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Dual Combination Therapy for Type 2 Diabetes
San Diego—Centers for Disease Control and Prevention data show that type 2 diabetes is a significant problem in the United States. Nearly 29 million Americans age 20 years or older have diabetes with the majority having type 2 diabetes. Diabetes pathophysiology is characterized by 8 core defects, including insulin resistance in the liver and muscle tissue. Additional factors, independent of insulin, also contribute to diabetes pathology, such as increased renal glucose absorption. Nearly half of patients with diabetes are not at the American Diabetes Association’s recommended target hemoglobin A1c (HbA1c) of <7.0%.
“[Type 2 diabetes is] not an easy condition to treat and [we] have no idea what causes it,” said Steven V. Edelman, MD, director, Diabetes Care Clinic VA Medical Center San Diego, at the AMCP meeting during a science and innovation theater covering the recent FDA approval of empagliflozin/linagliptin. Boehringer Ingelheim Pharmaceuticals, Inc. sponsored the event.
Empagliflozin/linagliptin is a sodium-glucose cotransporter-2 (SGLT-2) and dipeptidyl peptidase-4 (DPP-4) inhibitor combination product approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate. It is the first-in-class medication that simultaneously inhibits both SGLT-2 and DPP-4 in a once-daily tablet. The recommended dose is 10 mg empagliflozin/5 mg linagliptin. In patients tolerating the medicine, the dose may be increased to 25 mg empagliflozin/ 5 mg linagliptin once daily. Both doses are taken orally once daily with or with- out food. No dose adjustment is needed in patients with an estimated glomerular filtration rate ≥45 mL/min/1.73 m2, when co-administered with commonly prescribed medicinal products, and in patients with type 2 diabetes who also have hepatic impairment.
Add-On Therapy
Clinical findings showed that empagliflozin/linagliptin demonstrated superior HbA1c reductions and significant reductions in body weight versus the individual components in patients inadequately controlled on metformin, according to the study findings Dr. Edelman presented. He noted that empagliflozin/linagliptin is not indicated for weight loss.
A total of 686 patients with type 2 diabetes participated in a 52-week, phase 3 study to evaluate the safety and efficacy of empagliflozin/linagliptin. Patients inadequately controlled on at least 1500 mg of metformin per day entered a single- blind, placebo run-in period for 2 weeks, followed by assessment of eligibility. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized 1:1:1:1:1 to 1 of 5 active-treatment arms of empagliflozin/ linagliptin 10/5 mg, empagliflozin/linagliptin 25/5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or linagliptin 5 mg. The primary end point was HbA1c change from baseline after 24 weeks of treatment compared to the individual components. The key secondary end points were change from baseline in body weight with the combination compared to linagliptin and percentage of patients who achieved HbA1c <7%.
At week 24, there was significant improvement in adjusted mean HbA1c with both doses of empagliflozin/linagliptin compared to the individual components (P<0.0001). For patients receiving empagliflozin/linagliptin 10/5 mg, the mean HbA1c was reduced from a baseline of 8.0% to 6.9%, amounting to an adjusted mean reduction of 1.1%. For patients receiving empagliflozin/linagliptin 25/5 mg, the mean HbA1c was reduced from a baseline of 7.9% to 6.7%, amounting to an adjusted mean reduction of 1.2%. In comparison, the mean HbA1c was reduced from a baseline of 8.0% to 7.4%, 7.3%, and 7.3% in patients receiving empagliflozin 10 mg, empagliflozin 25 mg, and linagliptin 5 mg, respectively. This amounted to an adjusted mean reduction of 0.7%, 0.7%, and 0.6%, respectively. In a modified intent-to-treat analysis, mean HbA1c achieved with empagliflozin/linagliptin 10/5 mg was 6.9%; empagliflozin/linagliptin 25/5 mg, 6.7%; empagliflozin 10 mg, 7.3%; empagliflozin 25 mg, 7.4%; and linagliptin 5 mg, 7.3%.
In addition to lowering HbA1c, both doses of empagliflozin/linagliptin provided a significant reduction in body weight compared to linagliptin 5 mg (P<0.0001). An adjusted mean change of −3.1%, or 5.9 pounds, from a baseline of 191 pounds was observed in patients receiving empagliflozin/linagliptin 10/5 mg. An adjusted mean change of −3.4%, or 6.4 pounds, from a baseline of 187 pounds was observed in patients receiv- ing empagliflozin/linagliptin 25/5 mg. In comparison, there was an adjusted mean change of −0.7%, or 1.3 pounds, from a baseline of 187 pounds in patients receiving linagliptin 5 mg. An adjusted mean change of −3.0%, or 5.7 pounds, was observed with em- pagliflozin 10 mg, and a reduction of −3.5%, or 6.8 pounds, was observed with empagliflozin 25 mg.
Adverse Reactions
Adverse reactions reported in ≥5% of patients treated with empagliflozin/linagliptin 10/5 mg and 25/5 mg included urinary tract infection (UTI; 12.5% and 11.4%, respectively), nasopharyngitis (5.9% and 6.6%, respectively, and up- per respiratory infection (7% for both doses). Through 52 weeks, there were no discontinuations of empagliflozin/ linagliptin due to UTI. The overall incidence of hypoglycemia was <4% through 52 weeks with empagliflozin/ linagliptin 10/5 mg and 25.5 mg; and no reported cases of severe hypoglycemia. He noted that the use of a low-dose insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with empagliflozin/linagliptin.
For empagliflozin/linagliptin Important Safety Information, please visit www.glyxambi.com.—Eileen Koutnik- Fotopoulos
