GLP-1s and Heart Failure

I have written about the cardiovascular outcome data already. This is a narrower and, I think, more interesting story, because it concerns the form of heart failure that had almost nothing.

The condition, briefly

Heart failure comes in two broad forms. In reduced ejection fraction, the heart’s pumping is weak, and several drug classes have been proven over decades. In preserved ejection fraction (HFpEF), the heart squeezes normally but is stiff and fills poorly — pressure backs up, and you get breathless, swollen and exhausted on exertion.

HFpEF accounts for roughly half of all heart failure. It is strongly associated with obesity, hypertension and type 2 diabetes. And for a long time the honest summary of treatment was diuretics for symptoms and management of the associated conditions — the trials that worked in reduced ejection fraction largely did not replicate here.

There is a growing view that obesity-related HFpEF is not simply heart failure in someone who happens to be heavy, but a distinct phenotype in which the excess weight is a driver rather than a bystander. If that is right, treating the weight is treating the disease.

The trials

STEP-HFpEF, published in the NEJM in 2023, randomised people with HFpEF and obesity to semaglutide or placebo. Over 52 weeks it found significantly greater improvement in heart failure symptoms and physical limitation, better exercise capacity on a 6-minute walk test, and substantial weight loss. A companion trial extended the finding to participants with type 2 diabetes.

SUMMIT, published in 2024, randomised a comparable population to tirzepatide over a median of about 2 years and reported a reduction in the risk of worsening heart failure events, alongside symptom improvement.

Two things make these unusual. The endpoints include how people actually feel and function, which is what patients with HFpEF care about and what most trials fail to move. And they land in a condition where the shelf was close to empty.

The usual caution applies about who was studied: these were people with obesity and HFpEF, and the findings describe that group. The checks are in how to read a GLP-1 study.

The thing most likely to go wrong

Not the drug. The diuretic.

As weight and congestion fall, the diuretic dose that was correct when you were more congested becomes too much. The result is light-headedness, dehydration, rising creatinine, and occasionally a fall. It develops gradually enough that nobody attributes it to a dose that has not changed.

Ask for a scheduled diuretic review — every 3 months through active weight loss is a reasonable ask rather than waiting for symptoms — this is the same deprescribing pattern that applies to blood pressure medication and is described in the dizziness piece, but the stakes here are higher because the margins are narrower.

Two related points:

• Diuretics are on the standard hold list during any illness with vomiting or diarrhea, and in heart failure that decision needs your team rather than a general rule. Have it agreed in advance — sick day rules.
• Daily weights mean something different here. In heart failure a rising weight can indicate fluid retention rather than fat gain, and that distinction is clinical. Do not read your scale purely through a weight-loss frame; a 2 kg rise over 3 days with increasing breathlessness is a call to your heart failure team, not a bad week.

Muscle matters more here, not less

Cardiac cachexia and muscle wasting are recognised problems in heart failure and they predict worse outcomes. Layering rapid weight loss on top of that without a plan is the specific risk.

So the standard advice becomes more important rather than less: protein at 1.2–1.6 g/kg a day, 2 resistance sessions a week, and a slower titration than the schedule suggests. Exercise in heart failure should be prescribed rather than improvised — cardiac rehabilitation is the right route, and it is under-referred.

The argument in muscle is the whole game applies with the volume turned up, and the same reasoning that makes taking a GLP-1 after 65 a different conversation applies to a large share of this population.

What to ask your team

1. Does my HFpEF diagnosis support coverage? A documented heart failure diagnosis with trial evidence behind it is a materially different appeal to one framed around weight — the argument in what a GLP-1 actually costs.
2. Who is reviewing my diuretic, and when? Get a date, not a principle.
3. What weight change should prompt a call? Fluid and fat move the same scale in opposite clinical directions.
4. Can I be referred to cardiac rehabilitation? It is the safest route to the resistance training this plan depends on.
5. What are my sick day rules? Specifically for the diuretic, and for any ACE inhibitor, ARB or SGLT2 inhibitor.

And if you have heart failure with reduced ejection fraction rather than preserved, none of the above transfers automatically. That is a different condition with a different evidence base, and it is a conversation with your cardiologist rather than an extrapolation from these trials.