Thread by @EndoDialogues

✅ SGLT2 inhibitors (SGLT2i) were described a long time ago and are now popular for treating type 2 diabetes and much more.

From 1886 to 2024, it's time for an updated 🧵on SGLT2i!

In 1886, it was discovered that phlorizin, used to treat fever at that time, produced glucosuria.

Phlorizin is a non-selective sodium-glucose transporter inhibitor, meaning it inhibits both SGLT1 and SGLT2. But what is SGLT?

pubmed.ncbi.nlm.nih.gov/19892839/

SGLTs are the main glucose transport mediators in the GI tract (type 1) and kidneys (type 2).

Dietary glucose uptake is mainly mediated by SGLT1.

In physiologic conditions, 100% of the glomerular filtered glucose is reabsorbed (~90% mediated by SGLT2 and ~10% by SGLT1).

Phlorizin(SGLTi) has been known for over a century!

Phlorizin decreases glucose intestinal absorption (SGLT1i) and decreases tubular glucose reabsorption (SGLT1i and 2i).

🤔The obvious question is: why did it fail as a therapeutic tool?

Phlorizin⬆️ intestinal glucose = diarrhea and dehydration.

‼️For decades, most diabetologists didn't believe SGLTi would have any role in diabetes treatment.

But what about inhibiting SGLT2?

Potent and specific SGLT2i molecules were developed!
pubmed.ncbi.nlm.nih.gov/24729157/

SGLT2i phase 1 studies showed no adverse events and increased glucosuria in healthy people.

Interestingly, empagliflozin, now commercialized in both 10 and 25 mg, was given in doses as high as 800 mg!

pubmed.ncbi.nlm.nih.gov/27121669/

In March 2013, the first SGLT2i, canagliflozin, was approved by FDA.



At that time, it was just one of the several new drugs emerging in type 2 diabetes treatment, but an FDA requirement would change everything!jnj.com/media-center/p…

Since 2008, every new drug to treat T2D has to undergo a trial testing cardiovascular safety after the initial FDA approval.



That's why literature is abundant in non-inferiority CV trials for type 2 diabetes drugs.govinfo.gov/content/pkg/FR…

2015: EMPA-REG surprise!

The trial aimed to test the non-inferiority of empagliflozin for CV outcomes in pts with T2DM and high CV risk.

Result: empagliflozin was superior to placebo and reduced several MACE, including death from any cause.

pubmed.ncbi.nlm.nih.gov/26378978/

EMPA-REG main findings are CV benefits for pts with type 2 diabetes and high CV risk.

‼️Prespecified renal outcomes also improved in those assigned to empa, including fewer individuals requiring renal replacement therapy.

1 trial: 2 NEJM publications

pubmed.ncbi.nlm.nih.gov/27299675/

PAUSE HERE!

This is huge and not palatable in the early 2000s.

A new T2D drug that:
-Does not cause hypoglycemia;
-Has CV benefits including reduced death;
-Has renal benefits, including reducing renal
replacement therapy!

And this class is known since the 1800s!

2019: DECLARE-TIMI 58 Tested dapagliflozin non-inferiority for CV outcomes in pts with T2DM.

Population with fewer risk factors for CV outcomes than EMPA-REG.

Result: non-inferior. Did not show superiority as EMPA-REG. "Less sick" population.

pubmed.ncbi.nlm.nih.gov/30415602/

2019: DAPA-HF.

Dapagliflozin was tested in heart failure pts with ejection fraction ≤ 40%, regardless of diabetes, after showing potential improvement in HF as a secondary outcome.

Result: decreased hospitalization for HF, decreased death.

pubmed.ncbi.nlm.nih.gov/31535829/

2020: EMPEROR-Reduced

Empagliflozin tested in pts with heart failure and ejection fraction ≤ 40%, regardless of diabetes.

Result: decreased hospitalization for HF, decreased CV death.

pubmed.ncbi.nlm.nih.gov/32865377/

2020: DAPA-CKD

Dapagliflozin tested in pts with eGFR between 25 and 75 mL/min, regardless of diabetes.

Result: improved renal outcomes in those assigned to dapagliflozin, including less dialysis and, now unsurprisingly, decreased death from any cause.

pubmed.ncbi.nlm.nih.gov/32970396/

2021: EMPEROR-Preserved

Empagliflozin tested in pts with heart failure class II-IV and EF > 40%, regardless of diabetes.

Result: decreased hospitalization for HF - CV death was part of the positive 1ary combined outcome.

pubmed.ncbi.nlm.nih.gov/34449189/

2022: DELIVER

Dapagliflozin testes in pts with heart failure and EF> 40%, regardless of diabetes.

Results: decreased primary outcome of worsening HF or CV death.

pubmed.ncbi.nlm.nih.gov/36027570/

What about drawbacks?

Studies consistently showed an increased risk for genital infections and marginalized increased risk for urinary tract infections.

Euglycemic DKA is also a now well-known adverse effect associated with SGLT2i use.

Some experts advocate against using SGLT2i in pts with A1c > 9% as the drug class has lower efficacy in T2DM treatment in this setting and increases polyuria.

Also, there is an increased risk for euglycemic DKA.

It is also well known that SGLT2i, or SGLT1/2i such as sotagliflozin, may improve T1D glucose control, but the increased risks of DKA make its use debatable and not indicated at this time

pubmed.ncbi.nlm.nih.gov/30287422/

Data for SGLT2i are enormous and difficult to synthesize, but I hope this 🧵 is helpful for better understanding the class!

Feel free to add!🤛🤛