Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • The vast majority of clinical

    2022-05-16

    The vast majority of clinical studies have shown that chronic administration of GLP-1R agonists frequently lowers SBP/DBP in diabetic humans, which is consistent with preclinical studies, though the reported reductions are not as potent as those observed in their animal counterparts. In contrast, acute GLP-1/GLP-1R agonist treatment can transiently increase SBP/DBP (reviewed extensively in [17,56]), though reasons for these discrepant actions remain to be elucidated. With regards to chronic GLP-1R agonist administration, a 1-year treatment with exenatide significantly decreased SBP in T2D patients from the “Results from the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1)” trial [10], with ∼50% of patients that had a SBP ≥ 130 mm Hg at baseline, achieving a normal SBP by week 52. Similarly, 314 overweight/obese patients receiving exenatide (10 μg twice daily) for 82 weeks also demonstrated reductions in both SBP and DBP [8]. Furthermore, a retrospective analysis of 110 T2D patients treated with liraglutide (0.6, 1.2, or 1.8 mg daily) observed a GYKI 52466 dihydrochloride in SBP (∼5 mmHg) following the first 3 months of treatment [59]. In an analysis of 2665 patients from 3 separate randomized phase 3 trials, 26 weeks of treatment with liraglutide (1.2 or 1.8 mg once daily) in combination with either metformin, glimepiride, or metformin and rosiglitazone, significantly reduced SBP (2.29 to 6.71 mm Hg reductions) [20]. Finally, another study reported that a 20-week treatment with once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), followed by a non-blinded 2-year extension (final dose of 3.0 mg), produced an ∼4.6 mm Hg decrease in SBP in 268 obese non-diabetic patients [3]. With regards to atherosclerosis, only a limited number of studies have examined the impact of chronic GLP-1/GLP-1R agonist administration on clinically meaningful endpoints in T2D subjects. Rizzo and colleagues observed in 64 T2D patients without a history of coronary artery disease, that addition of liraglutide therapy (0.6 mg for 2 weeks followed by 1.2 mg daily for ∼7.5 months) on top of background metformin therapy (1500 mg daily) decreased carotid intima media thickness (IMT) by ∼0.25 mm [50]. Importantly, this improvement was found to be independent of changes in circulating glucose and lipid levels, and it should be noted that this study lacked a true placebo-controlled treatment arm as all patients were receiving background metformin. Similarly, addition of liraglutide therapy (0.6 mg for 2 weeks followed by 1.2 mg daily for ∼7.5 months) on top of background metformin therapy (1500 mg – 3000 mg daily) decreased carotid IMT by ∼0.14 mm in 29 patients with T2D and nonalcoholic fatty liver disease (NAFLD) [49]. These observations were once again independent of changes in circulating glucose and lipid levels, and were not seen in T2D patients without NAFLD. Analysis of the SUSTAIN-6 outcomes trial also reported reduced rates for coronary or peripheral revascularization procedures in T2D patients treated with semaglutide, suggestive of salutary antiatherosclerotic actions [27,36]. In addition, conclusions from a meta-analysis indicate that carotid IMT decreased statistically non-significantly via GLP-1 based therapies, though only 6 studies were included, and 4 of them involved a DPP-4 inhibitor as the agent to increase GLP-1 action. As alluded to previously, DPP-4 inhibitors influence circulating levels of a wide range of peptides that may impact cardiovascular risk factors and/or cardiac function [39,40,56], and thus their actions on carotid IMT could potentially be independent of increases in circulating GLP-1. Taken together, the preclinical and clinical evidence to date demonstrate favourable actions of GLP-1/GLP-1R agonists on vascular health (Fig. 1), but whether this is due to direct actions specifically on the vascular endothelium remains to be determined. It is important to note that while the improvement in SBP/DBP in the majority of these studies is associated with reductions in body weight, appreciable reductions in SBP/DBP usually appear rapidly and prior to any significant weight loss [56,57]. Hence, the vascular/endothelial actions of GLP-1/GLP-1R agonists may account for their antihypertensive and/or antiatherogenic actions in humans. Conversely, GLP-1/GLP-1R agonists also exert anti-inflammatory actions and improve circulating lipid profiles (see [11,17] for extensive review), which could indirectly contribute to GLP-1R agonist-induced protection against hypertension/atherosclerosis.