Dapagliflozin, the experimental diabetes medication being developed by Bristol-Myers Squibb and AstraZeneca was found to raise the risk of both bladder and breast cancers. The data were presented at the American Diabetes Association Meeting in San Diego, Calif. at the end of June.
Of the 5,478 patients in the long-term clinical program, 9 breast cancers and 9 bladder cancers were detected, that compared to 1 breast and 1 bladder cancer in the 3,156 patients who were part of the control group. Although it is possible that the patients already had the cancer prior to the start of the trial, because dapagliflozin is the first insulin-independent mechanism for treatment of diabetes, careful and thorough study of its effects are warranted. Committee members also felt that not enough data exist on the drug’s effect on the kidneys, another potential long-term safety concern.
AstraZeneca and Bristol-Myers Squibb have maintained their stance that the cancers are not likely to be caused by the drug because of the relatively short duration of the trials, and it is likely that the patients had cancer before they took part in the clinical trial. Company officials said that in preclinical studies, mice did not have a higher cancer incidence on the drug
Following the data release, a Food and Drug Administration (FDA) advisory committee voted 9 to 6 that dapagliflozin should not be approved for use because of the cancer risk concerns. The FDA said that although there are attractive features of the agent, there are too many unknowns with this drug in terms of safety and prolonged patient use.
“While I really liked the concept, we just don’t have enough right now, in my opinion, to ensure safety and efficacy and how to use it,” stated David Capuzzi of Thomas Jefferson University, one of the committee members who was part of the majority vote.
Dapagliflozin is being developed for both type I and type II diabetes. It belongs to the sodium-glucose transport proteins (SGLT2) class of drugs. The SGLT2 proteins are responsible for at least 90% of the glucose reabsorbed in the kidney. Dapagliflozin works independent of insulin by inhibiting SGLT2 transporter proteins which causes blood glucose to be eliminated through the urine. This drug sends sugar out through the urine and may be associated with weight loss. Dapagliflozin may also have a diuretic and hypotensive effect which is currently under investigation in clinical trials.
Two late-breaking abstracts were presented at the ADA meeting on the efficacy and safety of the drug.
In a 2-year longer-term efficacy and safety trial of add-on dapagliflozin vs glipzide in patients who had inadequate control with metformin(Drug information on metformin) alone, dapagliflozin results in sustained reduced body weight and reduced hypoglycemia. Dapagliflozin was found to be noninferior to glipzide in reducing hemoglobin A1c (HbA1c) levels. A higher frequency of urinary tract infections and genital infections were seen with dapagliflozin as compared to glipzide but were generally mild to moderate, conducive to treatment, and rarely led to discontinuation.
A second study evaluated dapagliflozin in combination with metformin compared to monotherapy with either agent for 24 weeks in type II diabetes patients. The combination group was found to be significantly more effective in lowering HbA1c levels than monotherapy. Urinary tract infections and genital infections were higher in the combination and dapagliflozin montherapy groups.
"This agent causes a relatively high incidence of [urinary tract infections], but I think it is an interesting agent with a unique mechanism of action," said independent commentator Joel Zonszein, MD, a professor of clinical medicine at the Albert Einstein College of Medicine, during the meeting.
Despite the potential cancer risk and increase in infections, dapagliflozin is still seen as a potentially attractive alternative to diabetes drugs currently on the market. Its unique mechanism of action of affecting insulin supply may work better in combination with other drugs and its weight-loss effect are both positives. Several of the committee members stated that they could have voted either way and changed their minds numerous times throughout the committee meeting. Because the cancer incidence numbers are quite small, it is hard to draw a definitive conclusion just yet. The committee members who voted yes thought that it would be impossible to do a large enough study to rule out the cancer risk before approval. These 6 panelists believe that a post-marketing study of dapagliflozin use would provide the cancer-risk data.
The cancer concern is quite important in light of the evidence that taking the leading type II diabetes drug, Actos (pioglitazone), increases risk of bladder cancer. The drug has been recalled in France and Germany after studies demonstrated that Actos may increase the risk of bladder cancer. The FDA has issued a bladder cancer warning but Actos remains on the market in the United States as the FDA continues to review the safety data.
The FDA is not bound by the advice of the FDA advisory committee and will make a final decision on whether to approve the drug by October 28, 2011.