Canagliflozin, one of a new breed of drugs that have been approved for treatment of type 2 diabetes, may be especially effective without needing to be used in combination with the drug metformin, researchers led by the University of Dundee have found.
Three drugs, canagliflozin, dapagliflozin and empagliflozin, that inhibit sodium-glucose co-transporter-2 (SGLT2) have been approved for treatment of type 2 diabetes in the USA and Europe within the last two years.
SGLT2 is the protein that reabsorbs glucose filtered out of blood by the kidneys back into the bloodstream. If you inhibit that process, more glucose appears in the urine and less in the blood, which is beneficial for a diabetic.
AMP-activated Protein Kinase
Research led by Professor Grahame Hardie, of the University of Dundee, working in collaboration with colleagues at the University of Glasgow and McMaster University in Canada, has suggested that one of the drugs, canagliflozin, may be particularly effective in treatment of type 2 diabetes.
“We have found that canagliflozin not only inhibits SGLT2 but also activates the AMP-activated protein kinase (AMPK), a signalling pathway that we discovered in Dundee back in the 1980s,” said Professor Hardie. “Dapagliflozin and empagliflozin do not do this nearly so effectively.
The significance of this is that activation of AMPK is also one of the main mechanisms of action of metformin, which is already the front-line drug for treatment of type 2 diabetes and is prescribed to more than 100 million people worldwide.
Pharmaceutical companies are currently carrying out clinical trials to test the efficacy of combinations of SGLT2 inhibitors and metformin. Our results suggest that, in the case of canagliflozin, it may not be necessary to add metformin, because canagliflozin is already activating AMPK.”
SGLT2 inhibitors are derived from phloretin, a natural product found in apples and first isolated in 1863. However, phloretin itself has side effects that the new synthetic derivatives avoid.
Canagliflozin, marketed as Invokana or Sulisent, is a drug of the gliflozin class or subtype 2 sodium-glucose transport (SGLT-2) inhibitors used for the treatment of type 2 diabetes.
Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine, corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.
This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other types of antidiabetic drugs such as sulfonylurea derivatives and insulin.
As with all SGLT-2 inhibitors, canagliflozin is associated with increased incidence of urinary tract infections, fungal infections of the genital area, thirst, elevations in LDL cholesterol, increased urination and episodes of low blood pressure. There are concerns that it may also increase the risk of diabetic ketoacidosis.
On May 15, 2015, the FDA issued a warning that certain SGLT2 diabetes drugs, including canagliflozin, may lead to ketoacidosis, a condition where the body produces higher levels of blood acid. The FDA is continuing to investigate the issue, and cautions that patients should not stop taking canagliflozin without first talking to their doctor.
On December 4, 2015, the FDA issued another safety communication for SGLT2 inhibitors, indicating that it would require new warnings to be added to the canagliflozin label about elevated blood acid levels and urinary tract infections.
The research was funded by the Wellcome Trust and the British Heart Foundation.
Simon A. Hawley et al.
The Na/glucose co-transporter inhibitor canagliflozin activates AMP-activated protein kinase by inhibiting mitochondrial function and increasing cellular AMP levels
Diabetes (2016). DOI: 10.2337/db16-0058