Lancet Diabetes Endocrinol. 2024 Nov;12(11):811-823. doi: 10.1016/S2213-8587(24)00221-3. Epub 2024 Oct 4.
Statins are the cornerstone treatment for patients with heterozygous familial hypercholesterolaemia but research suggests it could increase the risk of type 2 diabetes in the general population. A low prevalence of type 2 diabetes was reported in some familial hypercholesterolaemia cohorts, raising the question of whether these patients are protected against type 2 diabetes. Obesity is a well known risk factor for the development of type 2 diabetes. We aimed to investigate the associations of known key determinants of type 2 diabetes with its prevalence in people with heterozygous familial hypercholesterolaemia.
This worldwide cross-sectional study used individual-level data from the EAS FHSC registry and included adults older than 18 years with a clinical or genetic diagnosis of heterozygous familial hypercholesterolaemia who had data available on age, BMI, and diabetes status. Those with known or suspected homozygous familial hypercholesterolaemia and type 1 diabetes were excluded. The main outcome was prevalence of type 2 diabetes overall and by WHO region, and in relation to obesity (BMI ≥30·0 kg/m) and lipid-lowering medication as predictors. The study population was divided into 12 risk categories based on age (tertiles), obesity, and receiving statins, and the risk of type 2 diabetes was investigated using logistic regression.
Among 46 683 adults with individual-level data in the FHSC registry, 24 784 with heterozygous familial hypercholesterolaemia were included in the analysis from 44 countries. 19 818 (80%) had a genetically confirmed diagnosis of heterozygous familial hypercholesterolaemia. Type 2 diabetes prevalence in the total population was 5·7% (1415 of 24 784), with 4·1% (817 of 19 818) in the genetically diagnosed cohort. Higher prevalence of type 2 diabetes was observed in the Eastern Mediterranean (58 [29·9%] of 194), South-East Asia and Western Pacific (214 [12·0%] of 1785), and the Americas (166 [8·5%] of 1955) than in Europe (excluding the Netherlands; 527 [8·0%] of 6579). Advancing age, a higher BMI category (obesity and overweight), and use of lipid-lowering medication were associated with a higher risk of type 2 diabetes, independent of sex and LDL cholesterol. Among the 12 risk categories, the probability of developing type 2 diabetes was higher in people in the highest risk category (aged 55-98 years, with obesity, and receiving statins; OR 74·42 [95% CI 47·04-117·73]) than in those in the lowest risk category (aged 18-38 years, without obesity, and not receiving statins). Those who did not have obesity, even if they were in the upper age tertile and receiving statins, had lower risk of type 2 diabetes (OR 24·42 [15·57-38·31]). The corresponding results in the genetically diagnosed cohort were OR 65·04 (40·67-104·02) for those with obesity in the highest risk category and OR 20·07 (12·73-31·65) for those without obesity.
Adults with heterozygous familial hypercholesterolaemia in most WHO regions have a higher type 2 diabetes prevalence than in Europe. Obesity markedly increases the risk of diabetes associated with age and use of statins in these patients. Our results suggest that heterozygous familial hypercholesterolaemia does not protect against type 2 diabetes, hence managing obesity is essential to reduce type 2 diabetes in this patient population.
Pfizer, Amgen, MSD, Sanofi-Aventis, Daiichi-Sankyo, and Regeneron.
他汀类药物是治疗杂合子家族性高胆固醇血症患者的基石，但研究表明，它可能会增加普通人群患 2 型糖尿病的风险。一些家族性高胆固醇血症队列报告 2 型糖尿病的患病率较低，这引发了一个问题，即这些患者是否免受 2 型糖尿病的影响。肥胖是 2 型糖尿病发生的一个众所周知的危险因素。我们旨在研究已知的 2 型糖尿病主要决定因素与杂合子家族性高胆固醇血症患者 2 型糖尿病患病率之间的关联。
这是一项全球性的横断面研究，使用 EAS FHSC 登记处的个体水平数据，纳入年龄大于 18 岁、有临床或基因诊断为杂合子家族性高胆固醇血症且有年龄、BMI 和糖尿病状态数据的成年人。排除已知或疑似的纯合子家族性高胆固醇血症和 1 型糖尿病患者。主要结局是总体和按世界卫生组织区域划分的 2 型糖尿病患病率，以及与肥胖（BMI≥30.0kg/m²）和降脂药物作为预测因素的关系。根据年龄（三分位数）、肥胖和服用他汀类药物，将研究人群分为 12 个风险类别，使用逻辑回归研究 2 型糖尿病的风险。
在 FHSC 登记处的 46683 名成年人中，有 44 个国家的 24784 名有杂合子家族性高胆固醇血症的成年人有个体水平数据，其中 19818 名（80%）有杂合子家族性高胆固醇血症的基因确诊诊断。在总人群中，2 型糖尿病的患病率为 5.7%（1415/24784），在基因确诊组中为 4.1%（817/19818）。在东地中海（58/194，29.9%）、东南亚和西太平洋（214/1785，12.0%）和美洲（166/1955，8.5%）地区，2 型糖尿病的患病率高于欧洲（荷兰除外；527/6579，8.0%）。年龄增长、更高的 BMI 类别（肥胖和超重）和使用降脂药物与 2 型糖尿病的风险增加独立相关，与性别和 LDL 胆固醇无关。在 12 个风险类别中，在最高风险类别（年龄 55-98 岁、肥胖和服用他汀类药物）的人群中，发生 2 型糖尿病的概率高于最低风险类别（年龄 18-38 岁、无肥胖和未服用他汀类药物）（OR 74.42[95%CI 47.04-117.73]）。即使在年龄较高的上三分位数并服用他汀类药物的人群中，如果没有肥胖，其发生 2 型糖尿病的风险也较低（OR 24.42[15.57-38.31]）。在基因确诊组中的对应结果为，在最高风险类别中肥胖的患者（OR 65.04[40.67-104.02]）和不肥胖的患者（OR 20.07[12.73-31.65]）的风险更高。
大多数世界卫生组织区域的杂合子家族性高胆固醇血症成年人的 2 型糖尿病患病率高于欧洲。肥胖显著增加了这些患者与年龄和使用他汀类药物相关的糖尿病风险。我们的结果表明，杂合子家族性高胆固醇血症并不能预防 2 型糖尿病，因此，管理肥胖对于降低该患者人群的 2 型糖尿病发病率至关重要。
辉瑞、安进、默沙东、赛诺菲-安万特、第一三共和再生元。
