No Short‐term Effect of Oral Isotretinoin (13‐cis Retinoic Acid) on Lipoprotein(a) and HDL Subclasses LP‐A‐I and LP‐A‐I:A‐II in Healthy Volunteers

D ear S ir, Lipoprotein(a) (Lp(a)) plays an important role in atherogenesis and high plasma concentrations of Lp(a) are considered to be a risk factor for vascular diseases (for review see [1]). Although plasma levels of Lp(a) are almost entirely determined by inheritance, a limited number of drugs are described as influencing the levels of Lp(a) in humans (for review see [2, 3]). We have shown previously that retinoids, including all-trans retinoic acid (at-RA) and its 13-cis isomer (isotretinoin), decrease apo(a) synthesis and Lp(a) levels in primary cultures of cynomolgus monkey hepatocytes [4]. Recently, decreased levels of Lp(a) were found in 30 patients with severe acne, treated with 0.5 mg kg–1 day–1 isotretinoin [5]. In contrast, increased levels of Lp(a) were found in two acute promyelocytic leukaemia (APL) patients treated with at-RA [6]. In the present study, we have evaluated the short-term influence of isotretinoin on Lp(a) levels in 10 healthy men in a placebo-controlled study, performed initially to study the effect on fibrinolysis [7]. In humans, vitamin A derivative, isotretinoin (13-cis-RA) is shown to be effective in the treatment of dermatological diseases, but a side-effect of treatment with retinoids is hyperlipidemia. In general, very low density lipoprotein (VLDL) triglyceride levels and cholesterol levels, predominantly contained in low density lipoproteins (LDL), as well as apoB-100 levels, are increased after long-term isotretinoin treatment [8-11]. Little or no changes in HDL-cholesterol, apoA-I and apoA-II are found [8-11]. The effect of retinoids on the HDL subclasses LP-A-I and LP-A-I:A-II in healthy people is still unknown and was also evaluated in this study. LP-A-I is an HDL particle which only contains apoA-I and plays an important role in the protection against atherosclerosis. LP-A-I:A-II, an HDL particle containing both apoA-I and apoA-II, is less effective than LP-A-I in stimulating cholesterol removal from cells [12, 13]. The study was designed as a randomized, double-blind, placebo-controlled cross-over study with 10 healthy, nonsmoking male volunteers, between 21 and 26 years of age. Placebo and isotretinoin were administered b.d. (40 mg in the morning and 40 mg in the evening) for 5 days. The well-known effects of isotretinoin on skin and mucous membranes (e.g. dry skin, cheilitis) were seen in all subjects. Compared to treatment with placebo, isotretinoin caused significant increases in plasma levels of total cholesterol (+10%, P = 0.05) and apoB (+9%, P = 0.04) and an insignificant increase in plasma triglycerides (+35%, P = 0.08). Isotretinoin had no effect on plasma levels of LDL-cholesterol, HDL-cholesterol or on apoA-I, apoA-II, LP-A-I or LP-A-I:A-II ( Table 1). The interindividual variation of the Lp(a) concentration between the subjects (minimum 0.01 g L–1, maximum 0.39 g L–1) was high. After supplementation of the volunteers with isotretinoin, some men showed an increase and others a decrease in Lp(a) concentration, which altogether resulted in an unchanged plasma Lp(a) level ( Fig. 1; Table 1[link]). No association was found between baseline Lp(a) levels of the subjects and the change in Lp(a) after isotretinoin treatment (Δ Lp(a)after–before), indicating that high initial Lp(a) levels were also not affected by the drug. Lp(a) levels were not associated with any of the other measured parameters at baseline or after intervention with isotretinoin. The reason for the discrepancies between our in vivo data and the data described by Azuma et al. [6] is unclear. In the latter study only two APL patients were treated with 80 mg day–1 at-RA, whereas we treated 10 volunteers with an equal amount of isotretinoin in a placebo-controlled design. In the study of Azuma et al. [6], the Lp(a) levels were enhanced initially, but after about 2 weeks of treatment Lp(a) levels started to decrease gradually to the original levels. It is well-known that APL patients are metabolically unstable, which amongst other things is noticeable in the fluctuation of Lp(a) values [6], and elevated serum Lp(a) levels have been reported in leukaemia [14]. It cannot therefore be excluded that the disease did influence the effects of retinoids on lipoproteins and that the increase in Lp(a) is secondary to other changes. The discrepancy between our data and the Lp(a) decrease reported by Georgala et al. [5] may be related to the relatively high baseline levels of Lp(a) in the latter study or the relatively short treatment period in our study. The half-life of plasma Lp(a) has been reported to be between 2 and 3 days [15]. On the other hand, clear and significant changes in total cholesterol and apoB were observed in the same period in our study. Individual Lp(a) levels at baseline and after 5 days treatment with placebo (A) or isotretinion (B). Decreased or unchanged HDL and apoA-I levels were reported in most patient studies with retinoids [5, 9-11], but a partial normalization of low plasma HDL was observed in patients with cystic acne treated with isotretinoin [16]. Therefore, the distribution of apoA-I and apoA-II over the lipoprotein particles LP-A-I and LP-A-I:A-II was determined. We found no change in this distribution nor in the concentrations of apoA-I, apoA-II and HDL-cholesterol. No change or a slight decrease in the HDL level may be partially secondary to the reported increase in triglyceride-rich particles upon treatment with retinoids [11], which ultimately results in smaller HDL particles [17]. The latter are known to be more rapidly cleared than larger HDL particles [18]. Adverse effects on catabolism of triglyceride-rich particles elicited by retinoids in vivo may therefore over-shadow a potentially beneficial effect of the compounds on HDL levels. Studies showing no change or an increase in HDL-cholesterol, unlike a rise in plasma triglycerides [11, 16], may support this contention. In conclusion this study shows that short-term isotretinoin treatment of healthy males leads to increased cholesterol and apoB levels, but has no effect on plasma levels of Lp(a), apoA-I, apoA-II, LP-A-I, LP-A-I:A-II and HDL-cholesterol. This work was supported by The Netherlands Heart Foundation (grant 92.328 to Diana M. Neele). Received 19 November 1998; accepted 2 February 1999.