Lp(a) Lowering With Alirocumab Tied To Small Increase In Risk Of Type-2 Diabetes

Lowering elevated lipoprotein(a) levels with the PCSK9 inhibitor alirocumab may be associated with a slightly increased risk of developing type-2 diabetes, but the benefit appears to outweigh the potential risk, new research suggests.

"For a hypothetical patient with an Lp(a) level of 60 mg/dL, our analysis suggests that treatment with alirocumab for three years would reduce the absolute risk of a major adverse cardiovascular event by 1.6%, and increase the absolute risk of new-onset diabetes by 0.9%," Dr. Gregory G. Schwartz of the University of Colorado School of Medicine, in Aurora, told Reuters Health by email.

Mounting evidence points to Lp(a) as an important risk factor and a potential target of treatment in patients with atherosclerotic cardiovascular disease, including acute coronary syndrome (ACS), Dr. Schwartz said.

"A consistent population-based observation has been that lower Lp(a) levels are associated with greater prevalence of diabetes. The mechanisms underlying this association remain unknown and an unanswered question has been whether pharmacologic reduction of Lp(a) levels influences incidence of diabetes," he noted.

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The researchers addressed this question with data from more than 13,000 patients with ACS who took part in the ODYSSEY OUTCOMES trial. None of them had diabetes at baseline. Patients received background high-intensity statin treatment and were randomly allocated to treatment with the PCSK9 inhibitor alirocumab or placebo.

Over a median follow up of 2.7 years, 1,324 patients developed type-2 diabetes - 648 in the alirocumab group and 676 in the placebo group - corresponding to a treatment hazard ratio of 0.95 (95% confidence interval, 0.85 to 1.05), according to the Diabetes Care report.

Median baseline Lp(a) was 21.9 mg/dL. Alirocumab reduced Lp(a) by a median of 23% and the absolute reduction increased with the baseline level.

Treatment with alirocumab had a neutral overall effect on incident diabetes. However, the effect varied according to baseline Lp(a) level, Dr. Schwartz told Reuters Health.

"At low baseline Lp(a) levels, there was minimal absolute change in Lp(a) concentration with alirocumab, and fewer cases of incident diabetes with alirocumab than placebo," he noted.

"For example, in the lowest quartile of baseline Lp(a) (< 6.9 mg/dL), the treatment hazard ratio for incident diabetes was 0.79. But at high baseline levels of Lp(a) (i.e., above 50 mg/dL) alirocumab treatment was associated with more incident cases of diabetes than placebo. In the highest quartile of baseline Lp(a) (>=61.1 mg/dL), the treatment hazard ratio for incident diabetes was 1.09," Dr. Schwartz said.

There was significant interaction of baseline Lp(a) and treatment with alirocumab with respect to the risk of incident diabetes (P interaction=0.006), which supports the observation that the effect of alirocumab treatment on incident diabetes depended on baseline Lp(a) levels, Dr. Schwartz noted.

As previously reported, the ODYSSEY OUTCOMES trial showed that alirocumab reduced major adverse cardiovascular events compared to placebo, with greater absolute treatment benefit among patients with higher baseline Lp(a) levels (https://bit.ly/2PG3Ce6).

"Patients with ACS and elevated levels of Lp(a) are at especially high risk of recurrent cardiovascular events. Therefore, intensive treatment to reduce cardiovascular risk is warranted," Dr. Schwartz said.

Given the "substantial cardiovascular benefit and small incremental risk of incident diabetes observed with intensive statin treatment in high-risk patients, the cardiovascular benefits of treatment with a PCSK9 inhibitor in patients with ACS and elevated levels of Lp(a) appear to outweigh a small incremental risk of incident diabetes," he concluded.

Whether these findings apply to other Lp(a)-lowering therapies is unknown, the researchers say.

"Therapeutic agents currently under evaluation in clinical trials have the potential to reduce Lp(a) by more than 70% (i.e., much more than PCSK9 inhibitors). Whether these agents affect the risk of incident diabetes remains to be determined," Dr. Schwartz told Reuters Health.

The ODYSSEY OUTCOMES trial was funded by Sanofi and Regeneron Pharmaceuticals.

—Megan Brooks

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