TY - JOUR

T1 - Glucose-dependent insulinotropic peptide and risk of cardiovascular events and mortality

T2 - a prospective study

AU - Jujic, Amra

AU - Atabaki-Pasdar, Naeimeh

AU - Nilsson, Peter M.

AU - Almgren, Peter

AU - Hakaste, Liisa

AU - Tuomi, Tiinamaija

AU - Berglund, Lisa M.

AU - Franks, Paul W.

AU - Holst, Jens J.

AU - Prasad, Rashmi B.

AU - Torekov, Signe S.

AU - Ravassa, Susana

AU - Diez, Javier

AU - Persson, Margaretha

AU - Melander, Olle

AU - Gomez, Maria F.

AU - Groop, Leif

AU - Ahlqvist, Emma

AU - Magnusson, Martin

PY - 2020/5

Y1 - 2020/5

N2 - Aims/hypothesis Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. Methods GIP concentrations were successfully measured during OGTTs in two independent populations (Malmo Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. Results In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 x 10(-5)) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD. Conclusions/interpretation In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

AB - Aims/hypothesis Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. Methods GIP concentrations were successfully measured during OGTTs in two independent populations (Malmo Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. Results In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 x 10(-5)) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD. Conclusions/interpretation In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

KW - Cardiovascular

KW - Cardiovascular events

KW - Coronary artery disease

KW - GIP

KW - GLP-1

KW - Glucagon-like peptide 1

KW - Glucose-dependent insulinotropic peptide

KW - Mendelian randomisation

KW - Mortality

KW - MENDELIAN RANDOMIZATION ANALYSES

KW - POLYPEPTIDE

KW - OSTEOPONTIN

KW - LIRAGLUTIDE

KW - PREVALENCE

KW - DIAGNOSIS

KW - OUTCOMES

KW - LOCI

U2 - 10.1007/s00125-020-05093-9

DO - 10.1007/s00125-020-05093-9

M3 - Journal article

C2 - 31974732

VL - 63

SP - 1043

EP - 1054

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 5

ER -