FDA Approves Saxagliptin/Metformin Combo Pill for Type 2 Diabetes

The US Food and Drug Administration (FDA) has approved the first and only once-daily combination tablet featuring saxagliptin and extended-release (XR) metformin HCl (Kombiglyze XR; Bristol-Myers Squibb Co and AstraZeneca) to improve glycemic control in adults with type 2 diabetes mellitus.

The product represents a new treatment alternative for the nearly 50% of adult patients whose diabetes remains uncontrolled on their current regimen and offers a simplicity that may also enhance therapeutic compliance.

“Patients with type 2 diabetes in the United States can be taking four or five medications for various diseases and conditions, which can lead to complicated medication schedules,” said Howard Hutchinson, MD, AstraZeneca’s chief medical officer, in a company news release. “Kombiglyze XR combines two effective diabetes medications in a simple once-a-day dose for adult patients who need A1c reductions.”

By incorporating the complimentary mechanisms of a dipeptidyl peptidase 4 inhibitor (saxagliptin) and a biguanide (metformin), the combination therapy addresses all 3 key defects in type 2 diabetes: It increases insulin secretion in a glucose-dependent manner, suppresses hepatic gluconeogenesis, and improves insulin sensitivity.

“Type 2 diabetes is a chronic, progressive and multi-factorial disease, and over time, patients often require more than one medication to address the multiple defects associated with the disease,” said Matthew Mintz, MD, FACP, from the George Washington University School of Medicine, Washington, DC, in the news release. “Kombiglyze XR now provides patients with the first once-a-day [dipeptidyl peptidase 4] inhibitor and metformin XR combination tablet containing two complementary therapies that can improve key measures of glucose control including glycosylated hemoglobin levels, fasting plasma glucose and postprandial glucose, in a convenient once-a-day treatment regimen.”

Clinical Data

FDA approval was based primarily on data from 2 randomized, double-blind, 24-week, phase 3 clinical trials (n = 1306 and 743, respectively) of saxagliptin and metformin immediate-release (IR), administered as separate tablets, compared with metformin IR alone.

Results from the study of treatment-naive adults showed that use of saxagliptin 5 mg and metformin IR significantly decreased mean hemoglobin A1c levels from baseline compared with metformin IR alone (−2.5% vs −2.0%; P < .0001), significantly increasing the proportion of patients achieving A1c levels below 7% (60% vs 41%; P < .05). Statistically significant reductions in mean fasting plasma glucose and 2-hour postprandial glucose levels were also observed (−60 mg/dL vs −47 mg/dL [P < .05] and −138 mg/dL vs −97 mg/dL [P < .05], respectively).

Similarly, the addition of saxagliptin 2.5 mg and 5 mg to metformin IR among adults inadequately controlled on metformin alone significantly decreased mean A1c levels from baseline by 0.6% and 0.7%, respectively, compared with an increase of 0.1% with metformin alone (P < .0001 for both); both doses significantly increased the proportion of patients with A1c levels below 7% (37% and 44% vs 17%; P < .05 for both comparisons). Statistically significant reductions in fasting plasma glucose and 2-hour postprandial glucose levels were likewise observed (−14 mg/dL and −22 mg/dL vs +1 mg/dL [P < .05]; −62 mg/dL and −58 mg/dL vs −18 mg/dL [P < .05], respectively).

No clinical efficacy or safety study has been conducted specifically with saxagliptin and metformin XR. According to the FDA, metformin XR and IR tablets have a similar rate of absorption (as measured by area under the curve), whereas peak plasma levels of metformin XR are about 20% lower than those of the IR tablets at the same dose.

Data from a double-blind, randomized 24-week study suggest that patients receiving metformin IR therapy may safely be switched to metformin XR once-daily at the same total dose, up to 2000 mg once daily. Glycemic control should be closely managed after the switch, and dosage adjustments made accordingly.

Saxagliptin/metformin XR is available in 5 mg/500 mg, 5 mg/1000 mg, and 2.5 mg/1000 mg strengths. The starting dose should be individualized based on the patient’s current regimen and administered with the evening meal, with gradual dose titration to decrease the risk for metformin-related gastrointestinal events (maximum dose, 5 mg/2000 mg).

Adverse Reactions, Drug Interactions, and Contraindications

Coadministration of strong cytochrome P 450 isoenzyme 3A4/5 inhibitors (eg, ketoconazole) significantly increases saxagliptin concentrations, necessitating dose limitations to 2.5 mg/1000 mg once daily. Lower doses of concomitantly administered sulfonylureas may be needed to reduce the risk for saxagliptin-related hypoglycemia.

Hypoglycemia was reported in 3.4% of treatment-naive patients receiving saxagliptin 5 mg/metformin IR combination therapy compared with 4.0% of those receiving metformin IR alone. Among treatment-experienced patients, the incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg with metformin IR was 7.8% and 5.8%, respectively, compared with 5.0% for those receiving metformin IR monotherapy.

Adverse events reported in 5% or more of the treatment-naive study patients receiving combination therapy and occurring more commonly than with metformin alone included headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).

Metformin-related adverse events include diarrhea and nausea/vomiting; saxagliptin may cause respiratory tract infection, urinary tract infection, and headache.

Because of the metformin-related risk for lactic acidosis, patients should be warned against excessive alcohol intake. Treatment with saxagliptin/metformin is not recommended in hepatic impairment and contraindicated in renal impairment. Renal function should be monitored before initiation of therapy and at least annually thereafter; more frequent assessments are recommended for patients at risk for renal impairment, such as the elderly.

Treatment should be temporarily discontinued in patients undergoing radiologic studies with intravascularly administered iodinated contrast materials, and those undergoing surgical procedures associated with restricted intake of food and fluids.

As reported by Medscape Medical News, saxagliptin (Onglyza; Bristol-Myers Squibb Co) previously was approved for use alone or with metformin, a sulfonylurea (eg, glyburide), or a thiazolidinedione (eg, pioglitazone and rosiglitazone) to improve glycemic control in adults with type 2 diabetes mellitus.

More information on this new drug is available on the FDA Web site.

Clinical Implications

• The FDA has approved saxagliptin/metformin XR tablets at 5 mg/500 mg, 5 mg/1000 mg, and 2.5 mg/1000 mg once daily to improve glycemic control in adults with type 2 diabetes mellitus.
• An individualized dose of saxagliptin/metformin XR should be given once daily with the evening meal and titrated gradually to avoid metformin-related gastrointestinal events (maximum, 5 mg/2000 mg). Dosing should be limited to 2.5 mg/1000 mg daily with concomitant use of strong CYP 3A4/5 inhibitors. Lower doses of coadministered sulfonylureas may be needed to decrease the risk for hypoglycemia.
• Because of the metformin-related risk for lactic acidosis, patients should be warned against excessive alcohol intake. Treatment with saxagliptin/metformin XR is not recommended in hepatic impairment and is contraindicated in renal impairment. Treatment should be temporarily stopped during certain radiologic studies and for surgical procedures associated with restricted intake of food and fluids.