FDA Approves Novel Combination Pill for Type 2 Diabetes

Miriam E. Tucker
Medscape Medical News

The US Food and Drug Administration has approved the empagliflozin/linagliptin combination Glyxambi (Boehringer Ingelheim/Eli Lilly) as adjunctive treatment to diet and exercise for adults with type 2 diabetes.

The once-daily tablet is the first in the United States to combine a sodium glucose cotransporter 2 (SGLT2) inhibitor (empagliflozin) with a dipeptidyl peptidase-4 (DPP-4) inhibitor (linagliptin). The tablets contain 10 or 25 mg of empagliflozin and 5 mg of linagliptin.

A Boehringer Ingelheim representative told Medscape Medical News that the company "is in active discussions with various insurance companies about formulary coverage and is seeking for Glyxambi to be reimbursed at a copay level similar to other preferred branded products."

The product is not indicated for type 1 diabetes or those with pancreatitis.

The FDA approval was based on a phase 3 clinical trial comparing the combination of empagliflozin/linagliptin at both the 10/5 mg and 25/5 mg doses to the individual doses of both drugs. The study randomized 686 adults with type 2 diabetes who had baseline hemoglobin A1c (HbA1c) levels between 7.0% and 10.5% despite taking high-dose metformin (mean daily dose 1889 mg).

Complementary Mechanisms of Action?

The phase 3 data were published online January 12, 2015 in Diabetes Care by Ralph A DeFronzo, MD of the University of Texas Health Science Center, San Antonio, and colleagues.

"Empagliflozin/linagliptin as add-on to metformin provided greater glucose-lowering efficacy than the individual components, with a low risk of hypoglycemia. Empagliflozin/linagliptin was well tolerated, with safety profiles similar to the known safety profiles of empagliflozin and linagliptin," they say.

"These results suggest that immediate use of triple therapy in patients who have failed on metformin may provide advantages over the traditional staggered treatment approach," they add.

Dr DeFronzo has long been an advocate of so-called "triple therapy" and has previously trialed the novel approach of starting newly diagnosed patients with type 2 diabetes on three therapeutic agents simultaneously, claiming it can result in greater and more durable reductions in HbA1c, less hypoglycemia, and less weight gain compared with conventional, stepwise add-on treatment.

Indeed, there is some suggestion from another trial that the complementary mechanisms of action of SGLT2 inhibitors and DPP-4 inhibitors may offer these benefits. When given as initial therapy, empagliflozin and linagliptin in combination was associated with a low risk of hypoglycemia in another recently published phase 2 study, and there was no weight gain with the combination.

Phase 3 Trial Results

The results of the phase 3 trial showed that, at 24 weeks, those receiving empagliflozin/linagliptin achieved mean HbA1c levels of 6.9% with the 10/5 mg dose and 6.7% with the 25/5 mg dose, compared with 7.3% and 7.4% with empagliflozin 10 and 25 mg, respectively, and 7.3% with linagliptin 5 mg.

The proportions of patients who achieved HbA1c values less than 7% were 58% with the 10/5 mg combination dose and 62% with the 25/5 mg combination dose, compared with 28%, 33%, and 36% for empagliflozin 10 mg, empagliflozin 25 mg, and linagliptin 5 mg, respectively.

Patients taking the combination also loss slightly more than 3% of their body weight.

At 52 weeks, urinary tract infections (UTI) occurred in 12.5% of patients with the lower dose of empagliflozin and 11.4% with the higher dose, but no patients discontinued because of a UTI. Other common adverse events included nasopharyngitis (5.9% and 6.6%, respectively) and upper respiratory tract infection (7.0% for both doses).

However, study limitations "include the lack of a placebo arm, which means that the additive efficacy of empagliflozin/linagliptin compared with the individual components cannot be conclusively assessed, although only small changes from baseline in HbA1c with placebo would be expected," Dr DeFronzo and colleagues conclude.

The study was funded by Boehringer Ingelheim and Eli Lilly. Dr DeFronzo has served on scientific advisory boards for Boehringer Ingelheim, AstraZeneca, Janssen, Novo Nordisk, Takeda, and Lexicon; participated in speakers' bureaus for AstraZeneca and Novo Nordisk; and received grants/research support from AstraZeneca, Janssen, Bristol-Myers Squibb, Takeda, and Xeris Pharmaceuticals. Several coauthors are employees of Boehringer Ingelheim.

SOURCES:

FDA Approves Novel Combination Pill for Type 2 Diabetes. Medscape. Feb 02, 2015.

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