1/ RTing for balance, and because I agree with my colleague, @DrNadolsky.
But interestingly, the mechanism by which SGLT2i results in higher LDL and reduce TG could be relevant to the #LipidEnergyModel and how this may relate to the question of risk in this context...
But interestingly, the mechanism by which SGLT2i results in higher LDL and reduce TG could be relevant to the #LipidEnergyModel and how this may relate to the question of risk in this context...
2/ There's an interesting study from last year on this that caught my attention. Fair warning it is a transgenic mouse study, but at least it is mechanistic and thus decent for hypothesis-forming.
Let's unpack some key findings..
ncbi.nlm.nih.gov/pmc/articles/P…
Let's unpack some key findings..
ncbi.nlm.nih.gov/pmc/articles/P…
3/ Per @DrNadolsky above, it opens with:
"Sodium glucose cotransporter 2 (SGLT2) inhibition in humans leads to increased levels of LDL cholesterol and decreased levels of plasma triglyceride. Recent studies however, have shown this therapy to lower cardiovascular mortality."
"Sodium glucose cotransporter 2 (SGLT2) inhibition in humans leads to increased levels of LDL cholesterol and decreased levels of plasma triglyceride. Recent studies however, have shown this therapy to lower cardiovascular mortality."
4/ This paragraph is worth reading completely.
If you've followed me for a while, you know I hypothesize much of the reason for high LDL in low carbers is due to greater lipolysis of both adipose tissue *and* VLDL (with the latter being the precursor to LDL).
If you've followed me for a while, you know I hypothesize much of the reason for high LDL in low carbers is due to greater lipolysis of both adipose tissue *and* VLDL (with the latter being the precursor to LDL).
5/ Total and LDL-C cholesterol climb considerably on the SGLT2i, triglycerides fall substantially as well.
What can easily explain rising LDL-C along with falling TG?...
What can easily explain rising LDL-C along with falling TG?...
6/ "SGLT2 ASO, canagliflozin, and insulin treatments increased total TG lipase activity, as well as LpL activity in the post-heparin plasma. These increases were greater with SGLT2 ASO than with canaglifozin."
^ Greater rate of TG offloading from TG-rich lipoproteins
^ Greater rate of TG offloading from TG-rich lipoproteins
7/ "The increased LDL-c in the mice might be due to greater LpL-mediated conversion of VLDL to LDL. However, it is also possible that our treatments altered clearance of LDL from the circulation. To test this, we assessed LDL turnover."
How they test this is pretty cool...
How they test this is pretty cool...
8/ "...we measured the gene expression of LDLR and its post-transcriptional modulator PCSK9 in the liver. SGLT2 ASO treatment lowered mRNA levels of both genes (Figure 5b). Total hepatic LDLR protein levels decreased modestly in SGLT2 ASO treated mice (Figure 5c, d)."
9/ From Discussion:
"Both postprandial TG and VLDL-TG turnover were increased in ASO-treated mice, consistent with the increased LpL activity."
[LpL = lipoprotein lipase]
"Both postprandial TG and VLDL-TG turnover were increased in ASO-treated mice, consistent with the increased LpL activity."
[LpL = lipoprotein lipase]
10/ Last paragraph
11/ Returning to @DrNadolsky point, the reduction of CVD by SGLT2i could be due to many factors related to the drug (such as weight loss, reduced glucose, etc) in spite of higher LDL.
As always, we should be good scientists and keep all possibilities in our field of view...
As always, we should be good scientists and keep all possibilities in our field of view...
12/ However, SGLT2i is definitely on my radar given studies like this suggesting the "why" of higher LDL as due to greater VLDL turnover along with modestly reduced clearance.
This may further support "lipid profile centric" vs "lipoprotein centric" view of LDL assoc risk
This may further support "lipid profile centric" vs "lipoprotein centric" view of LDL assoc risk
