Antihyperglycemic agents on the horizon

Issue: December 2012

ByJames R. Taylor, PharmD, CDE

The next novel class of agents for type 2 diabetes will likely be the sodium-glucose co-transporter type 2 inhibitors.

These drugs reduce the reabsorption of glucose through inhibition of renal sodium-glucose co-transporter (SGLT). SGLT type 2 (SGLT2) is responsible for mediating about 90% of renal glucose reabsorption in the S1 segment of the proximal convoluted tubule, and SGLT1 accounts for the other 10%. Thus, inhibition of SGLT2 will inhibit most renal glucose reabsorption, resulting in glucosuria. Some other aspects to this class of agents are that they do not require functioning beta cells to be effective, and they do not cause hypoglycemia.

There are six SGLT2s in phase 3 of development: dapagliflozin (Forxiga; Bristol-Myers Squibb); canagliflozin (Johnson & Johnson); empagliflozin (Boehringer Ingelheim); ipragliflozin (Astellas Pharma); luseogliflozin (Taisho Pharmaceutical); and tofogliflozin (Chugai Pharmaceutical Co.). There are several others in earlier stages of development. Currently, dapagliflozin has the most published clinical trials.

Evidence in the literature

This year in Diabetes Care, Ferrannini and researchers studied dapagliflozin in 474 treatment-naive patients with type 2 diabetes. There were several parallel groups in the study who received 2.5 mg, 5 mg or 10 mg daily of dapagliflozin or placebo. In one group, dapagliflozin decreased HbA1c by 0.58% to 0.89%. However, in those who had high baseline HbA1cs (between 10% and 12%), HbA1c was reduced by 2.66% and 2.88%.

James R. Taylor

In 2010, a study presented by Nauck and researchers at the European Association for the Study of Diabetes compared the addition of dapagliflozin or glipizide with metformin in about 800 uncontrolled patients. HbA1c decreased by an average of 0.52% in both groups after 1 year of treatment. During this time, weight decreased by 3.22 kg in the dapagliflozin group and increased by 1.44 kg in the glipizide group. Similar results were seen in other studies involving dapagliflozin with metformin or glimepiride (HbA1c reduction of 0.67% to 0.84% and 0.58% to 0.82%, respectively).

Studies of canagliflozin have demonstrated similar results. In one such study by Rosenstock and researchers, five different doses of canagliflozin were evaluated in 451 patients uncontrolled on metformin alone. After 12 weeks, HbA1c decreased, on average, by 0.7% to 0.95% with the addition of canagliflozin. Doses of 300 mg once or twice daily produced HbA1c reductions at the higher end of that range. Weight also decreased significantly in the canagliflozin group, as compared with placebo or sitagliptin (Januvia, Merck). There was also evidence of improvement in beta-cell function with canagliflozin.

Safety, tolerability tested

The SGLT2s appear to be generally well tolerated, although there are some concerns. In some studies, urinary tract infections (UTIs) appeared more often among those patients taking an SGLT2 inhibitor compared with a sulfonylurea or placebo, and it is possible that the increased glucosuria caused by SGLT2s provides a medium for better bacterial growth. In fact, 4.2% to 8.8% of patients receiving dapagliflozin experienced signs and symptoms of UTIs (higher rates associated with higher doses) compared with 6.4% of patients assigned to placebo or glipizide. There was no difference between the two groups in number of diagnosed UTIs.

Adverse renal effects are also of potential concern based on the mechanism of action of these drugs, although short-term data do not currently suggest any adverse renal effects. A small potential risk for developing bladder or breast cancer emerged in some of the trials, however. Today, there have been nearly 4,500 patients exposed to at least one dose of dapagliflozin and nearly 1,900 patient-years. Of these, there have been seven cases of bladder cancer in dapagliflozin-treated patients and none in the control groups. Breast cancer was detected in nine of 4,287 patients in dapagliflozin group (0.2%) vs. 0 of 1,941 control group patients.

In January 2012, the FDA requested additional clinical trial data to clarify any possible risk for bladder or breast cancer associated with SGLT2s. This information will be reviewed before any of these drugs reach the market.

It is too early to tell whether there are any clinically significant differences between the SGLT2s, and numerous phase 3 trials are ongoing at this time. However, Foote and researchers published a nice review summarizing effects of these agents on cardiovascular outcomes. Additionally, reductions in systolic blood pressure (up to 5 mm Hg) have been reported in some trials and are believed to be related to the chronic osmotic diuresis caused by the glycosuria. There does not appear to be any effect on lipids, and we do not have sufficient data on major vascular outcomes at this time.

Overall, the SGLT2s appear to offer some benefits and will likely be used as one of several second-line options available to us. However, long-term safety and efficacy data are needed to more precisely define their role.

References:

Ferrannini E. Diabetes Care. 2012;33:2217-2224.
Foote C. Diab Vasc Dis Res. 2012;9:117-123.
Nauck MA. 52-week phase 3 study found investigational drug dapagliflozin plus metformin similar to glipizide plus metformin in improving HbA1c in adults with type 2 diabetes (abstract). Presented at: 46th Annual Meeting of the European Association for the Study of Diabetes; Sept. 20-24, 2010; Stockholm.
Rosenstock J. Diabetes Care. 2012;35:1232-1238.
Strojeck K. 24-week phase 3 study found investigational drug dapagliflozin improved HbA1c when added to glimepiride in adults with type 2 diabetes mellitus (abstract). Presented at: 46th Annual Meeting of the European Association for the Study of Diabetes; Sept. 20-24, 2010; Stockholm.

For more information:

James R. Taylor, PharmD, CDE, is a clinical associate professor in the department of pharmacy practice at the University of Florida, Gainesville. He can be reached at University of Florida, College of Pharmacy, P.O. Box 100486, Gainesville, FL 32610-0486; email: jtaylor@cop.ufl.edu.