I’m going to add a quote here from the article
The benefit of canagliflozin on hard clinical endpoints may be dose-dependent, with the 300 mg dose showing a higher efficacy and a similar safety profile
(Than the 100mg dose).
I’d be curious why many people here have decided to use lower doses of their preferred SGLT2-inhibitor. Given the very safe profile of these drugs, I’m having a hard time seeing why you wouldn’t just take the highest tested dose (eg 25mg empaglaflozin)
There might be a case for lower doses in females as they are more at risk of genital infections and there are speculations that in the ITP canagliflozin failed in females due to a too high dose. The results of the ongoing lower dose test will answer that. For males, I don’t see any rationale. I take the highest approved dose (10 mg dapagliflozin).
**[1]**Turkish STUDY: in a comparison of patients who were diabetic and on metformin and gliclazide one group received 10mg empagliflozin and the second 25mg. Both groups had a similar decline in A1c and FBG on both doses and no difference is impact on blood lipids. There was a slight tendency to lower BP on the 25mg dose and also greater weight loss. There were no significant differences in side effects.
The effect of low and high dose empagliflozin on HbA1c and lipid profile in type 2 diabetes mellitus: A real-world data
“There was no statistically significant difference in HbA1c decreases among patients who used 10 and 25 mg of empagliflozin (p=0.935) (Table 3). The decrement in FPG at 12th week was significantly different from baseline treatments (Tables 1, 2). However, there was not a statistically significant difference in FPG among patients who used 10 and 25 mg of empagliflozin (p=0.739) (Table 3) (Fig. 1).”
“There was no statistically significant difference relevant to the change in lipid parameters between patients who used 10 and 25 mg of empaglifosin, as well (p>0.05) (Table 3).”
However:
“When both empagliflozin groups were compared, there was a propensity of dose-dependent decline in blood pressure (p<0.05). The decrease in blood pressure in the 25 mg group of empagliflozin was −9.6±7.5 mmHg (systolic) and − 6.7±4.6 mmHg (diastolic), while the decrease in the group-1 was -6.8±5.1 mmHg (systolic) and -4.6±4.0 mmHg (diastolic) (for SBP p=0.032 and for DBP p<0.005) (Table 3, Fig. 2, 3).”
“The body weight losses of Group 1 and Group 2 were -2.6±1.2 and -3.8±2.0, respectively. When Group 1 and Group 2 were compared according to the amount of weight losses, there was a significant difference in support of the group using 25 mg of empagliflozin (p=0.021) (Fig. 4).”
**[2]**Meanwhile a Chinese analysis metastudy paper found dosage differences in effects, with 25mg found to be the best (and they also looked at a 50mg dose, not typically prescribed in the USA):
Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta-analysis based on randomized controlled trials
https://onlinelibrary.wiley.com/doi/10.1111/jcpt.13521
"Results
We identified 8264 articles, of which 23 RCTs with 10518 patients were included. Regarding haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), high-daily doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1> 5 > 10 > 25> 2.5 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships.
High-daily doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses in patients with T2DM."
**[3]**Finally, a Japanese paper that is very interesting - and found a higher dose of empagliflozin superior in select parameters:
Clinical Benefit of Switching from Low-Dose to High-Dose Empagliflozin in Patients with Type 2 Diabetes
Quote:
“Increasing the dose of empagliflozin significantly ameliorated BW, BMI, GGT, TG, fasting plasma glucose and HbA1c and increased Hct in patients with T2DM. Moreover, baseline DBP and TG were independent predictors for the improvement of HbA1c. These findings may provide useful information when
considering increasing the dosage of SGLT2 inhibitors in patients with T2DM who have inadequate glycemic control.”
And generally it is apparently accepted that:
Quote:
“Almost all SGLT2 inhibitors have been reported to have dose-dependent effects. For example, the recommended dosage of empagliflozin is 10 mg once daily before or after breakfast, and combination therapy with therapy with several antihyperglycemic drugs has been approved. When its efficacy is insufficient, an increased dose of up to 25 mg once daily is allowed.”
I might go up on my dose in the future. I was just starting low to see how I’d tolerate it. I have taken a full 5mg dose of Dapagliflozin 3 times without any issues though. As a female I was a bit concerned about potential genital infections. I did notice some vaginal irritation in the first week but started a women’s probiotic and applied topical estriol to the area and everything is fine.
115 for fasting BG is pretty high. It put you in that “pre” category. Mine is within 80-90 range. How do you measure your fasting BG? Poke your finger or go to a lab? Asking bc if I go to a lab, my BG always climbs (could be stress related). I wear glucose monitor so I watch how it goes up while I’m driving. My point is that your 115 reading could be also affected by cortisol.
My lab tested fasting blood glucose has always been 10-20 points higher at ~95 than finger prick and CGM. I figured it was somehow testing related (eg cortisol spike), but after starting on tirzepatide and empagliflozin it’s pretty consistently in the 70-80 range.
I’m hesitant to increase my empa dose from 12.5 to 25 because of the potential negative impact on strength and/or endurance training adaptations. Wish we knew a bit more about that
The thing is you can easily track your results over time (which I assume you’re already doing)… how much you’re lifting in your strength training routine, your VO2max, etc…
FWIW, I didn’t notice any effect of empagliflozin on my exercise, muscle or endurance, at either the 12.5mg/day dose or 25mg/day. Of course, I’m not doing extremely challenging exercise, so perhaps if I was an elite level athlete I might detect an effect. But I’m just doing regular stuff like jogging plus HIIT 4 times a week (200 minutes total), and some circuit training modes twice a week (complex squat routine with 45lbs weightvest 32 minutes continuous ATG with 5 minute intervals of jumping squats etc.). No empa effect that I can tell.
In contrast, I have absolutely experienced strong effects of rapamycin at 6mg/1-week. After 5-7 weeks on rapamycin, aches and pains in joints, tendons, muscles disappear. I recover from exercise much faster, and my capacity to exercise is increased (run faster in HIIT intervals), big impact on better endurance. I’m 67, but on rapa I feel like I’m exercising in my 30’s.
But this is n=1, and no doubt there are individual differences, so you just have to test yourself and see how it impacts you. Fortunately, that’s easy to do, it’s not some irreversible process - try 25mg/day, if negative, stop and go back to 12.5, trying won’t harm you, and might have positive effects. YMMV.
Efficacy for PTSD (mouse model):
My goal is to maintain BG in a normal healthy range without SGLT2 inhibitors or Metformin only through diet and lifestyle. So far so good.
Some people report elevation of blood lipids with SGLT2i. Perhaps tofogliflozin might be of interest in this context.
Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial
“Tofogliflozin is an SGLT2 inhibitor with high selectivity for SGLT2. Suzuki et al. measured the sodium-dependent glucose uptake in SGLT2-overexpressing cells and evaluated SGLT2 selectivity against SGLT1, expressed as the ratio of inhibitory concentration 50 (IC50) for each compound. Their study showed that tofogliflozin (2900-fold) was highly selective compared to dapagliflozin (610-fold), canagliflozin (290-fold), ipragliflozin (860-fold), empagliflozin (1100-fold), and luseogliflozin (1600-fold) [8]. Tofogliflozin also has a short elimination half-life (5–6 h) with a high level of urinary excretion [9], which reduces the risk of nocturnal hypoglycemia [10]. In addition to its effect on glycemic control, tofogliflozin improves high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels, decreases body weight and blood pressure, and elevates circulating adiponectin levels [11]. We previously investigated the effect of tofogliflozin on carotid artery intima-media thickness (IMT) [12], which is a marker of atherosclerosis [13], arterial stiffness [14], and patients’ quality of life (QOL) [15], in the “Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)” trial. Although tofogliflozin did not delay the progression of IMT thickening, it significantly improved glycemic control, body weight, body mass index (BMI), abdominal circumference, systolic blood pressure, HDL-C, arterial stiffness, and treatment-related QOL [12, 14, 15] during the 2-year intervention period.”
My BG elevates significantly after I taking high GI meal, sometimes it would elevate to prediabetic level.
I agree with you, I don’t want to take drug to control BG.
Because metformin has negative effect on testosterone and muscle mass to me.
Haven’t try SGLT2 but my BMI is only 22, I am afraid SGLT2 would have similar effect like metformin.
Berberine does not show much BG control effect on me.
Acarbose once caused me liver injury.
So I replace all my starchy food to quinoa, lentils and sweet potato, now my BG is much better. Low GI, high fiber food really amazing.
Good find! What’s the difference between the two “0”? And do we have the % difference in average and max lifespan? P-value?
I’m not sure, they seem to combine the 0 groups together for the final survival rate. It’s a large document and I haven’t looked at it carefully, I’m unsure if they have other data or where to get it, maybe the FDA has it (I started looking after this tweet by Alex Kesin: Should every drug go through mouse lifespan studies? - #5 by AnUser, drug developers probably have many such sources of information).
Unless I’m mistaken the high dose groups are doing better, but it doesn’t look like that on the graph to me. Higher dose groups had much lower body weight, as well, so could be a confounder.
At termination the survival rates were 64, 70, 78 and 66% in males
and 57, 64, 68 and 62% in females in 0 (groups 1 and 2 combined), 100, 300 and 700
mg/kg-treated groups, respectively
Dapagliflozin
I’m not sure the higher dose group were doing better.
Page 99:
"Appropriateness of Test Models
The sponsor chose empagliflozin doses of 0, 0, 100, 300 and 1000 mg/kg/day based on the recommendations of the ECAC. Overall treatment was well tolerated and the results showed no dose-limiting toxicity, except for excess mortality in the high dose male group which was terminated at week 97. As all high dose males and females were terminated at weeks 97 and 102, respectively, the high dose was considered adequate for tumor assessment and statistical evaluation. Exposure at the high dose (700 mg/kg) provided approximately 45x and 62x the maximum recommended human dose (MRHD) in males and females, respectively, based on total exposure (AUC0-24h)."
Page 100:
"Mortality
Decreased survival was observed in the 1000 mg/kg males that resulted in early termination for this group at week 97 (see sponsor’s figure below). At study termination 16 males and 17 females were present in the high dose (HD) group. Although, a submission to the Division and ECAC was not made to request early termination of the HD male group, it is likely ECAC would have concurred if the number of survivors had reached 15 or less, prior to week 100 of the study. increased mortality observed for the HD male group was due to urinary tract dilatation. Given that all HD males and females were terminated at week 97 and 102, respectively, the HD group is considered adequate for tumor assessment and statistical evaluation."
Page 101:
“In the males the most common non-neoplastic cause of death was attributed to urinary tract dilatation that showed a treatment-related increase in the low, mid and high dose males (see sponsor’s table below). These lesions account for the early termination of the HD male group, and were described as dilated renal pelves, distended urinary bladder and/or uteral dilatation and renal tubular cysts that were observed macroscopically with renal/uretal dilatation and chronic progressive nephropathy. All other causes of death were not dose related (sponsor’s table below).”
Also, the bodyweight story was more complicated and sex dependent. Page 102:
"Body Weights
Treatment with empagliflozin had no effect on the mean body weight in both males and females at the end of treatment (see table below). Mean body weights were, however, statistically significantly (ss) reduced in all empagliflozin-treated males for weeks 12 to 78, and did not correlate with the observed increased food consumption (vehicle 1 and 2 were combined for the analysis). The reduced mean body weight ranged from 5-10% and was not dose-dependent. Mean body weights were also ss reduced 3-7% in the 100 and 300 mg/kg males from weeks 86-94, respectively. Similar final body weight at the end of the study appears due to a downward trend in body weight of both control groups, rather than a change in the dosed groups.
In contrast, there was a statistically significant increase in body weight at weeks 2-26 in the 1000 mg/kg females (data not shown but see sponsor’s figure below). The increase in body weight ranged from 5-12% and was associated with increased food consumption. However, overall body weight for the duration of the study was not statistically significantly increased. Mean body weight was also ss increased at weeks 4-13 and week 18 in the 300 mg/kg females. The increase in body weight was of a lower magnitude compared to the high dose females and ranged from 3-7%."
So the survival rate was 64% in control, 70% for 100 mg/kg, 78% for 300 mg/kg, and 66% for 700 mg/kg for male rats?
Well, most seems at the 300 mg/kg dose and drops off at 700 and higher (1000). But note early termination, not favorable trends. Dose, poison etc. Some sex differences.
Amazing, thanks for sharing. So dapagliflozin and empagliflozin also increase lifespan in male mice. (We already had one Chinese paper on empagliflozin confirming that.) So it’s not only an SGLT1 effect @Neo.
Using the FDA conversion guide, 100 mg/kg = 650 mg/day, in a 80 kg human. The maximum approved dose is 25 mg/day. So there is no risk. But do empa and dapa also increase lifespan at these low doses?
