020 Guidance and the Case for Ongoing CVOTs

• FDA Regulatory Changes:
  • FDA relaxed the requirement for mandatory CVOTs for all new diabetes treatments in 2020 (15:46).
  • Dr. McGuire strongly criticizes this move, citing examples where only large outcomes trials detected rare but serious adverse effects (17:35).

    "I will say unequivocally ... they got this wrong. So we have to do these large scale outcomes trials."
    — Dr. McGuire [15:46]

• Historical Examples:
  • Key safety signals (anaphylaxis, GI bleeding, liver injury) only detected through large-scale trials.

5. Discussing Sulfonylureas and Active Comparators

• Controversy:
  • Questions about sulfonylureas’ CV safety due to product labeling and historical data (18:43).
• CAROLINA and CARMELINA Trials:
  • Linagliptin vs. glimepiride and linagliptin vs. placebo both showed neutral cardiovascular results.

    "At least we have one sulfonylurea that in a large scale randomized comparison shows probably no cardiovascular harm."
    — Dr. McGuire [20:25]

6. The Surpass CVOT: Methodologic Innovation and Results

Background and Rationale

• Active Comparator Design:
  • Surpass is the first major anti-hyperglycemic trial to test against an active, proven comparator (GLP-1 RA dulaglutide) rather than placebo (23:26).

    "We need to pivot to active comparative controlled trials testing against a proven anti-hyperglycemic therapy."
    — Dr. McGuire [23:52]

• Ethical Imperative:
  • Continuing placebo-controlled trials risks denying effective therapies to participants (27:12).

    "That becomes an ethical dilemma when you're putting people in trials because they're vulnerable."
    — Dr. McGuire [27:12]

Trial Execution & Findings

• Trial Design and Setting:
  • Surpass compared tirzepatide (GLP-1/GIP dual agonist) to dulaglutide (GLP-1 RA) and included over 13,000 participants (27:57).
  • Conducted during COVID-19 and geopolitical instability, yet achieved >99% follow-up (28:41).
• Outcomes:
  • Tirzepatide demonstrated non-inferiority to dulaglutide for MACE; point estimate HR 0.92 (8% RRR), just missed superiority (29:59).
  • Imputed placebo analysis suggested a 26% reduction in MACE — higher than any prior GLP-1 trial, though this is a modeled estimate, not direct evidence (31:32).

    “If we can prove that tirzepatide is not inferior to dulaglutide, we can also impute what we might have seen with the placebo. ... 26% reduction in cardiovascular death, MI, and stroke, which is the highest level of reduction in the field.”
    — Dr. McGuire [25:03]

• Sensitivity Analysis:
  • Comparison with similar patients from the REWIND trial yielded a 28% reduction over four years (31:13).

7. Looking Ahead: The Future of CVOTs

• Emerging Therapies and Outcomes Trials:
  • Shift from diabetes to obesity-centric trials; ongoing (even if not required) due to scientific and clinical importance (32:47).
  • Companies are electing to conduct large CVOTs for obesity and new anti-diabetic agents, expanding the evidence base.

    "Companies are racing towards doing cardiovascular outcomes assessment even though they don't have to do it."
    — Dr. McGuire [33:47]

Notable Quotes & Memorable Moments

• "We proved over these four trials that the DPP4 inhibitors are the perfect placebo for cardiovascular outcomes."
  — Dr. McGuire [05:44]

• "The ADA has now acknowledged with these comorbidities that metformin is no longer a first-line drug and it is at, at a minimum, a fourth-line drug."
  — Dr. McGuire [13:36]

• "I will say unequivocally ... they got this wrong. So we have to do these large scale outcomes trials."
  — Dr. McGuire [15:46]

• "At least we have one sulfonylurea that in a large scale randomized comparison shows probably no cardiovascular harm."
  — Dr. McGuire [20:25]

• “If we can prove that tirzepatide is not inferior to dulaglutide, we can also impute what we might have seen with the placebo. ... 26% reduction in cardiovascular death, MI, and stroke, which is the highest level of reduction in the field.”
  — Dr. McGuire [25:03]

• "Companies are racing towards doing cardiovascular outcomes assessment even though they don't have to do it."
  — Dr. McGuire [33:47]

Timestamps for Key Segments

| Segment | Timestamp | |--------------------------------------------------------|--------------| | Introduction and CVOT Historical Context | 00:02-03:35 | | DPP4 Inhibitors and Safety Trials | 05:44-08:18 | | EMPA-REG OUTCOME and the CVOT Paradigm Shift | 08:18-09:34 | | SGLT2 and GLP-1: Evidence and Treatment Models | 09:34-12:34 | | Standards of Care Evolution; Metformin’s Role | 13:36-14:43 | | FDA Relaxes CVOT Requirements | 15:46-17:35 | | Sulfonylureas, CAROLINA/CARMELINA Trials | 18:43-20:25 | | Surpass CVOT: Rationale and Methodology | 22:49-26:48 | | Surpass Results and Analytical Innovations | 27:45-32:34 | | Future of Outcomes Trials and Obesity Medications | 32:47-34:00 |

Conclusion

This episode provides an expert deep-dive into the changing landscape of diabetes drug development, emphasizing the importance of cardiovascular outcomes, evolution of standards of care, and the ethical/methodological shift toward active comparator trials. The conversation is especially valuable for clinicians making value-based prescribing decisions and those interested in how evidence translates to practice. The Surpass CVOT exemplifies future trial design, showcasing both scientific rigor and adaptability to new therapeutic landscapes.