A New Analysis Released at ADA: Lower Risk of Symptomatic Hypoglycemia with JANUVIA™ (sitagliptin) Compared to Glipizide on a Background of Metformin in Patients with Type 2 Diabetes

Lower Risk in Overall Study Population was Observed in Both Older (65 Years) and Younger (65 Years) Patients

SAN FRANCISCO. - A new analysis presented at the American Diabetes Association (ADA) 68th Annual Scientific Sessions showed treatment with JANUVIA™ (sitagliptin), Merck & Co., Inc.’s diabetes medicine, was associated with a 93 percent lower risk of having a confirmed symptomatic hypoglycemic event on a given day (p=0.001) compared to treatment with glipizide, a sulfonylurea. This 52-week intent to treat analysis was based on 37 events in the JANUVIA group (n=588) and 492 events in the glipizide group (n=584). Both agents were added to ongoing metformin therapy in patients with type 2 diabetes and were associated with similar reductions in A1Ci (0.5 percent for JANUVIA and 0.6 percent for glipizide in the intent-to-treat patient population).

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. JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis and angioedema.

Hypoglycemia is a common side effect of some oral diabetes medications. The risk of hypoglycemia observed in this study with JANUVIA compared to glipizide was lower in older patients (65 years) compared with younger patients (65 years). In the older age group (JANUVIA, n=120; glipizide, n=123), patients treated with JANUVIA had a 97 percent (29-fold) lower risk of confirmed hypoglycemia compared to patients treated with glipizide and, in the younger age group (JANUVIA, n=468; glipizide, n=461), patients treated with JANUVIA had a 91 percent (11-fold) lower risk of confirmed hypoglycemia compared to patients treated with glipizide (p0.001 for both analyses). Risk was assessed using a model which took into consideration treatment, most recent A1C prior to the event, time from randomization to the event, gender, age group and interaction terms.

As is typical with other anti-hyperglycemic agents used in combination with a sulfonylurea, when JANUVIA is used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

JANUVIA is a selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin system, which helps to regulate glucose by affecting the beta cells and alpha cells in the pancreas. Through DPP-4 inhibition, JANUVIA works only when blood sugar is elevated to address diminished insulin due to beta-cell dysfunction and uncontrolled production of glucose by the liver due to alpha-cell and beta-cell dysfunction. Glipizide is a sulfonylurea that lowers blood sugar by stimulating the pancreatic beta cells to release insulin regardless of glucose levels.

Hypoglycemia, or low blood sugar, occurs when the level of glucose in the blood drops too low for the body’s needs. Symptoms may include shakiness, dizziness, sweating, hunger, headache, pale skin color, sudden moodiness or behavior changes, clumsy or jerky movements, seizure, confusion and unconsciousness.

“When treating patients with type 2 diabetes, it is important for physicians to balance lowering blood glucose levels with avoiding hypoglycemia,” said Nir Barzilai, M.D., professor, department of Medicine and department of Molecular Genetics, director, Institute for Aging Research, Albert Einstein College of Medicine, New York.

In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidences 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 percent 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.

Lower risk of hypoglycemia with JANUVIA compared to glipizide
This analysis showed that treatment with JANUVIA was associated with a significantly lower risk of hypoglycemia compared to glipizide in patients with type 2 diabetes. Among patients with physician-confirmed symptomatic hypoglycemic events, those taking JANUVIA had a 93 percent lower risk of experiencing a hypoglycemic event compared to those taking glipizide (random effects hazard ratio [HR]=0.07, 95% CI 0.04-0.11, p=0.001).

The association between a lower risk of hypoglycemia with JANUVIA compared to glipizide was stronger in older patients (65 years) versus younger patients (65 years). In the older age group (65 years), patients treated with JANUVIA had a 29-fold or 97 percent lower risk of experiencing a hypoglycemic event compared to patients treated with glipizide (HR=0.03, 95% CI 0.01-0.11, p0.001). In the younger age group (65 years), patients treated with JANUVIA had an 11-fold or 91 percent lower risk of experiencing a hypoglycemic event compared to patients treated with glipizide (HR=0.09, 95% CI 0.06-0.15, p0.001).

The purpose of this pre-specified analysis was to evaluate the A1C-adjusted risk of a hypoglycemic event on a given day. In this analysis, recent A1C, time from randomization to event and gender were also significant covariates in the model (p0.001), impacting risk of hypoglycemia similarly in both treatment groups. The primary endpoint was patient reported and physician confirmed symptomatic hypoglycemic events with documented fingerstick glucose measurements (70 mg/dL or 3.9 mmol/L).

This analysis was based on a 52-week, randomized, double-blind, active-controlled study in which JANUVIA (100 mg once daily) or glipizide (up to 20 mg daily; mean daily dose 10 mg daily) was added to ongoing metformin therapy ( 1500 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 percent for JANUVIA and 0.6 percent for glipizide in the intent-to-treat patient population and 0.7 percent for JANUVIA and 0.7 percent for glipizide in the per protocol analysis, confirming the similar efficacy of JANUVIA compared to glipizide. The noninferiority of JANUVIA to glipizide may be limited to patients with A1C levels comparable to those included in this study (over 70 percent of patients had a baseline A1C less than 8 percent and over 90 percent had a baseline A1C less than 9 percent).

In the original study consisting of all reported cases, patients treated with glipizide experienced a significantly higher rate of hypoglycemia vs. JANUVIA (32 percent vs. 5 percent, respectively; p0.001). Additionally, patients in the group treated with JANUVIA experienced significant weight loss (mean -1.5 kg) from baseline, while patients treated with glipizide experienced significant weight gain (mean +1.1 kg) from baseline. The between-treatment difference was statistically significant (p0.001, JANUVIA vs. glipizide).

Dosing of JANUVIA
The recommended dose of JANUVIA is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (CrCl 50 mL/min). To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in end-stage renal disease (ESRD) patients requiring hemodialysis. For patients with moderate renal insufficiency (CrCl 30 to 50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl 30 mL/min) or with ESRD requiring dialysis, the dose of JANUVIA is 25 mg once daily. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.

Selected cautionary information for JANUVIA
Because JANUVIA is renally eliminated, and to achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, a dosage adjustment is recommended in patients with moderate renal insufficiency and in patients with severe renal insufficiency or with ESRD requiring hemodialysis or peritoneal dialysis. Safety and effectiveness of JANUVIA in pediatric patients have not been established. There are no adequate and well-controlled studies in pregnant women. JANUVIA should be used during pregnancy only if clearly needed. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman. There have been 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. Onset of these reactions occurred within the first three months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event and institute alternative treatment for diabetes.

Expanding clinical development program for sitagliptin family
Merck’s clinical development program for sitagliptin is robust and continues to expand with 55 studies completed or underway. It is estimated that approximately 12,000 patients have participated in the Company’s clinical studies, with about 7,400 of these patients being treated with sitagliptin. Additionally, in clinical studies, approximately 2,300 patients have been treated with sitagliptin for more than one year and, of these, approximately 500 patients have been treated for at least two years.