❗️SGLT2i were described a long time ago.
✅They are now popular drugs to treat type 2 diabetes, heart failure, and chronic kidney disease.
Want to know more? Time for a 🧵
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✅They are now popular drugs to treat type 2 diabetes, heart failure, and chronic kidney disease.
Want to know more? Time for a 🧵
1/20
In 1886, it was discovered that phlorizin, used to treat fever at that time, produced glucosuria.
Phlorizin is a non-selective sodium-glucose transporter (SGLT) inhibitor, meaning it inhibits both SGLT1 and SGLT2.
But what is SGLT?
pubmed.ncbi.nlm.nih.gov
2/20
Phlorizin is a non-selective sodium-glucose transporter (SGLT) inhibitor, meaning it inhibits both SGLT1 and SGLT2.
But what is SGLT?
pubmed.ncbi.nlm.nih.gov
2/20
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 SGLT1 and ~10% by SGLT2).
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Dietary glucose uptake is mainly mediated by SGLT1.
In physiologic conditions, 100% of the glomerular filtered glucose is reabsorbed (~90% mediated by SGLT1 and ~10% by SGLT2).
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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: why did it fail as a therapeutic tool?
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Phlorizin decreases glucose intestinal absorption (SGLT1i) and decreases tubular glucose reabsorption (SGLT1i and 2i).
The obvious question: why did it fail as a therapeutic tool?
4/20
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
5/20
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
5/20
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
6/20
Interestingly, empagliflozin, now commercialized in both 10 and 25 mg, was given in doses as high as 800 mg!
pubmed.ncbi.nlm.nih.gov
6/20
In March 2013, the first SGLT2i, canagliflozin, was approved by FDA almost 1 year after submission.
jnj.com
At that time, it was just one of the several new drugs to treat type 2 diabetes, but an FDA requirement would change everything.
7/20
jnj.com
At that time, it was just one of the several new drugs to treat type 2 diabetes, but an FDA requirement would change everything.
7/20
Since 2008, every new drug to treat type 2 diabetes has to run a trial to show cardiovascular safety after the initial FDA approval.
This is the reason why we read several non-inferiority CV trials for type 2 diabetes drugs.
govinfo.gov
8/20
This is the reason why we read several non-inferiority CV trials for type 2 diabetes drugs.
govinfo.gov
8/20
2015: EMPA-REG surprise!
The trial was designed to test empagliflozin non-inferiority 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
9/20
The trial was designed to test empagliflozin non-inferiority 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
9/20
EMPA-REG showed CV benefits for pts with type 2 diabetes and high CV risk.
Its data also showed benefits for CKD. Prespecified renal outcomes improved in pts taking empagliflozin, including fewer pts requiring renal replacement therapy.
pubmed.ncbi.nlm.nih.gov
10/20
Its data also showed benefits for CKD. Prespecified renal outcomes improved in pts taking empagliflozin, including fewer pts requiring renal replacement therapy.
pubmed.ncbi.nlm.nih.gov
10/20
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
11/20
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
11/20
2019: DAPA-HF.
As a secondary outcome, HF was improving, so dapagliflozin was tested in pts with heart failure and ejection fraction ≤ 40%, regardless of diabetes.
Result: decreased hospitalization for HF, decreased death.
pubmed.ncbi.nlm.nih.gov
12/20
As a secondary outcome, HF was improving, so dapagliflozin was tested in pts with heart failure and ejection fraction ≤ 40%, regardless of diabetes.
Result: decreased hospitalization for HF, decreased death.
pubmed.ncbi.nlm.nih.gov
12/20
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
13/20
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
13/20
2020: DAPA-CKD
Dapagliflozin testes in pts with eGFR between 25 and 75 mL/min, regardless of diabetes.
Result: improved outcomes in pts taking dapagliflozin, including less dialysis and decreased death from any cause.
pubmed.ncbi.nlm.nih.gov
14/20
Dapagliflozin testes in pts with eGFR between 25 and 75 mL/min, regardless of diabetes.
Result: improved outcomes in pts taking dapagliflozin, including less dialysis and decreased death from any cause.
pubmed.ncbi.nlm.nih.gov
14/20
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
15/20
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
15/20
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.
16/20
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.
16/20
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.
17/20
17/20
Dapagliflozin also failed to treat patients hospitalized with COVID-19, but it is arguable that this study (DARE-19) was underpowered.
The RECOVERY group is now investigating empagliflozin in this setting.
pubmed.ncbi.nlm.nih.gov
clinicaltrials.gov
18/20
The RECOVERY group is now investigating empagliflozin in this setting.
pubmed.ncbi.nlm.nih.gov
clinicaltrials.gov
18/20
SGLT2i are not approved to treat type 1 diabetes.
However, it has been shown that low-dose SGLT2i may improve glycemic control and reduce weight in pts with T1DM without major adverse events.
pubmed.ncbi.nlm.nih.gov
19/20
However, it has been shown that low-dose SGLT2i may improve glycemic control and reduce weight in pts with T1DM without major adverse events.
pubmed.ncbi.nlm.nih.gov
19/20
Data for SGLT2i are enormous and difficult to synthesize, but I hope this 🧵 has helped you better understand the class!
🤝🤝
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