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Doubling of Hemoglobin A1c on PCSK9 Inhibitor Therapy

Hemoglobin A1c trend before and after proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9I) therapy. Hemoglobin A1c values prior to PCSK9I therapy were in the range of 6.4% to 7.3%. After initiation of therapy, they slowly trended up, eventually doubled, and then improved after discontinuation of the medication.

A 70-year-old man with history of cerebrovascular accident, hyperlipidemia, and type 2 diabetes mellitus presented with polyuria, polydipsia, and weight loss. Severe hyperglycemia (serum glucose, 585 mg/dL) was present on admission. No precipitating factors were identified. Initial laboratory findings were also notable for elevated aspartate aminotransferase (703 IU/L) and alanine aminotransferase (779 IU/L). Diabetes mellitus, diagnosed 4 years prior to presentation, was managed with glipizide. Hemoglobin A1c (HbA1c) levels were in the range of 6.4% to 7.3% over that time. A history of persistently elevated low-density lipoprotein cholesterol (LDL-C) levels of greater than 200 mg/dL was present. Intolerance to 4 different statins, ezetimibe, and colesevelam had been reported. Evolocumab 140 mg biweekly was initiated. HbA1c was 6.7% at initiation of evolocumab therapy and subsequently increased to 7.8% 4 months later. Therapy was changed to alirocumab 150 mg biweekly for insurance reasons, and 5 months later HbA1c increased to 13.7% at time of admission (Figure). There was no concomitant change in diet, physical activity, or medications. Approximately 70 to 80 daily units of insulin were required to maintain euglycemia. Alirocumab was discontinued due to development of transaminitis. Three months later, insulin requirements decreased to 25 units total daily dose, and HbA1c decreased to 7.6%. No other changes in diet or lifestyle occurred during this time.

Lowering LDL-C is critical for the prevention of macrovascular complications of diabetes mellitus. Worsening glycemic control is a reported consequence of lowering LDL-C with statins. Current evidence on the effects of proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9I) therapy on glycemic control is unclear and conflicting. Some epidemiological and clinical studies show increased risk of diabetes mellitus with higher PCSK9 levels, whereas genetic studies concluded the opposite. Pooled analyses of phase 3 studies of alirocumab did not report increased onset of new diabetes.1 A 24-week randomized controlled trial of alirocumab did not show any statistically significant changes in measures of glycemic control in patients with type 1 and type 2 diabetes mellitus.2 HbA1c levels were also shown to be similar between evolocumab and placebo over 2.2 years.3However, a Mendelian randomization study, using PCSK9 genetic variants as representation of pharmacological inhibition of PCSK9, showed a higher risk of diabetes mellitus.4 Increased incidence of type 2 diabetes mellitus was found in association with loss-of-function mutations of PCSK9.5

No cases of severe hyperglycemia after initiation of PCSK9 inhibitors have been reported previously to our knowledge. Our patient showed a dramatic increase in glucose levels with PCSK9I treatment, especially after initiating alirocumab therapy, which reversed after its discontinuation. Additional long-term clinical studies on glycemic effects of PCSK9I therapy are needed to identify if worsening glycemic control is specific to a certain group of patients or with a specific drug in this class of medications. Mean HbA1c levels may under-recognize uncommon or idiosyncratic reactions. Close monitoring for dysglycemia may be warranted in patients being treated with PCSK9I therapy.

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– Raafia Memon, MD, Rana Malek, MD, Kashif M. Munir, MD

This article originally appeared in the January issue of The American Journal of Medicine.

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