Osaka, Japan, March 10, 2015 – Takeda Pharmaceutical Company Limited (Takeda) announced that a post hoc analysis of data from the global EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) cardiovascular (CV) safety outcomes trial was published in The Lancet. An analysis of data from the study showed that in patients with Type 2 diabetes and recent acute coronary syndrome (ACS), dipeptidyl peptidase 4 inhibitor (DPP-4i) alogliptin compared to placebo did not increase the risk of heart failure (HF) outcomes. Alogliptin (n=201, 7.4%) compared with placebo (n=201, 7.5%) had no effect on the extended exploratory post hoc composite endpoint of CV death and hospitalized heart failure (HHF) (HR=1.00, 95% CI, 0.82, 1.21). Patients with a history of HF prior to randomization had a higher risk of HF outcomes in EXAMINE. The sub-analysis showed that the risk of the composite of CV death and HHF was not increased with alogliptin (n=107, 13.9%) compared with placebo (n=120, 15.7%) (HR=0.90, 95% CI, 0.70, 1.17). In patients without a history of HF at baseline, there was also no increased risk of the composite endpoint of CV death and HHF for alogliptin (HR=1.14 [95% CI 0.85-1.54], p=0.337) versus placebo, although there was in this sub group of patients a small absolute increase in HHF for alogliptin versus placebo (0.9%).
Alogliptin is the first DPP-4i to report out results on CV safety outcomes in Type 2 diabetes patients that are at high risk due to recent ACS. Heart disease, or cardiovascular disease (CVD), is the leading cause of morbidity and mortality in patients with Type 2 diabetes, and is responsible for between 50 and 80 percent of deaths in people with diabetes.
"Patients with diabetes are at significantly higher risk of having heart disease or suffering a stroke, and it is critical that diabetes treatments adequately manage glucose levels without adversely affecting cardiovascular outcomes, such as hospitalized heart failure and cardiac death, " said Faiez Zannad, M.D., Professor of Therapeutics and Cardiology, Institut Lorrain du Coeur et des Vaisseaux, Centre d'Investigation Clinique Inserm, in France. "The publication of these post hoc analyses of data from EXAMINE is an opportunity to share findings that alogliptin compared with placebo did not increase the composite rate of cardiovascular mortality and hospitalized heart failure in this high risk population of patients with diabetes."
The EXAMINE trial was designed to evaluate CV safety following treatment with alogliptin in addition to standard of care, versus placebo in addition to standard of care, in patients with Type 2 diabetes and a recent ACS. The EXAMINE trial's primary composite endpoint (CV death, nonfatal myocardial infarction and nonfatal stroke) established non-inferiority of alogliptin compared to placebo in addition to standard of care, showing no increase in CV risk in a Type 2 diabetes patient population at high risk for CV events.
For the present study published in The Lancet, HF outcomes by quartile of baseline brain natriuretic peptide (BNP), as well as assessments of changes of N-Terminal proBNP (NT-proBNP) from baseline to six months were investigated.1 Patients in the highest quartile of baseline BNP were at the highest risk of HF outcomes; however, the risk of the composite endpoint of CV death and HHF was not increased with alogliptin (n=120, 17.5%) compared with placebo (n=121, 19.4%) (HR=0.90, 95% CI, 0.70, 1.16). Consistent with these outcomes, the change from baseline to 6 months for NT-proBNP was not different between alogliptin and placebo in this subgroup or in the overall study population.
About the EXAMINE Trial
EXAMINE randomized 5,380 patients in 49 countries with Type 2 diabetes with an ACS within the previous 15-90 days. The EXAMINE primary endpoint of non-inferiority compared to placebo in addition to standard of care was met, showing no increase in CV risk in a Type 2 diabetes patient population at high risk for CV events based on the primary composite endpoint of CV death, nonfatal myocardial infarction and nonfatal stroke. The primary endpoint occurred at similar rates in the alogliptin and placebo groups (in 11.3 percent of patients vs. 11.8 percent of patients during a median follow-up period of 18 months; HR, 0.96; upper boundary of the one-sided repeated CI, 1.16).
In the alogliptin group, 71.4 percent of patients received 25 mg, 25.7 percent received 12.5 mg, and 2.9 percent received 6.25 mg daily. Alogliptin doses were adjusted according to renal function: estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease formula ≥ 60 ml/min/1.73 m2, 25 mg daily; < 60 ml/min/1.73 m2 but ≥ 30 ml/min/1.73 m2, 12.5 mg daily; and < 30 ml/min/1.73 m2, 6.25 mg daily. Premature discontinuation of the study drug was similar in the alogliptin and placebo groups (20.9 percent of patients vs. 22.6 percent). The median duration of exposure to study drug was 533 days (interquartile range, 280 to 751 days). By the end of the study, the mean change from baseline in HbA1c was -0.33 percent and 0.03 percent in the alogliptin and placebo groups respectively, and the least square means difference in HbA1c between alogliptin and placebo was -0.36 percent (95 percent CI, -0.43, -0.28, p<0.001). In the analysis of the components of the primary endpoint, the hazard ratios were consistent with the overall result. Hazard ratios for death from any cause and CV death were consistent with the primary composite endpoint.
Takeda conducted the global EXAMINE trial in accordance with the United States (U.S.) Food and Drug Administration's (FDA) 2008 Guidance, titled "Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes," for all new Type 2 diabetes treatments.
Alogliptin is a DPP-4i for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise. DPP-4is are designed to slow the inactivation of incretin hormones GLP-1 and GIP. As a result, an increased amount of active incretins enables the pancreas to secrete insulin in a glucose-dependent manner, thereby assisting in the management of blood glucose levels.
Alogliptin is approved as a monotherapy and also in fixed-dose combination (FDC) with pioglitazone and metformin HCl for the treatment of Type 2 diabetes in adults as adjuncts to diet and exercise. These therapies are not for treatment of Type 1 diabetes or diabetic ketoacidosis.
Alogliptin is available in many markets across Australia, China, Europe, Japan, Mexico, South Korea and the U.S.
Alogliptin is indicated in adults aged 18 years and older with Type 2 diabetes mellitus to improve glycaemic control in combination with other glucose lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.
Important Safety Information
· ALOGLIPTIN is contraindicated in patients with a history of serious hypersensitivity reaction to alogliptin-containing products such as anaphylaxis, angioedema, or severe cutaneous adverse reactions.
· Acute pancreatitis: There have been post marketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue ALOGLIPTIN.
· Hypersensitivity: Hypersensitivity reactions, including anaphylactic reactions, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome have been observed for DPP-4 inhibitors. In clinical studies of alogliptin, anaphylactic reactions were reported with a low incidence.
· Hepatic effects: Post marketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. Baseline liver test panel is recommended. If liver injury is detected, promptly interrupt ALOGLIPTIN and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart ALOGLIPTIN if liver injury is confirmed and no alternative etiology can be found.
· Cardiac failure: Experience of ALOGLIPTIN use in clinical trials in patients with congestive heart failure of New York Heart Association (NYHA) functional class III and IV is limited and caution is warranted in these patients.
· Hypoglycemia: Insulin and insulin secretagogues are known to cause hypoglycemia. A lower dose of the insulin or insulin secretagogue may be required to minimize the risk when used in combination with ALOGLIPTIN.
· Most common adverse reactions: pooled phase 3 controlled studies (≥1/10 frequency) with ALOGLIPTIN: Upper respiratory infection, nasopharyngitis, headache, abdominal pain, gastroesophageal reflux disease, pruritis, and rash.
Please see local prescribing information for ALOGLIPTIN.
About Takeda's Diabetes Business
Takeda's heritage in diabetes globally includes significant contributions towards scientific discovery and exchange, starting with the discovery of the thiazolidinedione (TZD) pioglitazone, the more recent developments of alogliptin and the fixed-dose combinations (FDC) alogliptin and pioglitazone, and alogliptin and metformin HCl. The company's strong, diverse diabetes portfolio and available medications mark important milestones in Takeda's ongoing commitment to advancing patient care and helping to meet the individual needs of this growing patient population.
About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for people worldwide through leading innovation in medicine.
Additional information about Takeda is available through its corporate website, www.takeda.com.
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Elissa J. Johnsen
Takeda Pharmaceutical Company Limited
Corporate Communications Dept.