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Genetic variants of glucose-dependent insulinotropic polypeptide (GIP) signalling as proxy for body weight reduction
Frida Emanuelsson1,2,3, Børge G Nordestgaard2,3,4, Marianne Benn1,4
1Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Blegdamsvej 9, Copenhagen 2100, Denmark.
Background And Aims:
Anti-obesity therapies co-targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor achieve greater weight loss compared with glucagon-like peptide-1 receptor agonists. However, the implications for cardiovascular risk reduction and the mechanisms involved remain unclear. This study aimed to (i) investigate whether genetically proxied body weight reduction via the GIP receptor pathway lowers cardiovascular disease risk and (ii) compare the effect to polygenic weight reduction, excluding GIP-related genes, to assess if the observed benefits are attributable to weight loss per se or involve additional GIP-related effects.
Methods:
Genetic scores were constructed using four variants in GIP-related genes associated with lower body mass index (BMI) and 31 variants linked to lower BMI in general. Observational and one-sample Mendelian randomization (MR) analyses were performed in 408 056 individuals from the UK Biobank and two-sample MR analyses using summary statistics from 419 821 individuals in FinnGen.
Results:
In one-sample MR analyses, 1 kg/m² lower BMI via the GIP/GIPR score was associated with 29% lower risk of major adverse cardiovascular events (MACE) (P = .0002) and 43% lower risk of heart failure (P = 5 × 10⁻⁵). Corresponding lower risks with the polygenic BMI score were 3% (P = .002) and 13% (P < 1 × 10-300). Two-sample MR analyses showed similar results. Of the reduced risk via the GIP/GIPR score, BMI and glycated haemoglobin (HbA1c) mediated 13% and 22% of the lower risk of MACE and 16% and 17% of the lower risk of heart failure (all P ≤ 7 × 10-5).
Conclusions:
Genetic proxies for body weight reduction via GIP receptor targeting reduces the risk of MACE and heart failure, mediated partly through lower BMI and partly through lower HbA1c.
Insights
Targeting the glucose-dependent insulinotropic polypeptide (GIP) receptor for weight loss significantly reduces cardiovascular disease risk, including major adverse cardiovascular events and heart failure. These benefits are partly mediated by reductions in body mass index and HbA1c levels.
Area of Science:
- Cardiovascular Medicine
- Metabolic Disorders
- Pharmacogenomics
Background:
- Glucose-dependent insulinotropic polypeptide (GIP) receptor agonists offer superior weight loss compared to GLP-1 receptor agonists.
- Mechanisms and cardiovascular benefits of GIP receptor-targeted therapies require elucidation.
Purpose of the Study:
- To investigate if genetically proxied weight reduction via the GIP receptor pathway impacts cardiovascular disease (CVD) risk.
- To compare GIP-related weight reduction effects with general polygenic weight reduction to differentiate weight loss effects from GIP-specific actions.
Main Methods:
- Utilized Mendelian randomization (MR) and observational analyses in large cohorts (UK Biobank, FinnGen).
- Constructed genetic scores for GIP-related variants and general BMI-associated variants.
- Performed one-sample and two-sample MR analyses to assess causality.
Main Results:
- GIP/GIPR genetic score-associated BMI reduction correlated with significantly lower risks of major adverse cardiovascular events (MACE) and heart failure.
- General polygenic BMI reduction showed smaller, though significant, risk reductions for MACE and heart failure.
- Mediator analyses indicated BMI and HbA1c partially explained the CVD risk reduction from GIP/GIPR targeting.
Conclusions:
- Genetically proxied weight reduction via GIP receptor targeting confers substantial protection against MACE and heart failure.
- The benefits are partly mediated through reductions in body mass index and glycated hemoglobin (HbA1c).
- This suggests GIP receptor modulation offers cardiovascular benefits beyond general weight loss.
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