Yes - we agree - huge percentage of population is above, has pre- or full diabetes, etc.
I was asking in the context of many of us on this forum who have invested in being metabolically fit, lean, etc. do we think GLP-1a would be good for longevity in such a demographic?
Interesting. I thought it increased average insulin levels in people, is that not the case? Even if it only boosts insulin when triggered by glucose that might not be good in a generally metabolically healthy individual?
These agents will increase insulin secretion in the situation of having a significantly elevated glucose. However, they improve insulin sensitivity, and slow gastric emptying along with absorption of consumed calories.
How this plays out for most people is less area under the glucose curve, less need for insulin to be secreted, and thus your blood vessels seeing both less glucose and insulin.
I think there are a lot of people on these agents as part of their journey to metabolic health, where they simply can’t or won’t do it without these.
Mounjaro is as effective as a gastric bypass.
I have many patients with huge losses with low doses over time and it has enabled them to seriously improve their diet.
Some will get off them, but most … at least as of now may be on low doses long term.
Think we keep talking past each other
My questions are not with regards to the average American or “most people” - a largely agree with what you have been saying about those populations.
It’s about whether in a well optimized longevity and health seeker who is lean and of great metabolic fitness, is Glp-1a still a good option for longevity (like I for instance would argue that Rapa and Acar still are)?
And would Glp-1a not increase AUC of insulin in such a group.
No it wouldn’t because you’ll have slower absorption of calories resulting in lower peak glucose and less need for insulin, and you’ll be more insulin sensitive.
I don’t know what proportion of people on this board are truly at ideal body weight with minimal visceral fat? I’d think only some, there are probably a lot on the board who would benefit from weight loss…
But yes the argument for these is unclear in the rare individual who has naturally sorted out ideal weight and excellent insulin sensitivity.
Thanks Dr Fraser.
@adssx and @AlexKChen see above, the picture might be less bad re insulin levels in healthy people on GLP-1a than we had wondered elsewhere
(personally I’d still want to know more long term data about cancer risk if taking this for longevity/other things like dementia at this point if not overweight)
I know the researchers leading the GLP-1 RA RCTs for PD (exenatide, lixisenatide, and liraglutide): they’re also super excited about SGLT2’s potential for PD. Mayo Clinic just started a small trial of dapagliflozin for PD and LBD: ClinicalTrials.gov And a trial of empagliflozin might start soon after some showed it could reverse PD in animal models: Empagliflozin repurposing in Parkinson’s disease; modulation of oxidative stress, neuroinflammation, AMPK/SIRT-1/PGC-1α, and wnt/β-catenin pathways 2023
I also find it interesting that GLP-1 RA and SGLTi might rely on similar mechanisms on GIP levels via opposite ways: Sotagliflozin effects differ from empagliflozin only at breakfast
However, they highlight the effect of the two SGLT inhibitors, particularly sotagliflozin, on GIP levels, noting that recent research suggests that GIP inhibition may be cardioprotective, contrary to the development of GLP-1/GIP co-agonists to treat type 2 diabetes.
Walther and team suggest this paradox may be explained if GIP agonists work by “desensitizing” the GIP receptor, leading to a decrease rather than an increase in GIP receptor signaling.
"[T]he potential benefit of lower GIP levels on cardiovascular outcomes suggests the need for additional studies to determine if prolonged sotagliflozin-mediated lowering of plasma GIP levels contributes to improved cardiovascular outcomes observed with this drug,” they conclude.
There aren’t many studies comparing GLP1RA to SGLTi as they’re both super recent (2004 for GLP1-RA with the approval of exenatide and 2013 for flozins). But those I found show that SGLTi are as good if not significantly better than GLP1 for dementia prevention:
We also have one RCT (n= 119) by a good team showing improved cognition with empagliflozin: Effects of SGLT2 inhibition via empagliflozin on cognitive and physical impairment in frail diabetic elders with chronic kidney disease 2024 For GLP1-RA, we have way more RCTs, but “Results tends to show an improvement in some brain markers (e.g. hippocampal connections, cerebral glucose metabolism, hippocampal activation on functional magnetic resonance imaging), but without being able to demonstrate a strong correlation to cognitive scores.” (GLP-1 receptor agonists effect on cognitive function in patients with and without type 2 diabetes 2023)
Still, there’s a lot of intra-class variability. For instance for GLP1-RAs, researchers look at which ones have the highest uptake in the brain. And for SGLTi, “When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53–0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69–0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80–1.16]).” (Association of Sodium–Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study 2022)
SGLT inhibitors also cause weight loss: Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity 2019
For approved SGLT2 inhibitors there is on average some 1.5–2 kg weight loss (placebo-adjusted), for GLP1-RAs 2–4 kg, and for the combination 3–5 kg
It’s not massive, but for non-overweight people it’s good. I’ve been on dapagliflozin for 3 months and my body fat percentage (measured by DEXA) went from 16.6% (6mo ago) to 14.9% (yesterday). It’s probably not only dapagliflozin, but it’s still interesting. My weight stayed more or less constant.
Avgerinos et al found that in non-diabetics empagliflozin shifted metabolism towards a low-insulin, high-glucagon state which elevated fatty acids, and β-hydroxybutyrate levels: Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics 2022
I couldn’t find papers on this, but I think that in non-diabetic patients, GLP-1 RAs still promote insulin secretion in response to food intake. Since their body’s insulin production and glucose regulation are already in balance, the effect is to merely enhance the natural glucose-dependent insulin response.
(FWIW, I had reactive hypoglycemia; with my endocrinologist, we tried diet, acarbose, and metformin to no avail, then I suggested to try GLP1-RA after reading papers about their potential for reactive hypo. He objected that SGLTi might be better precisely because they don’t stimulate insulin secretion, quite the contrary. After 3 months of dapagliflozin, I don’t have reactive hypoglycemia anymore, and there are now many ongoing trials of SGLTi for reactive hypoglycemia.)
My conclusion: