Table 1.
Effects of canagliflozin on factors associated with cardiometabolic benefits and risks
| Parameter | Effect of canagliflozina | Potential SGLT2i‐associated mechanisms or effects of SGLT2i on factors | Predicted effect on CV outcomes |
|---|---|---|---|
| Hyperglycaemia | ↓ |
Urinary glucose excretion Potential secondary effects based on improvements in insulin sensitivity and/or beta‐cell function |
Reduction in chronic hyperglycaemia and glucose variability may improve CV outcomes |
| Plasma insulin | ↓ |
Decreases in plasma glucose reduce glucose stimulation of beta cells Increased insulin clearance |
Reduced hyperinsulinaemia may lower CV risk |
| Body weight and visceral adiposity | ↓ | Net caloric loss as a result of urinary glucose excretion |
Modest weight loss may reduce CVD risk in patients with T2DM Loss of visceral fat can lower CVD risk by reducing inflammation and the potential for atherogenesis |
| Blood pressure | ↓ | Osmotic diuresis, natriuresis, reduced intravascular volume, weight loss | Reductions in blood pressure can significantly reduce risk of CHD and mortality |
| Albuminuria | ↓ | Decreased urinary albumin excretion via reduction in GFR through reduction in glucose and sodium reabsorption in the proximal tubule |
Reduced albuminuria is associated with reduced risk of CV and renal disease and associated mortality May slow progression of diabetic nephropathy |
| Kidney function | ↑ | Reduced GFR through reduction in glucose and sodium reabsorption in the proximal tubule | May provide renoprotective benefits and slow progression of diabetic nephropathy |
| LDL‐C | ↑ | Possible metabolic effects of urinary glucose excretion and haemoconcentration |
Abnormalities in lipoprotein metabolism increase CV risk in T2DM Increasing LDL‐C may promote atherogenesis and increase risk for development of CVD |
| HDL‐C | ↑ |
Possible metabolic effects of urinary glucose excretion and haemoconcentration Associated with improvements in glycaemic control and reduced body weight |
Increased catabolism of HDL‐C in T2DM reduces cardioprotective effects SGLT2i may modulate the impact of T2DM on HDL‐C levels |
| Triglycerides | ↓ | Associated with improvements in glycaemic control and reduced body weight |
Increased triglyceride level is a primary lipid abnormality in T2DM Decreases in triglycerides with SGLT2i may reduce risk for development of CVD |
| Uric acid | ↓ | Increased delivery of glucose to transporters that exchange glucose for uric acid | May reduce risk for nephropathy, CHD, and mortality |
| Serum magnesium | ↑ | Consequence of mild osmotic diuresis and possibly alterations in renal handling of magnesium | May reverse magnesium deficiencies that are associated with cardiac hypertrophy, aortic stiffening, arrhythmias, and rapid declines in renal function |
| Haemoglobin/haematocrit | ↑ | Plasma volume contraction due to osmotic diuresis; increased haematopoiesis; increases in erythropoietin levels |
Results are mixed on CV effects of increased haemoglobin/haematocrit Increases in the EMPA‐REG OUTCOME study were associated with improvements in HF and mortality risk, but may increase risk of thrombotic events |
| Ketones | ↑ | Shift in substrate delivery to the heart and changes in cardiac insulin sensitivity | Improvements in myocardial and renal fuel metabolism may reduce CV risk, but there is also speculation about increased risk of thrombotic events |
CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; GFR, glomerular filtration rate; HDL‐C, high‐density lipoprotein cholesterol; HF, heart failure; LDL‐C, low‐density lipoprotein cholesterol; SGLT2i, sodium glucose co‐transporter 2 inhibitors; T2DM, type 2 diabetes mellitus. aArrows indicate the direction of statistically significant changes associated with canagliflozin treatment.