The Medieval Roots: Apple Bark and Phlorizin

‘An apple a day keeps the doctor away’—a phrase we’ve heard countless times during childhood, often used by parents to encourage fruit consumption. However, not many know that the original saying was not about the apple fruit itself but rather the bark of the apple tree. In the Middle Ages, apothecaries used apple tree bark as a standard remedy for diabetes. The bark contains ‘Phlorizin,’ the first natural substance to inhibit sodium-glucose cotransporters (SGLTs). This discovery laid the groundwork for the modern use of SGLT-2 inhibitors.

Canagliflozin: Pioneering the SGLT-2 Era

The therapeutic potential of SGLT-2 inhibitors has evolved significantly from the 18th century to today—not only in treating diabetes but also in addressing cardiorenal metabolic syndrome. Canagliflozin was the first SGLT-2 inhibitor approved for type 2 diabetes mellitus (T2DM)  in 2013. Since 2014, five major cardiovascular outcome trials have been conducted to assess the role of SGLT-2 inhibitors in heart failure, myocardial infarction, stroke, and chronic kidney disease. The CANVAS and CANVAS-R [1] trials demonstrated the superiority of Canagliflozin as an oral hypoglycemic agent in patients with diabetes, offering better cardiovascular outcomes. However, these trials failed to establish statistically significant renal outcomes, although they indicated a possible benefit in slowing albuminuria progression and reducing the composite outcome of sustained 40% reduction in estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes.

The subsequent CREDENCE[2] trial highlighted Canagliflozin’s significant effect on renal outcomes. It showed a 34% reduction in the relative risk of the renal-specific composite of end-stage kidney disease, creatinine level doubling, or death from renal causes. Additionally, the relative risk of end-stage kidney disease alone was lowered by 32%.

Dapagliflozin: A Heart Failure Breakthrough

Dapagliflozin, approved in 2014, sparked considerable interest among clinicians across various specialties. The DECLARE-TIMI 58[3] trial firmly established its superiority in lowering the rate of cardiovascular death and hospitalization for heart failure. Subsequently, the DAPA-HF[4 trial earned Dapagliflozin FDA approval for heart failure. 

Empagliflozin: Balancing Cost and Kidney Care

Empagliflozin followed suit, gaining recognition from the European Society of Cardiology after the EMPEROR-Preserved[5] trial, which further solidified its role in heart failure treatment.

Among patients with chronic kidney disease (CKD), Empagliflozin offers better cost-effectiveness in preventing composite renal and cardiovascular events in diabetic patients. At the same time, Dapagliflozin is more cost-effective in non-diabetic patients. Dapagliflozin demonstrates an excellent value in preventing cardiovascular disease. In contrast, Empagliflozin excels in slowing CKD progression. [6] The EMPACT-MI[7] trial showed that Empagliflozin significantly reduced the risk of first and total heart failure hospitalizations post-myocardial infarction. At the same time, Dapagliflozin was associated with a lower risk of genital infections[8]. According to a joint consensus from KDIGO and ADA (2022), Empagliflozin and Dapagliflozin are recommended for patients with CKD and eGFR>20 mL/min/1.73 m². For patients with eGFR ≤45 mL/min/1.73 m² and urinary albumin-to-creatinine ratio >200 mg/g, Empagliflozin is the preferred option.[9]

Sotagliflozin: Dual Inhibition and New Horizons

The latest addition to the SGLT-2 inhibitor class is Sotagliflozin, a novel dual inhibitor of SGLT-1 and SGLT-2 receptors. Approved by the FDA in 2023, Sotagliflozin reduces the risk of cardiovascular death, hospitalization for heart failure, and urgent visits. Its unique ability to inhibit SGLT-1 receptors delays postprandial intestinal glucose absorption, enhances glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) levels, and sets it apart from other SGLT-2 inhibitors.

The Trials That Shaped a Revolution

The SOLOIST-WHF[11] trial established Sotagliflozin’s mortality benefits and cardiovascular outcomes when initiated immediately after a decompensating event, making it the only SGLT-2 inhibitor with proven benefits for Type 1 diabetes patients. The study also suggested that SGLT-1 inhibition might provide ischemic benefits, though further investigation is required. [12]

Image 1-: . Teresa Salvatore et al, ‘An Overview of the ‘Cardiao-Protective 

Mechanisms of SGLT2 Inhibitors’ [10]

Image 2-: SCORED Trial

References-: 

[1] Bruce Neal and others, ‘Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes’, New England Journal of Medicine, 377.7 (2017), pp. 644–57, doi:10.1056/NEJMoa1611925.

[2] VladoPerkovic and others, ‘Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy’, New England Journal of Medicine, 380.24 (2019), pp. 2295–306, doi:10.1056/NEJMoa1811744.

[3] Stephen D. Wiviott and others, ‘Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes’, New England Journal of Medicine, 380.4 (2019), pp. 347–57, doi:10.1056/NEJMoa1812389.

[4] John J. V. McMurray and others, ‘Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction’, New England Journal of Medicine, 381.21 (2019), pp. 1995–2008, doi:10.1056/NEJMoa1911303.

[5] Stefan D. Anker and others, ‘Empagliflozin in Heart Failure with a Preserved Ejection Fraction’, New England Journal of Medicine, 385.16 (2021), pp. 1451–61, doi:10.1056/NEJMoa2107038.

[6] HilmiAlnsasra and others, ‘Dapagliflozin versus Empagliflozin in Patients with Chronic Kidney Disease’, Frontiers in Pharmacology, 14 (2023), doi:10.3389/fphar.2023.1227199.

[7] ‘Effect of Empagliflozin on Heart Failure Outcomes After Acute Myocardial Infarction: Insights From the EMPACT-MI Trial | Circulation’ <https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.124.069217?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org> [accessed 2 March 2025].

[8] HOJIN SHIN and others, ‘915-P: Head-to-Head Comparison of Dapagliflozin vs. Empagliflozin—Cardiovascular and Safety Events’, Diabetes, 73.Supplement_1 (2024), pp. 915-P, doi:10.2337/db24-915-P.

[9] ‘Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) – PubMed’ <https://pubmed.ncbi.nlm.nih.gov/36189689/> [accessed 2 March 2025].

[10] Teresa Salvatore and others, ‘An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors’, International Journal of Molecular Sciences, 23.7 (2022), p. 3651, doi:10.3390/ijms23073651.

[11] ‘Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure | New England Journal of Medicine’ <https://www.nejm.org/doi/full/10.1056/NEJMoa2030183> [accessed 2 March 2025].

[12] Elisabeth B. Stougaard and others, ‘Sotagliflozin, a Dual Sodium-Glucose Co-Transporter-1 and Sodium-Glucose Co-Transporter-2 Inhibitor, Reduces the Risk of Cardiovascular and Kidney Disease, as Assessed by the Steno T1 Risk Engine in Adults with Type 1 Diabetes’, Diabetes, Obesity and Metabolism, 25.7 (2023), pp. 1874–82, doi:10.1111/dom.15047.