RESUMO
BACKGROUND: Although there is clinical evidence for the safety and efficacy of single-drug therapy and some two-drug combinations for the treatment of hypertriglyceridemia, information is limited on the use of more than 2 drugs. OBJECTIVE: We evaluated the efficacy and safety of multidrug regimens (≥3 agents) in the management of hypertriglyceridemia. METHODS: The study included 40 individuals in an academic lipid referral clinic with mean follow-up of 1.98 years and an average use of 3.5 medications. RESULTS: During the study, mean body mass index decreased significantly (P=.0127), from 29.2kg/m(2) to 28.7kg/m(2), and mean hemoglobin A1C showed a trend towards decreasing (P=.06), from 7.9% to 7.2% in patients with diabetes (n=17). All lipid parameters decreased significantly: total cholesterol level decreased significantly from (mean±SD) 334.3±282.9mg/dL to 183.8±54.8mg/dL (P=.001, mean reduction of 45%), mean (± SD) triglyceride level decreased significantly from 1900.9±4576.8mg/dL to 300.7±372.2mg/dL (P=.02), median (range) triglyceride level decreased from 599 (242-28,550) mg/dL to 301 (40-1960) mg/dL (P < .001, mean reduction of 50%), and mean (± SD) non-high-density lipoprotein cholesterol decreased significantly from 189.9±131.6mg/dL to 138.4±49.1mg/dL (P=.014, mean reduction of 27%). There were no serious adverse effects (rhabdomyolysis or increased liver function tests >3 times upper limit of normal). CONCLUSION: In a 2-year follow-up of 40 individuals on multidrug therapy (average of 3.5 drugs) for severe hypertriglyceridemia, combination therapy was efficacious and well tolerated.
RESUMO
BACKGROUND: Autosomal dominant familial hypercholesterolemia (FH) attributable to mutations in the LDL receptor (LDLR) gene is one of the most common genetic disorders associated with significant morbidity and mortality. Definitive diagnosis would help to initiate appropriate treatment to prevent premature cardiovascular disease. Currently, clinical diagnosis of FH is imprecise, and molecular diagnosis is labor-intensive and expensive because of the size of the LDLR gene and number of coding exons. METHODS: We used PCR to amplify all exons, including exon/intron boundaries, and the promoter of the LDLR gene. Nine individuals from five families with typical findings for a clinical diagnosis of heterozygous FH, 2 heterozygous FH cell lines, and 50 control individuals were screened for mutations by denaturing HPLC (DHPLC) followed by direct sequencing of aberrantly migrating fragments. RESULTS: Mutations that were previously reported to be disease causing were identified in eight of nine individuals with FH and both cell lines (V502M, C146X, E207X, C660X, C646Y, and delG197), but none were found in controls. The one individual with FH in whom no mutation was found had a previously unreported change in the 5'-untranslated region of unknown significance. In addition, we identified several previously reported polymorphism both in controls and individuals with FH. CONCLUSIONS: DHPLC can be used to detect mutations causing FH. On the basis of our current experience with DHPLC, this method combined with confirmatory DNA sequencing is likely to be sensitive and efficient.