This is really strange… why would you go through all the expense and effort to get a drug approved and then withdraw it two years later. Anyone find any info on the reason for the withdrawl?
public-statement-zynquista-withdrawal-marketing-authorisation-european-union_en.pdf (97.8 KB)
Ah - found it… I think the danger is likely exaggerated (in the publication cited below), but good to be aware of it…
Before the FDA issued its decision on whether or not to approve the drug, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed the clinical trial data. The committee voted on whether or not it recommends that the FDA approve the drug. While the FDA is not required to follow the committee’s advice, it typically does. The committee was split on Zynquista. Eight members voted for approval of the drug, and eight voted against. Those that voted against were particularly concerned about the risk of diabetic ketoacidosis.
“I think it’s impossible to understate the concern about DKA (diabetic ketoacidosis) really just because the absolute increase is really remarkable,” Michael Blaha, MD, of Johns Hopkins Ciccarone Center for the Prevention of Heart Disease in Baltimore told MedPage Today at the time. “I am concerned about the prospect that this could be worse in the real world [outside of the trial setting].”
In March of 2019, the FDA officially rejected the approval of Zynquista (sotagliflozin). Lexicon and Sanofi ended their collaboration, and only Lexicon kept working on the drug. The company appealed the FDA’s decision, but the FDA stood firm and rejected that appeal in December of 2019. Meanwhile, the European Medicines Agency (EMA)—the European Union’s FDA equivalent—decides to approve the drug as an add-on to insulin treatment for those with Type 1 diabetes in April 2019.
Comparison of canagliflozen to Sotagliflozin. A mixed bag but I’d say Cana is a fine drug for glucose control even if sotaog has a longer lasting effect.
I agree.
Overall, this study suggests about 11% of users discontinued using SGLT2 inhibitors due to side effects (which I don’t consider too bad… about 90% continued ).
Side effects perceived to be related to adjuvant therapy
Side effects perceived to be related to the therapy were more commonly reported by GLP-1RA versus SGLT2i users (63.2% versus 36.6%, respectively). Gastrointestinal symptoms were the most reported side effects among GLP-1RA users (57.4% versus 1.2% of SGLT2i users; Figure 1(c)). Overall, among SGLT2i users, 11.8% reported genital mycotic infections, 9.0% reported urinary tract infections (UTIs), and 11% reported polyuria/dehydration. DKA was reported by 4.9% SGLT2i users and no GLP-1RA user. No episodes of pancreatitis were reported. Of the 43 GLP-1RA users who reported side effects, less than a third (32.3%) discontinued therapy because of the side effects (22.6% of all GLP-1RA users). For SGLT2i users, 9/30 patients (30%) who experienced side effects discontinued because of the reported side effects (11% of all SGLT2i users). Among those treated with SGLT2i in Poland versus United States, the nature and frequency of the reported side effects were comparable.
Just discussed this earlier today:
Seems like this could be addressed / monitored via continuous ketone monitoring (CKM)?
I wonder if regular use of methylene blue would help with Sglt2 related infections?
What makes you think that? Has MB been shown to help urinary tract infections?
LIstening to Dr Francisco Gonzalez-Lima on STEM-Talk #107, he talks about UTI cured by MB. Here’s a paper:
Interesting paper published last year and comparing all glucose-lowering drugs: Diabetes, antidiabetic medications and risk of depression – A population-based cohort and nested case-control study 2022
Conclusion: “Ever-use of metformin, DPP4 inhibitors, GLP1 analogs and SGLT2 inhibitors in patients with diabetes was associated with lower odds of depression compared to non-users with diabetes, while ever-use of insulin or sulfonylurea was associated with higher odds of depression (see Supplementary Table 5). Use of glitazones and acarbose did not significantly affect risk of depression, while use of SGLT2 inhibitors was associated with the lowest odds (ORSGLT2 0.55 (0.44–0.70)) (Fig. 2). In a post-hoc analysis using the non-diabetes population as reference, patients with diabetes using SGLT2 had even lower odds of depression compared to individuals without diabetes (ORSGLT2_non-diab 0.77 (0.61–0.98)).”
However, for metformin and GLP1, doses matter: only low-dose metformin (less than 2 g per day) and low-dose GLP1 (less than 3 µg exenatide per day) had this effect, while high doses had no positive effect or even higher odds of depression.
Is anyone taking Rybelsus?
It is the only oral GLP1 analog that I can find.
I am very interested in GLP1 analogs, but I am not interested in any injectables.
I’ve tried the oral. It’s easy to get from India. The only trick is you have to take it on a completely empty stomach and drink the smallest amount of water possible, and wait at least an hour. Otherwise, you basically don’t get any absorption. Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials - PubMed. I find that just one 7mg pill per week gives me enough appetite suppression to be impactful without much RHR elevation.
FWIW:
The current price from Jagdish Nikose:
1- Rybelsus 3mg Tablet , Semaglutide (3mg) = 45 USD for 10 Tablets.
2- Rybelsus 7mg Tablet , Semaglutide (7mg) = 50 USD for 10 Tablets.
I think the lower dosage is the one to use from the studies if you don’t have blood glucose problems.
How come? I thought you already were (a) lean and (b) not running around hungry anyway nowadays?
It seems to me that there are/can be health benefits for someone obese
Longevity wise for a non/obese person is seems more the opposite - especially as GLP-1s seem to increase insulin which generally is anti-longevity?
3mg is the starter dose for nausea/ramp up. 7mg is the normal dose. 14mg is the big dose. So 3mg isn’t worth it, since you could just take the 7 less often.
Men get UTIs. Especially in the setting of prostate dysfunction, it can be bad. Also one of the concerns is genital yeast infections.
Yes, this is supposedly a big problem in “real world” using SLGT2i in men. This concern was raised by a colleague of mine, she is a professor of clinical diet and functional medicine (MD) and raised that as a major risk. She also pointed that in active people they can lead to RED-S and that risk of euglycaemic ketoacidosis , serious complication, is often overlooked.
But since the overwhelming majority (99.9999+ %?) of SGLT2i drugs are used by diabetics, who are all immunosuppressed to a greater or lesser extent, I’d expect infection risk to be much lower in a non-diabetic user with a healthy immune system, wouldn’t you?
The infection risk is much lower in non-diabetics. I take a cranberry supplement preventatively.
Lately is also prescribed (at least in EU) for CV prevention to pre diabetics (HbA1c above 5.7).
All three conditions I mentioned are easily overlooked as yeast UTI is mostly asymptomatic in case of absence of complications. RED-S and euglycaemic ketoacidosis have really non specific symptoms and are mostly overlooked. Euglycaemic ketoacidosis is a more specific diabetes condition and probably risk in non diabetic is negligible but still present I guess.
My Methylene Blue arrives this weekend. My IQ will be 25 points higher by Monday! Or I’ll just have blue teeth.