Merck, known as MSD outside the United States and Canada, announced the primary results of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a placebo-controlled study of the cardiovascular (CV) safety of Merck’s DPP-4 inhibitor, Januvia (sitagliptin), added to usual care in more than 14,000 patients.
The study achieved its primary composite CV endpoint of non-inferiority (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina) compared to usual care without sitagliptin. Overall, the primary endpoint occurred in 11.4 per cent (n=839) of sitagliptin-treated patients compared with 11.6 per cent (n=851) of placebo-treated patients in the Intention-to-Treat (ITT) analysis (HR=0.98; 95 per cent CI [0.89-1.08]), and in 9.6 per cent of patients (n=695) in both the sitagliptin and placebo groups in the Per Protocol (PP) analysis (HR=0.98; 95 per cent CI [0.88-1.09]; p<0.001 for non-inferiority).
In addition, there was no increase in hospitalization for heart failure and rates of all-cause mortality were similar in both treatment groups, which were two key secondary endpoints. These data were presented at the 75th scientific sessions of the American Diabetes Association and were also published in the New England Journal of Medicine.
JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus. Januvia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Januvia 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 Januvia.
Januvia is contraindicated in patients with a history of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Januvia or with any other antidiabetic drug.
“Patients with type 2 diabetes need antihyperglycemic medicines to help control their blood sugar. Because these patients are at increased risk for cardiovascular complications, understanding the cardiovascular safety of these medicines is important,” said study co-chair, Rury Holman, professor of diabetic medicine and diabetes trials unit director, University of Oxford.
“The results from TECOS showed that sitagliptin did not increase the risk of cardiovascular events in a diverse group of patients with type 2 diabetes at high cardiovascular risk.”
TECOS was an event-driven study designed to assess the long-term CV safety of the addition of sitagliptin to usual care, compared to usual care without sitagliptin, in patients with type 2 diabetes and established CV disease. In addition to showing no increased risk for the primary composite CV endpoint, sitagliptin also met the secondary composite CV endpoint (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal MI, or nonfatal stroke), showing non-inferiority compared to usual care without sitagliptin (HR=0.99; 95 per cent CI [0.89-1.11]; p<0.001 for non-inferiority).
In additional secondary endpoints assessing time to first confirmed event, hospitalization for heart failure was reported in 3.1 per cent (n=228) of sitagliptin-treated patients and 3.1 per cent (n=229) of placebo-treated patients (HR=1.00; 95 per cent CI [0.83-1.20]). All-cause mortality was similar in both treatment groups, occurring in 7.5 per cent (n=547) of patients in the sitagliptin group and 7.3 per cent (n=537) in the placebo group (HR=1.01; 95 per cent CI [0.90-1.14]).
Acute pancreatitis was uncommon, occurring in 0.3 per cent of patients in the sitagliptin group (n=23) and 0.2 per cent of patients in the placebo group (n=12); the difference was not statistically different between groups (p=0.065). Pancreatic cancer was also uncommon, occurring in 0.1 per cent of patients in the sitagliptin group (n=9) and 0.2 per cent of patients in the placebo group (n=14), and was not statistically different between groups (p=0.322).
In additional secondary analyses of the composite of time to first hospitalization for heart failure or CV death, the first confirmed hospitalization for heart failure or CV death occurred in 7.3 per cent (n=538) in the sitagliptin group compared with 7.2 per cent (n=525) for placebo (HR=1.01; 95 per cent CI [0.90-1.14]). The proportion of patients with CV death was 5.2 per cent (n=380) in the sitagliptin group compared with 5.0 per cent (n=366) in the placebo group (HR 1.03; 95 per cent CI [0.89-1.19]).
The proportion of patients with non-CV death was 2.3 per cent in both treatment groups. Death due to infection was 0.6 per cent and 0.7 per cent in the sitagliptin and placebo groups, respectively. A slight reduction in eGFR (estimated glomerular filtration rate), a measure of renal function, was observed in both treatment groups during the study: at month 48, mean change from baseline in eGFR was -4.0 ± 18.4 mL/min/1.73m2 in the sitagliptin group compared to -2.8 ± 18.3 mL/min/1.73m2 for placebo.
“We believe the results of TECOS provide important clinical information about the cardiovascular safety profile of sitagliptin,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “The TECOS CV safety trial reflects the best efforts of clinical scientists at the University of Oxford, the Duke Clinical Research Institute and Merck on behalf of patients around the world who suffer from type 2 diabetes.”
To minimize any potential effect that differences in glucose control might have on CV outcomes, the study aimed to achieve similar glucose control (glycemic equipoise) between treatment groups. At four months, mean HbA1c level was 0.4 per cent lower in the sitagliptin group compared with placebo, and this narrowed to 0.1 per cent lower during patient follow-up. This resulted in an overall difference of -0.29 per cent in patients treated with sitagliptin versus placebo. Compared with patients treated with placebo, fewer patients treated with sitagliptin received additional antihyperglycemic agents during the study period (1,591 vs. 2,046 patients, respectively; p<0.001) and were less likely to start chronic insulin therapy (542 vs. 744 patients, respectively; p<0.001).
TECOS was led by an independent academic research collaboration between the University of Oxford Diabetes Trials Unit (DTU) and the Duke University Clinical Research Institute (DCRI), and was sponsored by Merck. A total of 14,735 patients from 38 countries were randomized between December 2008 and July 2012. Of these, 14,671 were included in the ITT analysis population, with 7,332 assigned to sitagliptin and 7,339 to placebo, in addition to existing therapy. The median patient follow-up was three years, with a maximum follow-up of 5.7 years.
Patients enrolled in the trial had type 2 diabetes with established CV disease in the coronary, cerebral, or peripheral arteries. Patients were at least 50 years of age, had a baseline HbA1c between 6.5 and 8.0 per cent, and were dose-stable for at least three months on either: monotherapy or dual combination therapy with metformin, pioglitazone or a sulfonylurea; or insulin as monotherapy or in combination with a stable dose of metformin. Participants were randomly assigned to treatment with sitagliptin 100 mg daily (50 mg daily if baseline eGFR was =30 and <50 mL/min/1.73m2) or matching placebo.
The primary non-inferiority hypothesis was assessed by determining whether the upper bound of the 95 per cent confidence interval around the hazard ratio for the risk of the primary composite CV endpoint (time to first event) between the sitagliptin and placebo groups in the PP population did not exceed 1.3, with a key supporting analysis in the ITT population. If non-inferiority on the primary composite CV endpoint was met, superiority was to be evaluated in the ITT population.
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with Januvia (sitagliptin), such as anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 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. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Januvia or with any other antidiabetic drug. In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in greater than or equal to 5 per cent of patients treated with Januvia as monotherapy and in combination therapy, and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis and headache.