TECOS, Merck's Cardiovascular Safety Trial of JANUVIA (sitagliptin), Met Primary Endpoint in Patients with Type 2 Diabetes

Findings Published in the New England Journal of Medicine and Presented at the American Diabetes Association Scientific Sessions

Treatment with Sitagliptin Did Not Increase the Risk of Major Adverse Cardiovascular Events in the Primary Composite Endpoint, or Hospitalization for Heart Failure, Compared with Placebo

KIRKLAND, QC, June 10, 2015 /CNW Telbec/ - Merck (NYSE: MRK) known as MSD outside Canada and the United States, announced the primary results of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a placebo-controlled study of the cardiovascular (CV) safety of MSD'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 percent (n=839) of sitagliptin-treated patients compared with 11.6 percent (n=851) of placebo-treated patients in the Intention-to-Treat (ITT) analysis (HR=0.98; 95% CI [0.89-1.08]), and in 9.6 percent (n=695) of patients in both the sitagliptin and placebo groups in the Per Protocol (PP) analysis (HR=0.98; 95% CI [0.88-1.09]; p<0.001 for non-inferiority).1,i 

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 on June 8 at the 75th Scientific Sessions of the American Diabetes Association and were also published in the New England Journal of Medicine.

"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 contains a robust and rich data set derived from over 14,000 diabetic patients followed for almost approximately 3 years," explained Dr. Paul Armstrong, Distinguished University Professor, Department of Medicine (Cardiology), University of Alberta. "With TECOS, we have learned that when sitagliptin is added to usual care it did not increase the risk of cardiovascular events and there was no increase in heart failure."

"The TECOS study provides important new information highlighting the cardiovascular and safety profile of sitagliptin," added Dr. Lawrence Leiter, Endocrinologist at St. Michael's Hospital in Toronto.

Additional Findings from the TECOS CV Safety Trial

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.ii  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% 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 percent (n=228) of sitagliptin-treated patients and 3.1 percent (n=229) of placebo-treated patients (HR=1.00; 95% CI [0.83-1.20]).i  All-cause mortality was similar in both treatment groups, occurring in 7.5 percent (n=547) of patients in the sitagliptin group and 7.3 percent (n=537) in the placebo group (HR=1.01; 95% CI [0.90-1.14]).i   

Acute pancreatitis was uncommon, occurring in 0.3 percent of patients in the sitagliptin group (n=23) and 0.2 percent 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 percent of patients in the sitagliptin group (n=9) and 0.2 percent of patients in the placebo group (n=14), and was not statistically different between groups (p=0.322).i

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 percent (n=538) in the sitagliptin group compared with 7.2 percent (n=525) for placebo (HR=1.02; 95% CI [0.90-1.15]).i The proportion of patients with CV death was 5.2 percent (n=380) in the sitagliptin group compared with 5.0 percent (n=366) in the placebo group (HR 1.03; 95% CI [0.89-1.19]).i

The proportion of patients with non-CV death was 2.3 percent in both treatment groups.i  Death due to infection was 0.6 percent and 0.7 percent 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.i

"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.ii  At four months, mean HbA1c level was 0.4 percent lower in the sitagliptin group compared with placebo, and this narrowed to 0.1 percent lower during patient follow-up.i This resulted in an overall difference of -0.29 percent in patients treated with sitagliptin versus placebo.i  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).i

Study Methods and Design

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 MSD.ii  A total of 14,735 patients from 38 countries were randomized between December 2008 and July 2012.i  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.i

Patients enrolled in the trial had type 2 diabetes with established CV disease in the coronary, cerebral, or peripheral arteries.i  Patients were at least 50 years of age, had a baseline HbA1c between 6.5 and 8.0 percent, 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.i  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 percent confidence interval for 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.i  If non-inferiority on the primary composite CV endpoint was met, superiority was to be evaluated in the ITT population.i

About JANUVIA

In Canada, JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus as monotherapy when metformin is inappropriate due to contraindications or intolerance or in combination with metformin, a sulfonylurea, or pioglitazone, or as an add-on to sulfonylurea + metformin or pioglitazone + metformin when the current regimen, with diet and exercise does not provide adequate glycemic control. JANUVIA is also indicated as add-on to premixed or long/intermediate acting insulin (with or without metformin) when diet and exercise plus insulin do not provide adequate glycemic control.

Important Selected Safety Information About Sitagliptin

There have been reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA should promptly be discontinued and appropriate management should be initiated. Risk factors for pancreatitis include a history of: pancreatitis, gallstones, alcoholism, or hypertriglyceridemia.

A limited number of patients with congestive heart failure participated in clinical studies of sitagliptin. In studies of sitagliptin in combination with metformin, patients with congestive heart failure requiring pharmacological therapy or NYHA Class III or IV congestive heart failure were excluded. Patients with Classes I and II were included in small number. Use in this population is not recommended.

A dosage adjustment is recommended in patients with moderate or severe renal insufficiency or with end-stage renal disease requiring hemodialysis or peritoneal dialysis. . 

For additional adverse experience information, consult the product monograph at www.merck.ca.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside Canada and the United States. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information about our operations in Canada, visit www.merck.ca.

Forward-Looking Statement

This news release includes "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the

United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck's ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2014 Annual Report on Form 10-K and the company's other filings with the

Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

The Product monograph and Patient information are available at www.merck.ca


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1 The primary hypothesis of non-inferiority of sitagliptin vs. placebo for the composite CV endpoint was based on the Per Protocol (PP) analysis.

i Green JB et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2015 June.

ii Green JB et al. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. American Heart Journal. 2013 Dec;166(6):983-989.e7.

 

SOURCE Merck Canada Inc.

For further information: Media Contact: Annick Robinson, (438) 837-2550; Investor Contact: Justin Holko, (908) 740-1879

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