Diabetes Care Volume 41, April 2018 e69

COMMENT ON DE CARVALHO ET AL. Proprotein Convertase Subtilisin/Kexin Ye-Xuan Cao and Jian-Jun Li Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient- Years. Diabetes Care 2018;41:364–367 Diabetes Care 2018;41:e69 | https://doi.org/10.2337/dc17-2563

We read with interest the article by de from future use. Hence, the analysis cov- Evidence suggested that statins moder- Carvalho et al. (1). This meta-analysis re- ering the SPIRE trials might be improper ately increased new-onset diabetes and ported the results from 68,123 individuals for current reference to the clinical HbA1c (3,4). PCSK9i are the most powerful (20 randomized clinical trials) during PCSK9i application. Importantly, we per- lipid-lowering drugs currently (5) and 78 weeks of follow-up and evaluated the formed similar meta-analysis without naturally aroused the same concerns. effects of proprotein convertase subtilisin/ SPIRE trials. The data suggested that Therefore, we should be more prudent to kexin type 9 inhibitors (PCSK9i) on glucose PCSK9ihadnoeffectoncirculatingFBGor evaluate the data to make a conclusion. metabolism. They revealed that PCSK9i in- HbA1c levels and that treatment duration Given the experience with statins, evi- creased fasting blood glucose (FBG) and or percent change of LDL cholesterol did dence from a larger number of partici- HbA1c (P , 0.001, respectively) compared not influence diabetes risk. Although the pants and longer follow-up clinical trials with placebo. Satisfactorily, PCSK9i had no analyses with or without SPIRE trials may concerning PCSK9i is required in the future. impact on the incidence of new-onset di- be a small difference point, the conclu- abetes but showed a positive association sion is quite meaningful. Originally, there Funding. This work was partially supported by between diabetes risks and the potency was a small increase in FBG and no change theCapitalHealthDevelopmentFund(201614035) (P = 0.029) and duration (P = 0.026) of in plasma HbA1c levels or new-onset dia- and Chinese Academy of Medical Sciences (CAMS) PCSK9i therapy. The research appears in- betes after bococizumab treatment when Major Collaborative InnovationProject (2016-I2M- formative clinically. However, we would compared with placebo. Thereby, the re- 1-011) awarded to J.-J.L. Duality of Interest. No potential conflicts of like to add several comments on this article. sults of the meta-analysis by de Carvalho interest relevant to this article were reported. First, in their analysis they included et al. (1) might be cautiously regarded due References SPIRE trials when calculating the change to the possibility of misunderstandings. 1. de Carvalho LSF, Campos AM, Sposito AC. Pro- fi of FBG and HbA1c posttreatment from Second, new-onset diabetes is de ned protein convertase subtilisin/kexin type 9 (PCSK9) e-LETTERS baseline. In fact, unlike evolocumab and as patients without diabetes at study entry inhibitors and incident type 2 diabetes: a system- alirocumab, bococizumab is not a fully and initiation of antidiabetes medication, atic review and meta-analysis with over 96,000 – humanized monoclonal antibody; it FPG $7.0 mmol/L, or HbA $ 6.5% post- patient-years. Diabetes Care 2018;41:364 367 1c 2. Ridker PM, Revkin J, Amarenco P, et al.; SPIRE –

; RESPONSES AND COMMENTS contains 3% of the murine sequence treatment. To investigate the risk of de- Cardiovascular Outcome Investigators. Cardiovas- in the antigen-binding complementarity- velopment of diabetes in patients given cular efficacy and safety of bococizumab in high- determining region (2). During bococizumab statins, Sattar et al. (3) and Preiss et al. risk patients. N Engl J Med 2017;376:1527–1539 treatment, nearly half the patients devel- (4) evaluated the development of diabe- 3. Sattar N, Preiss D, Murray HM, et al. Statins and oped antidrug antibodies, and 29% of pa- tes in participants without diabetes at risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–742 tients had neutralizing antibodies that baseline. Unfortunately, de Carvalho 4. Preiss D, Seshasai SR, Welsh P, et al. Risk of reduced the clinical efficacy, which never et al. (1) covered patients with diabetes incident diabetes with intensive-dose compared occurred in evolocumab and alirocumab at baseline, which might result in serious with moderate-dose statin therapy: a meta-analysis. therapy. Furthermore, no significant bias during the meta-analysis according JAMA 2011;305:2556–2564 fi 5. Zhang Y, Zhu CG, Xu RX, et al. Relation of cir- bene t was observed with respect to to our knowledge. Logically, the value of culating PCSK9 concentration to fibrinogen in pa- the primary end point. Thus, this PCSK9 their analysis might be limited by this tients with stable coronary artery disease. J Clin monoclonal antibody was withdrawn methodological imperfection. Lipidol 2014;8:494–500

Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China Corresponding author: Jian-Jun Li, [email protected]. © 2018 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.