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ADA 2013: Empagliflozin Update

Boehringer Ingelheim Pharmaceuticals, Inc., and Eli Lilly and Company are working together to pave a new pathway for type 2 diabetes patients with the sodium glucose co-transporter 2 (SGLT2) inhibitor, empagliflozin. The investigational agent is currently in Phase III clinical trials focusing on four pivotal trials that have concluded with promising results. There are approximately 25.8 million Americans and 371 million people worldwide who have either type 1 or type 2 diabetes, with the latter accounting for around 90 to 95 percent of all diabetes cases. The estimated cost in the U.S. for diabetes in 2012 was $245 billion….

SGLT2 inhibitors’ perceived mechanism of action is to block the glucose that is reabsorbed by the proximal tubules in the kidneys and excrete the excess glucose through the urine. Thus SGLT2 inhibitors are lowering blood glucose without causing significant hypoglycemia. Canagliflozin was the first drug of this class to gain FDA approval along with diet and exercise in March. Empagliflozin is going through phase III clinical trials, in a program that has enrolled more than 14,500 patients. The program involves more than 10 multinational clinical trials, and it will also include a large cardiovascular outcomes trial.

During the phase III clinical trials, empagliflozin was tested alone, in combination with metformin alone, with metformin and a sulfonyurea, and then compared to placebo for a duration of 24 weeks. Monotherapy showed reductions in the HbA1c by 0.62 percent and 0.68 percent for the 10mg and 25mg doses, respectively. Fasting plasma glucose levels decreased by as much as 30.6 mg/dL and a loss of 4.43 pounds was noted when taking the 25mg dose compared to placebo. Reductions in the systolic, diastolic, and uric acid levels were observed as well. In addition, there was a slight increase in LDLs but a decrease in triglycerides, and an increase in HDLs.

Empagliflozin given with metformin and a sulfonyurea showed a better reduction in the HbA1c when it was given as a 10mg dose (0.64 percent). When given with metformin alone it was better as a 25mg dose (0.64 percent). The 25mg dose of empagliflozin with metformin resulted in a greater weight loss (4.4lbs) when compared to metformin. Fasting plasma glucose decreased by as much as 13.06mg/dL in the higher dose of empagliflozin given in combination with metformin and a sulfonyurea.

During a 78 week, randomized, double-blind, placebo-controlled trial, empagliflozin was investigated as an add-on compound in adults with T2D on basal insulin. The basal insulin doses remained constant for the first 18 weeks. At 18 weeks, the placebo-adjusted reductions in HbA1c reached 0.7 percent in the 25mg dose. After the 18 weeks, the dose was adjusted at the investigators’ discretion. At week 78, the change in required daily insulin dose was decreased by 6.7 International Units IU for the 10 mg dose of empagliflozin. The lower dose proved to be more effective than the 25mg which decreased the basal insulin by 6.0 IU.

Empagliflozin was analyzed with patients who suffer from renal impairment. The patients with mild renal impairment received empagliflozin 10mg, empagliflozin 25mg or placebo. A 25mg dose of empagliflozin and placebo was given to the moderate or severe renal impairment patients. At week twenty-four, the reduction in HbA1c was highest in the 25mg dose for the patients with mild renal impairment, reducing the total by 0.68 percent. Fasting blood glucose decreased by 18.08 percent, weight loss of 5.14 lbs, and improvements in the systolic/diastolic blood pressure were observed as the most effective in the 25 mg dose of empagliflozin. Fifty-two weeks into the study, 41.2 percent of the empaglifozin 25 mg group reported drug related adverse events compared to the 32.6 in the placebo group. The observed adverse effects included: hypoglycemia, urinary tract infection, genital infection, volume depletion, and events consistent with bone fracture.

The most common adverse effects associated with sodium glucose co-transporter inhibitors are Urinary Tract Infections (UTIs) and Genital infections. Investigators analyzed the data pooled from the four pivotal phase III trials to evaluate the occurrence rates of the two. Compared to placebo, the incidence of UTIs is almost insignificant. The 10 mg dose of empagliflozin had the highest incidence of UTIs being 9.3 percent vs. 8.2 percent for placebo. There is only a 1.1 percent difference between the two. The 25mg dose only having a 7.5 percent occurrence rate shows how insignificant the UTIs actually are. Of the urinary tract infections that occurred, most were mild in intensity. However, the incidences of genital infections were higher than that of the placebo group. The 10mg dose group had an increase of 4.2 percent compared to the 0.7 percent increase seen by the placebo group. Most of the genital infections, however, were considered mild cases (2.9 percent).

Empagliflozin may not be the most effective monotherapy for patients with uncontrolled diabetes but the decreased report of urinary tract infections could make it a favorable choice over the other SGLT2-I, canagliflozin. The long-term effects of this class of drugs on the urinary tract remain to be seen.

References:

American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013; 36(4):1033-1046.

Barnett AH, et al. Empagliflozin in Patients with Type 2 Diabetes (T2DM) and Renal Impairment (RI). Poster No: 1104-P. Presented at the American Diabetes Association (ADA) 73rd Scientific Sessions®. June 21-25, Chicago, IL.

Hach T, et al. Empagliflozin Improves Glycemic Parameters and Cardiovascular Risk Factors in Patients with Type 2 Diabetes (T2DM): Pooled Data from Four Pivotal Phase III Trials. Poster No. 69-LB. Presented at the American Diabetes Association 73rd Scientific Sessions®. June 21-25, Chicago, IL

Häring H, et al. Empagliflozin as Add-On to Metformin Plus Sulfonylurea (SU) for 24 Weeks Improves Glycemic Control in Patients with Type 2 diabetes (T2DM). Poster No: 1082-P. Presented at the American Diabetes Association (ADA) 73rd Scientific Sessions®. June 21-25, Chicago, IL.

Häring H, et al. Empagliflozin as Add-On to Metformin for 24 Weeks Improves Glycemic Control in Patients with Type 2 diabetes (T2DM). Poster No: 1092-P. Presented at the American Diabetes Association (ADA) 73rd Scientific Sessions®. June 21-25, Chicago, IL.

International Diabetes Federation. Diabetes Atlas, 5th Edition: What is Diabetes? http://www.idf.org/diabetesatlas/5e/what-is-diabetes. Accessed on: June 18, 2013

Kim G, et al. Empagliflozin (EMPA) Increases Genital Infections but Not Urinary Tract Infections (UTIs) in Pooled Data from Four Pivotal Phase III Trials. Poster No. 74-LB. Presented at the American Diabetes Association 73rd Scientific Sessions®. June 21-25, Chicago, IL.

Roden M, et al. Empagliflozin Monotherapy Improves Glucose Control in Drug-Naïve Patients with Type 2 Diabetes (T2DM). Poster No: 1085-P. Presented at the American Diabetes Association (ADA) 73rd Scientific Sessions®. June 21-25, Chicago, IL.

Rosenstock J, et al. Empagliflozin as Add-On to Basal Insulin for 78 Weeks Improves Glycemic Control with Weight Loss in Insulin-Treated Type 2 Diabetes (T2DM). Poster No: 1102-P. Presented at the American Diabetes Association (ADA) 73rd Scientific Sessions®. June 21-25, Chicago, IL.

Compiled by:
 
David Joffe, BSPharm, CDE, Editor
Kori M. Lawie, Doctor of Pharmacy Candidate, FAMU

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