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Patients who achieved very low LDL (low-density lipoprotein) cholesterol levels on a PCSK9 inhibitor were not at any greater increased risk for worse outcomes -- except for cataracts, a meta-analysis found.

Adverse event rates over a median of 18 months were similar among patients taking alirocumab (Praluent), regardless of whether their LDL cholesterol dropped below 25 mg/dl or stayed at 25 mg/dl and higher.

On propensity score matching, however, cataracts were more common with very low LDL cholesterol (2.6% versus 0.8% for higher concentrations, HR 3.40, 95% CI 1.58-7.35), according to , of the University of Iowa in Iowa City, and colleagues, writing online in the .

The authors clarified that the higher cataract risk was observed only in those whose LDL cholesterol levels plummeted with alirocumab; overall, drug recipients shared the same incidence of cataracts with peers who received placebo or ezetimibe (Zetia).

Still, there are flashbacks of the HOPE (Heart Outcomes Prevention Evaluation)-3 study: , director of the General Cardiology Inpatient Service of Brigham and Women's Hospital in Boston, noted in an that the present cataract data are consistent with the trial that first linked lipid-lowering rosuvastatin (Crestor) with cataract surgeries.

"The data presented here, although reassuring, represent only the beginning of our understanding of the safety of this novel class of medications. The ongoing cardiovascular endpoint trials of alirocumab should provide not only a sense of the true cardiovascular benefit of these drugs but also a more accurate and nuanced understanding of their risks."

Much anticipated (and delayed), results from the FOURIER Cardiovascular Outcomes Trial -- slated for presentation at the American College of Cardiology annual meeting in March -- are expected to shed light on the clinical outcomes of PCSK9 inhibitors.

One is the issue of diabetes. In contrast with the JUPITER study -- which reported an excess of diabetes, insomnia, and hepatic steatosis in patients with LDL cholesterol <30 mg/dl -- Robinson and colleagues found no such link for patients with very low LDL cholesterol following alirocumab therapy.

Everett, however, was not convinced: "Genetic studies have reported that common variants in PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase that are associated with lower LDL cholesterol are also related to an increased risk for type 2 diabetes," he wrote. "These findings raise the possibility that the effects of statins and PCSK9 inhibitors on diabetes may be biologically intertwined with the LDL cholesterol-reducing effects of the medications."

For the study, the researchers pooled data from 14 double-blind trials in (phase II and III of) the ODYSSEY program, which randomized patients to alirocumab (n=3,340) or control (placebo or ezetimibe; n=1,894). Except for the group recruited in the ODYSSEY MONO and ODYSSEY ALTERNATIVE studies, all were on background statins.

A quarter of the alirocumab cohort had LDL cholesterol levels below 25 mg/dl for 10 months on average; 9.4% even dipped below 15 mg/dl.

The very low LDL readings were more likely for those who started with lower baseline LDL cholesterol in the first place and patients who received a higher dose of alirocumab. "Therefore, patients with the most need for the addition of alirocumab for further LDL cholesterol lowering (i.e., those with high baseline LDL cholesterol levels) are least likely to experience very low LDL cholesterol levels," the team wrote.

For physicians concerned about LDL cholesterol dipping too low, starting with the 75 mg dose may be desirable, Robinson's group suggested.

Regardless, "of the possible theoretical risks associated with LDL cholesterol levels <25 mg/dl (e.g., because of effects on cholesterol metabolism or transport), none were confirmed in laboratory tests. This included levels of cortisol and gonadal hormones and levels of fat-soluble vitamins A, D, and K, and the vitamin E/LDL cholesterol ratio."

The researchers cited the non-randomized nature and the relatively short follow-up period as limitations of the study.