Fasiglifam-induced liver injury in patients with type 2 diabetes: Results of a randomized controlled cardiovascular outcomes safety trial

the GRAND 306 Investigators, Venu Menon, A. Michael Lincoff, Stephen Nicholls, Stephen Nicholls, Kathy Wolski, Darren K. McGuire, Cyrus R. Mehta, Julio Rosenstock, Claudia Lopez, John Marcinak, Charlie Cao, Steven E. Nissen

Research output: Contribution to journalArticle

Abstract

OBJECTIVE To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ‡3-5 3 upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ‡3 3 ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for ‡10 3 ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63). CONCLUSIONS Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.

LanguageEnglish
Pages2603-2609
Number of pages7
JournalDiabetes Care
Volume41
Issue number12
DOIs
Publication statusPublished - 1 Dec 2018

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialised Nursing

Cite this

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title = "Fasiglifam-induced liver injury in patients with type 2 diabetes: Results of a randomized controlled cardiovascular outcomes safety trial",
abstract = "OBJECTIVE To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5{\%} confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ‡3-5 3 upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ‡3 3 ULN with fasiglifam compared with placebo was 2.1{\%} vs. 0.5{\%}, P < 0.001, and the incidence for ‡10 3 ULN was 0.31{\%} vs. 0.06{\%}, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5{\%} each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95{\%} CI 0.67, 1.63). CONCLUSIONS Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.",
author = "{the GRAND 306 Investigators} and Venu Menon and {Michael Lincoff}, A. and Stephen Nicholls and Stephen Nicholls and Kathy Wolski and McGuire, {Darren K.} and Mehta, {Cyrus R.} and Julio Rosenstock and Claudia Lopez and John Marcinak and Charlie Cao and Nissen, {Steven E.}",
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Fasiglifam-induced liver injury in patients with type 2 diabetes : Results of a randomized controlled cardiovascular outcomes safety trial. / the GRAND 306 Investigators.

In: Diabetes Care, Vol. 41, No. 12, 01.12.2018, p. 2603-2609.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fasiglifam-induced liver injury in patients with type 2 diabetes

T2 - Diabetes Care

AU - the GRAND 306 Investigators

AU - Menon, Venu

AU - Michael Lincoff, A.

AU - Nicholls, Stephen

AU - Nicholls, Stephen

AU - Wolski, Kathy

AU - McGuire, Darren K.

AU - Mehta, Cyrus R.

AU - Rosenstock, Julio

AU - Lopez, Claudia

AU - Marcinak, John

AU - Cao, Charlie

AU - Nissen, Steven E.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - OBJECTIVE To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ‡3-5 3 upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ‡3 3 ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for ‡10 3 ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63). CONCLUSIONS Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.

AB - OBJECTIVE To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ‡3-5 3 upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ‡3 3 ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for ‡10 3 ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63). CONCLUSIONS Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.

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U2 - 10.2337/dc18-0755

DO - 10.2337/dc18-0755

M3 - Article

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JF - Diabetes Care

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