Alirocumab May Have Greater CV Reduction Benefit in Patients With Diabetes

PCSK9 inhibitor and high cholesterol. Computer illustration of low-density lipoprotein (LDL, ‘bad’ cholesterol) molecules (round) bound to LDL receptor (LDLR) proteins, with a molecule of the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9, blue) bound to a PCSK9 inhibitor antibody (pink). When there are high levels of LDL cholesterol in the blood it builds up on the sides of blood vessels hardening them, a condition named atherosclerosis. This narrows the blood vessels and may block them. LDL receptors recognise and bind to LDL molecules to remove them from the bloodstream. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. But if PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol. Monoclonal antibodies that bind to and inhibit PCSK9 are being used to reduce the amount of cholesterol in the blood by improving the liver’s ability to recycle LDLRs.

After an acute coronary syndrome event, alirocumab may offer greater risk reductions for future cardiovascular events in patients with diabetes vs those without diabetes, according to study results published in The Lancet Diabetes & Endocrinology.

In the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; Identifier: NCT01663402), investigators sought to lower participants’ low-density lipoprotein (LDL) cholesterol levels beyond the typical range of 1.4 to 1.8 mmol/L provided by ezetimibe and statins, targeting concentrations of 0.65 to 1.30 mmol/L with alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. However, some research has indicated that statins may increase diabetes risk in a dose-dependent manner, raising concerns about intensive LDL cholesterol lowering. In this prespecified analysis of the ODYSSEY OUTCOMES trial, researchers investigated the efficacy and safety of alirocumab according to glycemic status.

Included in the study were 18,924 patients who had been hospitalized for acute coronary syndrome (myocardial infarction or unstable angina). Participants were randomly assigned to receive alirocumab or placebo every 2 weeks and were followed for a median of 2.8 years. At baseline, 28.8% of the population had diabetes, 43.6% had prediabetes, and 27.7% had normoglycemia; median LDL concentrations for the groups were 2.20 mmol/L, 2.28 mmol/L, and 2.23 mmol/L, respectively.

After 4 months of treatment, median LDL concentration in the alirocumab group was 0.80 mmol/L across all glycemic categories vs 2.25 to 2.28 mmol/L in the placebo group. Patients with diabetes were 2.09 times and 1.90 times more likely to experience a major adverse cardiovascular event than those with normoglycemia or prediabetes, respectively (both P <.0001).

This significantly higher risk profile resulted in greater risk reduction: alirocumab yielded a higher absolute reduction in cardiovascular events in patients with diabetes (2.3%) than in those with prediabetes (1.2%) or normoglycemia (1.2%; P =.0019 for interaction). Furthermore, alirocumab did not increase risk for new-onset diabetes; among patients without diabetes at baseline, the disease developed in 10.1% of the placebo group compared with 9.6% of the treatment group (hazard ratio, 1.00).

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Limitations to this study included that it began before newer antidiabetic medications were shown to reduce major cardiovascular events and mortality in patients with type 2 diabetes and stable cardiovascular disease. Whether the use of these drugs in this study population affected the observed benefit of alirocumab cannot be determined.

“[C]ompared with patients without diabetes, those with diabetes had twice the excess risk of cardiovascular events when LDL cholesterol was greater than 1.8 mmol/L despite intensive statin treatment,” said the researchers. “The patients with diabetes also derived twice as much benefit when alirocumab was used to target an LDL cholesterol concentration between 0.65 mmol/L and 1.30 mmol/L.

“These findings provide further evidence that future guidelines should recommend much lower LDL cholesterol targets for patients with vascular disease when diabetes is present.”

Disclosures: The ODYSSEY OUTCOMES trial was sponsored by Sanofi in collaboration with Regeneron Pharmaceuticals. Several authors reported associations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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Ray KK, Colhoun HM, Szarek M, et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial [published online July 1, 2019]. Lancet Diabetes Endocrinol. doi:10.1016/S2213-8587(19)30158-5