The clinician who ordered the panel was not concerned; I would still like to understand it.
The units are where I keep going wrong, so please be explicit about them.
I have sanity-checked the order of magnitude and it seems right, which is not the same as being right.
Is my approach right even if my number is wrong?
A hazard ratio from SURMOUNT-2 cannot be converted into an absolute risk reduction without the control-arm event rate, and that rate is the number people forget to carry across. The arithmetic: absolute reduction equals the control event rate minus the treated event rate, and the treated rate is approximately the control rate multiplied by the ratio. A hazard ratio of 0.80 against a 10 per cent control rate is a 2-point absolute reduction and a number needed to treat of 50; the same 0.80 against a 2 per cent control rate is 0.4 points and a number needed to treat of 250. Identical ratio, six-fold difference in what it is worth. Take the control-arm rate and the follow-up duration from the SURMOUNT-2 paper, not from the abstract, and do the subtraction yourself.
On the detail: the relevant distinction is between a trial that measured cardiovascular safety and one powered to demonstrate benefit. Several early trials did the first and are quoted as though they did the second.
Systolic blood pressure falls by about three to six millimetres of mercury at the doses studied, most of it early and much of it attributable to weight loss rather than to a direct vascular effect.
| Trial | Agent | n | Duration | Primary result |
|---|---|---|---|---|
| STEP 1 | Semaglutide 2.4 mg | 1,961 | 68 wk | −14.9 % vs −2.4 % weight |
| STEP 2 | Semaglutide 2.4 mg, T2DM | 1,210 | 68 wk | −9.6 % vs −3.4 % weight |
| SURMOUNT-1 | Tirzepatide 5/10/15 mg | 2,539 | 72 wk | −15 / −19 / −21 % weight |
| SURMOUNT-4 | Tirzepatide, withdrawal | 670 | 88 wk | Continued loss vs substantial regain |
| SELECT | Semaglutide 2.4 mg | 17,604 | ~40 mo | MACE HR 0.80 (0.72–0.90) |
| FLOW | Semaglutide 1.0 mg, CKD | 3,533 | ~3.4 yr | Renal composite reduced; stopped early |
| SURMOUNT-OSA | Tirzepatide, OSA | 469 | 52 wk | AHI reduced with and without PAP |
The underlying point is that the heart-failure question is separate again, and the evidence there is largely in the preserved-ejection-fraction population with obesity, where the trials measured symptoms and function rather than mortality.
Heart-rate elevation in this class is documented consistently enough across agents that it should be treated as a class effect rather than as a finding about any one molecule.
These are trial populations on licensed product. Research-grade material of unverified content is not the thing that was studied.
The outcome trials are the evidence; the mechanism is still an argument. Cite the first, be careful with the second.
Aggregated, published test results and vendor ratings built from submitted batches. Methodology stated, dataset browsable, no listing fees.
Browse resultsStart with the population. Cardiovascular benefit in established disease and cardiovascular benefit in primary prevention are different claims supported by different evidence.
Benefit appears to track exposure duration rather than switching on at a threshold, which is what you would expect from a mechanism working partly through weight, blood pressure and glycaemia rather than instead of them.
In practice, baseline risk decides how much the relative reduction is worth. The same twenty per cent applied to a one per cent annual risk and a five per cent annual risk produce very different absolute numbers.
Nothing here is medical advice. If cardiovascular risk is the actual question, it is a conversation for a clinician with your numbers in front of them.
Heart rate up a few beats, blood pressure down a few millimetres, events down about a fifth in high-risk populations. That is the honest summary.
On the detail: blood pressure falls by a few millimetres of mercury in this class, which is small individually and not small across a population.
Cardiovascular composites in this programme are typically cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. When one component drives the result, that is worth knowing, because the components differ in how much they matter.
SELECT randomised people with established cardiovascular disease and overweight or obesity but without diabetes to semaglutide 2.4 mg, and reported roughly a twenty per cent relative reduction in the primary composite. The absolute difference over about three years was on the order of one and a half percentage points.
Where a cardiovascular claim is made for an agent with no completed outcome trial, the honest statement is that the class evidence is suggestive and the agent-specific evidence does not yet exist.
The caveat that matters: none of this is a reason for anyone to alter cardiovascular medication, and I am not in a position to advise on that.
Read SELECT for the without-diabetes population and the earlier outcome trials for the with-diabetes one. They are not the same result.
edited 5 Feb 2025 by marta_okonkwo — fixed an arithmetic slip in the third paragraph
It helps to be literal here: the mechanism question and the outcome question are separate. The outcome data stand whether or not the mechanistic story is settled, and the mechanistic story is not settled.
A twenty per cent relative reduction on a baseline three-year event rate of eight per cent is an absolute reduction of about one and a half points, which is a number-needed-to-treat somewhere in the region of sixty to seventy. Both framings are true and they read very differently.
The cardiovascular safety requirement for new glycaemic agents is why these trials exist at all: regulators required an outcome programme, and the benefit finding was in that sense an unexpected dividend.
Ask for the absolute risk reduction and the number needed to treat. If a source will not give you both, it is selling something.
In practice, what the outcome trials established is that the class does not increase cardiovascular risk and, in the higher-risk populations studied, reduces it. Those are two separate findings from the same programme.
Resting heart rate rises by roughly two to four beats per minute across the class. The mechanism is not fully settled, the magnitude is consistent, and it has not translated into an adverse outcome signal in the trials that looked.
SELECT is the trial to read for primary-prevention-adjacent populations without diabetes; SUSTAIN-6 and LEADER are the diabetes-population outcome trials for semaglutide and liraglutide respectively.
Population, baseline risk, endpoint definition. In that order, then the effect size.
Ask PeptideStack is a static archive. Posting is closed, but the norms are worth stating: answer the question that was asked, show your working, cite the trial or the certificate, and say plainly where the evidence runs out.