Fasiglifam-induced liver injury in patients with type 2 diabetes

Results of a randomized controlled cardiovascular outcomes safety trial

the GRAND 306 Investigators

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.

Original languageEnglish (US)
Pages (from-to)2603-2609
Number of pages7
JournalDiabetes Care
Volume41
Issue number12
DOIs
StatePublished - Dec 1 2018

Fingerprint

Type 2 Diabetes Mellitus
Safety
Liver
Wounds and Injuries
Placebos
Chemical and Drug Induced Liver Injury
TAK-875
Incidence
Unstable Angina
United States Food and Drug Administration
G-Protein-Coupled Receptors
Hospitalization
Research Design
Stroke
Myocardial Infarction
Enzymes

ASJC Scopus subject areas

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

Cite this

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

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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.",
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AU - Menon, Venu

AU - Michael Lincoff, A.

AU - Nicholls, Stephen J.

AU - Jasper, Susan

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.

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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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