The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar.
Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes.
[8] A meta-analysis including 13 cardiovascular outcome trials found that SGLT-2 inhibitors reduce the risk for three-point major adverse cardiovascular events (MACE), especially in subjects with an estimated glomerular filtration rate (eGFR) below 60 ml/min, whereas GLP-1 receptor agonists were more beneficial in persons with higher eGFR.
[9] Likewise, the risk reduction due to SGLT-2 inhibitors was larger in populations with a higher proportion of albuminuria, but this relationship was not observed for GLP-1 receptor agonists.
This suggests a differential use of the two substance classes in patients with preserved and reduced renal function or with and without diabetic nephropathy, respectively.
[9] Two reviews have concluded that SGLT2 inhibitors benefit patients with atherosclerotic major adverse cardiovascular events.
[citation needed] In May 2015, the FDA issued a warning that gliflozins can increase risk of diabetic ketoacidosis (DKA, a serious condition in which the body produces high levels of blood acids called ketones).
SGLT2 inhibitors may need to be discontinued before surgery, and only recommended when someone is not unwell, is adequately hydrated and able to consume a regular diet.
[14] Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.
Using gliflozins in combination therapy with metformin can lower the risk of hypoglycemia compared to other type 2 diabetes treatments such as sulfonylureas and insulin.
[16] A European Medicines Agency review concluded that there is a potential increased risk of lower limb amputation (mostly affecting the toes) in people taking canagliflozin, dapagliflozin and empagliflozin.
[17] In August 2018, the FDA issued a warning of an increased risk of Fournier gangrene in patients using SGLT2 inhibitors.
However, it has been shown that binding of different sugars to the glucose site affects the orientation of the aglycone in the access vestibule.
It acts via selective and potent inhibition of SGLT-2, and its activity is based on each patient's underlying blood sugar control and kidney function.
Therefore, dapagliflozin reduces the blood glucose concentration with a mechanism that is independent of insulin secretion and sensitivity, unlike many other antidiabetic medications.
[41][42] Sodium and glucose are co-transported by the SGLT-2 protein into the tubular epithelial cells across the brush-border membrane of the proximal convoluted tubule.
The elimination half-life, bioavailability, protein binding, the blood concentration Cmax at time tmax, and other pharmacokinetic parameters of various medications of this class are present in table 2.
[53] However phlorizin is very unstable, it is rapidly degraded by glucosidases in the small intestines, so it can not be used as an oral administration medication to treat diabetes.