#89

The Effect of Semaglutide on Mortality and COVID-19–Related Deaths: An Analysis From the SELECT Trial

https://www.jacc.org/doi/10.1016/j.jacc.2024.08.007

These findings highlight the mortality benefit of semaglutide across a broad population of patients with CV disease and obesity. The robust reduction in non-CV death, particularly infectious deaths, was surprising and perhaps only detectable because of the COVID-19–related surge in non-CV deaths; however, these findings reinforce that overweight and obesity increase the risk of death because of many etiologies, which can be modified with potent incretin-based therapies like semaglutide.

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#90

What was the effect? I don’t want to click.

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#91

I would imagine by the price, packaging and top color (usually means nothing) they are from QSC. Here is your initial test report for that batch. It tested out at 99.389% and 11.43 mg that was validated by customer independent testing to be dose correct, but the purity degraded to ~98% due to humidity control issues. So if you were splitting the vile you are taking closer to 6 mg every 5 days which is essentially at max dose. Listen to this group. Titrate slowly and listen to your body. You are compounding so you are not stuck with having to make 2.5 mg jumps that can make you sick.

https://janoshik.com/tests/45822-Tirzepatide_10_mg_42IUSJYPJ3L6

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#92

Currently doing 0.5mg a day.
I still feel tired. My HRV has fallen from 80 to 25 and my RHR is higher. I started nebivolol 5mg to fell better.
I started vortioxetine because for few weeks I fell pretty bad mentally (used to be on antidepressants for years, was on nothing for about 2 months), so my HRV is not going to increase soon.

#93

I tried to warn you :grimacing:

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#94

The effect of GLP-1RAs on mood is weird; some people report feeling depressed, others the opposite.

Many recent papers looked at suicide ideation:

So the above papers seem to conclude that in terms of suicidal ideation risk, from the highest to the lowest risk we have: semaglutide > liraglutide > exenatide > dulaglutide > albiglutide.

Weirdly that’s the opposite of the BBB-crossing properties (transport into whole brain within one hour), per Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases 2023:
image

So the more the drug crosses the BBB the lower the suicidal ideation risk?

However, in terms of weight loss, I think it’s also semaglutide > liraglutide > exenatide > dulaglutide > albiglutide. So I thought that maybe the higher suicidal ideation risk in semaglutide users might be due to semaglutide users being more obese or overweight and obesity being associated with a higher risk of suicidal ideation. But apparently, that’s not the case (it could even be the opposite!): “Obesity is not associated with suicide ideation among U.S. young men and women. Overweight is associated with a lower risk of suicide ideation among young men.” The relationship between obesity and suicide ideation among young adults in the United States 2022. So it’s probably not that.

Still, the above order is also the one for HbA1c lowering potency. So, semaglutide users might have more advanced diabetes than exenatide users. Apparently “people with diabetes have double the risk of suicide or intentional self-injury compared with the general population” (not a great source). So this might explain the differences between GLP-1RAs :man_shrugging: .

So it’s very unclear… In the past two months, in JAMA only, different articles and editorials had opposite conclusions:

My two cents: There are intraclass differences, and grouping all GLP-1RAs into one category might lead to incorrect conclusions. People with a history of depression might prefer dulaglutide to semaglutide for glycemic control. For weight loss: unclear.

@DrFraser: what do you think?

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#95

I don’t know if you’ve seen or linked this one, published in Nature:

In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32–0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32–0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.

#96

I saw it but chose not to mention it as it compared semaglutide to “non-GLP1R agonist anti-obesity medications”: bupropion, naltrexone, orlistat, topiramate, phentermine and setmelanotide. I don’t think these drugs are great for your body. So I’m not surprised that semaglutide does better compared to those. I also think they’re not as effective for weight-loss but more affordable, so people on them could be poorer and may be subject to more financial strain? (Financial strain is associated with a higher risk of suicide: Financial Strain and Suicide Attempts in a Nationally Representative Sample of US Adults | American Journal of Epidemiology | Oxford Academic )

So I think this study is irrelevant unfortunately.

The best would be to look at people with T2D but neither overweight nor obese and compare individual GLP1-RA to SGLT2.

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#97

They did control for socioeconomic determinants of health, and with an anti-diabetes medication comparison as well, including SGLT2i’s. That analysis wasn’t in obese people either although the ozempic group had more obesity (but propensity score matching controls for it?).

The semaglutide group compared to the non-GLP1R agonist anti-diabetes medication group (insulin, metformin, sulfonylureas, alpha glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium/glucose co-transporter 2 (SGLT2) inhibitors)

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#98

Ah you’re right so they did two studies: One on "240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications and another one “in 1,589,855 patients with T2DM”.

I missed the adjustment for socioeconomic determinants of health. Thanks for correcting my mistake. Still, I think the study on obese/overweight people is not helpful for the reasons I mentioned previously.

The one with T2DM is more interesting. They compared semaglutide to non-GLP1R agonist anti-diabetes drugs: insulin, metformin, sulfonylureas, alpha glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, sodium/glucose co-transporter 2 (SGLT2) inhibitors.

Result: “The semaglutide group had a significantly lower risk for incident suicidal ideation than the matched non-GLP1R agonist anti-diabetes medication group (0.13% versus 0.36%; HR = 0.36, 95% CI = 0.25–0.53).”

However, they lumped all other antidiabetic drugs together. A very heterogenous category. According to Table 2 |, 43.6% of patients were on insulin and 61.5% on metformin. So is the real conclusion “Adding semaglutide to your T2DM regimen lowers the suicide risk compared to nonuse”?

I still think this paper isn’t helpful.

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#99

I suspect that patient characteristics and a proper control group lacking are big factors in the conclusions.

If you are on semaglutide, obesity is more likely involved than other drug selections. Although a difference between tirzepatide and semaglutide is interesting as the demographic on those two are likely much closer than with the older GLP-1’s.

Overall, I’m not at all convinced one way or the other. Will wait for more information before thinking this increases or decreases risks of suicide.

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#100

Am I wrong in thinking that all these are fairly tiny effects vs nonusers of any of these drugs? And are these effects, small as they are, more or less relevant based on why they are taken, for weght loss, for t2dm, for longevity? That is assuming these effects are real in the first place rather than statistical artifacts and noisy data.

#101

4x seems massive to me.

At the population level, maybe, but for people with a history of depression or suicidal attempts, definitely not. Better be alive and obese than thin but dead.

Of course, we don’t know yet if the effects are real.

Assuming these effects are real, and even if they might be small, it would be super interesting to know by which mechanism(s) drugs that do not cross the BBB have an impact on mental health. It might unlock other benefits (esp. re. neuroprotection).

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#102

Why do you say stuff like this?
4 times what?
What is the absolute risk?

#103

Some ROR are around 4x here: Experience with GLP-1s - #94 by adssx

Again, nothing is proven, these are association studies. But if true that would be massive.

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#104

I am not good at interpreting the results.
What do you think is the probable actual risk based on these studies, 1 in 10,1 in 100, etc?

#105

It’s a relative risk compared to non-use. So IF this is confirmed and causal, then it means that using drug Z would increase your risk of suicidal ideation by 4x. So, if you’ve never thought about this in your life, it will probably not change anything for you. If you have suicidal ideation once per year, then you might have it once per quarter. (I’m oversimplifying.)

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#106

RHR/HRV changes might be related to direct action of GLP-1 in the heart: Glucagon-like peptide-1 increases heart rate by a direct action on the sinus node | Cardiovascular Research | Oxford Academic

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#107

Is this action detrimental or not in non diabetic / non overweight individuals?

Interesting bit:

In anaesthetized pigs, neither cervical vagotomy, adrenergic blockers (alpha, beta, or combined alpha-beta blockade), ganglionic blockade (hexamethonium), nor inhibition of hyperpolarization-activated cyclic nucleotide–gated (HCN) channels (ivabradine) abolished the marked chronotropic effect of GLP-1.

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#108

“It is tempting to speculate that treatment of GLP-1 RAs might be combined with drugs targeting calcium clock dynamics or intracellular calcium levels, such as calcium channel blockers, or other downstream effectors, to prevent heart rate increases in patients receiving GLP-1 RAs where this may be considered beneficial.”

So, diltiazem might be the best choice (perhaps at a low dose) to reverse the elevated heart rate without affecting weight loss.

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