New 2017 Publications from EXAMINE

High-sensitivity C-reactive protein, low-density lipoprotein cholesterol and cardiovascular outcomes in patients with type 2 diabetes in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial.
Hwang YC, Morrow DA, Cannon CP, Liu Y, Bergenstal R, Heller S, Mehta C, Cushman W, Bakris GL, Zannad F, White WBDiabetes Obes Metab. 2017 Oct 24. doi: 10.1111/dom.13136. [Epub ahead of print] PMID: 29064626

Serial Measurement of High-Sensitivity Troponin I and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus in the EXAMINE Trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care).
Cavender MA, White WB, Jarolim P, Bakris GL, Cushman WC, Kupfer S, Gao Q, Mehta CR, Zannad F, Cannon CP, Morrow DA. Circulation. 2017 May 16;135(20):1911-1921. doi: 10.1161/CIRCULATIONAHA.116.024632. Epub 2017 Feb 28. PMID: 28246236

Baseline adiponectin concentration and clinical outcomes among patients with diabetes and recent acute coronary syndrome in the EXAMINE trial.
Bergmark BA, Cannon CP, White WB, Jarolim P, Liu Y, Bonaca MP, Zannad F, Morrow DA. Diabetes Obes Metab. 2017 Jul;19(7):962-969. doi: 10.1111/dom.12905. Epub 2017 Mar 17. PMID: 28195387

New Presentations from the EASD, Lisbon, Portugal, September 11-14, 2017

Cardiovascular Outcome Trials in Type 2 Diabetes: Lessons Learned and Future Outlook

Total Cardiovascular Events Analysis of the EXAMINE Trial of Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome

High Sensitivity C-Reactive Protein, Low-Density Cholesterol, and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Acute Coronary Syndrome From the EXAMINE Trial

Visit-to-Visit Blood Pressure Variability and Cardiovascular Outcomes in Patients with Type 2 Diabetes Following Acute Coronary Syndromes in the EXAMINE Trial

New 2016 Publications from EXAMINE

Cardiovascular Effects of Incretin-Based Therapies.
White WB, Baker WL. Annu Rev Med. 2016;67:245-60. doi: 10.1146/annurev-med-050214-013431. Review. PMID: 26768240

Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.
White WB, Wilson CA, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, Heller SK, Mehta CR, Nissen SE, Zannad F, Kupfer S; EXAMINE Investigators. Hypertension. 2016 Sep;68(3):606-13. doi: 10.1161/HYPERTENSIONAHA.116.07797. Epub 2016 Aug 1. PMID: 27480840

Relationship of Glycated Haemoglobin and Reported Hypoglycaemia to Cardiovascular Outcomes in Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome Events: The EXAMINE Trial

Ischemic Cardiac Outcomes and Hospitalizations According to Prior Macrovascular Disease Status in Patients with Type 2 Diabetes and Recent Acute Coronary Syndrome from the Examination of Cardiovascular Outcomes with Alogliptin Versus Standard of Care Trial

Cardiovascular Mortality in Patients with Type 2 Diabetes and Recent Acute Coronary Syndromes from the EXAMINE Trial

Diabetes Drug Shown Not to Increase Heart Failure Risk

Glucometer
A new study published in the medical journal The Lancet concludes that the diabetes drug Alogliptin does not carry significant increased risk for heart disease. (Shutterstock Photo)

By Chris DeFrancesco, UConn Today

People with the most common form of diabetes can take the new drug Alogliptin without concern for an increased risk of heart failure or cardiovascular disease, according to research by a UConn cardiologist just published in the British medical journal, The Lancet.

Dr. William White, professor of medicine and chief of the Calhoun Cardiology Center Division of Hypertension and Clinical Pharmacology at UConn Health, analyzed data from a global clinical trial called EXAMINE. Regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new diabetic therapies.

“This new analysis shows that Alogliptin was safe in patients with Type 2 diabetes who we considered at high cardiovascular risk because they had had an acute coronary syndrome before entering the trial,” says White.

Dr. William White is senior author of the study, which is based on a global clinical trial of the diabetes drug. (Janine Gelineau/UConn Health)
Dr. William White is senior author of the study, which is based on a global clinical trial of the diabetes drug. (Janine Gelineau/UConn Health)

Even in patients who had a history of heart failure – 28 percent of participants – there was no increase in hospitalization.

The information is significant because of the prevalence of heart disease morbidity and mortality in patients with Type 2 diabetes. According to the World Health Organization, heart disease is responsible for between 50 percent and 80 percent of deaths among diabetics.

Also, the findings contradict a previous clinical trial of another diabetes medication in the same drug class that showed a modest increase in heart failure risk, leading to a closer scrutiny of Alogliptin – an orally administered anti-diabetic drug in the DPP-4 inhibitor class – in the medical community.

EXAMINE is an acronym for “Examination of Cardiovascular Outcomes: Alogliptin vs. Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome.” The study included nearly 5,400 diabetics in 49 countries, all of whom were within 90 days of hospitalization for either a heart attack or chest pain related to coronary heart disease. The trial was funded by Japanese pharmaceutical company Takeda, which makes Alogliptin.

Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.
Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Lam H, White WBEXAMINE Investigators.
Lancet. 2015 May 23;385(9982):2067-76. doi: 10.1016/S0140-6736(14)62225-X. Epub 2015 Mar 10.
PMID: 25765696

Poster Presentations 2014 American College of Cardiology

Two posters were presented at the American College of Cardiology, held in Washington D.C., March 29-31, 2014.

Mortality in Patients with Type 2 Diabetes and Recent Acute Coronary Syndromes from the EXAMINE Trial

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Alogliptin in Patients with Type 2 Diabetes Mellitus and Recent Acute Coronary Syndromes

Heart Failure Outcomes and Safety in Heart Failure Patients in the EXAMINE Trial

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Published in New England Journal of Medicine

Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes

William B. White, M.D., Christopher P. Cannon, M.D., Simon R. Heller, M.D., Steven E. Nissen, M.D., Richard M. Bergenstal, M.D., George L. Bakris, M.D., Alfonso T. Perez, M.D., Penny R. Fleck, M.B.A., Cyrus R. Mehta, Ph.D., Stuart Kupfer, M.D., Craig Wilson, Ph.D., William C. Cushman, M.D., and Faiez Zannad, M.D., Ph.D., for the EXAMINE Investigators

Abstract

Background

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.

Methods

We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.

Results

A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, −0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.

Conclusions

Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.)

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