Gliflozin drugs are a class of pharmaceuticals that inhibit renal glucose reabsorption and therefore lower blood glucose. They act by inhibiting sodium-glucose transport protein 2 (SGLT2), and are therefore also called SGLT2 inhibitors. Gliflozins are used in the treatment of type II diabetes. As studied on canagliflozin, a member of this class, gliflozins enhance glycemic control as well as reduce body weight and systolic and diastolic blood pressure.
Discovery and development
Phlorizin is a molecule with SGLT inhibiting properties, and served an important role in the development of the gliflozin class of drugs.
- Dapagliflozin, the first SGLT2 inhibitor approved anywhere in the world in 2011 by the EU. It was approved for use in the United States under the brand name "Farxiga" by the Food and Drug Administration in 2014.
- Canagliflozin, was the first SGLT2 inhibitor to be approved for use in the United States and Canada under the brand name "Invokana" and is also marketed throughout the EU under the same name 
- Ipragliflozin (ASP-1941), produced by the Japanese company Astellas Pharma Inc. under the brand name "Suglat"; approved in Japan January 17, 2014.
- Tofogliflozin, approved in Japan under the brand names "Apleway" and "Deberza" by Sanofi and Takeda Pharmaceutical
- Empagliflozin, approved in the United States under the brand name "Jardiance".
- Sergliflozin etabonate, discontinued after Phase II trials
- Remogliflozin etabonate(BHV091009), in phase IIb trials by BHV Pharma. BHV (Brighthaven Ventures, LLC) is a private company acquired by Islet Sciences, Inc. in 2014.
- Ertugliflozin (PF-04971729 / MK-8835), in phase III trials
Mechanism of action
SGLTs are responsible for mediating glucose reabsorption in the kidneys, as well as in the gut and the heart. SGLT-2 is primarily expressed in the kidney on the epithelial cells lining the S1 segment of the proximal convoluted tubule. It is the major transport protein that promotes reabsorption from the glomerular filtration glucose back into circulation and is responsible for approximately 90% of renal glucose reabsorption. By inhibiting SGLT-2 it prevents renal reuptake from the glomerular filtrate and subsequently lowers the glucose level in the blood and promotes glucosuria.
Dapagliflozin is an example of SGLT-2 inhibitor, it is a competitive, highly selective inhibitor of SGLT. It acts via selective and potent inhibition of SGLT-2, and its activity is based on each patient’s underlying glycemic control and renal function. The results are decreased renal reabsorption of glucose, glucosuria effect increases with higher level of glucose in the blood circulation. Thereby dapagliflozin reduces the blood glucose concentration with a mechanism that is independent of insulin secretion and sensitivity, unlike many other antidiabetic drugs. Functional β-cells are not necessary for the activity of the drug so it is convenient for patients with diminished β-cell function.
Sodium and glucose is co-transported by the SGLT-2 protein into the tubular epithelial cells across the brush-border membrane of the proximal renal tubule. This happens because of the sodium gradient between the tubule and the cell, thereby it provides a secondary active transport of glucose. Glucose is later reabsorbed by passive transfer of endothelial cells into the interstitial glucose transporter protein.
|Drug||Bioavailability (%)||tmax (hours)||Protein Binding (%)||t1/2|
|Canagliflozin||65||1-2||99||100 mg = 10.6 hours, 300 mg = 13.1 hours|
|Dapagliflozin||78||1-2||91||10 mg = 12.9 hours|
|Empagliflozin||85||1.5||86.2||10 mg = 12.4|
tmax: Time to achieve maximum plasma concentration t1/2: Elimination half-life
In studies that were made on healthy people and people with diabetes type 2, who were given dapagliflozin in either single ascending dose (SAD) or multiple ascending dose (MAD) showed results that confirmed a pharmacokinetic profile of the drug. With dose-dependent concentrations the half-life is about 12–13 hours, Tmax 1–2 hours and it is protein-bounded, so the drug has a rapid absorption and minimal renal excretion.
Dapagliflozin disposition is not evidently affected by BMI or body weight, therefore the pharmacokinetic findings are expected to be applicable to patients with a higher BMI. Dapagliflozin resulted in dose-dependent increases excretions in urinary glucose, up to 47g/d following single-dose administration, which can be expected from its mechanism of action, dapagliflozin.
In some long term clinical studies that have been made on dapagliflozin, dapagliflozin was associated with a decrease in body weight which was statistically superior compared to placebo or other active comparators. It is primarily associated with caloric rather than fluid loss.
In May 2015, Food and Drug Administration issued a warning that the gliflozins canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis. Other side effects of gliflozins include increased risk of (generally mild) urinary tract infections, candidal vulvovaginitis and hypoglycemia.
Interactions are very important for SGLT2 inhibitors because most T2DM patients are taking many other medications. There is low risk of clinically relevant pharmacokinetics drug drug interactions because of the metabolic pathway of SGLT2. According to Bhartia and his co-workers, it is safe to consume dapagliflozin along with pioglitazone, metformin, glimepiride, or sitagliptin and dose adjustment is unnecessary for either drug. It is unlikely that food intake has clinical meaningful impact on the efficacy of dapagliflozin, therefore it can be administered without regard to meals.
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