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Association Between Familial Hypercholesterolemia and Prevalence of Type 2 Diabetes Mellitus. / Besseling, Joost; Kastelein, John J. P.; Defesche, Joep C. et al.
In: JAMA, Vol. 313, No. 10, 2015, p. 1029-1036.Research output: Contribution to journal › Article › Academic › peer-review
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TY - JOUR
T1 - Association Between Familial Hypercholesterolemia and Prevalence of Type 2 Diabetes Mellitus
AU - Besseling, Joost
AU - Kastelein, John J. P.
AU - Defesche, Joep C.
AU - Hutten, Barbara A.
AU - Hovingh, G. Kees
PY - 2015
Y1 - 2015
N2 - IMPORTANCE Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes. OBJECTIVE To assess the association between type 2 diabetes prevalence and familial hypercholesterolemia. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study in all individuals (n = 63 320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014. EXPOSURES Deleteriousness and nondeleteriousness of familial hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene (APOB) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations. MAIN OUTCOMES AND MEASURES Prevalence of type 2 diabetes. RESULTS The prevalence of type 2 diabetes was 1.75% in familial hypercholesterolemia patients (n = 440/25 137) vs 2.93% in unaffected relatives (n = 1119/38 183) (P <.001; odds ratio [OR], 0.62 [95% CI, 0.55-0.69]). The adjusted prevalence of type 2 diabetes in familial hypercholesterolemia, determined using multivariable regression models, was 1.44% (difference, 1.49% [95% CI, 1.24%-1.71%]) (OR, 0.49 [95% CI, 0.41-0.58]; P <.001). The adjusted prevalence of type 2 diabetes by APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12%(OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively (P for trend <. 001 in both comparisons). CONCLUSIONS AND RELEVANCE In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes
AB - IMPORTANCE Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes. OBJECTIVE To assess the association between type 2 diabetes prevalence and familial hypercholesterolemia. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study in all individuals (n = 63 320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014. EXPOSURES Deleteriousness and nondeleteriousness of familial hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene (APOB) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations. MAIN OUTCOMES AND MEASURES Prevalence of type 2 diabetes. RESULTS The prevalence of type 2 diabetes was 1.75% in familial hypercholesterolemia patients (n = 440/25 137) vs 2.93% in unaffected relatives (n = 1119/38 183) (P <.001; odds ratio [OR], 0.62 [95% CI, 0.55-0.69]). The adjusted prevalence of type 2 diabetes in familial hypercholesterolemia, determined using multivariable regression models, was 1.44% (difference, 1.49% [95% CI, 1.24%-1.71%]) (OR, 0.49 [95% CI, 0.41-0.58]; P <.001). The adjusted prevalence of type 2 diabetes by APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12%(OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively (P for trend <. 001 in both comparisons). CONCLUSIONS AND RELEVANCE In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes
U2 - 10.1001/jama.2015.1206
DO - 10.1001/jama.2015.1206
M3 - Article
C2 - 25756439
VL - 313
SP - 1029
EP - 1036
JO - JAMA
JF - JAMA
SN - 0098-7484
IS - 10
ER -
ID: 2582503