Table 1. Relationship of the use of SGLT2 inhibitors and ketone bodies in pre-clinical and clinical studies.
| Reference | SGLT2 inhibitor | Model | HF | Diabetes | Ketone body measured | Outcome |
|---|---|---|---|---|---|---|
| Al Jobori et al. 90 | EMPA | Human | No | T2DM and non-diabetic | β-OHB (µmol/L) | Significant increase in glucagon, FFA and β-OHB in T2DM vs. non-diabetic |
| Polidori et al. 103 | CANA | Human | No | T2DM | β-OHB and acetoacetate (µmol/L) | Increases in ketone bodies that were greater than other metabolic measures in patients with T2DM |
| Ferrannini et al. 87 | EMPA | Human | No | T2DM and non-diabetic | β-OHB (µmol/L) | Lower insulin to glucagon ratio favours ketogenesis. T2DM patients doubled fasting β-OHB levels |
| Daniele et al. 97 | DAPA | Human | No | T2DM | β-OHB and acetoacetate (µmol/L) | DAPA caused a shift from glucose to lipid oxidation and increased plasma ketone bodies concentration |
| Inagaki et al. 104 | CANA | Human | No | T2DM | Total ketone body (μmol/L) | Canagliflozin is tolerated by patients irrespective of their BMI, and total ketone body ≥ 1,000 μmol/L tented to be highest in patients with BMI ≤ 22 kg/m2 |
| Oldgren et al. 105 | DAPA | Human | No | T2DM | β-OHB (µmol/L) | No differences in plasma levels of β-OHB between DAPA vs the placebo group. DAPA reduced heart work but limited effects on myocardial function |
| Yabe et al. 106 | LUSEO | Human | No | T2DM | Ketone bodies (μmol/L) | Ketone bodies were significantly higher in the low carbohydrate and high glycaemic index diet |
| Verma et al. 107 | EMPA | C57BL/6J and db/db mice | No | Mouse surrogates for diabetes (db/db mice) | Total ketone body (μmol/L) | EMPA treatment is associated with an increase in ATP production but did not increase cardiac efficiency |
| Yurista et al. 102 | EMPA | Sprague-Dawley rats | Yes (MI) | Non-diabetic | Total ketone body (μmol/L) | EMPA increases circulating levels of total ketone body, increase ATP production and improves LVEF and cardiac remodelling |
| Santos-Gallego et al. 21 | EMPA | Yorkshire pigs | Yes (MI) | Non-diabetic | Total ketone bodies myocardial uptake (ng/g/min) | EMPA switches myocardial fuel to ketone bodies, FFA and BCAA. It also ameliorates adverse cardiac remodelling and improves LV systolic function |
| Moellmann et al. 108 | EMPA | Male db/db mice | Yes (DD) | Mouse surrogates for diabetes (db/db mice) | β-OHB and acetoacetate (µmol/L) | EMPA improves diastolic function regardless of changes in cardiac ketone body metabolism |
| Connelly et al. 109 | EMPA | Sprague-Dawley rats | Yes (DD) | Non-diabetic | β-OHB (µmol/d) | β-OHB does not differ in EMPA compared to the control group but improves LV mass and improves diastolic dysfunction |
ATP, Adenosine triphosphate; BCAA, branched-chain amino acids; BMI, body mass index; CANA, canagliflozin; DAPA, dapagliflozin; DD, diastolic dysfunction; EMPA, empagliflozin; FFA, free fatty acids; HF, heart failure; LUSEO, luseogliflozin; LV, left ventricle; LVEF, left ventricle ejection fraction; MI, myocardial infarction; SGLT2, sodium/glucose cotransporter-2; T2DM, type 2 diabetes mellitus; β-OHB, β-hydroxybutyrate.