Best Evidence Analyses and Commentary

SGLT-2 Inhibitors Likely Coming to U.S. Market
Ketal Patel, PharmD Candidate; Marcus Campbell, PharmD, BC-ADM
03/13/13

Diabetes mellitus (DM) is highly prevalent in the United States. According to American Diabetes Association (ADA), 25.8 million children and adults in the United States have diabetes.1 There are multiple classes of oral agents that are used for glycemic control.  One of the newest classes is the SGLT-2 (sodium-glucose cotransporter-2) inhibitors. SGLT-2 inhibitors work by inhibiting the reabsorption of glucose from the kidney. SGLT-2 is located primarily in the S1 segment of the proximal tubule where 90% of the filtered glucose is reabsorbed.2 Investigational SGLT-2 inhibitors include dapagliflozin, canagliflozin, and empagliflozin.3

The safety and efficacy of dapagliflozin was evaluated in a randomized, double-blind, placebo-controlled, trial in treatment naïve patients with type II diabetes. 4 A total of 485 patients with HbA1C of 7-10% were randomized to once daily placebo or dapagliflozin 2.5, 5, or 10 mg administered either in the morning (primary cohort) or in the evening (exploratory cohort). The primary efficacy endpoint was the change in HbA1C at week 24. Secondary efficacy endpoints included change from baseline in FPG (fasting plasma glucose) and body weight at week 24. Reductions in HbA1C from baseline to week 24 in dapagliflozin 5mg and 10mg once in the morning groups were statistically significant (p=0.0005, p<0.0001) compared to placebo. Reduction in FPG from baseline to week 24 in dapagliflozin 5 mg and 10 mg once in the morning groups were also statistically significant (p<0.001, p<0.0001) compared to placebo.  All endpoints in the exploratory evening cohort were comparable with the primary cohort. There was an increase in incidence in signs and symptoms suggestive of UTIs and genital infections in dapagliflozin groups, although the increase was not significant.4

In a randomized, 52 week, double blind, active-controlled noninferiority trial, the efficacy, safety and tolerability of dapagliflozin was compared to glipizide in 814 patients with type 2 diabetes who were receiving metformin monotherapy. Patients included in the study had HbA1C between 6.5-10% and were on a stabilized metformin regimen. Patients were randomized in a 1:1 ratio and received either dapagliflozin or glipizide titrated to max dose or goal fasting plasma glucose. The primary end point was change in HbA1C from baseline to week 52 and  secondary end points included  change in body weight at week 52, incidences of hypoglycemia and proportion of patients with more than 5% decrease in body weight at week 52. Change in HbA1C from baseline to week 52 for dapagliflozin was non-inferior to that of glipizide (-0.52%, -0.52% respectively). Absolute mean difference in body weight was statistically significant favoring dapagliflozin group compared to glipizide group (p<0.0001). The proportion of patients experiencing at least one hypoglycemic episode by week 52 was >10 fold lower in dapagliflozin group compared to glipizide. 5 Dapagliflozin demonstrated noninferiority of glycemic control in patients not well controlled with metformin monotherapy with a favorable side effect profile.

Across 11 phase 2-3 clinical trials, concern of an association with dapagliflozin and breast and bladder cancers arose.  There were nine bladder cancers reported in the 5,478 patients on the drug compared with one case in 3,156 controls; and there have also been nine cases of breast cancer in 2,223 women on the drug compared with just one in 1,053 female controls.

Similar to dapagliflozin, canagliflozin (Johnson & Johnson) has also demonstrated efficacy in lowering HbA1c.  In a 26 week, randomized, double-blind, placebo-controlled, phase 3 trial, HbA1c was significantly reduced in canagliflozin 100 mg and 300 mg groups compared to placebo (p<0.001 for both). Canagliflozin also reduced FPG, 2-hr post-prandial glucose, body weight and systolic blood pressure significantly (p<0.001) and increased HDL-C compared to placebo (p<0.01).6  

On Jan 09 2013, An FDA advisory panel expressed concerns about potential cardiovascular and bone-related safety risks with canagliflozin but still voted 10 to 5 to recommend approval.  The FDA is expected to make a decision in March, and is not mandated to follow the recommendation of its advisory panel. However, they did follow recommendations of the panel when approval of dapagliflozin was declined in January secondary to the concerns of cancer.  Another novel SGLT-2 inhibitor, empagliflozin, is also being investigated by Boehringer Ingelheim and Eli Lilly and the companies are seeking to file for new drug application this year.7,8 SGLT-2 inhibitors represents a promising novel therapeutic option for the treatment of type 2 diabetes. 

References

1.  Diabetes Statistics. American Diabetes Association. Cited on Jan 16, 2013.

2.   Songping H, Hagan D, Taylor J, Xin L, Meng W et al. Dapagliflozin, a Selective SGLT2 Inhibitor, Improves Glucose Homeostasis in Normal and Diabetic Rats. Diabetes. 57:1723-1729. 2008.

3.   Bhartia M, Tahrani A, and Barnett A. SGLT-2 Inhibitors in Development for Type 2 Diabetes Treatment. The Review of Diabetic Studies. 8(3):348-354. 2011.

4.   Ferranninni E, Ramos S, Salsali A, Tang W and List J. Dapagliflozin Monotherapy in Type 2 Diabetic Patients with Inadequate Glycemic Control by Diet and Exercise. Diabetes Care. 33:2217-2224. 2010.

5.   Nauck M, Prato S, Meier J, Duran-Garcia S, Rohwedder K et al. Dapagliflozin Versus Glipizide as Add-on Therapy in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin. A Randomized, 52-week, double blind, active-controlled non-inferiority trial. Diabetes Care. 34:2015-2022. 2011. 

6.  Stenlöf K, Cefalu WT, Kim KA, Alba M, and Usiskin K, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. Dec 26, 2012.  

7.  Canagliflozin. Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Food and Drug Administration. Center for Drug and Evaluation and Research. Jan 10, 2013.

8.  Dapagliflozin. Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Food and Drug Administration. Center for Drug and Evaluation and Research. Jul 19, 2011.

 

 


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