In Investigational Studies, New Uses of JANUVIA™ (sitagliptin) in Combination with Other Diabetes Medicines Resulted In Significant Blood Sugar-Lowering Efficacy for Patients with Type 2 Diabetes

NEW ORLEANS, June  6, 2009 - In two new investigational studies evaluating the efficacy and tolerability of Merck & Co., Inc. (MRK, NYSE)'s diabetes medicine JANUVIA, JANUVIA significantly improved blood sugar control.  One study evaluated JANUVIA as an addition to ongoing insulin therapy, with or without metformin, and the second evaluated JANUVIA in combination with pioglitazone as an initial treatment regimen.  Applications to use JANVUIA in these combinations and JANUMET™ (sitagliptin/metformin) in combination with insulin have been accepted by the FDA and are currently under review. These new studies were presented at the American Diabetes Association (ADA) 69^th Annual Scientific Sessions.

JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes.  JANUMET is indicated, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate.  JANUVIA and JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.  The labeling for both JANUVIA and JANUMET state that they have not been studied in combination with insulin.

"Due to the progressive nature of the disease, over time most type 2 diabetes patients require multiple drugs to achieve glycemic control," said John Amatruda, M.D., senior vice president and franchise head, Diabetes and Obesity, Merck & Co., Inc.  "If approved for use with insulin, JANUVIA and JANUMET will be additional options for patients with type 2 diabetes who are taking insulin and whose blood sugar is not at goal."

JANUVIA is a selective, once-daily DPP-4 inhibitor that enhances a natural body system called the incretin system to help regulate blood sugar by increasing levels of active GLP-1 and GIP hormones.  JANUVIA inhibits DPP-4 over 24 hours.  JANUMET is a fixed dose combination of JANUVIA and metformin, which targets all three key defects of diabetes: insulin deficiency from pancreatic beta cells, insulin resistance, and overproduction of glucose by the liver.  JANUVIA is the first approved medicine in the DPP-4 inhibitor class of oral treatments.  It has been approved in more than 80 countries and more than 11 million prescriptions have been dispensed for JANUVIA worldwide.

JANUVIA is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.  JANUMET is contraindicated in patients with renal disease, renal dysfunction, or abnormal creatinine clearance; and acute or chronic metabolic acidosis, including diabetic ketoacidosis.  The labeling for JANUMET contains a boxed warning for lactic acidosis, a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with JANUMET. 

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

Study of addition of JANUVIA to ongoing insulin therapy with or without metformin
In a 24-week study of 564 patients on long-acting, intermediate-acting or pre-mixed insulin, with or without metformin, the addition of JANUVIA (n=281) reduced A1C¹  by 0.6 percent (p<0.001) relative to placebo (n=283) from a mean baseline A1C of 8.7 percent (mean change from baseline -0.6 percent with JANUVIA, 0.0 percent with placebo).  Additionally, 13 percent of patients taking JANUVIA with insulin therapy achieved the American Diabetes Association A1C goal of less than 7.0 percent compared to 5 percent of patients taking placebo (p<0.001).

The primary efficacy endpoint of the study was change in A1C from baseline; analyses were based on all patients who received at least one dose of study treatment and who had both a baseline and at least one post-baseline A1C measurement.

A higher incidence of adverse events was reported with the addition of JANUVIA compared to placebo due mainly to an increased incidence of hypoglycemia (15.5 percent vs. 7.8 percent, respectively). The incidence of severe hypoglycemic events was 0.6 percent with JANUVIA vs. 0.3 percent with placebo. There was no change from baseline in body weight in either treatment group.

Study of initial combination therapy with JANUVIA and pioglitazone
In the second study, a total of 497 patients with baseline A1C  levels of 8.0 to 12.0 percent (mean baseline of 9.5 percent) received JANUVIA 100 mg once daily and pioglitazone 30 mg once daily or pioglitazone 30 mg once daily alone.  The primary endpoint was A1C change from baseline at week 24.  In this 24-week randomized, double-blind, placebo-controlled trial, initial treatment with JANUVIA and pioglitazone provided an A1C reduction of 2.4 percent from baseline (n=251) compared with 1.5 percent with pioglitazone alone (n=246), a between-group difference of 0.9 percent (p<0.001).  Additionally, 60 percent of patients treated with JANUVIA and pioglitazone achieved an A1C less than the American Diabetes Association recommended A1C goal of 7.0 percent at 24 weeks compared with 28 percent of patients given pioglitazone alone (p<0.001).

The study also assessed changes in A1C based on patients' baseline A1C levels.  Patients with a baseline A1C of 10.0 percent or more achieved a mean A1C reduction of 3.0 percent from baseline with JANUVIA and pioglitazone (n=99), compared with 2.1 percent for pioglitazone alone (n=88).  Patients with a baseline A1C of less than 10.0 percent had an A1C reduction of 2.0 from baseline (n=152), compared with 1.1 percent for pioglitazone alone (n=158).

Efficacy analyses were based on the full analysis set population, consisting of all randomized patients who received at least one dose of study treatment and who had both a baseline and at least one post-baseline measurement.

Initial combination therapy with JANUVIA and pioglitazone demonstrated similar incidences of hypoglycemia compared to pioglitazone alone (1.1 percent vs. 0.8 percent, respectively), gastrointestinal adverse events (5.7 percent vs. 6.9 percent, respectively), and edema (2.7 percent vs. 3.5 percent, respectively).  There was a larger mean increase from baseline in body weight in patients treated with sitagliptin plus pioglitazone than in those treated with pioglitazone alone (3.0 kg for the combination vs. 1.9 kg for pioglitazone, p=0.005).

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.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.

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 Adverse Reactions for JANUVIA
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 (>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. 

In a pre-specified pooled analysis of two monotherapy studies, an add-on to metformin study, and an add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia in patients treated with JANUVIA 100 mg was similar to placebo (1.2 percent vs. 0.9 percent).  Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required.  In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the incidence of hypoglycemia was 0.6 percent in patients given placebo, 0.6 percent in patients given sitagliptin alone, 0.8 percent in patients given metformin alone and 1.6 percent in patients given sitagliptin in combination with metformin.

Selected cautionary information for JANUMET
JANUMET should be avoided in patients with evidence of hepatic disease.  Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal.  Patients should be warned against excessive alcohol intake while receiving JANUMET.  Patients may require discontinuation of JANUMET and temporary use of insulin during periods of stress and decreased intake of fluids and food such as may occur with fever, trauma, infection or surgery.  Patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness should be evaluated promptly for evidence of ketoacidosis or lactic acidosis.  The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years).  When lactic acidosis occurs, it is fatal in approximately 50 percent of cases.

There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET.  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 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose.  If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes for the event, and institute alternative treatment for diabetes.

As is typical with other anti-hyperglycemic agents used in combination with a sulfonylurea, when sitagliptin was used in combination with metformin and a sulfonylurea or a sulfonylurea alone, a medication known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo in combination with metformin and a sulfonylurea.  Therefore, patients on sitagliptin also receiving an insulin secretagogue (e.g., sulfonylurea, meglitinide) may require a lower dose of the insulin secretagogue to reduce the risk of hypoglycemia.

Clinicians should be mindful that hypoglycemia could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.  Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other oral anti-diabetic drug.

Dosing of JANUMET
JANUMET is available as sitagliptin/metformin 50/500 mg and 50/1000 mg tablets.  It should be given twice daily with meals, with gradual dose escalation as needed to reduce the gastrointestinal (GI) side effects due to metformin.  In this formulation, the dose of sitagliptin remains constant (100 mg daily) and is combined with the two most widely prescribed doses of metformin (1000 mg daily or 2000 mg daily).  The recommended starting dose of JANUMET for patients not on prior metformin therapy and for those not adequately controlled on sitagliptin is 50/500 mg twice-daily with meals.  For patients already receiving metformin therapy, the starting dose should be based on the patient's current metformin regimen.  The total daily dose should not exceed 100 mg sitagliptin and 2000 mg metformin.  For patients taking metformin 850 mg twice daily, the recommended starting dose of JANUMET is 50/1000 mg twice daily.

Metformin and sitagliptin are known to be substantially excreted by the kidney.  The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function.  Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET.  In the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging can be associated with reduced renal function.  Any dose adjustment should be based on a careful assessment of renal function.  Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be assessed and verified as normal.

Selected Adverse Reactions for JANUMET
The most common adverse reactions reported in >/= 5% of patients started simultaneously on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Expanding clinical development program for sitagliptin family
Merck's clinical development program for sitagliptin is robust and continues to expand with more than 55 studies completed or underway.  It is estimated that approximately 7,400 patients have been treated with sitagliptin out of about 12,000 patients who have participated in the Company's clinical studies.  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.

About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.  Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs.  The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them.  Merck also publishes unbiased health information as a not-for-profit service.  For more information, visit www.merck.com.

Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995.  These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements.  The forward-looking statements may include statements regarding product development, product potential or financial performance.  No forward-looking statement can be guaranteed and actual results may differ materially from those projected.  Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise.  Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2008, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

JANUVIA™ and JANUMET™ are trademarks of Merck & Co., Inc.

¹ A1C is a measure of a person's average blood glucose over a two- to three-month period.

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