#407

While we are talking about a blend of agents, I am wondering if there are thoughts on DPP-4 inhibitors being used in conjunction with with GLP-1 agonists. Can they for instance, extend the half-lifes of GLP-1 agonists, particularly those such as dulaglutide which have short half-lifes, or do they only inhibit the degradation of physiologically produced GLP-1?

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#408

Really good question!

2 points, in the comparison of DPP-4-i vs GLP’s health outcomes seem significantly worse with DPP-4’s, which may represent that the GLPs are just such awesome drugs that they provide a multiple of the benefit, or it could be that the DPP-4’s are deleterious. The problem with the study with looking at Alzheimer’s Dementia was no control group. However, there are multiple studies indicating that DPP-4’s are beneficial for neurocognitive decline, but the mechanism is likely through increasing GLP/GIP endogenously. I’m not sure if the addition of DPP-4s to GLPs helps if getting an adequate dose of GLP/GIP medication like Tirzepatide?

I was thinking if the DPP-4i’s ended up crossing the BBB it could be a good way to increase GLP activity in the brain. Sadly, they don’t significantly cross the BBB.

So Vera-Health.ai does a good job answering this question - and my conclusion is that I generally don’t see a reason to Rx these meds except as a 4th agent for difficult to control T2DM.

Dipeptidyl peptidase-4 (DPP-4) inhibitors do not directly prolong the half-life or increase the effect of GLP-1 receptor agonists (GLP-1 RAs). Instead, they work by inhibiting the DPP-4 enzyme, which is responsible for degrading endogenous GLP-1 and GIP (glucose-dependent insulinotropic polypeptide). This inhibition results in increased levels of endogenous GLP-1 by preventing its breakdown, leading to a modest increase in GLP-1 levels, typically 2-3 times the baseline 6.

GLP-1 RAs, such as exenatide and liraglutide, are synthetic analogs of GLP-1 that are designed to resist degradation by DPP-4, thus having an inherently longer half-life. These drugs are engineered to have prolonged action independently of DPP-4 activity, which means their pharmacokinetics and pharmacodynamics are not significantly altered by concurrent DPP-4 inhibitor use 2.

While DPP-4 inhibitors enhance the duration of action of endogenous GLP-1, they do not directly increase the pharmacological effect of GLP-1 RAs. The complementary mechanism of action between DPP-4 inhibitors and GLP-1 RAs can enhance the overall incretin effect, but this does not translate into a direct prolongation of the half-life or increased effect of GLP-1 RAs themselves 8.

In clinical practice, the combination of DPP-4 inhibitors and GLP-1 RAs is generally not recommended due to overlapping mechanisms and limited additional benefit. Most guidelines suggest using either a DPP-4 inhibitor or a GLP-1 RA, but not both simultaneously, to manage type 2 diabetes mellitus (T2DM) 1.

In summary, DPP-4 inhibitors extend the half-life of naturally occurring GLP-1 by blocking its degradation, thereby sustaining its beneficial effects on glucose regulation. They do not directly increase the pharmacological effect of GLP-1 drugs, which are already designed to have prolonged action independently of DPP-4 activity. This distinction is crucial for understanding the complementary roles of DPP-4 inhibitors and GLP-1 receptor agonists in the management of T2DM.

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#409

Random question for those that are well versed on glucose/diabetes. I bought a glucose monitor 10 days ago and been using it often. As an example, this morning it showed 109. Last night I was at Costco and had for dinner a chicken bake and a strawberry sundae (on purpose wanted to see what glucose level would be if I ate sweets). 70 minutes after dinner it read 145 (I did not take any glucose medication other than a 250 mg metformin yesterday morning. In all the reading for past week the level has hoovered from about 105-145 despite what I’m taking acarbose or metformin or Empa (fasted state and after a meal) It seems however to go into mid 90’s at around 1-2PM twice that i measured (regardless of meds or no meds in the morning) which btw it so happens that I also get the lowest heart rate at about same time of the day also (usually 50-54 even lower than when at sleep usually 56-60 heart rate): Couple questions:

  1. Is it a good thing that the variation between fasted state and after meals (even with sweets) is not that high about 30. (110-140)
  2. how come the meds metformin 750mg and Empa 12.5 are barely making a difference (though I must admit just started taking them about two weeks ago, and don’t know if it takes longer to take effect)
  3. any comment as to why my heart rate drops so much at about 2PM, few days i noticed it dropped to 45-47? and it also seems to coincide with lowest glucose level (at least two times I measured around this time of day, 96, and 98)
    thanks,
#410

Ive been taking compounded semaglutide drops for two weeks now and it seems to be working. My weight loss had plateued but i lost two lbs last week and im trying to lose only 1 or 2. The first week i didnt lose any but it seemed maybe effective for a few days but i ate too much the first weekend, and i increased the dose.

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#411

I bet this is all a placebo effect. I don’t see any way a large peptide would penetrate the oral mucosa to any significant degree. I got a placebo effect from sublingual tirzepatide for a couple of weeks until I realized nothing was happening.

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#412

Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US 2024

Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups.
Our study population comprised patients with T2DM prescribed semaglutide between December 2017 and May 2021, before its approval for weight loss. Due to sample size limitations and a shorter follow-up time, we did not include patients prescribed semaglutide as Wegovy for obesity. However, we conducted stratified analyses by obesity status among T2DM patients and found a consistent decrease in first-time AD diagnosis regardless of obesity status. These findings suggest that semaglutide may have beneficial effects on delaying the onset of AD through mechanisms beyond weight loss.
Our study shows that semaglutide significantly reduces first-time AD diagnoses compared to other antidiabetic medications, suggesting potential benefits beyond insulin resistance improvement. This is further supported by the data comparing semaglutide with SGLT2i. Indeed, SGLT2i reduces blood glucose independent of insulin sensitivity and secretion. SGLT2i crosses the blood–brain barrier and has neuroprotective effects by reducing neuroinflammation, oxidative stress, mitochondrial dysfunction, and increasing brain-derived neurotrophic factor. A recent large population-based cohort study showed that SGLT2i was associated with a lower risk of dementia compared with DPP-4i. Our study shows that semaglutide was associated with significantly lower AD first-time diagnosis compared with SGLT2i, with an effect more profound than that of DPP4i. These findings align with prior research suggesting semaglutide may offer neuroprotective effects via pathways like neuroinflammation and mitochondrial function beyond insulin resistance improvement.

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So, it looks like semaglutide is best for neuroprotection? (@DrFraser) Similar finding in PD: Parkinson's disease - #236 by adssx Could tirzepatide be even better? And what about semaglutide + SGLT2i combination?

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Predicting Alzheimers & Dementia (and minimizing risk)
Predicting Alzheimers & Dementia (and minimizing risk)
#413

I’d not be making that conclusion on semaglutide being the winner. It could be. The issue is tirzepatide hasn’t been in wide use long enough to serve as a good comparator. We’d really want people to be on this before they get mild cognitive impairment in their spiral down to AD or Lewy Body Dementia. This all happens 10 years before diagnosis generally for AD.

So I’d argue that Mounjaro (Tirzepatide) needs to have been in wide use for over 10 years before we’ll get a proper understanding of risk reduction in comparison to other agents.

I think the same can be said for risk reduction in PD … we just haven’t had the drugs in wide use long enough to have meaningful change in outcomes in regard to getting diagnosable disease.

This is a good argument for starting these before you get MCI or before there are any symptoms, and yes adding an SGLT2-i.

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#414

To your point, Dr. Fraser: “there is a good argument for starting …(GLP agonists) before you get MCI . . . .”

I seem to be formulating a conviction that I need to get back on a GLP agonist, perhaps a small dose at a longer interval primarily as a neuro-protective measure because :

(1) I have pre-diabetic levels of FBG and PP glucose – going back many years. Also very low insulin. After reading about monogenic diabetes I have come to the conclusion that I have a GCK inactivating mutation. This cannot be confirmed without genetic testing, but the clinical indications support. It may well never progress to full blown diabetes but the H1AC of 5.9 is not great. It does not seem to be responding to metformin.

(2) research shows a correlation between low insulin and Alzheimers in women.

(3) family history of Alzheimers – mother, grandmother, aunt. I do not know nor can I discover whether any of them had high glucose or low insulin.

(4) GLP agonists increase the release of insulin. Paresh Dandona at UBuffalo found that (ten patients) were able to reduce of stop taking insulin while taking a GLP agonist.

When I put this together, the gestalt emerges that I should take a GLP as a preventative for cognitive impairment even if the glucose considered by itself is not at a threatening level.

3 mg of Rybelsus caused me to drop weight, which I do not need to do, and made me feel sick. Perhaps I did not stick with it long enough to “adjust”. That I had this response on only 3 mg seems to contradict the official guidance that 3 mg is not a “therapeutic” dose – it sure seems to have had the intended effect on me.

Now I am considering going back on 3 mg Rybelsus perhaps once a week or so (it has a half life of roughly a week) primarily for neuroprotection going forward.

BTW am also on 2.5 mg tadalafil every couple of days, also as a neuroprotective measure.

Would very much appreciate input . . . .

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#415

I am starting to favor a mix a dulaglutide and tirzepatide or retatrutide to get the full mix of crossing the BBB and having potent activation of peripheral GLP-1/GIP etc.
Have you had your ApoE tested? I have one ApoE4, this is why I’m being a little more aggressive at prevention at this point.
People typically get away with things like dulaglutide without huge weight loss. If you have a tendency to be a bit fat, a mix is good, if you risk sarcopenia, then dulaglutide monotherapy would be my pick.

Sadly the Tadalafil seems great for cardiovascular risk, but recent data has had me stop promoting it for neurocognitive decline. There definitely is a strong correlation between taking these drugs and having lower neurocognitive risk - but seems like this is all confounded, which is annoying. Still good for the vascular system.

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#416

Stimulation of insulin secretion from pancreatic β-cells by glucagon-like peptide 1 receptor (GLP-1R) agonists is known to be glucose-dependent. GLP-1R agonists potentiate glucose-stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations.

#417

Which would argue for adding a SGLT2i to the GLP-RA, so as to lower BG and thus potentiate less of the insulin release, as less insulin sloshing around in the system seems advisable vs cancer and generally aging… maybe?

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#418

Hopefully! That’s what I’m doing :grimacing:

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#419

I meant the winner among commercially available single GLP-1RAs (so excluding tirzepatide and products in the pipeline). Hopefully we’ll see more papers like that using more recent data and looking at different countries to find the best product.

Intuitively, I thought dulaglutide would be best based on its BBB crossing. But we now have two association studies pointing to semaglutide. Also: Novo Nordisk is spending millions for a large phase 3 trial of semaglutide on Alzheimer’s while Eli Lilly is doing nothing for dulaglutide. Surely they know best the potential of their drugs. Follow the money…

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#420

Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss? 2024

This primer aims to address whether muscle-related changes associated with weight loss treatments such as GLP-1 RAs may be maladaptive (ie, adversely affecting muscle health or function), adaptive (ie, a physiologic response to weight loss maintaining or minimally affecting muscle health or function), or perhaps an enhanced response to weight loss (ie, improved muscle health or function after treatment). Based on contemporary evidence with the addition of studies using magnetic resonance imaging, skeletal muscle changes with GLP-1 RA treatments appear to be adaptive: changes in muscle volume z-score indicate a change in muscle volume that is commensurate with what is expected given aging, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and prefrailty may influence the selection of appropriate candidates for these therapies because of risk for sarcopenia.

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Experience with GLP-1s
#421

Sema is not the best in class for weight loss with respect to GLP1-R’s

Tirzepatide (Tz) is great for weight loss and appetite suppression. BUT Retatrutide (Rt) it is better at weight loss with less appetite suppression. How is that possible? Even if you eat a bit more, Rt will still enable better weight loss. Here is a breakdown on 3 of the common GLP1-R drugs and how they work with regard to appetite and weight loss.

  1. Ozempic/Wegovy = Semaglutide - GLP1-R only, excellent appetite suppression and just OK weight loss.
  2. Mounjaro/Zepbound = Tirzepatide - GLP1-R + GIP, excellent appetite suppression and good weight loss - better than Sema
  3. Retatrutide - GLP1-R + GIP + GCGR, moderate appetite suppression, excellent weight loss - better than TZ

Each GLP1 drug will enable weight loss through 1) appetite reduction, 2) glucose management, 2) slowing digestion to increase fullness. Those 3 functions are a form of caloric restriction, eat less, use it more effectively and lose weight.

Adding GIP helps Tirzepatide with weight loss by increasing the feeling of “fullness” or satiety. This further enhances a reduction in caloric intake, eat less, lose more.

With Retatrutide it has the benefits of GLP1-R + GIP + GCGR. GCGR stimulates the most important type of fat in our body, brown fat and initiates thermogenesis, i.e. burning fat.

We have 3 basic fat types, 1) white (adipose), 2) beige (white in the process of turning brown) and 3) brown fat. Brown fat is what we want more of as it is thermogenic, it metabolizes (or burns) white fat. GCGR also helps white fat transition to beige and then on to brown. While the first 2 drugs in the above list work primarily by caloric restriction, Retatrutide is the only one that actually increases fat burning regardless of caloric input.

This means that with Rt you can theoretically eat more and still lose weight effectively. 1 shot a week, could not be easier.

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#422

Interesting insight into the social media “muscle loss” hype with GLP1-R’s. I’ve posted my opinion on this previous to seeing this information.

My opinion was based on being a butcher when I was a kid :slight_smile: and a lover of steak as an adult.

I’ve used the steak analogy a few times. Take a look at Wagyu steak and it’s all about the marbling, i.e. inter-muscular fat. This fat affects the size of the “muscle”, it fluffs it up. Now put that cow on a diet and the muscle will absolutely shrink due to the fat loss. I think a lot of people jumped on the muscle size reduction as an complete indicator of muscle loss when it’s not all muscle fiber loss, a lot of the “size” is inter-muscular fat loss.

Yes some muscle fibre may be lost in any weight loss program but it is relatively easy to counter that with weigh bearing exercise and adequate intake of quality protein.

I was previously corrected by another member on the performance of my Withings Body Cardio scale, which indicates a way higher amount of muscle than it should. BUT, while that data may not be correct as far as an absolute number of my muscle weight, it does show a trend over time. For me that trend is basically flat. FWIW - As a percentage my muscle has gone up as my fat content has gone down.

Intermuscular adipose tissue (IMAT) is fat that is located between and around skeletal muscle groups, and is also known as skeletal muscle fat or lipids. It is considered an ectopic fat depot, similar to visceral adipose tissue (VAT) in the abdomen.

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#423

Oral version of Novo diabetes drug protects heart health in large study 2024

The medicine, which Novo sells as Rybelsus, cut the risk of cardiovascular complications by 14% when added to standard therapies in people with diabetes and heart disease.
Novo intends to ask the Food and Drug Administration around the end of 2024 to approve the medication to protect the heart health of people with diabetes. Should the FDA agree, Novo’s pill would join diabetes medicines like Boehringer Ingelheim and Eli Lilly’s Jardiance and AstraZeneca’s Farxiga, which are proven to have similar benefits.
Novo said that roughly half of study volunteers got a so-called SGLT2 inhibitor like Jardiance or Farxiga during the trial and likely benefited from taking them. Nonetheless, Rybelsus was associated with a reduction in the risk of infarctions, strokes and death, though Novo didn’t disclose more specifics beyond the 14% figure in Monday’s announcement.

SOUL: Oral Semaglutide Cuts CV Events in Diabetic Patients 2024

The majority of patients enrolled in SOUL were taking metformin and about 70% had CAD, 42% had CKD, 21% had cerebrovascular disease, and 15.7% had symptomatic PAD. Additionally, nearly one-quarter had heart failure and 49% were taking an sodium-glucose cotransporter 2 (SGLT2) inhibitor at some point during the trial.
On the basis of these results, which are expected to be presented at a scientific conference in 2025, Novo Nordisk said it plans to file for a label expansion for Rybelsus with both the US Food and Drug Administration and the European Medicines Agency by early next year.

Really good news. Can’t wait for the detailed results to see the effect of the SGLT2i + Rybelsus combination. And also stratification by BMI.

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#424

I know I keep boring in on this point, but this is in people with morbidities, diabetes CVD or both. It stands to reason that medications designed to help with disease - help with disease, altough it’s fantastic that they cross help synergistically. What this does for those without these morbidities would be the really interesting news. Specific n=1 respose matters most to individuals, regardless of general statistical cohort response. But I am very happy for those these drugs help.

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#425

You’re wrong. Semaglutide was designed for diabetes, not for overall cardiovascular health. So far only SGLT2i had cardiovascular benefits beyond pure glycemic control. So this is big news. So for people with diabetes or prediabetes, rybelsus might be the best option (compared to, for instance, metformin).

Of course, we need more data on semaglutide on people without these morbidities.

(Btw, I’m not diabetic, I started oral semaglutide a few weeks ago; I’ll report my results; so far, I have lost a few kg (and fat % has slightly decreased), and my HOMA-IR has decreased for the first time (from 1.4 to 1.1, previously SGLT2i had no effect on my HOMA-IR). TBC…)

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#426

Would you mind sharing the dosage, and if possible, the source of your oral semaglitude. Have gotten a quote from one person, but I like to stick with product that other people have already tried (and it worked for them) before. There is always the fear of getting fake/non-working meds from oversees. thanks

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