#204

After 2 months of daily oral semaglutide 7 mg:

  • Lost 4 kg (5% of my initial 84 kg)
  • According to my Withings, fat % decreased by 1 point and muscle increased by 1 point (it looks like I lost fat indeed)
  • Fasting insulin & fasting glucose decreased a bit (poke @Neo) so HOMA-IR went from ~1.3 to 0.9 => That was my goal (+ neuroprotection)
  • I don’t have good data for it, but my heart rate seems to have increased. I had to take bisoprolol at the same time (for PVCs), and it didn’t lower my HR much.

Nothing remarkable beyond that. I don’t have many side effects except occasionally nausea after coffee.

I’m considering stopping it given the HR increase, my low HRV (I don’t have data before semaglutide unfortunately), the occasional nausea, the lack of “longevity” data (animals, MR, mechanistic rationale, “clocks”, RCTs on non-diabetic/non-obese humans, etc.), and the recent failed exenatide trial in PD (although there are large ongoing trials of oral semaglutide in AD and PD and I did notice feeling a bit “sharper” on semaglutide).

7 Likes
#205

So no fatigue or impaired quality of sleep? The intersubject variability in side effects of the GLP meds never ceases to amaze me. I was exhausted during the day on 7mg Rybelsus and had to take naps at lunch.

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#206

I didn’t notice any impact on energy levels, fatigue, or sleep. But n=1, and I tried other things at the same time, so it’s hard to conclude definitively.

#207

It looks like tirze is worse than normal GLP-1RAs for RHR: Impact of a dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta-analysis 2023

Our study showed not only that there was a greater increase in heart rate in the TZP group than in the control, GLP-1RA and non-GLP-1RA groups, but also that the 15-mg dose of TZP had the strongest impact on increasing heart rates compared with the other five inventions, with a TZP dose-response impact on heart rate. Further research on the effects of TZP treatment-related increases in heart rate is required.

I hope they’ll develop GLP-1RAs that don’t increase heart rate.

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#208

Does not look too bad for low doses. It seems there is a lot of individual variability.
Here is a plot from their supporting information.
BTW the Dahl 2022 study that skews everything to the left is on patients not in good shape: with type 2 diabetes taking titrated insulin glargine, metformin, BMI 33.4, BP 137, A1C 8.3 etc.

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#209

Also: heart rate is higher in people who are overweight or with diabetes. So despite losing a lot of weight and/or improving a lot their diabetes, their HR increased on TZP. So the comparison shouldn’t be to placebo or baseline but to equivalent weight-loss by another method (let’s say intense exercise + calorie restriction) and then I think the HR increase would appear quite high.

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#210

The other important consideration is how long the HR increase lasts. I believe in the phase 2 retatrutide trial, for instance, the HR came back down, but it took a while (6 months?).

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#211

Here again, with a 25% weight loss + improvement of glycemic control, the HR should be significantly below the baseline. Going back to baseline is not okay. For diabetic and obese people that’s fine, it’s worth it. But otherwise I don’t think so.

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#212

I’ll have to check the data. I think the HR was still coming down when the study ended, so it may have kept going.

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#213

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Hmm I don’t know, it was coming down on a couple the higher doses but not so much in some of the other dose groups. Will be interesting to see data from the much larger and longer phase 3 study.

In any case, one would have to weight the potential health negative of increased HR against (for instance) the health benefit of reduction in visceral fat even in a person who isn’t obese or diabetic.

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#214

Im aware that there are many studies showing associations between low resting heat rate and/or high HRV with positive health outcomes. Are there any studies that have looked at drug-induced increases in resting heart rate and/or reductions in HRV and health outcomes?

Are we jumping the gun here in assuming that because GLP-1s (or any other drug) increase resting heart rate, this is a bad thing?

In a similar line of thinking, VO2 max is thought to be highly correlative to longevity. If I have a VO2max of 50 and then take a drug that reduces it to 45, am I any worse off? I would almost argue no. VO2max is not causal of longevity, it’s a marker of all the work you have done (an integrator as Peter Attia puts it). Just because a drug reduces it by 5, does it actually change the causal inputs to longevity?

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#215

As a follow up to this, let’s consider the converse. If I take a beta blocker to “artificially” reduce my resting heart rate, am I healthier? Equivalent to the reduction in resting heart rate from a consistent training program? If so, why isn’t everyone on this forum on a beta blocker?

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#216

I think there’s evidence that a lower RHR is causally associated to longer lifespan. So yes, it’s a tradeoff

Beta blockers cause other issues such as new onset diabetes (with maybe the exception of nebivolol and carvedilol?) or Parkinson’s disease (for beta2 per association studies and MR). Otherwise they seem to extend lifespan at low dose in mice.

1 Like
#217

Could you share this? I’d be curious to learn more.

Interesting. Let’s take Ivabradine instead then. Ivabradine directly reduces heart rate without reducing cardiac contractility (as beta blocker and calcium channel blockers do) according to wikipedia. This sounds like a cleaner pharmacological intervention for reducing heart rate.

Interestingly, the authors of this article specifically mentioned in the conclusions:

Ivabradine had a neutral effect on mortality, suggesting that a pure RHR lowering agent did not reduce CVD mortality, all-cause mortality and improve the lifespan.

In mice, Ivabradine seems to extend lifespan.

Heart rate correlates inversely with life span across all species, including humans. In patients with cardiovascular disease, higher heart rate is associated with increased mortality, and such patients benefit from pharmacological heart rate reduction. However, cause-and-effect relationships between heart rate and longevity, notably in healthy individuals, are not established. We therefore prospectively studied the effects of a life-long pharmacological heart rate reduction on longevity in mice. We hypothesized, that the total number of cardiac cycles is constant, and that a 15% heart rate reduction might translate into a 15% increase in life span. C57BL6/J mice received either placebo or ivabradine at a dose of 50 mg/kg/day in drinking water from 12 weeks to death. Heart rate and body weight were monitored. Autopsy was performed on all non-autolytic cadavers, and parenchymal organs were evaluated macroscopically. Ivabradine reduced heart rate by 14% (median, interquartile range 12-15%) throughout life, and median life span was increased by 6.2% (p = 0.01). Body weight and macroscopic findings were not different between placebo and ivabradine. Life span was not increased to the same extent as heart rate was reduced, but nevertheless significantly prolonged by 6.2%.

Median lifespan of control appears to be ~900 days. Looks pretty convincing to me in mice.

Screenshot 2024-11-29 at 5.25.00 PM

This review has some interesting conclusions

Elevated heart rate: RISK factor or risk marker

Several clinical trials performed during recent decades have investigated the effect of interventions with heart rate lowering properties in patients with heart disease. Interventions with beta blockers [71] and cardiac glycoside [93] demonstrated decreased risk of adverse events in risk populations.
However, beta-blockers and cardiac glycosides have pleiotropic effects [94,95] and do not exclusively target heart rate. The most intriguing question in relation to elevated RHR is, whether high heart rate is a mere marker of risk, or if elevated heart rate is an independent risk factor. If high RHR is in fact a true risk factor it may be a possible target for intervention. The f-current is only present in the sinus node, and thus inhibition induces selective heart rate reduction. Within the last few years, three large randomized controlled trials of the f-current inhibitor ivabradine have tested the effect of selective heart rate reduction in different heart patient populations.

In the BEAUTIFUL trial almost 11,000 patients with coronary artery disease and left ventricular ejection fraction, <40% were included and randomized to ivabradine or placebo in addition to usual care. In the intervention arm, heart rate was reduced by 6 bpm. In this trial, a reduction in heart rate significantly decreased the risk of admission for fatal or non-fatal myocardial infarction and coronary revascularization [96]. In a subgroup analyses, it was found that a patients with heart rates above 70 bpm were of particular risk of coronary events [97]. Ivabradine versus placebo in heart failure was subsequently tested in the SHIFT trial of 6500 patients with left ventricular ejection fraction below 35%, with sinus rhythm and heart rate above 70 bpm [98]. Ivabradine resulted in a significant reduction in the primary endpoint of cardiovascular death or hospital admission for worsening heart failure, which was mainly driven by reductions in hospitalizations for heart failure. However, there was no significant difference in all-cause or cardiovascular death between the ivabradine and placebo group. The SIGNIFY study [99] was conducted in 19,000 patients with stable coronary artery disease and preserved ejection fraction. In these patients, there was no difference in the primary composite outcome of death from cardiovascular causes and non-fatal myocardial infarction. A subanalysis revealed an increased risk of the primary endpoint in patients with a Canadian Cardiovascular Society (CCS) score of II or higher, although patients in the ivabradine group experienced less symptoms compared to patients in the placebo group. Altogether, these results of heart rate reduction with ivabradine in addition to usual care in patients with cardiovascular disease have been somewhat disappointing. It has been argued that the discrepancies between study findings suggest that heart rate reduction is more beneficial in patients with left ventricular dysfunction than in patients with coronary artery disease [100]. Others have argued that the evidence from these trials point toward a beneficial effect of ivabradine in the particular subpopulation of patients with non-ischemic heart failure where the event rate reduction in the treatment arm of the SHIFT trial was similar to the event rate reduction from digoxin in a comparable population [93]. The current indication for ivabradine in heart disease is mainly patients with heart failure on optimal treatment and with a RHR above 70 bpm [101].

Mendelian randomization seems to indicate a causal link

We observed that a genetically predicted resting heart rate increase of 5 beats per minute was associated with a 20% increase in mortality risk (hazard ratio 1.20, 95% confidence interval 1.11-1.28, P = 8.20 × 10-7) translating to a reduction in life expectancy of 2.9 years for males and 2.6 years for females.

All in all, I’m not sure what to make of this. Ivabradine seems like it might have interesting potential as a longevity promoting agent and I wish there was more research on it.

2 Likes
#218

Sheesh, my heart rate is still higher. Six months is a long time to deal with this. On one hand, I’d back down my dose to lower it. On the other hand, I have a nice little level of appetite suppression from it I don’t want to lose.

1 Like
#219

I’ve never heard of this drug until now. Thanks for bringing it to my attention. I kind of want to get my hands on some.

5mg Nebivolol lowers it a little, but when I increase the dose, I get really nasty fatigue so I am stuck on 5mg, which isn’t lowering it enough. I’m also on thyroid hormone, which also raises it a bit, but I feel a trillion times better than when I don’t take thyroid hormone.

Blood pressure is great but it’s not fun when my heart is beating faster than I’m accustomed to.

2 Likes
#220

According to Liner AI, Nebivolol may be slightly more potent at reducing RHR. However, Ivabradine specifically targets the sinoatrial node of the heart, which I believe @Davin8r said GLP1’s act upon, so I guess it would be a better option in this instance?

Liner AI
“Both Nebivolol and Ivabradine are effective medications for reducing heart rate, but they have differing mechanisms of action and overall effects.

Nebivolol’s Heart Rate Reduction

Nebivolol is a third-generation beta-blocker that not only reduces heart rate but also lowers peripheral resistance and increases stroke volume, resulting in a slight increase in cardiac output . In clinical studies, the effectiveness of 5 mg Nebivolol in lowering heart rate has been demonstrated, with reductions noted compared to placebo . The unique hemodynamic profile of Nebivolol, which includes nitric oxide-mediated vasodilatory effects, contributes to its efficacy in reducing heart rate and improving endothelial function .

Ivabradine’s Heart Rate Reduction

On the other hand, Ivabradine specifically targets the I(f) current in the sinoatrial node of the heart, providing selective heart rate lowering without affecting myocardial contractility . Clinical studies have shown that Ivabradine is significantly more effective than some traditional beta-blockers like metoprolol in reducing heart rate . This makes it particularly suitable for patients requiring heart rate control without the additional effects on blood pressure associated with beta-blockers .

Comparative Effectiveness

In a comparative study, 5 mg Nebivolol led to a reduction in heart rate of approximately 21.7 beats per minute, while Ivabradine caused a reduction averaging 13.89 beats per minute . Although both drugs lowered heart rate effectively, Nebivolol appeared to have a more substantial impact in this particular study context.

Conclusion

Overall, while both 5 mg Nebivolol and 5 mg Ivabradine are effective at reducing heart rate, Nebivolol may be considered more effective based on specific study outcomes. However, the choice between these medications should also consider individual patient characteristics, clinical context, and the specific outcomes desired, such as cardiovascular risks and coexisting conditions.“

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#221

It’s the MR you shared. But other papers suggest the same thing from what I recall.

Good find. I’ve just sponsored ivabradine in the MMC.

1 Like
#222

Retatrutide-

GLP-1R agonists are thought to primarily mediate weight loss by reducing food intake [49,53]. There is observational data to infer an additive and possibly synergistic effect of exercise with GLP-1R agonism on weight loss, suggesting non-anorectic mechanisms that are not well characterized [5,66]. The contribution of GcgR agonism to weight loss appears to be primarily mediated by an increase in energy expenditure as suggested by our data; it is hypothesized that hepatic glucose mobilization for consumption in peripheral tissues, including the fat, is primarily responsible.

The data presented here demonstrate that the potency of GcgR agonism defines the maximal weigh-lowering capacity of the triple agonist, presumably through multiple mechanisms of increased energy expenditure, insofar as increasing in vitro GcgR potency with respect to cAMP production prognosticates in vivo weight reduction

Critically, our data suggest that the differentiating factor for this superior weight loss effect is achieved through an increase in energy expenditure, given the elevated energy expenditure in combination with similar reductions in food intake between maximally effective triple agonist and tirzepatide (and other co-agonist) groups

Glucagon is broadly thought to have cardio-stimulatory effects via GcgR expressed on the myocardium [58]. GcgR mono-agonists are known to increase heart rate and contractility, which has led to the suggestion for them to be used as a treatment for low cardiovascular output in acute settings. However, human efficacy data for this strategy is scant.

Dose-dependent increases in heart rate and decreases in systolic blood pressure were observed, which returned to near BL by Day 29.

Dose-dependent increase in heart rate and incidents of mild to moderate cardiac arrythmias raise cardiovascular safety concerns and signify that carrying out long-term cardiovascular outcome trials (CVOTs) will be critical.

Glucagon enhances metabolic rates by stimulating oxygen consumption in brown adipose tissue (BAT), as revealed by increased BAT temperature in rats (61, 62). Glucagon also exerts lipolytic effects on the white adipose tissue by inhibiting lipogenesis and stimulating lipolysis (34). The lipolytic effect is mediated by the activation of the hormone-sensitive lipase (HSL) in the adipocytes (63) and it is amplified by indirect mechanisms including the secretion of growth hormone (64), cortisol (65), and epinephrine (66).

Indeed, glucagon stimulates the formation of ketone bodies by constantly supplying nonesterified fatty acid to the liver (68, 69) and blocking the hepatic glycolytic pathway (70). These result in enhanced fatty acid oxidation in the mitochondria and potentiation of hepatic ketogenesis (34, 70)

Avik Ray (2023) Retatrutide: a triple incretin receptor agonist for obesity management, Expert Opinion on Investigational Drugs, 32:11, 1003-1008, DOI: 10.1080/13543784.2023.2276754

Knerr PJ, Mowery SA, Douros JD, Premdjee B, Hjøllund KR, He Y, Kruse Hansen AM, Olsen AK, Perez-Tilve D, DiMarchi RD, Finan B. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice. Mol Metab. 2022 Sep;63:101533. doi: 10.1016/j.molmet.2022.101533. Epub 2022 Jul 7. PMID: 35809773; PMCID:

Franco Folli, Finzi, G., Manfrini, R., Galli, A., Casiraghi, F., Centofanti, L., Berra, C., Fiorina, P., Davalli, A. M., Stefano La Rosa, Perego, C., & Higgins, P. (2023). Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. American Journal of Physiology-Endocrinology and Metabolism, 325(5), E595–E609. https://doi.org/10.1152/ajpendo.00236.2023

6 Likes
#223

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Given the apparent afib risk, it might be worth sticking with diltiazem, although I have no real-world experience with either med. I wonder if @DrFraser has ever prescribed ivabradine?

1 Like