Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management

Khankari, Nikhil K.; Keaton, Jacob M.; Walker, Venexia; Lee, Kyung Min; Shuey, Megan M.; Clarke, Sue; Heberer, Kent; Miller, Donald R.; Reaven, Peter D.; Lynch, Julie; Vujkovic, Marijana; Edwards, Todd L.

doi:10.1016/j.ebiom.2022.104038

Cited by 12 publications

(14 citation statements)

References 38 publications

(43 reference statements)

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“…The newest Mendelian randomization study showed that, for PCSK9-mAbs, LDL-C lowering per standard deviation decrease in PCSK9 expression indicated a modest T2DM risk reduction. However, after adjustment for other lipids and physical activity, the relationship between PCSK9-mAbs application and T2DM was not observed ( 16 ). This suggests that the use of PCSK9-mAbs may not be associated with increased risk of HAEs.…”

Section: Research Status Of the Relationship Between Pcsk9 And Pcsk9-...mentioning

confidence: 99%

Advanced progress of the relationship between PCSK9 monoclonal antibodies and hyperglycemic adverse events

Zhang

Wang

et al. 2023

Front. Cardiovasc. Med.

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Purpose of ReviewLong-term use of statins had been confirmed to cause an increase in hyperglycemic adverse events (HAEs), whose mechanism has been well understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (PCSK9-mAbs), a kind of new lipid-lowering drug, can effectively reduce plasma low-density lipoprotein cholesterol levels in patients with CHD and have been widely used. However, animal experiments, Mendelian randomization studies, clinical researches and Meta-analyses which focused on the relationship between PCSK9-mAbs and HAEs had reached different conclusions, which has attracted great attention from clinicians.Recent FindingsThe newest FOURIER-OLE randomized controlled trial followed PCSK9-mAbs users for over 8 years, whose results suggested that long-term use of PCSK9-mAbs did not increase the incidence of HAEs. Newest Meta-analyses also indicated that there was no relationship between PCSK9-mAbs and NOD. Meanwhile, genetic polymorphisms and variants related to PCSK9 might have effects on HAEs.ConclusionAccording to the results of current studies, there is no significant relationship between PCSK9-mAbs and HAEs. However, longer-term follow-up studies are still needed to confirm it. Although PCSK9 genetic polymorphisms and variants may affect the possible occurrence of HAEs, there is no need to perform relevant genetic testing before applying PCSK9-mAbs.

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Section: Research Status Of the Relationship Between Pcsk9 And Pcsk9-...mentioning

confidence: 99%

Advanced progress of the relationship between PCSK9 monoclonal antibodies and hyperglycemic adverse events

Zhang

Wang

et al. 2023

Front. Cardiovasc. Med.

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“…Medications evaluated in this series were grouped in to three sets: 1) experimental, the gene-based medication set described previously; 2) diabetes/control (-), medications that are prescribed for the treatment of T2DM; and 3) control (+), medications belonging to classes that had previously described increasing effects on glucose or HbA1c or were implicated in a previous MR study 41 . The complete list of medications and their corresponding set are available in Supplemental Tables 1a and b.…”

Section: Self-controlled Case Series Study Designmentioning

confidence: 99%

“…We replicated a previously published approach using S-PrediXcan summary statistics as the instrumental variable in an MR analysis to proxy therapeutic targets 41 .Tissuespecific GPGE summary statistics for each trait and T2D were combined to calculate the IVW MR association as follows:…”

Section: Mendelian Randomizationmentioning

confidence: 99%

A genetically supported drug repurposing pipeline for diabetes treatment using electronic health records

Shuey

Lee

Keaton

et al. 2022

Preprint

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Objectives The identification of novel uses for existing drug therapies has the potential to provide a rapid, low-cost approach to drug (re)discovery. In the current study we developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. Design We developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. This approach mapped genetically predicted gene expression signals from the largest genome-wide association study for type 2 diabetes mellitus to drug targets using publicly available databases to identify drug-gene pairs. These drug-gene pairs were then validated using a two-step approach: 1) a self-controlled case-series (SCCS) using electronic health records from a discovery and replication population, and 2) Mendelian randomization (MR). Setting The SCCS experiments were completed using two EHRs: the Million Veterans Program (USA) as the discovery and the Vanderbilt University Medical Center (Tennessee, USA) as the replication. Results After filtering on sample size, 20 candidate drug-gene pairs were validated and various medications demonstrated evidence of glycemic regulation including two anti-hypertensive classes: angiotensin-converting enzyme inhibitors as well as calcium channel blockers (CCBs). The CCBs demonstrated the strongest evidence of glycemic reduction in both validation approaches (SCCS HbA1c and glucose reduction: -0.11%, p=0.01 and -0.85 mg/dL, p=0.02, respectively; MR: OR=0.84, 95% CI=0.81, 0.87, p=5.0x10-25). Conclusions Our results support CCBs as a strong candidate medication for blood glucose reduction in addition to cardiovascular disease reduction. Further, these results support the adaptation of this approach for use in future drug-repurposing efforts for other conditions.

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“…Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a liver serine protease that regulates LDL-C metabolism. However, it remains unclear whether lowering LDL-C with PCSK9 inhibitors leads to an increased risk of diabetes as findings from previous studies are inconsistent, [1][2][3][4] suggesting the need for close blood glucose monitoring in patients using PCSK9 inhibitors. HMG-CoA reductase (HMGCR) inhibitors, also known as statins, are the most commonly used lipid-lowering drugs.…”

Section: Introductionmentioning

confidence: 99%

Estimating the effect of lipid‐lowering agents on novel subtypes of adult‐onset diabetes

Ye,

Guo,

et al. 2024

Diabetes Metabolism Res

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AimsThe aims of the present study were to assess the effects of lipid‐lowering drugs [HMG‐CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, and Niemann–Pick C1‐Like 1 (NPC1L1) inhibitors] on novel subtypes of adult‐onset diabetes through a Mendelian randomisation study.Materials and MethodsWe first inferred causal associations between lipid‐related traits [including high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG), apolipoproteins A‐I, and apolipoproteins B] and novel subtypes of adult‐onset diabetes. The expression quantitative trait loci of drug target genes for three classes of lipid‐lowering drugs, as well as genetic variants within or nearby drug target genes associated with LDL‐C, were then utilised as proxies for the exposure of lipid‐lowering drugs. Mendelian randomisation analysis was performed using summary data from genome‐wide association studies of LDL‐C, severe autoimmune diabetes, severe insulin‐deficient diabetes (SIDD), severe insulin‐resistant diabetes (SIRD), mild obesity‐related diabetes (MOD), and mild age‐related diabetes.ResultsThere was an association between HMGCR‐mediated LDL‐C and the risk of SIRD [odds ratio (OR) = 0.305, 95% confidence interval (CI) = 0.129–0.723; p = 0.007], and there was an association of PCSK9‐mediated LDL‐C with the risk of SIDD (OR = 0.253, 95% CI = 0.120–0.532; p < 0.001) and MOD (OR = 0.345, 95% CI = 0.171–0.696; p = 0.003). Moreover, NPC1L1‐mediated LDL‐C (OR = 0.109, 95% CI = 0.019–0.613; p = 0.012) and the increased expression of NPC1L1 gene in blood (OR = 0.727, 95% CI = 0.541–0.977; p = 0.034) both showed a significant association with SIRD. These results were further confirmed by sensitivity analyses.ConclusionsIn summary, the different lipid‐lowering medications have a specific effect on the increased risk of different novel subtypes of adult‐onset diabetes.

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Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management

Cited by 12 publications

References 38 publications

Advanced progress of the relationship between PCSK9 monoclonal antibodies and hyperglycemic adverse events

Advanced progress of the relationship between PCSK9 monoclonal antibodies and hyperglycemic adverse events

A genetically supported drug repurposing pipeline for diabetes treatment using electronic health records

Estimating the effect of lipid‐lowering agents on novel subtypes of adult‐onset diabetes

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