Secondary Analysis of EXAMINE Trial Finds Highest Risk of Cardiovascular Death for Patients Previously Hospitalized with Heart Failure

Study Will Be Presented at 76th Scientific Sessions and Published Concurrently in Diabetes Care

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Jun 11, 2016, 01:30 ET

NEW ORLEANS, June 11, 2016 /PRNewswire-USNewswire/ -- People with type 2 diabetes and heart disease who experience non-fatal cardiovascular events are at increased risk of cardiovascular-related death, and those previously hospitalized for heart failure are at highest risk, according to new analysis of data from the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial. The study is being published online in Diabetes Care concurrent with its presentation on June 10, 2016, at the American Diabetes Association's 76th Scientific Sessions in New Orleans.

Initial results from the EXAMINE trial, one of the first major cardiovascular outcomes studies of people with type 2 diabetes and coronary heart disease, were previously reported in 2013[1]. The initial findings demonstrated that the DPP-4 inhibitor alogliptin did not increase risk of death or non-fatal cardiovascular events, such as stroke, myocardial infarction (heart attack), hospitalization for heart failure (HHF) or unstable angina (UA), compared to placebo.

In this new analysis, the same group of researchers evaluated the subsequent risk of cardiovascular mortality for EXAMINE's 5,380 patients with type 2 diabetes, randomized to alogliptin (n=2,701) or placebo (n=2,679), beginning 15 to 90 days following an acute coronary syndrome—a broad term for any condition in which is the heart's blood supply is blocked. Patients received standard care for both type 2 diabetes and cardiovascular risk factors throughout the study and were seen at outpatient visits every three months during the first year and every four months for the remainder of their participation in the trial—a median duration of 18 months.

During the course of the trial, 736 patients (13.7 percent) experienced at least one non-fatal cardiovascular event, including heart attacks (5.9 percent, n=316), stroke (1.1 percent, n=57), hospitalization for heart failure (HHF) (3.0 percent, n=159) and unstable angina (UA) (3.8 percent, n=204).

In total, 326 patients died during EXAMINE. The majority of deaths (n= 233) in the EXAMINE trial were among patients who did not experience a non-fatal cardiovascular event. However, those patients who did experience non-fatal cardiovascular events were at increased risk of cardiovascular-related death compared to those who did not experience non-fatal cardiovascular events. Cardiovascular-related deaths were defined as deaths from cardiac and cerebrovascular causes, as well as any other death without a known cause.

Patients with type 2 diabetes admitted to the hospital for heart failure during the trial (n=159) were at the highest increased risk for death due to cardiovascular causes. The data indicates their cardiovascular morbidity was more than four times higher: 20.1 percent (n=32) died of cardiovascular-related causes, compared to 3.7 percent of the total 4,644 patients (n=172) who did not experience a non-fatal cardiovascular event during the trial.

The subsequent mortality rates for those who experienced a non-fatal stroke (8.8 percent of 57 patients, n= 5) or non-fatal heart attack (8.2 percent of 316, n= 26) during follow-up were twice as high compared to those who did not experience a non-fatal cardiovascular event. Of the 204 patients who were admitted to the hospital for unstable angina (UA), 3.4 percent (n=7) subsequently died from cardiovascular-related causes.

Patients treated with the DPP-4 inhibitor alogliptin experienced no significant difference in mortality rates (4.1 percent), compared to those treated with placebo (4.9 percent, HR = 0.85, 95% CI, 0.66-1.10).

"Heart failure is a powerful predictor of mortality in patients with both type 2 diabetes and coronary heart disease," said lead investigator William B. White, MD, Professor of Medicine, The Pat and Jim Calhoun Cardiology Center, UConn Health. "This study suggests that we have an important opportunity to evaluate and understand the factors underlying incident heart failure in order to improve prevention strategies. These findings emphasize how critical it is to aggressively make use of evidence-based, secondary preventive therapies, which should be considered a standard in the clinical management of patients with type 2 diabetes who are at high risk for cardiovascular disease."

The American Diabetes Association's 76th Scientific Sessions, to be held June 10-14, 2016, at the Ernest N. Morial Convention Center in New Orleans, is the world's largest scientific meeting focused on diabetes. The 2016 Scientific Sessions is expected to attract more than 16,000 attendees and offers researchers and health care professionals from around the world the opportunity to share ideas and learn about the significant advances in diabetes research, treatment and care. During the five-day meeting, attendees receive exclusive access to more than 2,500 original research presentations, participate in provocative and engaging exchanges with leading diabetes experts, and can earn Continuing Medical Education (CME) or Continuing Education (CE) credits for educational sessions. The program is grouped into eight theme areas: Acute and Chronic Complications; Behavioral Medicine, Clinical Nutrition, Education and Exercise; Clinical Diabetes/Therapeutics; Epidemiology/Genetics; Immunology/Transplantation; Insulin Action/Molecular Metabolism; Integrated Physiology/Obesity; and Islet Biology/Insulin Secretion. Margaret A. Powers, PhD, RD, CDE, President, Health Care & Education, will deliver her address on Saturday, June 11, and Desmond Schatz, MD, President, Medicine & Science, will present his address on Sunday, June 12. The top eight abstracts of this year's Scientific Sessions will be presented on Tuesday, June 14, in the Presidents Oral Session. In total, the 2016 Scientific Sessions includes 378 abstracts in 50 oral sessions, 2,021 poster presentations including 59 moderated poster discussions, and 335 published-only abstracts. The Association's 2016 Scientific Achievement Awards and Lectures are:

Barbara B. Kahn, MD, Banting Medal for Scientific Achievement, the Association's highest honor. Kahn will deliver the Banting Medal Lecture, "Adipose Tissue, Inter-organ Communication, and the Path to T2D," on Sunday, June 12.
Tamas L. Horvath, DVM, PhD, Outstanding Scientific Achievement Award (OSAA), will present his OSAA Lecture, "Hunger-promoting Hypothalamic Neurons Control System Metabolism and Drive Complex Behaviors and Longevity," on Monday, June 13.
Sheri R. Colberg-Ochs, PhD, FACSM, Outstanding Diabetes Educator, will present her Lecture, "From Froot Loops^® to Fitness—My Journey as an Educator and PWD," on Saturday, June 11.
Edward W. Gregg, PhD, Kelly West Award for Outstanding Achievement in Epidemiology, will deliver his Lecture, "The Changing Tides of the Diabetes Epidemic—Smooth Sailing or Troubled Waters Ahead?," on Sunday, June 12.

Additional scientific research will be presented during 110 Symposia and nine Professional Interest Group sessions. The 76th Scientific Sessions also includes presence from more than 130 corporate and organizational exhibitors in nearly 100,000 square feet of exhibit space. Join the Scientific Sessions conversation on Twitter, #2016ADA.

[1] White, WB, Cannon, CP, Heller, SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369:1327-1335.

About the American Diabetes Association
The American Diabetes Association is leading the fight to Stop Diabetes^® and its deadly consequences and fighting for those affected by diabetes. The Association funds research to prevent, cure and manage diabetes; delivers services to hundreds of communities; provides objective and credible information; and gives voice to those denied their rights because of diabetes. Founded in 1940, the Association's mission is to prevent and cure diabetes, and to improve the lives of all people affected by diabetes. For more information, please call the American Diabetes Association at 1-800-DIABETES (1-800-342-2383) or visit diabetes.org. Information from both of these sources is available in English and Spanish. Find us on Facebook (American Diabetes Association), Twitter (@AmDiabetesAssn) and Instagram (@AmDiabetesAssn).

76th Scientific Sessions
News Briefing: Cardiovascular Disease and Diabetes, Sunday,
June 12, 9:15 a.m.-10:00 a.m. CT

Moderated Poster Discussion: Oral Agents—Short-Term Effects to Long-Term Outcomes; Sunday General Poster Session
Poster Presentation: Poster Hall (Halls D-E) ePoster Theater B; Poster Hall (Halls D-E)
Session Time: Saturday, June 11, 2016, 11:30 a.m.-12:30 p.m.; Sunday, June 12, 2016, 12:00 noon-2:00 p.m.

1090-P Mortality Findings from the EXAMINE Trial

Author Block: WILLIAM B. WHITE, STUART KUPFER, CHRISTOPHER P. CANNON, CYRUS R. MEHTA, SIMON R. HELLER, CRAIG WILSON, GEORGE L. BAKRIS, WILLIAM C. CUSHMAN, STEVEN E. NISSEN, RICHARD M. BERGENSTAL, PENNY FLECK, FAIEZ ZANNAD, Farmington, CT, Deerfield, IL, Boston, MA, Sheffield, United Kingdom, Chicago, IL, Memphis, TN, Cleveland, OH, Minneapolis, MN, Nancy, France

The EXAMINE trial patients had elevated cardiovascular (CV) risk due to type 2 diabetes and a recent (15-90 days) acute coronary syndrome (ACS). We evaluated the risk of CV death in patients randomized to treatment with alogliptin or placebo and following major non-fatal CV events that occurred during the trial. In 5380 patients, overall rates of CV death were 4.1% for alogliptin and 4.9% for placebo (HR = 0.85, 95% CI, 0.66-1.10). Patients were followed until the first post-randomized non-fatal CV event of myocardial infarction (MI), stroke, hospitalized heart failure (HHF), and hospitalization for unstable angina (UA) and then to death or censoring. Time-updated multivariable Cox models were used to estimate the risk of death following each event. There were a total of 736 patients (13.7%) who experienced at least one first non-fatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). CV death occurred subsequently in 8.2% of those experiencing an MI event, 20.1% of those experiencing a HHF event, 8.8% of those experiencing a stroke, and 3.4% of those experiencing UA, versus 3.7% (n = 172) of the 4644 patients without a non-fatal CV event. Compared with patients who did not experience a non-fatal event, the adjusted hazard ratio for death was 1.83 (95% CI, 1.29-2.59, p = 0.006) after MI, 3.91 (95% CI, 2.77-5.51, p < 0.0001) after HHF, 1.74 (95% CI, 0.77-3.94, p = 0.186) after stroke, and 0.81 (95% CI, 0.41-1.58, p = 0.527) after admission for UA. Mortality rates following a non-fatal event were comparable on alogliptin and placebo. In EXAMINE, the majority of deaths occurred in patients who did not experience a non-fatal CV event, although the risk of death was markedly higher following a non-fatal event, particularly HHF. These findings illustrate ongoing opportunities to reduce mortality in patients with type 2 diabetes and CV diseases.

Author Disclosure Block:
W.B. White: Other Relationship; Author; Takeda Development Center Americas, Inc. S. Kupfer: Employee; Author; Takeda Development Center Americas, Inc. C.P. Cannon: Consultant; Author; Boehringer Ingelheim GmbH, CSL Behring, Essentialis, Inc., GlaxoSmithKline, Kowa Company, Ltd., Merck & Co., Inc, Takeda Development Center Americas, Inc., LipoMedix, Pfizer Inc., Regeneron Pharmaceuticals, Inc., Sanofi U.S., Bristol-Myers Squibb Company. Research Support; Author; Accumetrics, Inc., Arisaph Pharmaceuticals, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline, Merck & Co., Inc. C.R. Mehta: Employee; Author; Cytel Inc. S.R. Heller: Consultant; Author; Novo Nordisk Inc, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Sanofi-Aventis Deutschland GmbH, Merck & Co., Inc. Research Support; Author; Medtronic, Inc.. Speaker's Bureau; Author; Takeda Development Center Americas, Inc., Novo Nordisk Inc, Sanofi-Aventis Deutschland GmbH, Eli Lilly and Company. C. Wilson: Employee; Author; Takeda Development Center Americas, Inc. G.L. Bakris: Research Support; Author; Bayer HealthCare, Medtronic, Inc., Relypsa, Inc., Takeda Development Center Americas, Inc., AbbVie Inc. Other Relationship; Author; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., NxStage. W.C. Cushman: Research Support; Author; Eli Lilly and Company, Merck & Co., Inc. Other Relationship; Author; Takeda Development Center Americas, Inc. S.E. Nissen: Research Support; Author; Novo Nordisk Inc, Takeda Development Center Americas, Inc., AstraZeneca, Pfizer Inc., Eli Lilly and Company. R.M. Bergenstal: Advisory Panel; Author; Boehringer Ingelheim GmbH, Eli Lilly and Company, Halozyme Therapeutics, Johnson & Johnson, Novo Nordisk Inc, Roche USA, Sanofi U.S., Takeda Development Center Americas, Inc.. Research Support; Author; Boehringer Ingelheim GmbH, Eli Lilly and Company, Halozyme Therapeutics, Johnson & Johnson, Merck & Co., Inc, Novo Nordisk Inc, Roche USA, Sanofi U.S., Takeda Development Center Americas, Inc. P. Fleck: Former Employee; Author; Takeda Development Center Americas, Inc. F. Zannad: Research Support; Author; Roche Diagnostics. Other Relationship; Author; Air Liquide, Bayer HealthCare, Biomérieux, Biotronik, Boston Scientific, CVRx, Janssen Pharmaceuticals, Inc., Novartis AG, Pfizer Inc., ResMed, Sanofi U.S., Servier, St. Jude Medical, Takeda Development Center Americas, Inc., Mitsubishi, CardioRenal Diagnostics.