Glucose-lowering drugs with cardiovascular benefits as modifiers of critical elements of the human life history

Avogaro, Angelo; Kreutzenberg, Saula Vigili de; Morieri, Mario Luca; Fadini, Gian Paolo; Prato, Stefano Del

doi:10.1016/s2213-8587(22)00247-9

Cited by 8 publications

(5 citation statements)

References 123 publications

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“…Hence, the GIP system may substitute for the disrupted GLP-1 system, as observed in mice ( 51 ). Furthermore, our results may support the recent hypothesis that the GLP-1 and GLP-1R system modifies central parts of human life history, such as energy maintenance and defense against pathogens, by which, that is, hyperglycemia and expansion of fat mass may lead to inappropriate activation of the immune system, conjointly increasing the risk of cardiovascular complications ( 52 ). Beyond the glucose-lowering and weight-loss effects, GLP-1R agonism has shown promising cardiovascular benefits in patients with metabolic dysfunction ( 53 , 54 ).…”

Section: Discussionsupporting

confidence: 85%

Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes

Melchiorsen

Sørensen

Bork-Jensen

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Impact of lost GLP-1 receptor function in human physiology. Objective Identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. Methods We sequenced GLP1R in 8,642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cAMP formation and beta-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signalling (LoS) variants and cardiometabolic phenotypes in 2,930 patients with type 2 diabetes and 5,712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330,566 unrelated Caucasian exome-sequenced participants in the UK Biobank cohort. Results We identified 36 nonsynonymous variants in GLP1R of which 10 had a statistically significant loss in GLP-1-induced cAMP signalling compared to wildtype. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on HbA1c. Conclusion Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as non-carriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants.

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Section: Discussionsupporting

confidence: 85%

Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes

Melchiorsen

Sørensen

Bork-Jensen

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…The extraordinary success of GLP-1 RAs in T2DM treatment is based on the properties of the incretin hormone GLP-1, which increases the insulin secretory response to an oral glucose load, suppresses glucagon secretion, decelerates gastric emptying, and reduces food seeking [ 3 , 29 ]. Oral semaglutide, which is a combination of the GLP-1 RA semaglutide and the absorption-enhancer sodium N-amino caprylate, represents the first oral GLP-1 RA.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, regardless of structural homology, they reduce the risk of chronic diabetic complications, including major adverse cardiovascular events, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with T2DM [ 2 ]. Interestingly, GLP-1RAs seem to reduce the rate of cardiovascular and renal endpoints even beyond their ability to lower glucose concentrations [ 3 , 4 ], and this could be ascribed to body weight reduction and to the amelioration of blood pressure and lipid profile [ 5 , 6 , 7 ], as well as to their anti-inflammatory activity [ 4 , 8 , 9 ]. In other words, GLP-1 RAs address cardiometabolic risk factors comprehensively [ 1 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, GLP-1RAs seem to reduce the rate of cardiovascular and renal endpoints even beyond their ability to lower glucose concentrations [ 3 , 4 ], and this could be ascribed to body weight reduction and to the amelioration of blood pressure and lipid profile [ 5 , 6 , 7 ], as well as to their anti-inflammatory activity [ 4 , 8 , 9 ]. In other words, GLP-1 RAs address cardiometabolic risk factors comprehensively [ 1 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Real-World Retrospective Study into the Effects of Oral Semaglutide (As a Switchover or Add-On Therapy) in Type 2 Diabetes

Candido,

Gaiotti,

Giudici

et al. 2023

JCM

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(1) Background: Oral semaglutide represents the first oral GLP-1 RA approved for the treatment of type 2 diabetes mellitus (T2DM). This real-world retrospective study aimed at evaluating its effectiveness and tolerability in the treatment of patients with T2DM when patients switched from a glucose-lowering agent to it and when it was added to the usual therapy. (2) Methods: Adult patients with T2DM taking oral semaglutide and followed in the ASUGI Diabetes Center were identified with the use of electronic medical records between October 2022 and May 2023. (3) Results: A total of 129 patients were recruited. The median follow-up was 6 months. Be it as a switchover or as an add-on therapy, oral semaglutide significantly reduced HbA1c and BMI. Switching from DPPIV inhibitors to oral semaglutide was associated with a significant reduction in HbA1c and BMI, switching from SGLT2 inhibitors was associated with a significant reduction in HbA1c, and switching from sulphonylureas was associated with a significant reduction in BMI. The median HbA1c change was associated with baseline HbA1c. SBP significantly decreased in the add-on group. Oral semaglutide was well tolerated. (4) Conclusions: This study shows that in the real-world setting, oral semaglutide is effective and safe as a switchover or as an add-on therapy for the treatment of T2DM.

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“…Clinical strategies have been proposed to combat obesity mainly through drug administration and bariatric surgery ( 6 , 7 ). Antiobesity drugs previously approved by the FDA, such as sibutramine, deoxyephedrine, carbamate and fenfluramine, have shown serious side effects, and some are no longer available or are unsuitable for long-term use ( 8 – 10 ). Bariatric surgeries, like Roux-en-Y gastric bypass (RYGB), gastric banding as well as sleeve gastrectomy, are confirmed to be more effective than drug therapy, but they have not been widely accepted due to their high cost, high risk, possible complications and sequelae ( 7 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the extraction, purification, structural-property correlations, and antiobesity mechanism of traditional Chinese medicine-derived polysaccharides: a review

Zhi,

Chang,

Wang

et al. 2024

Front. Nutr.

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Traditional Chinese medicine (TCM) has displayed preventive and therapeutic effects on many complex diseases. As natural biological macromolecules, TCM-derived antiobesogenic polysaccharides (TCMPOs) exhibit notable weight-loss effects and are seen to be a viable tactic in the fight against obesity. Current studies demonstrate that the antiobesity activity of TCMPOs is closely related to their structural characteristics, which could be affected by the extraction and purification methods. Therefore, the extraction, purification and structural-property correlations of TCMPOs were discussed. Investigation of the antiobesity mechanism of TCMPOs is also essential for their improved application. Herein, the possible antiobesity mechanisms of TCMPOs are systematically summarized: (1) modulation of appetite and satiety effects, (2) suppression of fat absorption and synthesis, (3) alteration of the gut microbiota and their metabolites, and (4) protection of intestinal barriers. This collated information could provide some insights and offer a new therapeutic approach for the management and prevention of obesity.

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Glucose-lowering drugs with cardiovascular benefits as modifiers of critical elements of the human life history

Cited by 8 publications

References 123 publications

Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes

Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes

Real-World Retrospective Study into the Effects of Oral Semaglutide (As a Switchover or Add-On Therapy) in Type 2 Diabetes

Recent advances in the extraction, purification, structural-property correlations, and antiobesity mechanism of traditional Chinese medicine-derived polysaccharides: a review

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