Saxagliptin/Metformin (Kombiglyze XR) for Type 2 Diabetes

Saxagliptin/Metformin (Kombiglyze XR) for Type 2 Diabetes
The Medical Letter on Drugs and Therapeutics • March 21, 2011 (Issue 1360)

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Metformin (Glucophage, and others) is generally preferred as the first-line agent for treatment of type 2 diabetes, but most patients subsequently require treatment with more than one drug.1 Many combination products have been marketed; the latest of these combines saxagliptin2 with extended-release (ER) metformin as Kombiglyze XR.

MECHANISM OF ACTION — Saxagliptin, an oral dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, slows breakdown of glucagon-like peptide-1 (GLP-1), which increases release of insulin from pancreatic beta cells and decreases release of glucagon from pancreatic alpha cells. Metformin decreases hepatic glucose production and increases insulin sensitivity in peripheral tissues.

CLINICAL STUDIES — Monotherapy vs. Combination Therapy – FDA approval of Kombiglyze XR was based on two 24-week double-blind, placebo-controlled trials, one in treatment-naive patients and the other in patients inadequately controlled on immediate-release (IR) metformin alone. Neither study actually used the fixed-dose combination; patients treated with both drugs took separate co-administered saxagliptin and IR metformin tablets. IR and ER metformin have a similar area under the curve (AUC), but peak plasma levels of ER metformin are about 20% lower. The results of these trials are summarized in Table 1. In both, the change in glycosylated hemoglobin (A1C) was greater and more patients achieved an A1C of <7% with saxagliptin and metformin together, compared to those treated with either drug alone.

Addition of Saxagliptin vs. Sitagliptin to Metformin – An 18-week double-blind, non-inferiority trial in 801 patients inadequately controlled on a stable dose of IR metformin (mean dose about 1800 mg/day) compared the addition of 5 mg daily of saxagliptin to addition of 100 mg of sitagliptin (Januvia) once daily. The 2 drugs were similarly effective (A1C decreased 0.52% vs. 0.62%). Hypoglycemic events and weight loss occurred with similar frequency.3

Addition of Saxagliptin vs. Glipizide to Metformin – A 52-week double-blind, non-inferiority trial in 858 patients not controlled on a stable dose of IR metformin (mean dose about 1900 mg/day) compared the addition of 5 mg of saxagliptin once daily to addition of glipizide (titrated from 5 mg up to 20 mg) twice daily. The drugs were similarly effective (A1C decreased 0.74% vs. 0.80%), but hypoglycemic events were much more common with glipizide (36.3% vs. 3%). Patients lost a mean of 1.1 kg with saxagliptin and gained 1.1 kg with glipizide.4

ADVERSE EFFECTS — Headache, nasopharyngitis and diarrhea were the most common adverse effects reported with saxagliptin/metformin in clinical trials. Nausea, vomiting, abdominal pain, metallic taste and flatulence can occur with metformin alone. Modest weight loss occurs with metformin alone and with the 2 drugs taken together. The incidence of hypoglycemia with both drugs was low and similar to the rate with metformin alone.

Lactic acidosis is a rare but potentially fatal complication that can occur with accumulation of metformin. Like metformin alone, Kombiglyze XR is contraindicated in patients with severe renal dysfunction, should be temporarily suspended for surgical procedures, and should be withheld for at least 48 hours before and after radiologic studies with IV iodinated contrast material. It is contraindicated in patients with severe hepatic impairment.

The long-term safety of DPP-4 inhibitors such as saxagliptin is unknown.

PREGNANCY — The combination of saxagliptin and metformin is classified as category B (no evidence of risk, no adequate studies in pregnant women) for use in pregnancy.

DRUG INTERACTIONS — Saxagliptin is metabolized by CYP3A4; strong inhibitors of this isozyme such as clarithromycin (Biaxin, and others) or itraconazole (Sporanox, and others) may increase serum concentrations of saxagliptin. The dose of Kombiglyze XR should be limited to 2.5/1000 mg once daily in patients taking strong inhibitors of CYP3A4.

DOSAGE AND ADMINISTRATION — Kombiglyze XR is taken once daily with the evening meal to minimize the gastrointestinal effects of metformin. The tablets should be taken whole and not crushed, chewed or split. For patients not adequately controlled on metformin alone, the usual starting dose is based on the previous dose of metformin. The maximum daily dose of Kombiglyze XR is 5 mg of saxagliptin and 2000 mg of metformin. Patients who cannot take more than 2.5 mg of saxagliptin and either are not already taking metformin or require more than 1000 mg of metformin should take the drugs individually.

CONCLUSION — Treatment with the new fixed-dose combination of saxagliptin and extended-release metformin (Kombiglyze XR) may be more convenient than taking the individual drugs separately, but with less dosing flexibility. Adding saxagliptin to metformin may cause less weight gain and less hypoglycemia than adding a sulfonylurea such as glimepiride (Amaryl, and others), but the retail cost of this combination is much higher than taking generic metformin plus a sulfonylurea separately. Clinical experience with saxagliptin is limited and its long-term safety is unknown.