Discussion
To date, contrasting results have been reported on whether FCHL patients are prone to develop T2D in comparison to controls.12 13 The present study shows that one out of four FCHL patients developed T2D after 15 years of follow-up. The six times higher risk to develop T2D compared with their spouses was explained by insulin resistance and fatty liver at baseline. Similar results were obtained in the ultrasound subcohort, in which the presence of fatty liver and the subcutaneous and visceral fat compartments were assessed by ultrasound.
Our results are in line with a recent meta-analysis that showed that fatty liver is a risk factor for future T2D.7 In contrast to previous studies,22 23 we did not observe an association between abdominal obesity and incident T2D. Visceral obesity is a strong determinant of hepatic fat accumulation,24 which also explains why it is incorporated (as waist circumference) in the FLI algorithm.20 We do, however, not believe that inclusion of waist circumference in the FLI formula explains the absent association between abdominal obesity and future T2D in this cohort, since similar outcomes were obtained when fatty liver was assessed by ultrasound and waist circumference was replaced by SAT-US and VAT-US in the ultrasound cohort.
In the present study, use of lipid-modifying drugs at baseline was associated with incident T2D. Previous studies have convincingly shown that statins increase T2D risk, although with a high number needed to harm (≈ 200).25 It is therefore unlikely that statin use is a major determinant of the onset T2D in this relatively small cohort of FCHL patients. Indeed, repeat analysis including only those FCHL patients who did not receive lipid-modifying treatment showed a similar increased risk of incident T2D (although some of these individuals have received treatment in the follow-up period14). Altogether it is more likely that the contribution of baseline use of lipid-modifying drugs to incident T2D is at least in part explained by collinearity with the FCHL affected state, since use of lipid-modifying drugs was particularly confined to FCHL patients (table 2).
This study corroborates the suggestion that the liver plays a central role in the pathogenesis of cardiometabolic complications in FCHL.26 Stable isotope studies have shown that HOMA-IR is associated with hepatic insulin resistance (r=0.59),27 which in turn is associated with intrahepatic triglycerides (r=0.60).28 We and others have shown that HOMA2-IR and fatty liver are determinants of the lipid phenotype expression (in particular the hypertriglyceridemic phenotype) in FCHL.5 16 29 The current study shows that HOMA2-IR and fatty liver are also determinants of incident T2D in FCHL. Our findings also support to perform periodical screening for incident T2D in this high-risk population, in agreement with current guidelines.30
This study has several strengths and limitations. Its main strength is that this is one of the largest FCHL cohorts with long-term follow-up on clinically relevant endpoints. Moreover, for a substantial subcohort we have not only a surrogate marker, but also ultrasound data on the presence of fatty liver. One main limitation is that the group of spouses, used as a reference in this study, and the absolute numbers of incident T2D cases were relatively small resulting in limited statistical power and wide CIs. Second, we used a FLI≥60 as a surrogate of fatty liver in the overall cohort, which has a high positive likelihood ratio to rule in fatty liver.20 As hitherto mentioned, the inclusion of BMI, waist circumference, and plasma triglycerides in the FLI algorithm complicates the assessment of other baseline factors associated with incident T2D in this cohort, in particular abdominal obesity and the FCHL affected state (which includes elevated plasma triglycerides). These limitations have been overcome by the use of ultrasound as an alternative measure of fatty liver in a subset of the overall cohort, which yielded strikingly similar outcomes. Ultrasound has good test characteristics to diagnose moderate and severe hepatic fat accumulation.31 Third, since we realized that not all participants would visit our research facility during the follow-up visit, we decided to use the self-reported, clinical diagnosis of T2D as a primary outcome measure in all participants, which may be subjective to several sources of bias. Although we confirmed all T2D diagnoses by checking the medical records, there still could be recall bias. Furthermore, it is conceivable that FCHL patients, but not unaffected relatives and spouses, have received periodical checks of serum glucose levels as a part of their cardiovascular risk surveillance, which would increase the likelihood of a T2D diagnosis in this specific group (detection bias). We do, however, not believe that both sources of bias have had a major influence on the outcomes of the current study, since we detected only three newly-diagnosed T2D (of which two in FCHL patients) in those individuals who visited the research ward at follow-up. Detection bias should have resulted in a ‘catch-up’ of newly-diagnosed T2D in those who did not receive periodical screening, that is, non-affect relatives and spouses. This was clearly not the case.
In conclusion, the present longitudinal study shows that FCHL patients have a high risk to develop future T2D, which is explained by insulin resistance and fatty liver at baseline. This study further corroborates the suggestion that the liver plays a central role in the pathogenesis of cardiometabolic complications in FCHL and supports periodical screening for T2D in this high-risk population.