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PCSK9 Inhibition and Risk of Diabetes: Should We Worry?
Stefano Carugo1,2, Cesare R Sirtori3, Alberto Corsini3
1Department of Clinical Sciences and Community Health, Università Degli Studi Di Milano, Milan, Italy.
Purpose Of Review:
Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD).
Recent Findings:
While safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment. Considering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL-C but may increase new-onset diabetes (NOD) risk. Careful patient monitoring, especially early in treatment, suggests PCSK9 inhibitor therapy is generally safe.
Area of Science:
- Cardiovascular Medicine
- Metabolic Disorders
- Pharmacology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly reduce low-density lipoprotein-cholesterol (LDL-C).
- Achieving very low LDL-C levels necessitates evaluating potential adverse effects, including new-onset diabetes (NOD).
Purpose of the Study:
- To investigate the association between PCSK9 inhibitor use and the risk of new-onset diabetes.
- To reconcile conflicting evidence from clinical trials and genetic studies regarding NOD risk with PCSK9 inhibition.
Main Methods:
- Review of meta-analyses and cardiovascular outcome trials (FOURIER, ODYSSEY).
- Analysis of Mendelian randomization studies.
- Evaluation of post-marketing safety reports.
Main Results:
- Cardiovascular outcome trials and meta-analyses did not show an increased incidence of NOD.
- Mendelian randomization studies suggested an increased NOD risk.
- Post-marketing reports indicated mild hyperglycemia, not diabetes, primarily within the first six months of treatment with evolocumab and alirocumab.
Conclusions:
- While genetic studies suggest a potential NOD risk, clinical trial and real-world data indicate minimal concern.
- Careful patient monitoring, particularly during the initial treatment phase, and identifying susceptible individuals are crucial.
- PCSK9 inhibitor therapy, with appropriate monitoring, is considered safe regarding NOD risk.
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