Highly Potent Statin Stands Out for Diabetes, Cataract Risks

Two high-intensity statin regimens showed similar clinical efficacy when directly compared in secondary prevention, but one was associated with a greater risk of diabetes and cataracts in results from the LODESTAR trial.

Whether they had been randomized to rosuvastatin (Crestor) or atorvastatin (Lipitor), people with existing coronary artery disease (CAD) had no statistically significant difference in the incidence of 3-year combined all-cause death, myocardial infarction (MI), stroke, and coronary revascularization (8.7% vs 8.2%; HR 1.06, 95% CI 0.86-1.30).

As for safety, the rosuvastatin group had a higher incidence of new-onset diabetes requiring initiation of diabetes medication (7.2% vs 5.3%; HR 1.39, 95% CI 1.03-1.87) and cataract surgery (2.5% vs 1.5%; HR 1.66, 95% CI 1.07-2.58), Myeong-Ki Hong, MD, PhD, of Severance Hospital and Yonsei University College of Medicine in Seoul, Korea, and colleagues reported in The BMJ.

The investigators noted that it is unclear how a particular statin could be tied to new-onset diabetes, whereas excess cataracts may be related to rosuvastatin’s more potent LDL cholesterol lowering — namely the prevention of epithelial cell development within the crystalline lens.

Importantly, greater LDL cholesterol lowering with rosuvastatin did not translate to fewer clinical events. Recent evidence suggests that in people already on statin therapy, it is inflammation, not cholesterol per se, that is the bigger contributor to residual cardiovascular risk.

“Therefore, when using rosuvastatin over atorvastatin as a statin regimen in people with coronary artery disease, a greater reduction in LDL cholesterol levels can be expected; however, meticulous monitoring and appropriate lifestyle interventions should be considered to mitigate the risk of new onset diabetes mellitus or cataracts,” Hong and colleagues wrote.”

“To determine whether the increase in new onset diabetes mellitus and cataract surgery is directly related to the statin treatment, the underpinning mechanism for these relations and the possible mechanism for a drug effect still require further investigations,” they cautioned.

The question of whether statin-related new-onset diabetes is a drug or a drug class effect has been subject to controversy ever since 2009’s JUPITER randomized trial reported an increase in new-onset diabetes mellitus among statin users.

Other safety endpoints did not differ between the two potent statins.

LODESTAR was a 2 × 2 factorial randomized trial designed to compare two statin dosing strategies with either of the two study statins. The main finding was that the treat-to-target LDL cholesterol strategy was noninferior to the high-intensity statin strategy for major clinical outcomes.

The present secondary analysis included 4,400 adults with CAD (mean age 65 years, 28% women) who had been randomized to rosuvastatin or atorvastatin. All were enrolled from 12 hospitals in South Korea. One in three had diabetes. Over 55% had undergone percutaneous coronary intervention. Approximately a quarter of the cohort was already on high-intensity statins before randomization, and over half were already on moderate-intensity statin therapy.

After patients received their study medications, the mean daily dose of rosuvastatin and atorvastatin was 17.1 mg and 36.0 mg, respectively, over 3 years. Mean LDL cholesterol reached 1.8 mmol/L versus 1.9 mmol/L (P<0.001) during this time.

Hong’s group cautioned that the investigators did not perform sample size estimation for LODESTAR with regards to randomization by statin type. Other limitations include the trial’s open-label design, small number of events, inclusion of only Asians, and relatively short follow-up duration.

“Further studies evaluating the association between statin type, new onset diabetes mellitus, and future cardiovascular events, as well as those evaluating the effects of ezetimibe on new onset diabetes mellitus are required,” study authors urged.

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