From genes to hypercholesterolemia: The benefits of inclisiran therapy for GCKR polymorphisms in a statin-intolerant patient – A clinical case

Abstract

Background and Aims: A 73-year-old female with severe dyslipidemia, hypertension, type 2 diabetes mellitus, and diabetic nephropathy was referred to the lipid clinic due to an acute elevation in creatinine levels secondary to statin therapy. Her medical history included familial hypercholesterolemia, coronary artery disease, and recurrent transient ischemic attacks. Her treatment consisted of nifedipine, nebivolol, clopidogrel, insulin glargine, and memantine. Methods: Given statin-intolerance and familial hypercholesterolemia, a genetic test was performed and revealed an uncertain variant in the glucokinase regulator (GCKR) gene, which follows a heterozygous autosomal dominant inheritance pattern and has an allele frequency of 0.37% in the Latino population (Table 1). Initial laboratory analyses confirmed dyslipidemia, with lipid levels as follows: total cholesterol (TC) 608 mg/dL, low-density lipoprotein cholesterol (LDL-C) 375 mg/dL, triglycerides (TG) 513 mg/dL, and Lipoprotein(a) (Lp(a)) 117 mg/dL. A calcium score of 62 AU indicated mild calcification. Results: New treatment consisted of Inclisiran and Omega-3 fatty acids. Over the course of 28 weeks, all lipid markers showed significant reductions, including a 56.15% decrease in LDL-C (Table 2). However, Lp(a) levels remained unchanged. These results suggest a positive treatment response, likely due to the effects of Inclisiran on lipoprotein particles, potentially influenced by the identified GCKR indeterminate gene. Conclusions: The GCKR gene encodes the glucokinase regulatory protein (GKRP), which plays a key role in regulating glucose and lipid metabolism in the liver. Evidence supports the benefits of Inclisiran therapy for statin-intolerant individuals, particularly those with familial hypercholesterolemia unrelated to LDL receptor defects. While it has been shown to effectively lower LDL-C levels, even though no reduction in Lp(a) levels was observed in this case, Inclisiran may help prevent further lipid accumulation when conventional therapies are not tolerated.