WHITEHOUSE STATION, N.J., June 25, 2011 – In a new post-hoc analysis based on the American Association of Clinical Endocrinologists (AACE/ACE) diabetes algorithm presented at the American Diabetes Association (ADA) 71st Annual Scientific Sessions, significantly more patients with type 2 diabetes treated with JANUMET® (sitagliptin/metformin HCl) tablets achieved blood sugar goals after 18 weeks compared to metformin as initial therapy.
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. JANUMET has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET.
"Close to half of all patients with type 2 diabetes have not achieved adequate blood sugar control, and patients often require combination therapy to reach blood sugar goals," said Barry J. Goldstein, M.D., Ph.D., Vice President and Therapeutic Area Head, Diabetes and Endocrinology, Merck Research Laboratories. "The results of this post-hoc analysis provide additional data regarding the use of combination therapy with JANUMET for appropriate patients."
"The incidence of type 2 diabetes continues to rise in the U.S. and globally, and it is important to help patients achieve blood sugar goals," said Helena Rodbard, M.D., endocrinologist and former AACE president and Co-Chair of the Algorithm Task Force. "It is critical for physicians to work with patients to develop a personalized diabetes treatment plan in accordance with guidelines, such as the AACE/ACE diabetes treatment algorithm."
Sitagliptin, a component of JANUMET, enhances the body's own ability to lower blood sugar levels by increasing the levels of active incretins, i.e., GLP-1 and GIP. In combining the DPP-4 inhibitor sitagliptin with the most commonly used first-line treatment, metformin, JANUMET targets all three key defects of diabetes: insulin deficiency from pancreatic beta cells, insulin resistance, and overproduction of glucose by the liver.
JANUMET is contraindicated in patients with renal disease or renal dysfunction (serum creatinine levels greater or equal to 1.5 mg/dL in males and greater or equal to 1.4 mg/dL in females) or abnormal creatinine clearance; acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma; or history of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components of JANUMET), such as anaphylaxis or angioedema.
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.
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis.
When sitagliptin was used in combination with a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or insulin. Therefore, patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.
There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUMET. After initiating JANUMET, observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUMET.
About the Study and Post-Hoc Analysis
A post-hoc analysis of a large, randomized, double-blind study comparing initial therapy with JANUMET to initial therapy with metformin in patients with type 2 diabetes with an A1C of greater than or equal to 7.5 percent was conducted to examine A1C goal attainment based on stratified A1C categories of the AACE/ACE diabetes treatment algorithm.
The original study included 1,250 patients with a mean A1C baseline of 9.9 percent. Patients were uptitrated to JANUMET (sitagliptin/metformin 50/1,000 mg twice daily) or metformin (1,000 mg twice daily). The primary efficacy endpoint of the study was A1C change from baseline at 18 weeks. At week 18, 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).
In the post-hoc analysis, nearly half (48.6 percent) of patients with a baseline A1C between 7.5 and 9.0 percent who initiated therapy with JANUMET achieved the AACE/ACE A1C goal of less than or equal to 6.5 percent at Week 18 compared with 23.1 percent of patients who initiated metformin monotherapy (p< 0.001). Patients in this baseline group taking JANUMET as initial therapy achieved mean A1C reductions from baseline of 1.5 percent (n=183), compared to 1.0 percent with metformin alone (n=182).
In patients with a baseline A1C of greater than 9.0 percent, 24.0 percent achieved the A1C goal of less than or equal to 6.5 percent taking JANUMET as initial therapy, compared with 12.8 percent taking metformin alone (p< 0.001). Patients in this baseline group taking JANUMET as initial therapy achieved mean A1C reductions from baseline of 3.0 percent (n=341), compared to 2.3 percent with metformin alone (n=345).
In patients with a baseline A1C of less than or equal to 7.5 percent, 68.6 percent achieved the A1C goal of less than or equal to 6.5 percent taking JANUMET as initial therapy, compared with 40.5 percent taking metformin alone (p< 0.01). Patients in this baseline group taking JANUMET as initial therapy achieved mean A1C reductions from baseline of 0.9 percent (n=35), compared to 0.7 percent with metformin alone (n=37).
Selected risk information for JANUMET
Lactic acidosis is a rare but serious complication that can occur because of metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized immediately.
Measure renal function before initiation of therapy with JANUMET and periodically thereafter. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and JANUMET discontinued if evidence of renal impairment is present.
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metformin.
Temporarily discontinue JANUMET in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. Avoid use in patients with hepatic disease. Temporarily discontinue for intercurrent serious conditions, infection, or surgery.
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, JANUMET should be temporarily discontinued at the time of or before the procedure, withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been re-evaluated and found to be normal.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other oral anti-diabetic drug.
When lactic acidosis occurs, it is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.
Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients greater or equal to 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.
When sitagliptin was used in combination with metformin and a sulfonylurea or insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used with metformin and a sulfonylurea or insulin. Therefore, patients also receiving insulin or an insulin secretagogue (eg, sulfonylurea) may require a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. The incidence (and rate) of hypoglycemia based on all reports of symptomatic hypoglycemia were: 16.4% (0.82 episodes/patient-year) for sitagliptin 100 mg in combination with metformin and glimepiride, 0.9% (0.02 episodes/patient-year) for placebo in combination with metformin and glimepiride, 8.2% (0.61 episodes/patient-year) for placebo in combination with metformin and insulin, and 15.3% (0.98 episodes/patient-year) for sitagliptin in combination with metformin and insulin.
Adverse reactions with sitagliptin in combination with metformin and rosiglitazone through Week 18 were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54 they were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use but 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 postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of JANUMET, such as 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.
In clinical studies, the most common adverse reactions reported, regardless of investigator assessment of causality, in greater than or equal to 5% of patients treated with either sitagliptin in combination with metformin or placebo were as follows: diarrhea (7.5% vs 4.0%), upper respiratory tract infection (6.2% vs 5.1%), and headache (5.9% vs 2.8%). In patients treated with sitagliptin in combination with metformin and sulfonylurea or placebo in combination with metformin and sulfonylurea: hypoglycemia (16.4% vs 0.9%) and headache (6.9% vs 2.7%). In patients treated with sitagliptin in combination with metformin and insulin or placebo in combination with metformin and insulin: hypoglycemia (15.3% vs 8.2%). Other adverse events with an incidence of greater or equal to 5% included nasopharyngitis for sitagliptin monotherapy and diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache for metformin therapy.
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