EXAMINE Trial Post-Hoc Analyses of Mortality Data Regarding Cardiovascular Safety of Alogliptin Presented at American Diabetes Association's 76thScientific Sessions and Published in Diabetes Care

Osaka, Japan, 11 June 2016 – Takeda Pharmaceutical Company Limited [TSE: 4502], (“Takeda”) announced the publication of a post-hoc analysis 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 (CVOT), which suggested that in patients with Type 2 diabetes and recent acute coronary syndrome (ACS), the risk of death, including CV death, was not higher with the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin compared to placebo during a median follow-up period of 18 months.¹ Trial results reported that in both groups of patients the occurrence of an additional non-fatal CV event, including myocardial infarction (MI), stroke, and unstable angina, was common and increased the risk of death, particularly after hospitalization for heart failure (HHF). This data was presented at the American Diabetes Association’s 76^th Scientific Sessions, and also published in Diabetes Care. 

“Heart disease, or CV disease, is the leading cause of death in patients with Type 2 diabetes,² and is responsible for between 50 and 80 percent of deaths in people with diabetes,³ so it’s critical we have a clear understanding of the impact these medications have on patients with Type 2 diabetes who are at a high risk for CV diseases such as those involved in EXAMINE,” said William B. White, MD, Professor, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, Connecticut, U.S., on behalf of the EXAMINE Steering Committee and Investigators. “The post-hoc analysis indicates that mortality, including CV mortality, was not higher with alogliptin versus placebo when studied for 18 months. These data provide additional important information for the healthcare professional in evaluating treatments for people living with Type 2 diabetes.”

In the EXAMINE trial, death from any cause occurred in 153 patients on alogliptin (5.7%) and 173 patients on placebo (6.5%) [HR = 0.88, 95% CI: 0.71-1.09].¹ Mortality rates following a first CV event were highest
in patients who had experienced HHF first in both the alogliptin and placebo groups compared to those that did not experience any major CV event. The rate of death following HHF was 25.9% in patients treated with alogliptin as compared to 28.4% in patients on placebo.

Takeda will be presenting eight abstracts at the meeting, including a post-hoc analysis from the EXAMINE trial studying the tolerability of alogliptin as a triple therapy with metformin and sulfonylureas (SU).⁴ It compared 550 patients treated with alogliptin, metformin, and a SU, to 505 patients treated with placebo, metformin and a SU, and followed patients for up to 40 months (median 18 months). The analysis reported that there was no significant difference in hypoglycaemia (8.8% alogliptin vs. 6.7% placebo, p=0.161) or serious hypoglycaemia (1.30% alogliptin vs. 0.43% placebo, p=0.088), and had suggested that the triple therapy was effective and well tolerated. 

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 diverse diabetes portfolio show Takeda’s ongoing commitment to advancing patient care and helping to meet the individual needs of this growing patient population.

About the EXAMINE Trial
EXAMINE, a large, randomized, double-blind, placebo-controlled outcomes study, was completed as a result of the U.S. FDA 2008 Guidance, titled “Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,” for all Type 2 diabetes treatments under development since the issuance of the guidance.^5,6 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 who were at high risk for major adverse cardiovascular events (MACE) due to recent acute coronary syndrome (ACS).⁵ The trial’s primary objective was to evaluate non-inferiority of CV risk based on a primary composite endpoint of CV death, nonfatal myocardial infarction (MI) and nonfatal stroke.

EXAMINE randomized 5,380 patients in 49 countries with Type 2 diabetes with an ACS within the previous 15-90 days.⁵ 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 MI and nonfatal stroke. The primary endpoint occurred at similar rates in the alogliptin (n=305) and placebo (n=316) groups (in 11.3 percent of patients vs. 11.8 percent of patients during a median follow-up period of 18 months; hazard ratio (HR), 0.96; upper boundary of the one-sided repeated CI, 1.16). These data reported that alogliptin does not increase CV risk in Type 2 diabetes patients at high-risk for MACE due to a recent ACS.

About Alogliptin
Alogliptin is a DPP-4 inhibitor for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise. DPP-4 inhibitors are designed to slow the inactivation of incretin hormones glucagon-like peptide-1 (GLP) GLP-1 and glucose-dependent insulinotropic peptide (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.

Takeda launched alogliptin in Japan in 2010. Since that time alogliptin and/or its FDC therapies have been approved in over 30 countries across the globe including Brazil, China, the European Union, Mexico, Russia, South Korea and the United States. Diabetes prevalence continues to grow worldwide, with more than 415 million people impacted by diabetes.² As the disease becomes increasingly prevalent, Takeda remains focused on expanding access of alogliptin, especially in emerging markets.

INDICATIONS

Alogliptin

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.

Alogliptin/Metformin

Alogliptin/Metformin is indicated in the treatment of adult patients aged 18 years and older with type 2 diabetes mellitus: as an adjunct to diet and exercise to improve glycaemic control in adult patients, inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of alogliptin and metformin; in combination with pioglitazone (i.e., triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and pioglitazone; in combination with insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control.

Alogliptin/Pioglitazone

Alogliptin/Pioglitazone is indicated as a second or third line treatment in adult patients aged 18 years and older with type 2 diabetes mellitus: as an adjunct to diet and exercise to improve glycaemic control in adult patients (particularly overweight patients) inadequately controlled on pioglitazone alone, and for whom metformin is inappropriate due to contraindications or intolerance; in combination with metformin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in adult patients (particularly overweight patients) inadequately controlled on their maximal tolerated dose of metformin and pioglitazone. In addition, Alogliptin/Pioglitazone can be used to replace separate tablets of alogliptin and pioglitazone in those adult patients aged 18 years and older with type 2 diabetes mellitus already being treated with this combination.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS – for Alogliptin, Alogliptin/Metformin and Alogliptin/Pioglitazone

Acute Pancreatitis - Postmarketing events of acute pancreatitis have been reported for alogliptin and have been associated with DPP-4 inhibitors. After initiation of alogliptin, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Alogliptin/Metformin or Alogliptin/Pioglitazone should be promptly discontinued and appropriate management should be initiated.

Hypersensitivity Reactions - Postmarketing events of serious hypersensitivity reactions in patients with alogliptin such as angiodema and severe cutaneous adverse reactions including Stevens-Johnson syndrome have been reported and have been associated with DPP-4 inhibitors. If a serious hypersensitivity reaction is suspected, Alogliptin/Metformin or Alogliptin/Pioglitazone should be discontinued.

Hepatic Effects - Postmarketing reports of hepatic dysfunction including hepatic failure, sometimes fatal, have been received. Baseline liver test panel is recommended. Patients should be observed closely for possible liver abnormalities. Perform liver tests promptly in patients who report symptoms that may indicate liver injury. If an abnormally is found and an alternative etiology is not established, consider discontinuation of Alogliptin/Metformin or Alogliptin/Pioglitazone.

Hypoglycemia - Insulin and insulin secretagogues are known to cause hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with alogliptin, Alogliptin/Metformin or Alogliptin/Pioglitazone.

WARNINGS AND PRECAUTIONS – for Alogliptin/Metformin

Lactic Acidosis - Lactic Acidosis is very rare, but serious and potentially fatal metabolic complication that can occur due to metformin accumulation. Reported cases have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing other associated risk factors such as excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. In particular, elderly patients have a tendency to have decreased renal function; hence treatment of the elderly should be accompanied by careful monitoring of renal function (creatinine clearance). If renal acidosis is suspected, treatment with Alogliptin/Metformin should be discontinued.

Renal Function - Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increase with the degree of impairment of renal function. Thus patients with raised serum creatinine levels (or serum creatinine levels >135 mcmol/L in males and > 110 mcmol/L in females or creatinine clearance < 60 mL/min) should not receive alogliptin and metformin. Appropriate assessment of renal function is recommended prior to initiation of treatment and periodically thereafter.

WARNINGS AND PRECAUTIONS - for Alogliptin/Pioglitazone

Hepatic Function - Alogliptin/Pioglitazone must not be used in patients with hepatic impairment.

Fluid Retention and Cardiac Failure - Pioglitazone, like other thiazolidinediones, can cause fluid retention, which may exacerbate or precipitate heart failure. Patients with heart failure should be monitored for its signs and symptoms, and discontinuation of pioglitazone should be considered if any deterioration in cardiac status occurs.

Edema - Dose-related edema may occur. Use with caution in patients with edema.

Bladder Cancer - Data suggest an increased risk of bladder cancer in pioglitazone users. Data also suggest that the risk increased with duration of use. Do not use Alogliptin/Pioglitazone in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria urgency as these may be due to bladder cancer.

WARNINGS AND PRECAUTIONS - for Alogliptin

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.

CONTRAINDICATIONS

Alogliptin
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.

Alogliptin/Metformin
Alogliptin/Metformin is contraindicated in patients with known hypersensitivity to alogliptin, metformin hydrochloride, or any of its components. Additionally, due to the metformin hydrochloride component, Alogliptin/Metformin is contraindicated in patients with the following conditions: Renal disease or renal dysfunction and Diabetic ketoacidosis, diabetic coma or pre-coma.

Alogliptin/Pioglitazone
Alogliptin/Pioglitazone is contraindicated in patients with known hypersensitivity to alogliptin, pioglitazone or any of its components. Initiation of alogliptin/pioglitazone treatment is contraindicated in patients with cardiac failure (NYHA Class III or IV).

DRUG INTERACTIONS

Use with CYP2C8 strong inhibitors (i.e., gemfibrozil or inducers (i.e., rifampin) may require dose adjustment.

ADVERSE REACTIONS

Alogliptin - Adverse reactions include upper respiratory infection, nasopharyngitis, headache, abdominal pain, gastroesophageal reflux disease, pruritis, and rash.

Alogliptin/Metformin - Adverse reactions include gastroesophageal reflux disease, headache, upper respiratory tract infection, pruritis, nasopharangitis, hypersensitivity reactions, hepatic failure and acute pancreatitis, lactic acidosis, decreased vitamin B12, diarrhea, nausea, vomiting, flatulence, abdominal pain, anorexia, rash and taste disorder.

Alogliptin/Pioglitazone – Adverse reactions include upper respiratory tract infections, sinusitis, headache, nausea, dyspepsia, abdominal pain, pruritis, myalgia, oedema peripheral, weight increased.

Please consult with your local regulatory agency for approved labeling in your country.

About Takeda Pharmaceutical Company
Takeda Pharmaceutical Company Limited is a global, R&D-driven pharmaceutical company committed to bringing better health and a brighter future to patients by translating science into life-changing medicines. Takeda focuses its research efforts on oncology, gastroenterology and central nervous system therapeutic areas. It also has specific development programs in specialty cardiovascular diseases as well as late-stage candidates for vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as its presence in emerging markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.