New therapeutic option for diabetes

A new drug for type 2 diabetes—dapagliflozin—acts independently of insulin, improves blood sugar control, and lowers bodyweight, according to a paper published in The Lancet.

The drug could offer a new therapeutic option for diabetes patients who have inadequate blood sugar control with the first line drug, metformin.

The paper, written by Professor Clifford Bailey of Aston University, Birmingham (UK) and colleagues, has been published in the journal’s special issue on the American Diabetes Association meeting held recently.

Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. It works by preventing reabsorption of glucose in the kidneys and promoting excretion of glucose in the urine.

Thus, the drug reduces high levels of blood glucose (hyperglycaemia) without affecting insulin-dependent systems. Since many complications of diabetes are related to high concentrations of blood glucose, directly lowering blood glucose is a legitimate target for new drugs for diabetes.

In the study, the authors assessed the efficacy and safety of dapagliflozin in patients not managing to control their blood sugar with the first-line treatment of metformin.

This phase 3 randomised controlled trial assessed 546 adult patients with diabetes, who were receiving daily metformin, yet had inadequate blood sugar control. 

Patients were randomly assigned to one of three doses of dapagliflozin or placebo orally once daily (2.5mg 137 patients, 5mg 137 patients, 10mg 135 patients, placebo 137 patients). 

All patients continued to receive metformin at their pre-study doses. The primary outcome was improvement in blood sugar control measured by haemoglobin A1c (HbA1c) levels at 24 weeks.

A total of 534 patients were included in the final analysis (dapagliflozin 2.5mg 135 patients; 5mg 133; 10mg 132; placebo 134). 

Mean HbA1c decreased by 0.3% in the placebo group, compared with 0.67% in the 2.5mg group, 0.70% in the 5mg group and 0.84% in the 10mg group. 

Hypoglycaemia (abnormally low blood sugar) was reported at similar frequency in both groups. Symptoms of genital infections were more common in the dapagliflozin groups (between 8% and 13%) compared with placebo (5%).

This is likely to reflect the extra glucose that is eliminated in the urine. Serious adverse events were rare and occurred at similar rates in all four groups.

Mean bodyweight loss was 0.9kg per person in the placebo group, compared with 2.2kg in the dapagliflozin 2.5mg group, 3.0kg in the 5mg group, and 2.9kg in the 10mg group.

Although bodyweight loss would be expected due to the mechanism of action of dapagliflozin (a mild diuretic effect), continuing weight reduction plus reduced waist circumference over the course of the study suggested patients were losing fat as well as water.

“This trial shows that dapagliflozin can improve blood glucose control in patients who have inadequate control with metformin. The drug acts independently of insulin, lowers weight, and is not associated with risk of hypoglycaemia. Safety and tolerability of the drug were also confirmed.

Therefore, addition of dapagliflozin to metformin provides a new therapeutic option for treatment of type 2 diabetes,” the authors say.

In an accompanying comment, Markolf Hanefeld of the Centre for Clinical Studies at Dresden (Germany) and Thomas Forst of The Institute for Clinical Research and Development in Mainz (Germany), say: “The net balance of this novel group of oral antidiabetic drugs looks promising…because of the role of glucotoxicity in the pathophysiology of type 2 diabetes, and in view of weight loss and low risk of hypoglycaemia, SGLT2 inhibitors in the future might also be considered for treatment of early-stage and late-stage type 2 diabetes.”