Evaluating the impact of glucokinase activation on risk of cardiovascular disease: a Mendelian randomisation analysis

Abstract

Background Glucokinase activators (GKAs) are an emerging class of glucose lowering drugs that activate the glucose-sensing enzyme glucokinase (GK). Pending formal cardiovascular outcome trials, we applied two-sample Mendelian randomisation (MR) to investigate the impact of GK activation on risk of cardiovascular diseases. Methods We used independent genetic variants in or around the glucokinase gene meanwhile associated with HbA1c at genome-wide significance (P < 5 × 10−8) in the Meta-Analyses of Glucose and Insulin-related traits Consortium study (N = 146,806; European ancestry) as instrumental variables (IVs) to mimic the effects of GK activation. We assessed the association between genetically proxied GK activation and the risk of coronary artery disease (CAD; 122,733 cases and 424,528 controls), peripheral arterial disease (PAD; 7098 cases and 206,541 controls), stroke (40,585 cases and 406,111 controls) and heart failure (HF; 47,309 cases and 930,014 controls), using genome-wide association study summary statistics of these outcomes in Europeans. We compared the effect estimates of genetically proxied GK activation with estimates of genetically proxied lower HbA1c on the same outcomes. We repeated our MR analyses in East Asians as validation. Results Genetically proxied GK activation was associated with reduced risk of CAD (OR 0.38 per 1% lower HbA1c, 95% CI 0.29–0.51, P = 8.77 × 10−11) and HF (OR 0.54 per 1% lower HbA1c, 95% CI 0.41–0.73, P = 3.55 × 10−5). The genetically proxied protective effects of GKA on CAD and HF exceeded those due to non-targeted HbA1c lowering. There was no causal relationship between genetically proxied GK activation and risk of PAD or stroke. The estimates in sensitivity analyses and in East Asians were generally consistent. Conclusions GKAs may protect against CAD and HF which needs confirmation by long-term clinical trials.

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

“…We also evaluated impacts of GK activation on these outcomes using GCK SNPs associated with FPG as IVs. The results were overall consistent with our previous analysis using GCK SNPs associated with HbA1c as IVs [ 26 ]. In contrast to the impaired GK-GKRP interaction, GK activation did not influence the lipid traits.…”

“…In 2022, the first GKA (dorzagliatin) had been approved for treatment of T2D in China and so far, no data (more than 52 weeks) are available on its long-term effects. A previous MR study investigated the impact of GK activation (instrumented by GCK SNPs associated with HbA1c) on cardiovascular outcomes, suggesting its possible protective effects against CAD and HF [ 26 ]. However, it should be noted that some GKAs have been associated with dyslipidaemia, notably hypertriglyceridemia [ 16 ] although this was not reported with Dorzagliatin [ 23 , 24 ].…”

“…In our previous work, we investigated the influence of GK activation on cardiovascular disease risk using Mendelian randomization (MR) analysis and reported that target-specific glucose-lowering through GK activation might confer protection against coronary artery disease (CAD) and heart failure (HF) [ 26 ]. Importantly, the cardiovascular benefits of GK-targeted glucose-lowering exceeded that due to non-targeted glucose-lowering [ 26 ]. In the present study, we sought to discern how different GK activating mechanisms might influence long-term cardiovascular outcomes via their impacts on lipid-related traits.…”

Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes

“…55,60 The second point is that, unlike some antidiabetic drugs such as SGLT-2 inhibitors or GLP-1 receptor agonists, which have been demonstrated to have special mechanisms to improve cardiovascular outcomes, GK activators build their efficacy directly on the recovery of GK target to achieve ideal glucose control, which may have stronger protective effects on coronary artery disease and heart failure than nontargeted glucose-lowering regimens. 61 Because impaired glucose homeostasis occurs at a very early stage of diabetes, studies with a larger population of patients with diabetes and prediabetes will add more clinical evidence to the long-term benefits of GK activation.…”

Multifaceted nature of young-onset diabetes - can genomic medicine improve the precision of diagnosis and management?

“…Indeed, some of the loci associated with type 2 diabetes lie within the coding or non-coding regions of MODY genes [24,25,86] . One example is the common variants of GCK and GCK-regulating proteins associated with glucose/lipid traits and ESKD [87] . Mendelian randomization analysis suggested that genetic proxies of GCK were causally linked to cardiovascular disease [88] .…”