Abstract
I read with interest the recent case report 1 describing paradoxical decreases in high-density lipoprotein cholesterol (HDL-C) with simvastatin and atorvastatin in a patient with type 2 diabetes mellitus. The accompanying editorial 2 highlighted papers reporting paradoxical decreases in HDL-C by certain fibrates. I had previously reported that paradoxical decreases in HDL-C were actually quite common (in 43 out of 94 patients, 46%, on fenofibrate). 3
The editorial also stated that there were no reports to the author's knowledge of a paradoxical decrease in HDL-C with nicotinic acid use. However, I now wish to highlight a recent case where I believe that nicotinic acid, in the form of Tredaptive® (m/r nicotinic acid 1 g and laropiprant 20 mg; Merck Sharp & Dohme Ltd, Hertfordshire, UK), was associated with a paradoxical reduction in HDL-C which was reversed when the agent was stopped. I believe this to be the first reported case in the literature.
A 40-year-old man of south-east Asian ethnicity was referred to the lipid clinic in 2005. He had recently been an inpatient with acute pancreatitis and was noted to have a mixed hyperlipidaemia, predominantly hypertriglyceridaemia (fasting cholesterol 8.36 mmol/L, triglycerides 31.0 mmol/L and HDL-C 1.34 mmol/L). There was no evidence of gallstones and alcohol consumption was less than 15 units per week. He admitted to a very-high-fat diet but had a normal body mass index of 22.7 kg/m2. He smoked 15 cigarettes per day. He had been commenced on Fenofibrate 200 mg daily (Lipantil Micro®; Abbott Healthcare Products Ltd, Southampton, UK) and at the clinic his fasting lipids demonstrated cholesterol 4.48 mmol/L, triglycerides 7.1 mmol/L and HDL-C 0.87 mmol/L. His fenofibrate was increased to 267 mg daily (Lipantil Micro®).
Apo E genotyping was not consistent with Type III hyperlipidaemia. All other biochemical analyses, including plasma glucose, renal function, liver profile and thyroid profile, were normal and remained so. Total cholesterol, HDL-C and triglycerides were measured by standard methods for Roche Modular (HDL-C plus third generation; Roche Diagnostics Ltd, West Sussex, UK). The coefficients of variation (CV%) for total cholesterol, HDL-C and triglycerides were 2.7%, 1.8% and 2.4%, respectively.
In March 2006, his lipid profile was as follows: cholesterol 3.89 mmol/L, triglycerides 3.55 mmol/L and HDL-C 0.69 mmol/L. Reduction in HDL-C is a phenomenon that I frequently see with fenofibrate 3 and as I was satisfied with his cholesterol and triglycerides, he remained on fenofibrate 267 mg daily (Lipantil Micro®).
During the next few years his lipid results remained relatively stable. In February 2009, his triglycerides had risen to 5.3 mmol/L and HDL-C had fallen further to 0.59 mmol/L. Omacor® (omega-3-acid ethyl esters; Abbott Healthcare Products Ltd) 4 g daily was commenced. In May 2010, his cholesterol was 3.64 mmol/L, triglycerides 4.1 mmol/L and HDL-C 0.48 mmol/L. In view of the falling HDL-C, I replaced his Lipantil Micro® 267 mg daily with Tredaptive® one tablet daily.
In December 2010, his fasting lipids were as follows: cholesterol 5.88 mmol/L, triglycerides 19.7 mmol/L and HDL-C 0.27 mmol/L. He denied any non-compliance with medications. He was having some generalized mild itch which he related to his Tredaptive®. The HDL-C result was verified by ultracentrifugation (0.25 mmol/L).
His Tredaptive® was stopped and he went back onto Lipantil Micro® 267 mg daily. A lipid profile in March 2011 demonstrated cholesterol 4.98 mmol/L, triglycerides 4.97 mmol/L and HDL-C 0.74 mmol/L.
I believe that this man experienced a paradoxical reduction in HDL-C with fenofibrate which is a phenomenon that has been previously described in almost 50% of our patients (also seen with other fibrates). There was a further significant 44% reduction in HDL-C when he was taking Tredaptive® and this recovered fully when the Tredaptive was stopped and fenofibrate recommenced. There is some uncertainty regarding his compliance with Tredaptive® as his triglycerides were also high (19.7 mmol/L) alongside the low HDL-C (0.27 mmol/L), but in the past when he was not taking any lipid-lowering medication, his baseline HDL-C was 1.34 mmol/L. He has always denied any compliance issue.
In summary, I believe that this case demonstrates paradoxical lowering of HDL-C with both fenofibrate (a common phenomenon in my experience) and a further significant lowering with nicotinic acid (Tredaptive®). The actual mechanism(s) by which this decrease occurs is unclear. I am unaware of any previous reports in the literature describing a paradoxical decrease in HDL-C with nicotinic acid use, but clinicians should remain alert to this possibility.
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