Evaluating the impact of glucokinase activation on risk of cardiovascular disease: a Mendelian randomisation analysis
Ke Wang1, Mai Shi1,2, Chuiguo Huang1
1Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region, China.
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.
Insights
Glucokinase activators (GKAs) show potential for reducing cardiovascular disease (CVD) risk, particularly coronary artery disease and heart failure. Further clinical trials are needed to confirm these protective effects of GKAs.
Area of Science:
- Pharmacology
- Genetics
- Cardiovascular Medicine
Background:
- Glucokinase activators (GKAs) are a novel drug class targeting the glucose-sensing enzyme glucokinase (GK).
- Cardiovascular outcome trials for GKAs are pending, necessitating alternative methods to assess cardiovascular risk.
- Mendelian randomization (MR) offers a genetic approach to investigate causal relationships between GK activation and cardiovascular diseases.
Purpose of the Study:
- To investigate the impact of glucokinase (GK) activation on the risk of major cardiovascular diseases using a two-sample Mendelian randomization (MR) approach.
- To assess whether genetically proxied GK activation confers protection against coronary artery disease (CAD), peripheral arterial disease (PAD), stroke, and heart failure (HF).
- To compare the cardiovascular protective effects of GK activation with those of general HbA1c lowering.
Main Methods:
- Utilized independent genetic variants associated with HbA1c as instrumental variables (IVs) to mimic GK activation.
- Employed genome-wide association study (GWAS) summary statistics for CAD, PAD, stroke, and HF in European and East Asian populations.
- Performed MR analyses to assess the causal effect of genetically proxied GK activation on cardiovascular disease risk, with sensitivity analyses and cross-ancestry validation.
Main Results:
- Genetically proxied GK activation was associated with a significantly reduced risk of coronary artery disease (CAD) and heart failure (HF).
- The protective effects of GK activation on CAD and HF were more pronounced than those attributed to non-targeted HbA1c reduction.
- No significant causal relationship was found between genetically proxied GK activation and the risk of peripheral arterial disease (PAD) or stroke.
Conclusions:
- Glucokinase activators (GKAs) may offer protective benefits against coronary artery disease (CAD) and heart failure (HF).
- These findings suggest a potential role for GKAs in cardiovascular disease prevention.
- Confirmation through long-term clinical outcome trials is recommended to validate the cardiovascular benefits of GKAs.
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