Merck & Co., Inc. announced that the US Food and Drug Administration (FDA) has approved expanded labelling for Januvia (sitagliptin), the only DPP-4 inhibitor available in the United States for the treatment of type 2 diabetes.

Januvia is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes. Januvia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Januvia has not been studied in combination with insulin. The new regimens with Januvia described in the updated labelling include, as an adjunct to diet and exercise, initial therapy in combination with metformin; add-on therapy to a sulfonylurea (glimepiride) when the single agent alone does not provide adequate glycemic control; and, add-on therapy to the combination of a sulfonylurea (glimepiride) and metformin when dual therapy does not provide adequate glycemic control.

New data contained in three studies support the efficacy and safety of Januvia. Initial therapy with the combination of Januvia and metformin provided substantial A1C reductions. Januvia demonstrated similar efficacy to a sulfonylurea (glipizide) in patients inadequately controlled on metformin. Januvia also provided significant placebo-adjusted A1C reductions in patients being treated with a sulfonylurea (glimepiride), with or without metformin.

The expanded labelling for Januvia was also updated, within Warnings and Precautions, to include post-marketing reports of hypersensitivity reactions in patients treated with Januvia. These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The expanded labelling also includes a contraindication for patients with history of a serious hypersensitivity reaction to sitagliptin, including anaphylaxis and angioedema.

Since its initial approval in October 2006, over two million prescriptions have been written for Januvia. In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with Januvia were similar to placebo. In these clinical studies, the most common adverse reactions reported with Januvia (greater than or equal to 5 per cent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection and headache. In clinical trials in combination with a sulfonylurea (glimepiride), with or without metformin, Januvia demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycemia.

Initial therapy with the combination of Januvia and metformin provides significantly greater A1C reductions with a similar GI tolerability profile compared to metformin alone Januvia as initial therapy in combination with metformin is supported by a randomised, double-blind, placebo-controlled factorial study in 1,091 patients with type 2 diabetes who experienced inadequate glycemic control with diet and exercise alone. In this study, the mean reduction of A1C relative to placebo at 24 weeks was 2.1 per cent with initial therapy combining Januvia 100 mg daily and metformin 2000 mg daily (n=178) from a mean baseline A1C of 8.8 per cent (p <0.001). The mean placebo-adjusted A1C reductions in the other arms of the study were 1.6 per cent with Januvia 100 mg daily and metformin 1000 mg daily (n=183); 1.3 percent with metformin 2000 mg dailies (n=177); 1.0 per cent with metformin 1000 mgiv daily (n=178); and 0.8 per cent with Januvia (n=175), (p<0.001 for all treatment groups versus placebo).

At 24 weeks, 66 per cent of patients treated with the initial combination of Januvia 100 mg daily and metformin 2000 mg daily achieved the American Diabetes Association's (ADA) goal A1C level of <7 percent vs. 38 per cent of patients treated with metformin 2000 mg daily alone. In the other arms of the study, 43 per cent of patients treated with Januvia 100 mg daily and metformin 1000 mg daily, 23 per cent of patients treated with metformin 1000 mg daily, and 20 per cent of patients treated with Januvia achieved the ADA goal A1C level of <7 per cent.

This study also included an open label cohort of an additional 117 patients with severely elevated baseline A1C (mean: 11.2 per cent). These patients experienced a significant mean A1C reduction from baseline of 2.9 per cent at 24 weeks with initial therapy combining Januvia 100 mg daily and metformin 2000 mg daily.

This study also compared the efficacy of Januvia to two common doses of metformin in a subset of patients not on any anti-hyperglycaemic agent at study entry. In this patient population, patients treated with Januvia experienced a mean A1C reduction from baseline of 1.1 per cent compared to 1.1 per cent in patients treated with metformin 1000 mg daily and 1.2 per cent in patients treated with metformin 2000 mg daily.

"The substantial A1C reductions that are seen when Januvia is used in combination with metformin as first-line therapy in patients with type 2 diabetes are meaningful to me as a clinician. The data show that this approach helped many patients achieve their A1C goal and the rate of gastrointestinal side effects was similar to that seen with metformin alone," said Barry J. Goldstein, M.D., Ph.D., professor of medicine, Biochemistry and Molecular Pharmacology; director, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College, Philadelphia, PA.

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the physician.

In the factorial study, initial therapy with Januvia and metformin was not associated with an increased risk of gastrointestinal adverse reactions beyond those commonly seen with metformin alone. In a pooled analysis of four other placebo-controlled clinical studies with Januvia, not including initial therapy with Januvia and metformin, the incidence of selected gastrointestinal adverse reactions in patients treated with Januvia was abdominal pain (2.3 per cent Januvia; 2.1 percent placebo); nausea (1.4 per cent Januvia; 0.6 per cent placebo); and diarrhoea (3.0 per cent Januvia; 2.3 per cent placebo).

The incidence of hypoglycaemia was similar across treatment groups (0.6 per cent in patients on placebo, 0.6 per cent in patients given JANUVIA alone, 0.8 per cent in patients given metformin alone, and 1.6 per cent in patients given Januvia in combination with metformin). The most common adverse reactions reported with Januvia and metformin as initial therapy (greater than or equal to 5 per cent) compared to metformin alone were upper respiratory infection (6.2 per cent vs. 5.2 per cent) and headache (5.9 per cent vs. 3.8 per cent).

Januvia demonstrated similar efficacy compared to a sulfonylurea (glipizide) with significantly less hypoglycaemia, and patients treated with Januvia experienced mean weight loss from baseline of 1.5 kg.

The efficacy of Januvia was also evaluated in a 52-week, double blind, glipizide-controlled noninferiority trial predominantly in patients with mildly to moderately elevated A1C levels (mean baseline A1C 7.5 per cent). Patients were treated with either Januvia 100 mg daily or glipizide up to 20 mg daily (mean daily dose 10 mg daily). This study showed that Januvia achieved the pre-specified bounds for noninferiority vs. a sulfonylurea (glipizide). After one year, the mean A1C reduction from baseline was 0.5 per cent for Januvia and 0.6 per cent for glipizide in the intent-to-treat patient population and 0.7 per cent for Januvia and 0.7 per cent for glipizide in the per protocol analysis, confirming the similar efficacy of Januvia compared to glipizide.