Examining risk for type 2 in patients with genetic dyslipidemia conditions.
Familial combined hyperlipidemia (FCHL) is a form of dyslipidemia stemming from genetic predisposition and is common for patients who have survived premature heart attacks. There is an increase in very-low-density lipoprotein (VLDL) seen in FCHL due to low clearance and overproduction caused by genetics. Characteristics of FCHL include insulin resistance, fatty liver, and obesity. FCHL is common in women 65 and younger and men 55 and younger who have survived myocardial infarctions. In practice, type 2 diabetes has been criteria for exclusion in diagnosing FCHL. This is partly because there are genes that may offer protection from the development of type 2 diabetes in patients diagnosed with FCHL, such as the glucokinase regulatory protein, which is shared amongst the designated population. The purpose of this longitudinal cohort study is to examine the prevalence and risk factors of type 2 diabetes in cases of FCHL.
The original study ran from 1998 to 2005. It included a total of 596 subjects, comprised of patients with FCHL along with their family members and spouses who were unaffected at baseline. The incidence of type 2 diabetes was self-reported by the subjects and confirmed by patients’ medical records. This was the primary outcome of this study. Alanine aminotransferase (ALT) levels, blood glucose, blood pressure, height, lipids, waist circumference, and weight were all measured at baseline. Low-density lipoprotein (LDL) cholesterol levels were calculated using the Friedwald formula. To measure the levels of insulin resistance and fatty liver, the homeostasis model assessment for insulin resistance (HOMA2-IR) and fatty liver index (FLI) was utilized. In three years from 2002 to 2005, a sub-cohort of 275 patients underwent ultrasounds of their livers and visceral or subcutaneous fat. Statistical data were analyzed by means with standard deviations and interquartile ranges for cases non-normal distribution. Linear and logistic regressions were used for continuous variables and dichotomous variables. The proportional hazard models required a sensitivity analysis for the combination of the newly diagnosed and clinically diagnosed incidences of type 2 diabetes.
Data was only acquired for 76% of the patients at baseline for follow-up with a median of 15 years. The prevalence of type 2 diabetes in the subjects with FCHL was statistically significant in that there was an increase compared to their spouses (19.2 per 1000 person-years vs. 2.8 per 1000 person-years; HR: 6.3, 95% CI: 2.4 to 16.8). There was absolutely no difference found amongst the relatives and spouses who were unaffected (HR: 0.9, 95% CI: 0.3 to 2.6). Statistical analysis with a proportional hazard Cox regression revealed that a HOMA2-I and FLI score of 60 and above was directly associated with type 2 diabetes incidence. Body mass index and waist circumference were not found to be independent factors in a median follow up of 11 years.
To conclude, the findings of this study support that the liver is vital in the pathophysiology of metabolic and cardiovascular complications in patients with FCHL. It is suggested that this patient population undergo periodic testing for type 2 diabetes and that they are at high risk of developing the disease. While this is one of the largest cohorts followed for a longitudinal study on patients with FCHL, the study has limitations. One limitation seen in this study is that the patients self-reported their diagnosis of type 2 diabetes, and the incidence of type 2 diabetes cases did not hold a strong statistical power. Future studies could include patients that are diagnosed during the study and monitored by healthcare workers in congruence with the research, as well as add a control group who have no history of type 2 diabetes or FCHL and are not married to the subjects that have been diagnosed with FCHL, ultimately expanding validity of these findings.
- Previously there was conflicting data on whether patients with familial combined hyperlipidemia had a higher incidence of type 2 diabetes.
- This longitudinal cohort study that took place over 15 years revealed that patients with FCHL are a significantly higher risk for developing type 2 diabetes compared to those without it.
- While fatty liver and insulin resistance were found to be predictors of type 2 diabetes in this population, it is recommended that periodic screening be done for type 2 diabetes since patients with FCHL are at high risk of developing the disease.
Brouwers MCGJ, de Graaf J, Simons N, et al. Incidence of type 2 diabetes in familial combined hyperlipidemia. BMJ Open Diabetes Research and Care, 2020; 8:e001107. doi: 10.1136/bmjdrc-2019-001107
Mia Flowers, PharmD. Candidate of Florida Agricultural & Mechanical University School of Pharmacy