The Pharmacogenetics of Metformin

Pharmacokinetic and dynamic studies in healthy volunteers and patients with type 2 diabetes

Mette Marie Hougaard Christensen

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

Resumé

For several years, metformin has been the glucose-lowering agent of choice for most patients with type 2 diabetes. However, the clinical response to metformin therapy varies considerably, and approximately one third of the patients can be categorized as poor responders. Five main SoLute Carrier (SLC) transporters seem to determine the distribution of metformin. Hence, the hypothesis of our project was that genotype-dependent SLC expression contributes significantly to the observed inter-individual variability in the response to and the pharmacokinetics of metformin. The thesis contains the sum of results from three pharmacogenetic trials conducted to evaluate this specific hypothesis.

The objective of the first study was to evaluate the effect of genetic variations in organic cation transporter 1 and 2 (OCT 1 and 2), multidrug and toxin extrusion transporters 1 and 2-K (MATE 1 and 2-K) and plasma membrane monoamine transporter (PMAT) on the trough steady-state plasma concentration of metformin and HbA1c in a cohort of Danish type 2 diabetic patients. In brief, we demonstrated a huge variability in the trough steady-state metformin plasma concentration and that OCT1 activity affected the steady-state pharmacokinetics but not the response to metformin. Our follow-up studies in healthy individuals did not support these findings, and genetic variation in OCT1 is no longer believed to be of major importance for the trough values or the endogenous glucose production during metformin therapy.

The main objective of the second study was to investigate the impact of a genetic variation in OCT2 (rs316019) on the renal clearance of metformin in healthy individuals. Alone, the OCT2 variant neither affected the renal nor the secretory clearance of metformin. But when the results were adjusted for the MATE1 (rs2252281) genotype, both the renal and the secretory clearance of metformin increased significantly for individuals with one or two OCT2 variant alleles who carried only MATE1 reference alleles. The findings suggest that the OCT2 variant may have a dominant impact on the renal and secretory clearance of metformin, and that the genetic variation in OCT2 and in MATE1 may have counteracting effects on the renal clearance of metformin. Currently, the clinical implications of the observed gene-gene interaction seem sparse as the frequency of patients with a susceptible genotype constellation is low and the fact that empiric dose escalation can overcome an increased clearance of metformin.

The objective of the third study was to determine the steady-state pharmacokinetics and the effect of metformin on the endogenous glucose production in healthy volunteers with different numbers of reduced-function alleles in OCT1. We observed that metformin during a prolonged fast stimulates the glycolytic glucose utilization and lactate production and that this apparently triggers a compensatory rise in the glucose counter-regulatory hormones and subsequently an increase in the endogenous glucose production. There was no effect of reduced-function OCT1 alleles on any of the measured outcomes or the steady-state pharmacokinetics of metformin. Together with the observation that individuals with reduced-function OCT1 alleles have a decreased transport of metformin into the hepatocytes, our results suggest that the liver may not be the primary site of action of metformin.

We reject our main hypothesis as it appears that none of the well-established genetic polymorphisms in the five main SLC transporters sufficiently explain the in clinic observed variation in response to metformin therapy. However, we find that in combination with a more robust type 2 diabetic phenotype, some of the variants may end up as relevant covariates that potentially decrease the observed variability in the metformin response. Our results warrant a pharmacogenetic tracer study in type 2 diabetic patients with different numbers of reduced-function alleles in OCT1 in order to optimally evaluate the pivotal function of metformin.
OriginalsprogEngelsk
Antal sider128
StatusUdgivet - 24. nov. 2015

Citer dette

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title = "The Pharmacogenetics of Metformin: Pharmacokinetic and dynamic studies in healthy volunteers and patients with type 2 diabetes",
abstract = "For several years, metformin has been the glucose-lowering agent of choice for most patients with type 2 diabetes. However, the clinical response to metformin therapy varies considerably, and approximately one third of the patients can be categorized as poor responders. Five main SoLute Carrier (SLC) transporters seem to determine the distribution of metformin. Hence, the hypothesis of our project was that genotype-dependent SLC expression contributes significantly to the observed inter-individual variability in the response to and the pharmacokinetics of metformin. The thesis contains the sum of results from three pharmacogenetic trials conducted to evaluate this specific hypothesis.The objective of the first study was to evaluate the effect of genetic variations in organic cation transporter 1 and 2 (OCT 1 and 2), multidrug and toxin extrusion transporters 1 and 2-K (MATE 1 and 2-K) and plasma membrane monoamine transporter (PMAT) on the trough steady-state plasma concentration of metformin and HbA1c in a cohort of Danish type 2 diabetic patients. In brief, we demonstrated a huge variability in the trough steady-state metformin plasma concentration and that OCT1 activity affected the steady-state pharmacokinetics but not the response to metformin. Our follow-up studies in healthy individuals did not support these findings, and genetic variation in OCT1 is no longer believed to be of major importance for the trough values or the endogenous glucose production during metformin therapy.The main objective of the second study was to investigate the impact of a genetic variation in OCT2 (rs316019) on the renal clearance of metformin in healthy individuals. Alone, the OCT2 variant neither affected the renal nor the secretory clearance of metformin. But when the results were adjusted for the MATE1 (rs2252281) genotype, both the renal and the secretory clearance of metformin increased significantly for individuals with one or two OCT2 variant alleles who carried only MATE1 reference alleles. The findings suggest that the OCT2 variant may have a dominant impact on the renal and secretory clearance of metformin, and that the genetic variation in OCT2 and in MATE1 may have counteracting effects on the renal clearance of metformin. Currently, the clinical implications of the observed gene-gene interaction seem sparse as the frequency of patients with a susceptible genotype constellation is low and the fact that empiric dose escalation can overcome an increased clearance of metformin.The objective of the third study was to determine the steady-state pharmacokinetics and the effect of metformin on the endogenous glucose production in healthy volunteers with different numbers of reduced-function alleles in OCT1. We observed that metformin during a prolonged fast stimulates the glycolytic glucose utilization and lactate production and that this apparently triggers a compensatory rise in the glucose counter-regulatory hormones and subsequently an increase in the endogenous glucose production. There was no effect of reduced-function OCT1 alleles on any of the measured outcomes or the steady-state pharmacokinetics of metformin. Together with the observation that individuals with reduced-function OCT1 alleles have a decreased transport of metformin into the hepatocytes, our results suggest that the liver may not be the primary site of action of metformin.We reject our main hypothesis as it appears that none of the well-established genetic polymorphisms in the five main SLC transporters sufficiently explain the in clinic observed variation in response to metformin therapy. However, we find that in combination with a more robust type 2 diabetic phenotype, some of the variants may end up as relevant covariates that potentially decrease the observed variability in the metformin response. Our results warrant a pharmacogenetic tracer study in type 2 diabetic patients with different numbers of reduced-function alleles in OCT1 in order to optimally evaluate the pivotal function of metformin.",
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The Pharmacogenetics of Metformin : Pharmacokinetic and dynamic studies in healthy volunteers and patients with type 2 diabetes. / Christensen, Mette Marie Hougaard .

2015. 128 s.

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

TY - BOOK

T1 - The Pharmacogenetics of Metformin

T2 - Pharmacokinetic and dynamic studies in healthy volunteers and patients with type 2 diabetes

AU - Christensen, Mette Marie Hougaard

PY - 2015/11/24

Y1 - 2015/11/24

N2 - For several years, metformin has been the glucose-lowering agent of choice for most patients with type 2 diabetes. However, the clinical response to metformin therapy varies considerably, and approximately one third of the patients can be categorized as poor responders. Five main SoLute Carrier (SLC) transporters seem to determine the distribution of metformin. Hence, the hypothesis of our project was that genotype-dependent SLC expression contributes significantly to the observed inter-individual variability in the response to and the pharmacokinetics of metformin. The thesis contains the sum of results from three pharmacogenetic trials conducted to evaluate this specific hypothesis.The objective of the first study was to evaluate the effect of genetic variations in organic cation transporter 1 and 2 (OCT 1 and 2), multidrug and toxin extrusion transporters 1 and 2-K (MATE 1 and 2-K) and plasma membrane monoamine transporter (PMAT) on the trough steady-state plasma concentration of metformin and HbA1c in a cohort of Danish type 2 diabetic patients. In brief, we demonstrated a huge variability in the trough steady-state metformin plasma concentration and that OCT1 activity affected the steady-state pharmacokinetics but not the response to metformin. Our follow-up studies in healthy individuals did not support these findings, and genetic variation in OCT1 is no longer believed to be of major importance for the trough values or the endogenous glucose production during metformin therapy.The main objective of the second study was to investigate the impact of a genetic variation in OCT2 (rs316019) on the renal clearance of metformin in healthy individuals. Alone, the OCT2 variant neither affected the renal nor the secretory clearance of metformin. But when the results were adjusted for the MATE1 (rs2252281) genotype, both the renal and the secretory clearance of metformin increased significantly for individuals with one or two OCT2 variant alleles who carried only MATE1 reference alleles. The findings suggest that the OCT2 variant may have a dominant impact on the renal and secretory clearance of metformin, and that the genetic variation in OCT2 and in MATE1 may have counteracting effects on the renal clearance of metformin. Currently, the clinical implications of the observed gene-gene interaction seem sparse as the frequency of patients with a susceptible genotype constellation is low and the fact that empiric dose escalation can overcome an increased clearance of metformin.The objective of the third study was to determine the steady-state pharmacokinetics and the effect of metformin on the endogenous glucose production in healthy volunteers with different numbers of reduced-function alleles in OCT1. We observed that metformin during a prolonged fast stimulates the glycolytic glucose utilization and lactate production and that this apparently triggers a compensatory rise in the glucose counter-regulatory hormones and subsequently an increase in the endogenous glucose production. There was no effect of reduced-function OCT1 alleles on any of the measured outcomes or the steady-state pharmacokinetics of metformin. Together with the observation that individuals with reduced-function OCT1 alleles have a decreased transport of metformin into the hepatocytes, our results suggest that the liver may not be the primary site of action of metformin.We reject our main hypothesis as it appears that none of the well-established genetic polymorphisms in the five main SLC transporters sufficiently explain the in clinic observed variation in response to metformin therapy. However, we find that in combination with a more robust type 2 diabetic phenotype, some of the variants may end up as relevant covariates that potentially decrease the observed variability in the metformin response. Our results warrant a pharmacogenetic tracer study in type 2 diabetic patients with different numbers of reduced-function alleles in OCT1 in order to optimally evaluate the pivotal function of metformin.

AB - For several years, metformin has been the glucose-lowering agent of choice for most patients with type 2 diabetes. However, the clinical response to metformin therapy varies considerably, and approximately one third of the patients can be categorized as poor responders. Five main SoLute Carrier (SLC) transporters seem to determine the distribution of metformin. Hence, the hypothesis of our project was that genotype-dependent SLC expression contributes significantly to the observed inter-individual variability in the response to and the pharmacokinetics of metformin. The thesis contains the sum of results from three pharmacogenetic trials conducted to evaluate this specific hypothesis.The objective of the first study was to evaluate the effect of genetic variations in organic cation transporter 1 and 2 (OCT 1 and 2), multidrug and toxin extrusion transporters 1 and 2-K (MATE 1 and 2-K) and plasma membrane monoamine transporter (PMAT) on the trough steady-state plasma concentration of metformin and HbA1c in a cohort of Danish type 2 diabetic patients. In brief, we demonstrated a huge variability in the trough steady-state metformin plasma concentration and that OCT1 activity affected the steady-state pharmacokinetics but not the response to metformin. Our follow-up studies in healthy individuals did not support these findings, and genetic variation in OCT1 is no longer believed to be of major importance for the trough values or the endogenous glucose production during metformin therapy.The main objective of the second study was to investigate the impact of a genetic variation in OCT2 (rs316019) on the renal clearance of metformin in healthy individuals. Alone, the OCT2 variant neither affected the renal nor the secretory clearance of metformin. But when the results were adjusted for the MATE1 (rs2252281) genotype, both the renal and the secretory clearance of metformin increased significantly for individuals with one or two OCT2 variant alleles who carried only MATE1 reference alleles. The findings suggest that the OCT2 variant may have a dominant impact on the renal and secretory clearance of metformin, and that the genetic variation in OCT2 and in MATE1 may have counteracting effects on the renal clearance of metformin. Currently, the clinical implications of the observed gene-gene interaction seem sparse as the frequency of patients with a susceptible genotype constellation is low and the fact that empiric dose escalation can overcome an increased clearance of metformin.The objective of the third study was to determine the steady-state pharmacokinetics and the effect of metformin on the endogenous glucose production in healthy volunteers with different numbers of reduced-function alleles in OCT1. We observed that metformin during a prolonged fast stimulates the glycolytic glucose utilization and lactate production and that this apparently triggers a compensatory rise in the glucose counter-regulatory hormones and subsequently an increase in the endogenous glucose production. There was no effect of reduced-function OCT1 alleles on any of the measured outcomes or the steady-state pharmacokinetics of metformin. Together with the observation that individuals with reduced-function OCT1 alleles have a decreased transport of metformin into the hepatocytes, our results suggest that the liver may not be the primary site of action of metformin.We reject our main hypothesis as it appears that none of the well-established genetic polymorphisms in the five main SLC transporters sufficiently explain the in clinic observed variation in response to metformin therapy. However, we find that in combination with a more robust type 2 diabetic phenotype, some of the variants may end up as relevant covariates that potentially decrease the observed variability in the metformin response. Our results warrant a pharmacogenetic tracer study in type 2 diabetic patients with different numbers of reduced-function alleles in OCT1 in order to optimally evaluate the pivotal function of metformin.

M3 - Ph.D. thesis

BT - The Pharmacogenetics of Metformin

ER -