STEP-HFpEF: semaglutide in heart failure with preserved EF — March 2026

SarahChen_PharmD said:

I'm 55 years old and want to share my perspective on cardiovascular risk as an older member of this community.

Adding the part of the answer the thread has not reached. The dose-response is real but shallow at the top. Across STEP 1 and STEP 4 the gap between 1.7mg and 2.4mg is a couple of percentage points of body weight on average, and the average is carrying a wide spread — plenty of people at 1.7mg sit above the 2.4mg mean. If a dose is working and tolerable, "working" is the relevant variable, not "maximal".

I would rather be corrected than agreed with, if it comes to it.

SarahChen_PharmD said:

I'm 55 years old and want to share my perspective on cardiovascular risk as an older member of this community.

I want to bring up the cardiovascular angle on cardiovascular risk.

The SELECT trial demonstrated a 20% reduction in MACE with semaglutide 2.4mg[1]. This is practice-changing because the CV benefit appears to be independent of the degree of weight loss — suggesting direct vascular and anti-inflammatory mechanisms.

For cardiovascular risk, this means we need to think beyond the primary outcome and consider the cardiovascular implications. The all-cause mortality reduction (HR 0.81) is the most clinically meaningful signal.

One thing that is still open after SarahChen_PharmD’s answer:

Whether anyone has held at a sub-maximal dose long term and kept the result, or whether the maintenance data only exists at 2.4mg?

Dr.NateNeph said:

I want to bring up the cardiovascular angle on cardiovascular risk.

NNT calculation for cardiovascular risk clinical endpoints: NNT = 1/ARR (absolute risk reduction).

From SELECT trial: MACE at 39 months — 6.5% semaglutide vs 8.0% placebo. ARR = 1.5%. NNT = 67 over 3.3 years.

Compare to established therapies:

These NNTs are clinically meaningful and comparable to accepted cardiovascular interventions.

Dr.NateNeph said:

I want to bring up the cardiovascular angle on cardiovascular risk.

Metabolic syndrome resolution on cardiovascular risk: I went from meeting 3 of 5 diagnostic criteria to meeting ZERO after 14 months of treatment.

The 5 criteria (and my journey):

1. Waist circumference: 53" → 35" ✅ Resolved
2. Triglycerides: 273 → 98 ✅ Resolved
3. HDL: 37 → 55 ✅ Resolved
4. Blood pressure: 143/95 → 121/75 ✅ Resolved
5. Fasting glucose: 123 → 89 ✅ Resolved

Metabolic syndrome reversal is, in my view, the most medically significant outcome of GLP-1 therapy.