New data presented at the 20th World Diabetes Congress of the International Diabetes Federation (IDF) compared two strategies for the initiation of treatment for patients with type 2 diabetes. In the first phase (18 weeks), the treatment effects of JANUMET (a fixed-dose combination of sitagliptin and metformin) and metformin as initial therapy were compared. In the second phase (26 weeks), the treatment strategies of initiating JANUMET versus initiating metformin were compared (investigators used their clinical discretion, based upon glucose and A1C values, to add other diabetes treatments to the initially assigned treatment regimen when necessary to achieve blood sugar control). At the end of this 44-week study, mean A1C results were consistent with those observed at week 18 (-2.4 percent JANUMET vs. -1.8 percent metformin), which was the primary end point. Patients initially treated with JANUMET achieved greater mean A1C reductions at 44 weeks compared with those initially treated with metformin (-2.3 percent vs. -1.8 percent) even after physicians were encouraged to add other therapies to help patients achieve target blood sugar goals.
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. JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. The labeling for JANUMET states that it has not been studied in combination with insulin.
Metformin, along with a diet and exercise regimen, is often chosen as the first medication to give newly-diagnosed patients with type 2 diabetes, with the intention of later adding medications as needed to achieve or maintain A1C targets. However, this approach has been found to often lead to long periods of elevated blood sugar levels before additional treatment is initiated. Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are at the physician’s discretion.
“Close to half of current type 2 diabetes patients have not achieved adequate blood sugar control,” said Barry J. Goldstein, M.D., Ph.D., Vice President of Clinical Research, Diabetes and Obesity, Merck & Co., Inc. “The significance of this study is that despite the ability for physicians to add other therapies as necessary for patients to achieve desired A1C levels, those starting treatment with JANUMET achieved greater A1C reductions after 44 weeks compared with those starting treatment with metformin. These findings support the initial use of combination therapy for appropriate patients at diagnosis with type 2 diabetes, with treatments such as JANUMET.”
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.
About the Study
This large, randomized, double-blind study of initial therapy with JANUMET compared to metformin included 1,246 patients with 625 patients randomized to JANUMET and 621 patients randomized to metformin. Doses were titrated over 4 weeks to a maximum dose of 50/1000 mg sitagliptin/metformin twice daily or metformin 1000 mg twice daily.
At week 18 of this 44-week study, which was the primary endpoint, patients taking JANUMET achieved mean A1C reductions of 2.4 percent from a baseline of 9.9 percent, compared with 1.8 percent from a baseline of 9.8 percent for patients taking metformin alone, for a between-group difference of 0.6 percent (p<0.001). At the conclusion of the study (week 44), patients taking JANUMET as initial therapy achieved mean A1C reductions of 2.3 percent, compared with 1.8 percent for patients taking metformin, resulting in a significant between-group difference of 0.5 percent (p<0.001). In addition, 46 percent of patients achieved A1C levels at the American Diabetes Association goal of less than 7.0 percent with JANUMET compared with 30 percent of patients treated with metformin, a difference of 50 percent between the treatment groups (p<0.001), and 28 percent of patients achieved the International Diabetes Federation goal of less than 6.5 percent with JANUMET compared to 17 percent of patients treated with metformin (p<0.001).
This study consisted of two phases. In the first phase (18 weeks), the treatment effects of JANUMET and metformin as initial therapy were compared. In the second phase (26 weeks),
investigators used their clinical discretion, based upon glucose and A1C values, to add other diabetes treatments to the regimen of study participants taking either JANUMET or metformin when necessary to achieve blood sugar control. Antihyperglycemic treatment was initiated by the investigators in this second phase of the study nearly twice as often in the metformin group compared with the JANUMET group (16.7 percent vs. 8.8 percent of patients, respectively).
Prespecified adverse events of special interest included hypoglycemia and selected gastrointestinal-related adverse experiences (abdominal pain, nausea, vomiting, and diarrhea). The incidence of hypoglycemia was 3.0 percent for JANUMET vs. 3.7 percent for metformin. The incidences of selected gastrointestinal-related adverse experiences for patients taking JANUMET, compared to patients taking metformin, were as follows: abdominal pain (3.0 percent vs. 5.3 percent, respectively); diarrhea (13.8 percent vs. 18.0 percent, respectively); nausea (5.9 percent vs. 7.1 percent, respectively); and vomiting (3.0 percent vs. 2.9 percent, respectively). Patients in both groups experienced similar effects on weight (-1.1 kg JANUMET; -1.2 kg metformin).
About JANUMET
JANUMET targets all three key defects of type 2 diabetes: insulin deficiency from pancreatic beta cells, insulin resistance, and overproduction of glucose by the liver. JANUMET has been approved in over 60 countries and to date, there have been more than 3 million prescriptions dispensed in the U.S. alone.
Selected cautionary information for 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 of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.
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.
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Prescribing information and patient product information for JANUMET is available at www.januvia.com.
Justine O'Malley
Global Human Health Communications
Merck & Co., Inc.
+1 908 423-2021
+1 908 735-1194 (F)
Justine_Omalley@Merck.com
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