Clinical Evidence and Proposed Mechanisms for Cardiovascular and Kidney Benefits from Sodium–Glucose Co-transporter-2 Inhibitors

Neumiller, Joshua J.; Lienhard, Fredrick J; Alicic, Radica Z.; Tuttle, Katherine R.

doi:10.17925/ee.2022.18.2.106

Cited by 5 publications

(4 citation statements)

References 65 publications

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“…Currently, the role of the inflammatory response in promoting the pathological processes in T2DM and its impact on affected tissues and organs is well recognized. Several studies have provided insights into the mechanisms by which T2DM induces inflammation and oxidative stress. – It is indisputably beneficial to modulate the inflammatory response in T2DM patients. – The cardiovascular, renal, and other organ-protective effects of novel antidiabetic medications have been attributed to their anti-inflammatory properties . Colonic inflammation, with its detrimental effects on the mucosal barrier, bacterial infection, and insulin resistance, has been implicated in various diseases, including diabetes.…”

Section: Discussionmentioning

confidence: 99%

“… 16 – 20 It is indisputably beneficial to modulate the inflammatory response in T2DM patients. 21 – 25 The cardiovascular, renal, and other organ-protective effects of novel antidiabetic medications have been attributed to their anti-inflammatory properties. 26 Colonic inflammation, with its detrimental effects on the mucosal barrier, bacterial infection, and insulin resistance, has been implicated in various diseases, including diabetes.…”

Section: Discussionmentioning

confidence: 99%

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Inulin Inhibits the Inflammatory Response through Modulating Enteric Glial Cell Function in Type 2 Diabetic Mellitus Mice by Reshaping Intestinal Flora

Li,

Duan,

Wang

et al. 2023

ACS Omega

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Inulin, a commonly used dietary fiber supplement, is capable of modulating the gut microbiome. Chronic inflammation resulting from metabolic abnormalities and gut flora dysfunction plays a significant role in the development of type 2 diabetes mellitus (T2DM). Our research has demonstrated that inulin administration effectively reduced colonic inflammation in T2DM mice by inducing changes in the gut microbiota and increasing the concentration of butyric acid, which in turn modulated the function of enteric glial cells (EGCs). Experiments conducted on T2DM mice revealed that inulin administration led to an increase in the Bacteroidetes/Firmicutes ratio and the concentration of butyric acid in the colon. The anti-inflammatory effects of altered gastrointestinal flora and its metabolites were further confirmed through fecal microbiota transplantation. Butyric acid was found to inhibit the activation of the κB inhibitor kinase β/nuclear factor κB pathway, regulate the expression levels of interleukin-6 and tumor necrosis factor-α, suppress the abnormal activation of EGCs, and prevent the release of inflammatory factors by EGCs. Similar results were observed in vitro experiments with butyric acid. Our findings demonstrate that inulin, by influencing the intestinal flora, modifies the activity of EGCs to effectively reduce colonic inflammation in T2DM mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inulin Inhibits the Inflammatory Response through Modulating Enteric Glial Cell Function in Type 2 Diabetic Mellitus Mice by Reshaping Intestinal Flora

Li,

Duan,

Wang

et al. 2023

ACS Omega

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“…Semaglutide might indirectly improve CV and kidney-related outcomes, but the exact mechanisms by which GLP-1RAs exert beneficial effects on CV and kidney parameters are not yet elucidated, in contrast to the well-established intrarenal tubulo-glomerular feedback mechanism of SGLT2is [ 13 ]. However, the known effects of GLP-1RAs on glucose control might contribute to improvements in MACE and kidney-related outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to the established kidney-related effects of SGLT2is from kidney outcomes trials [ 13 ], there are currently no data from kidney outcomes trials demonstrating efficacy of GLP-1RAs regarding kidney-related endpoints [ 16 ]. However, several CVOTs have included participants with reduced kidney function [ 2 – 5 , 14 ], enabling the introduction of GLP-1RAs in guidelines and consensus statements addressing CKD treatment [ 10 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis

Rossing,

Bain,

Bosch-Traberg

et al. 2023

Cardiovasc Diabetol

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Background Semaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects. This post hoc analysis investigated the association between major adverse cardiovascular events (MACE) and baseline kidney parameters and whether the effect of semaglutide on MACE risk was impacted by baseline kidney parameters in people with T2D at high cardiovascular risk. Methods Participants from the SUSTAIN 6 and PIONEER 6 trials, receiving semaglutide or placebo, were categorised according to baseline kidney function (estimated glomerular filtration rate [eGFR] < 45 and ≥ 45–<60 versus ≥ 60 mL/min/1.73 m2) or damage (urine albumin:creatinine ratio [UACR] ≥ 30–≤300 and > 300 versus < 30 mg/g). Relative risk of first MACE by baseline kidney parameters was evaluated using a Cox proportional hazards model. The same model, adjusted with inverse probability weighting, and a quadratic spline regression were applied to evaluate the effect of semaglutide on risk and event rate of first MACE across subgroups. The semaglutide effects on glycated haemoglobin (HbA1c), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated. Results Independently of treatment, participants with reduced kidney function (eGFR ≥ 45–<60 and < 45 mL/min/1.73 m2: hazard ratio [95% confidence interval]; 1.36 [1.04;1.76] and 1.52 [1.15;1.99]) and increased albuminuria (UACR ≥ 30–≤300 and > 300 mg/g: 1.53 [1.14;2.04] and 2.52 [1.84;3.42]) had an increased MACE risk versus those without. Semaglutide consistently reduced MACE risk versus placebo across all eGFR and UACR subgroups (interaction p value [pINT] > 0.05). Semaglutide reduced HbA1c regardless of baseline eGFR and UACR (pINT>0.05); reductions in BW were affected by baseline eGFR (pINT<0.001) but not UACR (pINT>0.05). More participants in the lower eGFR or higher UACR subgroups experienced SAEs versus participants in reference groups; the number of SAEs was similar between semaglutide and placebo arms in each subgroup. Conclusions MACE risk was greater for participants with kidney impairment or damage than for those without. Semaglutide consistently reduced MACE risk across eGFR and UACR subgroups, indicating that semaglutide provides cardiovascular benefits in people with T2D and at high cardiovascular risk across a broad spectrum of kidney function and damage. Trial registrations NCT01720446; NCT02692716.

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The Impact of Glucagon-Like Peptide-1 Receptor Agonist on the Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review

et al. 2023

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Background Since 2005, the cardioprotective effects of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have garnered attention. The cardioprotective effect could be an added benefit to the use of GLP-1 RA. This systematic review and meta-analysis aimed at summarizing observational studies that recruited type 2 diabetes individuals with fewer cardiovascular (CV) events before enrolling in the research. Methods Systematically, the databases were searched for observational studies reporting compound CV events and deaths in type 2 diabetics without having the risk of cardiovascular diseases (CVDs) compared to other glucose-lowering agents. A meta-analysis was carried out using random effects model to estimate the overall hazard ratio (HR) with a 95% confidence interval (CI). Five studies were found eligible for the systematic review including a total of 64,452 patients receiving either liraglutide (three studies) or exenatide (two studies). Results The pooled HR for major adverse cardiac event (MACE) and extended MACE was 0.72 (95% CI: 0.65 - 0.93, I 2 = 68%) and 0.93 (95% CI: 0.89 - 0.98, I 2 = 29%), respectively. The pooled HR for hospitalization due to heart failure (HHF) and occurrence of HF was 0.84 (95% CI: 0.77 - 0.91, I 2 = 79%) and 0.83 (95% CI: 0.75 - 0.94, I 2 = 95%), respectively. For stroke, GLP-1 RA was associated with a significant risk reduction of 0.86 (95% CI: 0.75 - 0.98, I 2 = 81%). There was no significant myocardial infarction (MI) risk reduction with GLP-1 RA. As for all-cause mortality, the pooled HR for the occurrence of all-cause mortality was 0.82 (95% CI: 0.76 - 0.88, I 2 = 0%). The pooled HR for the occurrence of CV death was 0.75 (95% CI: 0.65 - 0.85, I 2 = 38%). GLP-1 RA therapy was associated with a significantly low risk of MACE, extended MACE, all-cause mortality, and CV mortality. Except for MACE, the heterogenicity among the studies was low. Conclusion We conclude that GLP-1 RA is associated with a low risk of CV events composites and mortality. The findings support the cardioprotective effect of GLP-1 RA.

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Clinical Evidence and Proposed Mechanisms for Cardiovascular and Kidney Benefits from Sodium–Glucose Co-transporter-2 Inhibitors

Cited by 5 publications

References 65 publications

Inulin Inhibits the Inflammatory Response through Modulating Enteric Glial Cell Function in Type 2 Diabetic Mellitus Mice by Reshaping Intestinal Flora

Inulin Inhibits the Inflammatory Response through Modulating Enteric Glial Cell Function in Type 2 Diabetic Mellitus Mice by Reshaping Intestinal Flora

Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis

The Impact of Glucagon-Like Peptide-1 Receptor Agonist on the Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review

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