From the Guidelines
SGLT2 inhibitors work by blocking sodium-glucose cotransporter 2 proteins in the kidneys, preventing glucose reabsorption and causing increased urinary glucose excretion, which lowers blood glucose levels in diabetic patients, and they offer significant cardiovascular and renal benefits, as demonstrated in the most recent study by 1.
Mechanism of Action
The mechanism of action of SGLT2 inhibitors involves blocking the sodium-glucose cotransporter 2 proteins in the kidneys, which prevents glucose reabsorption and causes increased urinary glucose excretion, thereby lowering blood glucose levels in diabetic patients. This action also leads to a reduction in blood pressure, improved cardiac metabolism, decreased inflammation, and enhanced cardiac function, as noted in 1 and 1.
Cardiovascular Benefits
For cardiovascular outcomes, SGLT2 inhibitors reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular mortality by 10-30%, as shown in the EMPA-REG OUTCOME trial 1 and the CANVAS Program 1. These benefits are likely due to the mechanisms mentioned earlier, including reduced blood pressure, improved cardiac metabolism, decreased inflammation, and enhanced cardiac function.
Renal Protection
For renal protection, SGLT2 inhibitors slow kidney disease progression by reducing albuminuria, preserving glomerular filtration rate, and decreasing the risk of end-stage kidney disease by 30-40%, as demonstrated in the DAPA-CKD trial 1. This is achieved through reduced glomerular hyperfiltration, decreased inflammation, and improved tubular function.
Common SGLT2 Inhibitors
Common SGLT2 inhibitors include:
- Empagliflozin (10-25mg daily)
- Dapagliflozin (5-10mg daily)
- Canagliflozin (100-300mg daily)
These medications are particularly beneficial for diabetic patients with established cardiovascular disease, heart failure, or chronic kidney disease, as noted in 1 and 1. However, patients should be monitored for side effects, including genital infections, urinary tract infections, and volume depletion, especially when initiating therapy.
Key Points
- SGLT2 inhibitors offer significant cardiovascular and renal benefits beyond glycemic control.
- They reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular mortality.
- They slow kidney disease progression and decrease the risk of end-stage kidney disease.
- Common SGLT2 inhibitors include empagliflozin, dapagliflozin, and canagliflozin.
- Patients should be monitored for side effects, especially when initiating therapy, as recommended in 1 and 1.
From the FDA Drug Label
1 Mechanism of Action Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2 By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
1 Mechanism of Action SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT G), and thereby increases urinary glucose excretion (UGE)
The mechanism of action of SGLT2 inhibitors, such as empagliflozin 2 and canagliflozin 3, involves the inhibition of SGLT2 in the proximal renal tubules, which reduces the reabsorption of filtered glucose and increases urinary glucose excretion. This leads to a decrease in renal glucose reabsorption and an increase in glucose excretion, resulting in a lowering of blood glucose levels.
- Key effects:
- Reduction in renal glucose reabsorption
- Increase in urinary glucose excretion
- Lowering of blood glucose levels
- Main mechanism: Inhibition of SGLT2 in the proximal renal tubules.
From the Research
Mechanism of SGLT2 Inhibitors
- SGLT2 inhibitors work by blocking the reabsorption of glucose in the proximal convoluted tubules, resulting in increased glycosuria 4
- This mechanism is insulin-independent and not limited by the degree of insulin resistance or beta-cell dysfunction 4, 5
- SGLT2 inhibitors also have a natriuretic effect, leading to plasma volume contraction and decreases in systolic and diastolic blood pressures 6
Effects on Diabetes
- SGLT2 inhibitors lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus 7, 5
- They have comparable efficacy in HbA1c reduction as compared to metformin, sulfonylureas, and slightly better than gliptins 4
- SGLT2 inhibitors can be used at any stage of diabetes, along with a potential for use in type 1 diabetes 4
Renal Outcomes
- SGLT2 inhibitors reduce estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria 6
- They exert renal protection by suppressing inflammation and fibrosis 8
- SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control 5
Cardiovascular Outcomes
- SGLT2 inhibitors have been shown to reduce the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and heart failure hospitalizations 6
- They may have a beneficial effect on blood pressure and lipids 4
- The EMPA-REG OUTCOME trial reported a 14% reduction in the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin 6