GLP-1s vs. Heart Disease

Happy Thursday!

This morning, I got a phone call from my mom that rattled me.

She told me that my dad’s first cousin, who is 66 years old, had just suffered a heart attack.

The doctors said he had a 100% blockage. He’s in the hospital now, alive, but the outcome is still up in the air.

It hit me hard because even though he and I don’t talk often, it’s still family.

And it’s a reminder that cardiovascular disease doesn’t just happen to “other people.”

It happens in every family, in every town, all across the world, several times per day.

In fact, on average, there are between 55,000-70,000 heart attacks every single day.

My dad’s cousin is not a peptide user, and of course that wasn’t my first thought when Mom called.

But once we got past the shock, we found ourselves discussing how GLP-1 peptides have fundamentally changed the game for heart attack prevention.

They aren’t magic pills, and they don’t replace lifestyle, but they are one of the first tools in decades that actually move the needle on reducing heart attack risk itself.

Today’s email is my deep-dive on the best tools we have so far to help stop heart attacks and death from cardiovascular disease.

CVD is Still the #1 Killer

Heart disease is the number one killer worldwide.

Every year, nearly 18 million people die from cardiovascular disease, and in the U.S. alone, 1 in every 5 deaths is from heart disease.

What’s frustrating is that many of these deaths are preventable with lifestyle changes, but the reality is that most people don’t live like professional athletes.

That’s why the drug advances of the last decade matter so much.

We now have therapies that directly reduce the chance of heart attacks, strokes, and cardiovascular death.

For years, all we had were statins, blood pressure meds, and stents. And the amount of deaths from CVD continue to mount.

However, the last decade gave us two categories of drugs that stand out.

GLP-1 receptor agonists and SGLT2 inhibitors.

What makes them revolutionary is that they go beyond glucose lowering to actually change outcomes.

They change whether or not people end up in the hospital with heart attacks.

And they’ve done it consistently in huge randomized trials.

How GLP-1s Reduce Heart Attacks

Let’s start with the GLP-1 story.

If you’ve been reading my work, you know these peptides first came to light for diabetes and obesity. But then the cardiovascular outcome trials started rolling in.

• Semaglutide 2.4 mg (SELECT trial): Over 17,000 people with obesity and prior heart disease, but no diabetes. Result? A 20% reduction in major adverse cardiovascular events (MACE: CV death, non-fatal MI, non-fatal stroke). That’s massive.

• Liraglutide (LEADER trial): In type 2 diabetics with high CV risk, liraglutide reduced MACE by 13%, and importantly, lowered cardiovascular death.

• Dulaglutide (REWIND trial): Included people with and without diabetes. Over ~5 years, it cut MACE by 12%.

• SUSTAIN-6 with semaglutide: Showed a 26% drop in MACE.

Mechanistically, GLP-1s lower inflammation, improve endothelial health, modestly reduce blood pressure and triglycerides, and cause weight loss.

Yet, subgroup analyses show the cardiovascular benefits aren’t fully explained by weight loss.

That means GLP-1 signaling itself is cardioprotective.

For someone like my cousin, that’s the kind of tool that can literally rewrite his odds for survival.

How SGLT2 Inhibitors Reduce Heart Attacks

Now let’s look at the other powerhouse, the SGLT2 inhibitor class (drugs like empagliflozin (Jardiance), canagliflozin (Invokana), and dapagliflozin (Farxiga)).

These started out as glucose-lowering pills too, but what they really do is reshape heart and kidney outcomes.

• EMPA-REG OUTCOME (empagliflozin): In type 2 diabetics with heart disease, it reduced MACE by 14%, cardiovascular death by 38%, and heart failure hospitalization by 35%.

• CANVAS Program (canagliflozin): Similar MACE reduction (~14%) plus renal benefits.

• DECLARE-TIMI 58 (dapagliflozin): Neutral on MACE in lower-risk populations, but still showed a 27% reduction in HF hospitalizations.

• VERTIS-CV (ertugliflozin): Neutral on MACE but again reduced HF events.

Mechanistically, SGLT2 inhibitors work through natriuresis (sodium excretion), osmotic diuresis, improved ventricular loading, and shifting metabolism toward ketones, making the heart more energy efficient.

What you see in trials is an early reduction in heart failure and cardiovascular death, which is exactly what you want in a drug aimed at high-risk patients.

Why the Combo is the Future

Here’s where it gets exciting.

GLP-1s seem strongest at preventing atherothrombotic events (heart attacks and strokes driven by plaque rupture).

SGLT2 inhibitors shine at preventing heart failure and sudden cardiovascular death.

Put them together, and you cover both sides of cardiovascular risk.

A 2024 BMJ analysis found that people on both a GLP-1 and an SGLT2 inhibitor had lower risks of MACE and serious kidney events than either therapy alone.

Other meta-analyses suggest the combination can reduce MACE by 30% or more compared to monotherapy.

Imagine a 66-year-old man who’s overweight, has type 2 diabetes, and just had a heart attack.

Historically, his 5-year outlook would be grim.

Today, with the availability of GLP-1 + SGLT2 inhibitors, his chance of avoiding another heart attack or dying from cardiovascular disease dramatically improves.

Where Retatrutide and Future Agents Fit

Let’s look at where things are headed.

Because if the early stage GLP-1s did this well, imagine how much better things will get.

Retatrutide, the GLP-1/GIP/glucagon triple agonist, is still in trials.

The TRIUMPH-OUTCOMES study will give us MACE data over the next 5 years.

For now, phase 2 data show 24% bodyweight reduction, big drops in triglycerides and ApoC-III, and improved blood pressure.

Those are all surrogate markers of reduced cardiovascular risk.

Pairing retatrutide with an SGLT2 inhibitor could very well be the most powerful pharmacological combo we’ve ever had for preventing heart attacks, though we need to wait for the outcomes data before claiming it outright.

The Human Side

So where does that leave us?

With hope, but not a hall pass.

For my dad’s cousin, lying in the hospital bed right now, these drugs could change the trajectory of his life if he survives this event.

For my mom, who asked what could have been done, the answer is a combination of living the lifestyle (diet, fasting, exercise, stress control), and leveraging these new therapies when appropriate.

GLP-1s and SGLT2 inhibitors are not panaceas.

They don’t erase decades of poor habits, poor diet, and inactivity.

But they do provide a second chance.

For anyone reading this who has struggled with health choices, this is good news.

The future of cardiovascular prevention is brighter than ever.

But as always, you still have to live the life.

Final Thoughts

This morning’s phone call was a reminder that heart disease is always close to home.

My family member’s situation shows both the fragility of life and the opportunity we now have.

For the first time, we can talk not only about lowering cholesterol or sugar, but about directly reducing heart attacks and cardiovascular death with therapies like GLP-1s and SGLT2 inhibitors.

If you or someone you love is at risk, don’t ignore this.

Don’t be afraid, but do take control of your life and implement the changes necessary to ensure you live the happiest, healthiest, most fulfilled life possible.

Best,

Hunter Williams