Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator

Adrian Vella, Jennifer L.R. Freeman, Imogene Dunn, Kit Keller, John B. Buse, Carmen Valcarce

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The therapeutic success of interventions targeting glucokinase (GK) activation for the treatment of type 2 diabetes has been limited by hypoglycemia, steatohepatitis, and loss of efficacy over time. The clinical characteristics of patients with GK-activating mutations or GK regulatory protein (GKRP) loss-of-function mutations suggest that a hepatoselective GK activator (GKA) that does not activate GK in cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes while limiting hypoglycemia and liver-associated adverse effects. Here, we review the rationale for TTP399, an oral hepatoselective GKA, and its progression from preclinical to clinical development, with an emphasis on the results of a randomized, double-blind, placebo- and active-controlled phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a clinically significant and sustained reduction in glycated hemoglobin, with a placebo-subtracted least squares mean HbA1c change from baseline of −0.9% (P < 0.01). Compared to placebo, TTP399 (800 mg/day) also increased high-density lipoprotein cholesterol (3.2 mg/dl; P < 0.05), decreased fasting plasma glucagon (−20 pg/ml; P < 0.05), and decreased weight in patients weighing ≥100 kg (−3.4 kg; P < 0.05). TTP399 did not cause hypoglycemia, had no detrimental effect on plasma lipids or liver enzymes, and did not increase blood pressure, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK.

Original languageEnglish (US)
Article numbereaau3441
JournalScience Translational Medicine
Volume11
Issue number475
DOIs
StatePublished - Jan 16 2019

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Glucokinase
Hypoglycemia
Liver
Type 2 Diabetes Mellitus
Placebos
Tissue Preservation
Mutation
Glycosylated Hemoglobin A
Fatty Liver
Least-Squares Analysis
Glucagon
Hyperglycemia
HDL Cholesterol
Fasting
Blood Pressure
Lipids
Weights and Measures
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. / Vella, Adrian; Freeman, Jennifer L.R.; Dunn, Imogene; Keller, Kit; Buse, John B.; Valcarce, Carmen.

In: Science Translational Medicine, Vol. 11, No. 475, eaau3441, 16.01.2019.

Research output: Contribution to journalArticle

Vella, Adrian ; Freeman, Jennifer L.R. ; Dunn, Imogene ; Keller, Kit ; Buse, John B. ; Valcarce, Carmen. / Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. In: Science Translational Medicine. 2019 ; Vol. 11, No. 475.
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