Special Edition: The Cardiovascular Outcome Trials – Origin and Perspective

Podcast: Diabetes Core Update
Episode Date: October 21, 2025
Host: Dr. Neil Skolnik
Guest: Dr. Steve Nissen

Episode Overview

In this special episode, Dr. Neil Skolnik hosts a conversation with Dr. Steve Nissen, a leading cardiologist and clinical trialist, to trace the history, rationale, and paradigm-shifting impact of Cardiovascular Outcomes Trials (CVOTs) in diabetes care. Dr. Nissen recounts the events that led to the FDA mandating CVOTs, how initial signals of harm from diabetes drugs triggered a move away from relying solely on A1C as a surrogate measure, and highlights the evolution towards outcome-focused drug development and approval. The discussion offers a rich, inside perspective on a watershed change in clinical practice and research, offering lessons for clinicians and young physician-scientists alike.

Key Discussion Points & Insights

1. Rethinking A1C and Surrogate Endpoints

[01:46 - 05:00]

• Dr. Nissen describes longstanding doubts about relying on surrogate endpoints (like A1C reduction) as proof of clinical benefit in diabetes medications.
• The initial wake-up call arose with muraglitazar, a dual PPAR agonist, which, despite improving glycemic and lipid measures, doubled cardiovascular events compared to placebo.
• The catalyst for action was legal: a lawsuit forced the FDA to post trial data publicly, allowing Dr. Nissen and his team to independently analyze the data and identify harm.

Notable Quote:

“A drug can have biochemical effects that may not in fact predict its true biological effects... it did not make sense that a drug could be approved... simply by showing that it lowered blood sugar.”
— Dr. Steve Nissen [02:10]

2. The Rosiglitazone Saga

[05:01 - 13:21]

• Following muraglitazar, Dr. Nissen investigated rosiglitazone after noting worrisome trends in two major trials (ADOPT and DREAM).
• Serendipitously found a website with unpublished GSK trial data as a result of a legal settlement (Spitzer lawsuit).
• Conducted a meta-analysis revealing a ~40% increased risk of myocardial infarction, published rapidly in the NEJM.
• The publication led to public controversy, professional isolation, and intense criticism, but spurred a critical reevaluation of drug approval processes.

Notable Quote:

“I sent a one-word email to my statistician, Kathy Wolsky, entitled ‘Eureka, I have found it.’”
— Dr. Steve Nissen [08:46]

Memorable Moment:

• Dr. Nissen describes being “persona non grata” among endocrinologists after the rosiglitazone meta-analysis made front-page news and caused patient panic.

3. The FDA Mandate for Cardiovascular Outcomes Trials

[13:21 - 21:14]

• Dr. Nissen proposed to the FDA a two-stage non-inferiority approval process:
  • First, demonstrate no harm (hazard ratio upper bound <1.8), then post-market, show more robust safety (upper bound <1.3).
• Initial skepticism came from the diabetes community and industry, fearing a barrier to innovation.
• Prominent support came from leaders like Dr. Rob Califf and Dr. Rory Holman.
• Over time, the requirement was shown to ultimately benefit industry and, critically, patient care by differentiating truly effective therapies.

Notable Quotes:

“At least one... said if you do what Dr. Nissen is proposing, there will never be another diabetes drug... But they actually ended up being beneficiaries.”
— Dr. Steve Nissen [19:00]

“The idea was not to put a shell on new drug development, but to make sure that the medical community ultimately got good information about both the benefits and risks of new therapies.”
— Dr. Steve Nissen [14:54]

4. Evolution and Impact of CVOTs

[21:14 - 26:35]

• FDA embraced Dr. Nissen’s proposal; trials now required to rule out major cardiovascular harm before and after market approval.
• Major CVOTs (e.g., EMPA-REG OUTCOME) changed standards of care by showing unexpected cardiovascular and renal benefits of newer drug classes (SGLT2 inhibitors, GLP-1 agonists).
• Demonstrated secondary benefits (renal, heart failure prevention), leading to new lines of research and dedicated trials.

Notable Quote:

“What happens when you do a comprehensive outcome trial is you can see a broad range of both benefits and risks.”
— Dr. Steve Nissen [24:40]

5. The Legacy and Future of Diabetes Drug Development

[26:35 - 29:28]

• FDA has recently removed the mandatory CVOT requirement (as of 2020) because market and clinical expectations have shifted; payers and clinicians now demand evidence of outcome benefits.
• The bar continues to rise: new drugs must now be tested not just against placebo, but compared to existing standard-of-care medications with proven outcome benefits.
• Future direction: head-to-head trials and combination therapies (triple agonists, oral GLP-1s) are poised to define the next era.

Notable Quote:

“We’re now entering a new era when we will have to study new drugs in comparison to drugs with established cardiovascular, renal and other benefits. And it just raises the bar even further.”
— Dr. Steve Nissen [28:11]

Notable Moments & Quotes

• On Courage in Science:

  “Have the courage of your convictions... be willing to be a little disruptive and be willing to get into good trouble because sometimes good trouble leads to good outcomes and better care for patients.”
  — Dr. Steve Nissen [29:41]

• On Standards of Practice:

  “We’ve now moved so far away from a glucocentric approach... if you look at the current ADA standards of care, that term seems a little bit odd and old, but that’s where we were at the time.”
  — Dr. Neil Skolnik [18:03]

Key Timestamps for Important Segments

| Timestamp | Segment Description | |-------------|-------------------------------------------------------------------------------------------------| | 01:46 | Beginnings of skepticism toward surrogate endpoints and A1C-centric drug approvals | | 05:00 | The miraglitazar case and the role of legal action in transparency | | 08:45 | Discovery and analysis of unpublished GSK rosiglitazone trial data | | 11:17 | The aftermath: public and professional response to NEJM publication | | 14:19 | FDA response: advisory panel, proposal for two-stage approval | | 16:38 | Explanation of non-inferiority thresholds (hazard ratios 1.8 and 1.3) | | 22:49 | The EMPA-REG OUTCOME trial and emergence of unexpected CV benefits | | 25:53 | Marketplace self-correction and the “raising of the bar” for new therapies | | 27:17 | Challenges for young scientists; why Dr. Nissen limited authorship to protect early-career docs | | 28:11 | Future: head-to-head outcome trials and ongoing elevation of standards | | 29:41 | Closing advice to clinicians and future physician-scientists |

Conclusion

This episode offers a behind-the-scenes account of how modern diabetes drug development standards were forged out of crisis, controversy, and courageous advocacy. Dr. Nissen’s detailing of scientific, regulatory, and industry dynamics provides valuable lessons in evidence-based medicine, the pitfalls of surrogate endpoints, the necessity of advocating for patient-centered outcomes, and the importance of scientific integrity and resilience. The legacy of CVOTs is a transformed landscape where only drugs with proven benefits in hard clinical outcomes set the standard—and where clinicians and patients now expect and demand more from therapy than just numbers.

For further exploration:
For more information about diabetes research and standards, visit the American Diabetes Association’s journals website at www.diabetesjournals.org.