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ForumsCardiovascular OutcomesSemaglutide cardiovascular benefit independent of weight loss — looking for input

Semaglutide cardiovascular benefit independent of weight loss — looking for input

Dr.PeteFamMed Mon, Apr 27, 2026 at 1:38 AM 21 replies 664 viewsPage 1 of 5
Dr.PeteFamMed
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Apr 27, 2026 at 1:38 AM#1

This gets cited here weekly, usually second-hand, so it is worth setting out what it does and does not establish.

SELECT is the trial that changed the framing of this class, because it was an outcome trial rather than a weight trial: about a 20% relative reduction in major adverse cardiovascular events in people with established cardiovascular disease and overweight or obesity, without diabetes. The effect appeared earlier than the weight-loss curve can comfortably explain, which is the basis for arguing that some of the benefit is direct — anti-inflammatory and vascular — rather than purely a consequence of weight.

Where I think it is weakest: the subgroup findings are the part I trust least — with enough subgroups something is always significant, and these were not all pre-registered.

The question I want answered is how much of the SELECT benefit is plausibly independent of the weight loss, and whether that distinction changes anything practical. I would rather have one careful answer than five confident ones.

Note on sourcing:
Figures above are from the primary publication rather than the press summary. If a number here disagrees with one you have, post yours and we will work out which of us is reading a secondary source.
23 18hyun_seoul, jim_asheville, matt_MKE and 20 others
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LarryQC_SD
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Apr 27, 2026 at 1:59 AM#2
Dr.PeteFamMed said:
SELECT is the trial that changed the framing of this class, because it was an outcome trial rather than a weight trial: about a 20% relative reduction…

All true, with one condition: that curve is for people who reached the dose on schedule. Anyone who slowed the ladder for tolerability is on a different, flatter curve, and comparing yourself with the published mean will make you feel like a non-responder when you are not.

Last edited: Apr 27, 2026 at 2:59 AM
22 17paul_denver, TinaHashiRN, robert_kc and 19 others
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Dr.RenalNash
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Apr 27, 2026 at 2:20 AM#3
Dr.PeteFamMed said:
SELECT is the trial that changed the framing of this class, because it was an outcome trial rather than a weight trial: about a 20% relative reduction…

Pushing back on Dr.PeteFamMed here. The "earlier than weight loss explains" argument is weaker than this thread makes it sound. Blood pressure and inflammatory markers move fast and are downstream of early weight loss, so the mechanism is not as cleanly separable as the summaries imply.

Happy to go further on any of that.

21 16Dr.NutriCornell, pam_stl, wei_SG and 18 others
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Dr.RaviCardio
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Apr 27, 2026 at 2:41 AM#4

Short answer first, then the reasoning. Albumin binding above 99% is the whole reason weekly dosing works, and it is also why the trough matters more than the peak. People who dose late are not losing a peak, they are letting the trough fall, and the appetite effect tracks the trough.

20 15hans_munich, jason_sac26, chris_chi24 and 17 others
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mike_mealprep
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Apr 27, 2026 at 4:35 AM#5
LarryQC_SD said:
All true, with one condition: that curve is for people who reached the dose on schedule.

That holds for the injectable. The oral formulation has different absorption behaviour and the dose numbers are not interchangeable, which is worth saying out loud because people quote them as if they were.

19 14sophie_paris, mel_PDX, Dr.AddMedPHL and 16 others
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