SAN DIEGO – The investigational glucose-lowering agent dapagliflozin produced sustained glycemic efficacy and weight loss after 2 years in a phase III extension study of 624 patients with type 2 diabetes.
Genital and urinary tract infections were increased during the initial 52 weeks and through the 2-year extension. New data on cancers showed no overall excess, but there were increases in certain types of cancers, Dr. Michael A. Nauck reported in a late-breaking poster presentation at the annual scientific sessions of the American Diabetes Association.
Dr. Michael A. Nauck
Bristol-Myers Squibb and AstraZeneca’s dapagliflozin is a selective SGLT2 inhibitor that reduces hyperglycemia independently of insulin by promoting urinary glucose excretion. In the initial 52-week double-blind trial presented last fall at the meeting of the European Association for the Study of Diabetes, a total of 814 patients with type 2 diabetes who were inadequately controlled on metformin alone were randomized to up to 10 mg/day of dapagliflozin or up to 20 mg/day of glipizide as add-on therapy to 2,000 mg/day of metformin.
In both groups, there were identical mean reductions in hemoglobin A1c of 0.52 percentage points from a baseline mean of 7.72% (the primary end point of noninferiority). However, dapagliflozin was associated with a 3.2 kg mean weight loss, whereas the glipizide group gained an average of 1.4 kg. Hypoglycemia was also dramatically less with dapagliflozin than with glipizide, 3.5% vs. 40.8%, Dr. Nauck, head of the Diabetes Center, Bad Lauterberg, Germany, reported at EASD.
In the extension study, which was primarily aimed at assessing safety, patients continued to receive dapagliflozin (n = 315) or glipizide (n = 309) added to metformin. At the end of year 2, there was a 0.32 percentage point drop from baseline in HbA1c with dapagliflozin, compared with just 0.14 with glipizide. Body weight loss was also sustained, at 3.70 kg, compared with a gain of 1.36 kg with glipizide. Just as at 1 year, hypoglycemia was significantly lower at 2 years with dapagliflozin, 4.2%, compared with 45.8% with glipizide.
On active questioning, the proportion of patients who reported signs, symptoms, and events suggestive of urinary tract infection was 13.5% for dapagliflozin, compared with 9.1% for glipizide. And for signs, symptoms, and events suggesting genital infections, the difference was 14.8% vs. 2.9%, respectively. The difference was even greater for the women, with 23.3% reporting genital infection, compared with 5.9% with glipizide. However, most infections occurred during the first year, were mild to moderate in intensity, and responded to standard care. There was one discontinuation in each arm because of a UTI and three in the dapagliflozin arm because of genital infection in the first year. There were no discontinuations from either type of infection during the second year, Dr. Nauck reported.
In all dapagliflozin studies to date, there have been no imbalances in malignant tumors. However, there were increases in two specific tumor types. Nine bladder cancers occurred among 5,478 patients on dapagliflozin and in one of 3,156 patients in control groups. A total of 6 of these 10 had hematuria at baseline and 5 were diagnosed within a year after the study start. Nine breast cancers have also occurred in 2,223 women on dapagliflozin and one in 1,053 women in control groups. All were diagnosed within a year after study start.
In preclinical studies, dapagliflozin was not shown to be genotoxic or carcinogenic and the agent has no known off-target pharmacology. The SGLT2 receptor is not expressed in the breast or in the bladder, Dr. Nauck noted.
These clinical and preclinical data have been shared with the Food and Drug Administration and other health authorities and were reviewed fully at the scheduled Endocrinologic and Metabolic Drugs Advisory Committee on July 19. In a 9-6 vote, the committee recommended against approval, citing concerns about bladder and breast cancer incidence among treated patients in the clinical trial, compared with controls.
Dr. Nauck said that patients who are at risk for more urinary tract and genital infections from diabetes plus glycosuria would need to be defined, and that dapagliflozin should be preferentially used in those at low risk. "Attempts to define strata for low and high risk are urgently needed, because generally, infection rates up to more than 20% are hardly acceptable. It should be noted that, as with all novel diabetes medications, clinical studies aiming at a reduction in diabetic complications have yet to be started and are not currently available."
As for the tumor findings, "a numerical excess was found in dapagliflozin vs. comparator-treated patients regarding bladder and breast cancer. These findings, based on the small numbers and short follow-up do not prove a causal relationship, but warrant further studies to finally assess any risk concerning the promotion of tumor growth. Also, a true benefit needs to be shown in large-scale studies assessing clinical outcomes, because one needs to judge the benefits and risks in relation to each other."