Tirzepatide for Heart Health: Breakthrough Results

This newsletter has always been rooted in science. Today, I’m experimenting with a new format: a close look at one major clinical trial and what its findings mean for you as a GLP-1 therapy user. At the end, there’s a short poll - please let me know if this approach feels useful and whether you’d like to see more posts like this.

For this first review, I’ve teamed up with Dawid White, a nurse practitioner and a science geek. He was a patient in one of the phase 3 retatrutide trials for weight loss, which sparked his own interest in GLP-1 medications. Professionally, he shares a passion to help patients with obesity or Type 2 diabetes obtain benefit from these medications. Together we’re unpacking the groundbreaking SURPASS-CVOT trial.

David also runs his own blog The Incretin Space where he dives into recent research in even greater depth, so if you enjoy exploring the science behind these breakthroughs, I highly recommend checking it out.

What Was the SURPASS-CVOT Study?

Cardiovascular disease is still the leading cause of death in people living with diabetes and obesity. SURPASS-CVOT trial enrolled more than 13,000 participants across 30 countries and followed them for over four and a half years.

The primary goal was to test whether tirzepatide could prevent major heart problems like heart attack, stroke, or cardiovascular death beyond its known effects on glucose and weight.

Patients were randomized to receive tirzepatide (Mounjaro) or dulaglutide (Trulicity), making it the longest and most rigorous head-to-head test of tirzepatide to date.

Understanding the GIP hormone

To see why tirzepatide is so effective, we need to look at two hormones: GIP and GLP-1. Tirzepatide is unique because it activates both, and their receptors are found in heart and blood vessel tissue. This might seem odd for hormones tied to nutrient intake, but it’s crucial for cardiovascular health.

After a meal, GIP boosts blood flow, especially to fat tissue, partly by producing nitric oxide in vessel linings. Nitric oxide relaxes vessels, lowering resistance and blood pressure while improving fat processing. GIP also slightly raises heart rate, balancing the drop in blood pressure. Trial data confirm tirzepatide users see small increases in heart rate and drops in blood pressure, not just from weight loss. GLP-1 helps too, lowering pressure by increasing urination. When both are activated, these effects combine and strengthen.

GIP may also protect vessels by reducing inflammation and limiting excess muscle cell growth in their walls. This matters because stiffened arteries contribute to high blood pressure, poor flow, and plaque buildup. By slowing these changes, GIP may further reduce heart disease and death risk.

Cardiovascular Trial Evidence

MACE means major adverse cardiovascular events, which is a way for doctors to group together the most serious heart-related problems. Usually, it includes having a heart attack, having a stroke, or dying from heart disease. Sometimes, MACE will also cover things like needing emergency treatment for a blocked heart artery or being hospitalized for heart failure. In simple terms, it’s a count of the worst things that can happen to the heart and blood vessels.

Now let’s review trial evidence. Several major trials have evaluated GLP-1 therapies for cardiovascular outcomes: SUSTAIN-6, SELECT, FLOW, and REWIND. All trials showed reductions in MACE.

Most showed fewer strokes and heart attacks, with SUSTAIN reporting ~40% reduction. SELECT and FLOW demonstrated significant reductions in cardiovascular death, and SELECT plus FLOW showed ~20% all-cause mortality reduction. REWIND was close, though its lower dulaglutide dose may have limited effect.

Here is the data in a graph with significant results bolded.

What SURPASS-CVOT Trial Adds on Tirzepatide?

So what happens when GIP is added? In short, tirzepatide achieves similar or better reductions in cardiovascular events and death and far more striking reductions in all-cause mortality.

The SURPASS-CVOT trial compared tirzepatide - a dual GIP/GLP-1 agonist - to dulaglutide, a GLP-1 mono-agonist, in obese diabetics over roughly four years. The primary focus was on cardiovascular outcomes including MACE, with secondary outcomes covering mortality, weight loss, blood sugar control, and kidney function.

Notably, tirzepatide was non-inferior to dulaglutide in preventing MACE, with a trend toward better outcomes over time. Importantly, tirzepatide significantly reduced all-cause mortality by 39% compared to an indirect placebo - a reduction not seen with other GLP-1 therapies to this extent.

This is especially impressive given that most patients were already on statins and had well-controlled cholesterol.

Tirzepatide also showed superior improvements in key risk factors: A1c dropped by 1.7% versus 0.9%, weight decreased by over 25 pounds compared to 10, and systolic blood pressure declined more substantially.

Summary and Perspective

Rare is the trial that shows such compelling evidence of superiority over other medications.

As a medical professional, looking at this data, if my diabetics aren’t on tirzepatide I am having a discussion with them about either starting it, or switching to it if they’re on semaglutide.

We know tirzepatide is better at weight loss, but now we can point to this data and say it’s better or matches mono-agonist GLP-1 medications across the board. In blunt terms, do you want to quite frankly want to lower your chance of dying of anything medically related? Take tirzepatide to treat your diabetes. 

As a GLP-1 patient it makes me feel personally better about my own long term health seeing these results. 

I’m certainly not diabetic but it isn’t difficult to extrapolate these data outwards to non-diabetic patients. While we have to wait 2 more years for the SURMOUNT-MMO trial which will examine tirzepatide in the same context as SURPASS-CVOT but in non-diabetics and with a true placebo, I imagine those results will show similar benefits.

At the end of the day, faced with my own mortality, I can imagine I will be taking these medications as long as I can. Not only am I at a healthy weight now, but my quality of life has significantly improved and if these medications can help sustain that and reduce my risk of dying, it is worth it to me. 

My final thought is this, while these results are truly amazing, we are mere months away from the release of topline phase 3 retatrutide data, and that drug is even MORE effective than tirzepatide for weight reduction, lipids, blood pressure, GFR and more, we might see something even more shocking in terms of health benefits. Stay tuned! 

Scientific References for this article:

_{Glucose-dependent insulinotropic polypeptide (GIP) - ScienceDirect}

_{Microsoft PowerPoint - EASD25 CVOT Symposium_Lilly Deck_FINAL_18SEP2025}

_{Tirzepatide Once Weekly for the Treatment of Obesity | New England Journal of Medicine}

_{Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes | New England Journal of Medicine}

_{Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes | New England Journal of Medicine}

_{Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial - The Lancet}

_{Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes | New England Journal of Medicine}