Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Ezetimibe on Risk of New-Onset Diabetes: A Systematic Review and Meta-Analysis of Large, Double-Blinded Randomized Controlled Trials

Chiu, Sarah; Pratt, Cristina; Feinn, Richard; Chatterjee, Saurav

doi:10.1177/1074248420924983

Cited by 17 publications

(7 citation statements)

References 28 publications

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“…For positive control outcomes, our findings corroborate previous trials 8 , 11 , 45 , 46 and MR studies 47 , 48 , 49 , 50 that genetically mimicked cardiovascular medications were generally associated with IHD, diabetes, or both as expected.…”

Section: Discussionsupporting

confidence: 89%

Unraveling Potential Sex‐Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization

Kwok,

Schooling

2023

JAHA

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Background Establishing the sex‐specific efficacy of cardiovascular medications is pivotal to evidence‐based clinical practice, potentially closing the gender gap in longevity. Trials large enough to establish sex differences are unavailable. This study evaluated sex‐specific effects of commonly prescribed cardiovascular medications on lifespan. Methods and Results In a two‐sample Mendelian randomization study, established genetic variants mimicking effects of lipid‐lowering drugs, antihypertensives, and diabetes drugs were applied to genetic associations with lifespan proxied by UK Biobank maternal (n=412 937) and paternal (n=415 311) attained age. Estimates were obtained using inverse variance weighting, with sensitivity analyses where possible. For lipid‐lowering drugs, genetically mimicked PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors were associated with longer lifespan, particularly in men (2.39 years per SD low‐density lipoprotein cholesterol reduction [95% CI, 0.42–4.36], P for interaction=0.14). Genetically mimicked treatments targeting APOC3 , LPL , or possibly LDLR were associated with longer lifespan in both sexes. For antihypertensives, genetically mimicked β‐blockers and calcium channel blockers were associated with longer lifespan, particularly in men ( P for interaction=0.17 for β‐blockers and 0.31 for calcium channel blockers). For diabetes drugs, genetically mimicked metformin was associated with longer lifespan in both sexes. No associations were found for genetically mimicked statins, ezetimibe, or angiotensin‐converting enzyme inhibitors. Conclusions PCSK9 inhibitors, β‐blockers, and calcium channel blockers may prolong lifespan in the general population, particularly men. Treatments targeting APOC3 , LPL , or LDLR and metformin may be relevant to both sexes. Whether other null findings are attributable to lack of efficacy requires investigation. Further investigation of repurposing should be conducted.

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Section: Discussionsupporting

confidence: 89%

Unraveling Potential Sex‐Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization

Kwok,

Schooling

2023

JAHA

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“…Neither LDL-C lowering (38.7 mg/dL) nor the use of PCSK9 inhibitors was associated with the incidence of diabetes, respectively, risk ratio = 1.07 (95%CI 1.03-1.11) and risk ratio = 1.00 (95%CI 0.93-1.07) [58]. In line with this evidence, other meta-analyses failed to detect a raised risk of hyperglycaemia or diabetes [59][60][61]. To quantify the safety of PCSK9 inhibitors with a specific focus on type 2 diabetes was also the topic of a Cochrane analysis.…”

Section: Meta-analyses Of Clinical Studiesmentioning

confidence: 80%

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Carugo

Sirtori

Corsini

et al. 2022

Curr Atheroscler Rep

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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. Summary 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.

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“…In this study, a positive diabetes signal was observed only with evolocumab (ROR = 2.5) and not with alirocumab. Although diabetes and worsening glycemic control were not found to be associated with PCSK9 inhibitors in clinical trials ( Carvalho et al, 2017 ; Chiu et al, 2020 ), it has been suggested that the FOURIER trial may not be robust enough to detect diabetes risk ( van Bruggen and Luijendijk, 2019 ). However, in the present study, the lower risk of metabolism and nutrition disorders of PCSK9 inhibitors compared to statins provide reassurance regarding their clinical benefit.…”

Section: Discussionmentioning

confidence: 99%

Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS

Feng

Tong

et al. 2022

Front. Pharmacol.

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Objective: We aimed to evaluate alirocumab- and evolocumab-related adverse events (AEs) in real-world compared with all other drugs, overall and by gender and age subgroups; we also aimed to compare their risks of cognitive impairment, musculoskeletal disorders and diabetes with various statins and ezetimibe.Methods: We retrospectively extracted AE reports from the FDA Adverse Event Reporting System (FAERS) database during July 2015-June 2021. Disproportionality analyses were performed using reporting odds ratios (RORs) to detect AE signals of alirocumab and evolocumab in the overall population and in different age and gender subgroups, respectively.Results: Compared with all other drugs, both alirocumab and evolocumab had a significant signal in “musculoskeletal and connective tissue disorders” (ROR1 = 2.626, 95% CI 2.552–2.702; ROR2 = 2.575, 95% CI 2.538–2.613). The highest ROR value of 2.311 (95% CI 2.272–2.351) was for “injury, poisoning and procedural complications” and was found in patients aged ≥65 years on evolocumab. The most frequent AEs were “general disorders and administration site conditions” and “musculoskeletal and connective tissue disorders” for all subpopulations. At the preferred term level, the most frequent AE signal was myalgia for alirocumab and injection site pain for evolocumab, overall and by subgroups. Compared with statins/ezetimibe, PCSK9 inhibitors exhibited lower ROR values for adverse events associated with SOC “nervous system disorders”, “psychiatric disorders” and “metabolism and nutrition disorders” (all RORs < 1), but mixed results for musculoskeletal disorders. Compared with all other drugs, undocumented AEs, such as acute cardiac event (ROR = 30.0, 95% CI 9.4–95.3) and xanthoma (ROR = 9.3, 95% CI 3.4–25.5), were also reported.Conclusion: Real-world evidence showed that PCSK9 inhibitors were associated with an increased risk of musculoskeletal and connective tissue disorders and general disorders and administration site conditions, overall and by subgroups. Muscle toxicity, injection site reactions, and influenza-like illness were significant AE signals. Compared with various statins and ezetimibe, PCSK9 inhibitors have shown a favorable safety profile in muscle-related events, cognitive impairment and diabetes. Some undocumented AE signals were also reported. Due to the limitations of spontaneous reporting databases, further studies are still needed to establish causality and validate our results.

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Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Ezetimibe on Risk of New-Onset Diabetes: A Systematic Review and Meta-Analysis of Large, Double-Blinded Randomized Controlled Trials

Cited by 17 publications

References 28 publications

Unraveling Potential Sex‐Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization

Unraveling Potential Sex‐Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS

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