Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial

Spósito, Andrei C.; Breder, Íkaro; Barreto, Joaquim; Breder, Jéssica Cunha; Bonilha, Isabella; Lima, Marcus; Oliveira, A. N.; Wolf, Vaneza Lira Waldow; Luchiari, Beatriz; Carmo, Helison R. do; Munhoz, Daniel; Oliveira, Dayane Carvalho Ramos Salles de; Coelho‐Filho, Otávio R.; Coelho, Otávio Rizzi; Matos‐Souza, José R.; Moura, Filipe A.; Carvalho, Luiz Sérgio F.; Nadruz, Wilson; Quinaglia, Thiago; Kimura-Medorima, Sheila T.

doi:10.1186/s12933-022-01584-8

Cited by 11 publications

(10 citation statements)

References 40 publications

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“…41,49,50 An RCT has shown that the short-term addition of evolocumab to empagliflozin in individuals with T2DM improves endothelial function, suggesting an additional role for the combination of the two agents in reducing cardiovascular risk. 51 The present study revealed that PCSK9 inhibitors alone increase the risk of SIDD and MOD, and it also demonstrated that statins alone increase the risk of SIRD. However, the effects of combining the two drugs on diabetes risk need to be further explored and monitored more carefully.…”

Section: Exposuresupporting

confidence: 66%

“…Available data suggest that PCSK9 inhibitors reduce LDL‐C by up to 60% more when applied in a statin background and are associated with a clinically significant reduction in cardiovascular events 41,49,50 . An RCT has shown that the short‐term addition of evolocumab to empagliflozin in individuals with T2DM improves endothelial function, suggesting an additional role for the combination of the two agents in reducing cardiovascular risk 51 . The present study revealed that PCSK9 inhibitors alone increase the risk of SIDD and MOD, and it also demonstrated that statins alone increase the risk of SIRD.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Exposuresupporting

confidence: 66%

Section: Discussionmentioning

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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“…Conversely, Zainordin et al [ 25 ] showed that 12 weeks of dapagliflozin add-on therapy to metformin and insulin did not alter FMD, and that there was no significant difference in FMD between the control and dapagliflozin groups. Sposito et al [ 26 ] showed that 16-week treatment with empagliflozin did not alter FMD. The EMBLEM trial, a multicenter, randomized, placebo-controlled, double-blind trial, showed that empagliflozin administered for 24 weeks did not alter the reactive hyperemia peripheral arterial tonometry index as an indication of endothelial function in patients with type 2 diabetes [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study

Kishimoto¹,

Higashi²,

Imai³

et al. 2023

Cardiovasc Diabetol

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Background We assessed the impact of 24 months of treatment with ipragliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on endothelial function in patients with type 2 diabetes as a sub-analysis of the PROTECT study. Methods In the PROTECT study, patients were randomized to receive either standard antihyperglycemic treatment (control group, n = 241 ) or add-on ipragliflozin treatment (ipragliflozin group, n = 241) in a 1:1 ratio. Among the 482 patients in the PROTECT study, flow-mediated vasodilation (FMD) was assessed in 32 patients in the control group and 26 patients in the ipragliflozin group before and after 24 months of treatment. Results HbA1c levels significantly decreased after 24 months of treatment compared to the baseline value in the ipragliflozin group, but not in the control group. However, there was no significant difference between the changes in HbA1c levels in the two groups (7.4 ± 0.8% vs. 7.0 ± 0.9% in the ipragliflozin group and 7.4 ± 0.7% vs. 7.3 ± 0.7% in the control group; P = 0.08). There was no significant difference between FMD values at baseline and after 24 months in both groups (5.2 ± 2.6% vs. 5.2 ± 2.6%, P = 0.98 in the ipragliflozin group; 5.4 ± 2.9% vs. 5.0 ± 3.2%, P = 0.34 in the control group). There was no significant difference in the estimated percentage change in FMD between the two groups (P = 0.77). Conclusions Over a 24-month period, the addition of ipragliflozin to standard therapy in patients with type 2 diabetes did not change endothelial function assessed by FMD in the brachial artery. Trial registration Registration Number for Clinical Trial: jRCT1071220089 (https://jrct.niph.go.jp/en-latest-detail/jRCT1071220089).

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“…SGLT2i are known for impairing endothelial dysfunction. Adding a PCSK9 inhibitor to SGLT2i treatment improved endothelial function assessed by FMD and the plasma concentrations of nitrate, nitrite, and isoprostane [ 64 ]. PCSK9 drugs suppress endothelial cell proinflammatory activation and reduce apoptosis in endothelial cells, smooth muscle cells, and macrophages [ 65 ].…”

Section: Endothelial Dysfunction Markers and Pcsk9 Inhibitorsmentioning

confidence: 99%

“…Treatment with a PCSK9 inhibitor given to type 2 diabetes (T2D) patients (110 individuals) along with SGLT2i treatment improved FMD and the bioavailability of NO. Increased NO may contribute towards improving endothelial dysfunction [ 64 ].…”

Section: Endothelial Dysfunction Markers and Pcsk9 Inhibitorsmentioning

confidence: 99%

The Anti-Thrombotic Effects of PCSK9 Inhibitors

Péč,

Benko,

Jurica

et al. 2023

Pharmaceuticals

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Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is established by solid evidence. PCSK9 inhibitors have proven to be a valuable and practical resource for lowering the LDL cholesterol of many patients in recent years. Their inhibitory effect on atherosclerosis progression seems to be driven not just by lipid metabolism modification but also by LDL-independent mechanisms. We review the effect of PCSK9 inhibitors on various mechanisms involving platelet activation, inflammation, endothelial dysfunction, and the resultant clot formation. The main effectors of PCSK9 activation of platelets are CD36 receptors, lipoprotein(a), oxidised LDL particles, tissue factor, and factor VIII. Many more molecules are under investigation, and this area of research is growing rapidly.

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Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial

Cited by 11 publications

References 40 publications

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

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

Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: sub-analysis of the PROTECT study

The Anti-Thrombotic Effects of PCSK9 Inhibitors

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