Association of GLP1R polymorphisms with the incretin response: The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH)

Abstract

ABSTRACT PAPER 1 Objective: Polymorphisms in the gene encoding the glucagon-like peptide-1 receptor (GLP1R) are associated with type 2 diabetes, fasting glucose, and postprandial glucose, but their effects on incretin levels remain unclear. We evaluated the physiologic and hormonal effects of GLP1R genotypes before and after interventions that influence glucose physiology. Methods: We analyzed 5 type 2 diabetes-associated variants, rs761387, rs10305423, rs10305441, rs742762, and rs10305492 in GLP1R in 868 diabetes-free individuals and recorded biochemical data before and after a 5-mg glipizide challenge and a 75-g oral glucose tolerance test (OGTT) performed after administration of 500 mg of metformin twice daily over two days. We used an additive mixed-effects model to evaluate the association of these variants with glucose, insulin, and incretin levels over multiple timepoints. Incretin levels were measured in 143 of 868 participants. Results: The G-risk allele at rs761387 was associated with higher total GLP-1 (2.61 pmol/L, 95% CI 1.0.72–4.50, p=0.01) and total GLP-1 (2.61 pmol/L, 95% CI 0.04–5.18, p=0.04) per allele across multiple timepoints during the OGTT. After glipizide challenge, the G allele was associated with higher insulin levels per allele (2.01 IU/ml, 95% CI 0.26–3.76, p=0.02). The other variants were not associated with any of the outcomes tested. Conclusions: Genetic variation at GLP1R is associated with differences in GLP-1 levels following an oral glucose load, highlighting altered incretin signaling as a potential mechanism by which GLP1R variation increases T2D risk. ABSTRACT PAPER 2 Objective: Both sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the glucagon-like pepetide-1 receptor agonists (GLP-1 RA) are recommended second-line therapies for patients with type 2 diabetes (T2D) and high cardiovascular (CV) risk. However, selecting a single agent can be challenging without head-to-head trials. We sought to compare to the efficacy of individual SGLT-2i and GLP-1 RA drugs on CV outcomes. Methods: We selected randomized clinical trials (RCT) of SGLT-2i and GLP-1 RA drugs in OVID, MEDLINE, Web of Science, EMBASE, and Scopus that followed ≥1,000 adult participants with T2D for ≥52 weeks. Using a Bayesian hierarchical fixed-effect network metaanalysis of individual drugs, we modeled time-to-event for MACE as a composite outcome, hospitalization for heart failure (HHF), and MACE components. Results: Canagliflozin showed the greatest reduction in the risk of MACE (Hazard Ratio [HR] 0.62, 95% CI 0.4-0.82, compared to placebo), non-fatal myocardial infarction (MI) (HR 0.58, 95% CIs 0.37-0.89) and stroke (0.59, 95% CI 0.35-0.98). Semaglutide, albiglutide, and empagliflozin had similar effect as canagliflozin in reducing the risk of MACE only. Oral semaglutide was the most efficacious at reducing the risk of CV death (HR 0.49, 95% CI 0.26- 0.88) followed by empagliflozin, canagliflozin, and liraglutide. SGLT2i drugs lowered the risk of HHF by 24-64%. None of the GLP-1 RAs lowered the risk of HHF. Conclusions: While we found evidence for the cardioprotective effects of several GLP-1 RAs, canagliflozin, a SGLT2i, was ranked as the highest efficacy at reducing the risk of MACE, and its components non-fatal MI, and stroke alone. The entire class of SGLT2i drugs lowered the risk of HHF, supporting current recommendations to initiate a SGLT2i in patients with T2D and heart failure.