Initial Therapy with JANUMET™ (sitagliptin/metformin) Provided Significantly Greater Blood Sugar Lowering Compared to Metformin Alone in Patients with Type 2 Diabetes
In Separate Post-hoc Analyses, JANUVIA™ (sitagliptin) Provided Significant Blood Sugar Lowering, Sustained over Two Years
NEW ORLEANS - New data presented at the American Diabetes Association (ADA) 69th Annual Scientific Sessions showed that initial treatment with JANUMET™ (sitagliptin/metformin) provided greater blood sugar improvements in drug-naïve patients with type 2 diabetes, compared with metformin alone. In separate post-hoc analyses, data pooled from studies of 104 weeks in duration showed JANUVIA™ (sitagliptin), when taken alone (two studies) or in combination with metformin (two studies), provided significant blood sugar lowering, which was sustained over two years.
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.
“In this study, initial combination therapy with the fixed-dose combination JANUMET for the treatment of type 2 diabetes helped patients achieve blood sugar goals more effectively than metformin alone,” said Barry J. Goldstein, M.D., Ph.D., vice president of Clinical Research, Diabetes and Obesity, Merck & Co., Inc. (MRK, NYSE). “For physicians who treat patients who need to lower their blood sugar levels, this may be useful information.”
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.
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 compound in the DPP-4 inhibitor class of oral treatments. It has been approved in over 80 countries and to-date, there have been more than 11 million prescriptions 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 of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.
Initial therapy with JANUMET compared with metformin alone
This large, randomized, double-blind study of initial therapy with JANUMET, a fixed dose combination of sitagliptin and metformin, compared to metformin alone, included 1,250 drug-naïve patients with a mean A1C¹ baseline of 9.8 percent. Patients were randomized to JANUMET (sitagliptin/metformin 50/1,000 mg twice daily) or metformin (1,000 mg twice daily) for 44 weeks. The primary study hypotheses were addressed after 18 weeks. After 18 weeks, patients taking JANUMET as initial therapy achieved mean A1C reductions from baseline of 2.4 percent (n=560), compared with 1.8 percent for patients taking metformin alone (n=566), a significant between-group difference of 0.6 percent (p less than 0.001).
The study included analyses of subgroups by baseline A1C:
* Patients with baseline A1C levels less than 8.0% achieved mean A1C reductions from baseline of 1.1% with JANUMET (n=87), compared to 0.8% with metformin alone (n=101).
* Patients with baseline A1C levels between greater or equal to 8.0% and 9.0% achieved mean A1C reductions from baseline of 1.6% (n=125), compared to 1.1% with metformin alone (n=110).
* Patients with baseline A1C levels between greater or equal to 9.0% and 10.0% achieved mean A1C reductions from baseline of 2.0% (n=99), compared to 1.7% with metformin alone (n=95).
* Patients with baseline A1C levels between greater or equal to 10.0% and 11.0% achieved mean A1C reductions from baseline of 2.9% (n=99), compared to 2.1% with metformin alone (n=111).
* Patients with baseline A1C levels greater or equal to 11% achieved mean A1C reductions from baseline of 3.6% (n=151), compared to 2.7% with metformin alone (n=149).
Significantly more patients taking JANUMET as initial therapy achieved the American Diabetes Association A1C goal of less than 7.0 percent, compared with patients taking metformin alone (49 percent vs. 34 percent, respectively; p less than 0.001). The primary efficacy endpoint of the study was A1C change from baseline at 18 weeks; 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 measurement.
The incidence of overall clinical adverse experiences was similar in both groups. Prespecified adverse events of special interest included hypoglycemia and selected gastrointestinal-related adverse experiences (abdominal pain, nausea, vomiting, and diarrhea). In this study, the incidence of hypoglycemia was not significantly different between the groups (2.1 percent for JANUMET; 1.8 percent for metformin; p=0.686). Patients taking JANUMET, compared to patients taking metformin alone, had significantly lower incidences of abdominal pain (1.1% vs. 3.8%, respectively; p=0.002) and diarrhea (12.0% vs. 16.8%, respectively; p=0.015), with similar incidences of nausea (5.6% and 6.3%, respectively; p=0.622) and vomiting (2.9% and 2.6%, respectively; p=0.735). Patients in both groups experienced weight loss of 1.6 kg from baseline.
Efficacy with JANUVIA Over 2 Years
In a post-hoc pooled analysis of data from two clinical trials evaluating JANUVIA as monotherapy, A1C over time was examined in 147 patients with a baseline A1C of 7.5 to 10.0 percent who were not taking any diabetes treatment at the screening visit. The mean A1C in the cohort of patients (n=32) completing two years of sitagliptin monotherapy decreased from a baseline of 8.3 to 6.9 percent.
Because diabetes is a progressive disease, the studies had established criteria to specify when patients should start additional antihyperglycemic therapy or discontinue from the studies, and these criteria became stricter over time. These criteria included measurements of FPG and A1C. The post-hoc statistical analysis excluded data from patients who had missing A1C and after they had started additional medicines.
Overall, 67 out of 147 patients (46%) in the monotherapy group received glycemic rescue medication or discontinued treatment because patients did not meet the progressively stricter glycemic criteria and/or did not meet the investigator’s expectations of glycemic improvement over the 2 years of study.
Similarly, in a post-hoc pooled analysis of data from two clinical trials evaluating the addition of JANUVIA to metformin therapy, A1C over time was examined in 852 patients with a baseline A1C of 7.0 to 10.0 percent who were taking metformin only (more than/=1500 mg/day) at the screening visit. The mean A1C in the group (n=347) completing two years of treatment with JANUVIA as add-on therapy decreased from a baseline of 7.7 to 6.9 percent.
In this study, 283 out of 852 patients (33%) in the group that added JANUVIA to metformin received glycemic rescue medication or discontinued treatment due to lack of efficacy (i.e., patients not meeting the progressively stricter, protocol-specified glycemic criteria and/or not meeting the investigator’s expectations of glycemic improvement) over the two years.
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 more than 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 more than 30 to less than 50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl less than 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 (more than 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 more than/= 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.
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.
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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