Dataset Information

Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta-Regression Analysis.

ABSTRACT:

Background

Prior research suggests clinical effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are mediated by changes in glycated hemoglobin, body weight, systolic blood pressure, hematocrit, and urine albumin-creatinine ratio. We aimed to confirm these findings using a meta-analytic approach.

Methods and results

We updated a systematic review of 9 GLP-1RA and 13 SGLT2i trials and summarized longitudinal mediator data. We obtained hazard ratios (HRs) for cardiovascular, renal, and mortality outcomes. We performed linear mixed-effects modeling of LogHRs versus changes in potential mediators and investigated differences in meta-regression associations among drug classes using interaction terms. HRs generally became more protective with greater glycated hemoglobin reduction among GLP-1RA trials, with average HR improvements of 20% to 30%, reaching statistical significance for major adverse cardiovascular events (ΔHR, 23%; P=0.02). Among SGLT2i trials, associations with HRs were not significant and differed from GLP1-RA trials for major adverse cardiovascular events (P_interaction=0.04). HRs for major adverse cardiovascular events, myocardial infarction, and stroke became less efficacious (ΔHR, -15% to -34%), with more weight loss for SGLT2i but not for GLP-1RA trials (ΔHR, 4%-7%; P_interaction<0.05). Among 5 SGLT2i trials with available data, HRs for stroke became less efficacious with larger increases in hematocrit (ΔHR, 123%; P=0.09). No changes in HRs by systolic blood pressure (ΔHR, -11% to 9%) and urine albumin-creatinine ratio (ΔHR, -1% to 4%) were found for any outcome.

Conclusions

We confirmed increased efficacy findings for major adverse cardiovascular events with reduction in glycated hemoglobin for GLP1-RAs. Further research is needed on the potential loss of cardiovascular benefits with increased weight loss and hematocrit for SGLT2i.

SUBMITTER: Rodriguez-Valadez JM

PROVIDER: S-EPMC11010086 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta-Regression Analysis.

Rodriguez-Valadez José M JM Tahsin Malak M Masharani Umesh U Park Meyeon M Hunink M G Myriam MGM Yeboah Joseph J Li Lihua L Weber Ellerie E Berkalieva Asem A Avezaat Luuk L Max Wendy W Fleischmann Kirsten E KE Ferket Bart S BS

Journal of the American Heart Association 20240216 4

<h4>Background</h4>Prior research suggests clinical effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are mediated by changes in glycated hemoglobin, body weight, systolic blood pressure, hematocrit, and urine albumin-creatinine ratio. We aimed to confirm these findings using a meta-analytic approach.<h4>Methods and results</h4>We updated a systematic review of 9 GLP-1RA and 13 SGLT2i trials and summarized longitudinal mediato ...[more]

PMID: 38362889

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Project description:BackgroundIt is unclear whether there are false positive or negative results in the effects of sodium-glucose transporter 2 (SGLT2) inhibitors on various cardiovascular and renal outcomes in patients with type 2 diabetes. We aimed to explore this issue by a meta-analysis with trial sequential analysis.MethodsWe included randomized trials evaluating the effects of SGLT2 inhibitors on cardiorenal endpoints in type 2 diabetic patients. Eight endpoints evaluated in the study were fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure (CVD or HHF), all-cause death (ACD), cardiovascular death (CVD), hospitalization for heart failure (HHF), and kidney function progression (KFP). Meta-analysis and trial sequential analysis was conducted for each endpoint.ResultsSeven randomized trials of SGLT2 inhibitors were included for pooled analysis. Compared with placebo, SGLT2 inhibitors significantly reduced the risk of MACE (HR 0.89, 95% confidence interval [CI] 0.84-0.94), MI (HR 0.91, 95% CI 0.84-0.99), CVD (HR 0.86, 95% CI 0.79-0.93), CVD or HHF (HR 0.77, 95% CI 0.73-0.82), HHF (HR 0.67, 95% CI 0.62-0.74), KFP (HR 0.63, 95% CI 0.56-0.70), and ACD (HR 0.88, 95% CI 0.83-0.94), whereas SGLT2 inhibitors did not have significant effects on stroke (HR 0.98, 95% CI 0.88-1.09). Trial sequential analyses for MI and stroke showed that cumulative Z curve did not cross trial sequential monitoring boundary and required information size, whereas those for the other 6 endpoints showed that cumulative Z curve crossed trial sequential monitoring boundary and/or required information size.ConclusionsCompared with placebo, SGLT2 inhibitors conclusively reduce the risk of MACE, CVD or HHF, ACD, CVD, HHF, and KFP in patients with type 2 diabetes, whereas the effects of SGLT2 inhibitors on MI and stroke are not conclusive and need to be further assessed in future studies with the adequate sample size to reject or accept the effect size.

Project description:BackgroundThe nonsteroidal mineralocorticoid antagonist finerenone is a new addition to the list of agents (angiotensin converting enzyme inhibitors and sodium glucose cotransporter 2 inhibitors) conferring renal protection to patients with diabetic kidney disease. Two recent meta-analyses using the fixed effect model in patients with chronic kidney disease (both diabetic and nondiabetic populations) came to a conflicting conclusion on the effect of finerenone on eGFR decline. This meta-analysis was undertaken exclusively in the type 2 diabetes (T2D) population to explore the robustness and heterogeneity of the effect size by conducting a random effects model meta-analysis along with draft plots and prediction intervals.Materials and methodsA database search was conducted using the Cochrane library, PubMed, and Embase to identify relevant citations. Analysis was conducted on the 14th of September 2022, using RevMan 5.4.1 and RStudio (2022.07.1, Build 554). The hazard ratio was used as the effect size for the renal composite, while the standardized mean difference (SMD) was used to estimate the effect size of eGFR decline and reduction in the urine albumin creatinine ratio (UACR). The Cochrane risk-of-bias was used to assess the quality of the studies. The primary outcome assessed was the renal composite defined as kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes.ResultsA pooled population of 13,943 patients from four citations was included for analysis. The Cochrane risk of bias was used to assess the quality of the studies. There was a significant 16% reduction in the renal composite (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) [HR: 0.84, 95% CI 0.77-0.92, 2: 0, I2: 0%). Finerenone was also associated with reduction in UACR (SMD: -0.49, 95% CI -0.53 to -0.46, τ2: < 0.0001, I2: 0%, prediction interval: -0.57 to -0.41) and prevention of decline in eGFR (SMD: -0.32, 95% CI -0.37 to -0.27, τ2: < 0.0001, I2: 0%, prediction interval: -0.43 to -0.21) without any evidence for significant heterogeneity. Except for an increase in hyperkalaemia (RR: 2.22, 95% CI 1.93-2.24), adverse events were observed with fineronone compared to placebo (RR: 1.00, 95% CI 0.98-1.01).ConclusionThere are significant benefits in renal outcomes associated with finerenone treatment in T2D patients with established chronic kidney disease with a side effect profile comparable to placebo.

Project description:Background Finerenone and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), while the relative efficacy has not been determined. Methods The databases of PubMed, Embase and Cochrane were searched for relevant cardiovascular or renal outcome trials of SGLT2i or finerenone. The end points were major adverse cardiovascular events (MACE), nonfatal stroke (NS), myocardial infarction (MI), hospitalization for heart failure (HHF), cardiovascular death (CVD), and renal composite outcome (RCO). Network meta-analysis was performed using Bayesian networks to obtain pooled hazard ratios (HR) and 95% confidence intervals (CI). The probability values for ranking active and placebo interventions were calculated using cumulative ranking curves. Results 1024 articles were searched, and only 9 studies were screened and included in this meta-analysis with 71793 randomized participants. Sotagliflozin (HR 0.72 95%CI 0.59-0.88, SUCAR=0.93) and canagliflozin (HR 0.80 95%CI 0.67-0.97, SUCAR=0.73) can significantly reduce the risk of MACE compared with placebo. Canagliflozin (HR 0.64 95%CI 0.48-0.86, SUCAR=0.73), sotagliflozin (HR 0.66 95%CI 0.50-0.87, SUCAR=0.69) and empagliflozin (HR 0.65 95%CI 0.43-0.98, SUCAR=0.68) can significantly reduce the risk of HHF compared with placebo. Empagliflozin (HR 0.62 95%CI 0.43-0.89, SUCAR=0.96) can significantly reduce the risk of CVD compared with placebo. Empagliflozin (HR 0.61 95%CI 0.39-0.96, SUCAR=0.74), canagliflozin (HR 0.66 95%CI 0.46-0.92, SUCAR=0.63), and dapagliflozin (HR 0.53 95%CI 0.32-0.85, SUCAR=0.88) can significantly reduce the risk of RCO compared with placebo. Finerenone has reduced the risk of MACE, MI, HHF, CVD and RCO to varying degrees, but they do not show significant difference from placebo and each SGLT2i. Conclusion Both SGLT2i and finerenone could reduce the risk of MACE, HHF, MI, CVD, RCO. Finerenone has no obvious advantage than SGLT2i on the effects of cardiovascular and renal protective. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022375092.

Project description:BackgroundThe consistency of cardiovascular risk reduction by antidiabetes medications across racial and ethnic groups remains unclear. The aim of this study was to analyze racial/ethnic patterns in the results of cardiovascular outcomes trials of antidiabetes medications in people with type 2 diabetes.MethodPubMed and Cochrane library databases were searched from the inception dates to December 2020. Cardiovascular outcome trials in type 2 diabetes that randomized participants to antidiabetes medication or control treatment and reported results by race/ethnic groups or region were included.ResultsA total of 19 studies were included in this meta-analysis. Among White participants, treatment with antidiabetes medications significantly decreased the risk of composite cardiovascular outcomes when compared with placebo treatment (OR = 0.88, 95% CI 0.83-0.94, p < 0.05). Among Asian participants, antidiabetes medications also significantly decreased the risk of composite cardiovascular outcomes when compared with control treatment (OR = 0.80, 95% CI 0.74-0.86, p < 0.05). A similar pattern was found when analyzing the effects of antidiabetes medications vs. control treatment in other racial/ethnic groups comprising mostly Hispanics and Pacific Islanders (OR = 0.87, 95% CI 0.78-0.98, p < 0.05). However, among Black participants, treatment with antidiabetes medications resulted in nominal but non-significant decreases in the composite cardiovascular outcomes when compared with control treatment (OR = 0.84, 95% CI 0.62-1.14, p = 0.26).ConclusionsThe present meta-analysis showed cardiovascular safety of antidiabetes medications in people with type 2 diabetes from all racial/ethnic groups studied; however, significant composite cardiovascular risk reductions were demonstrated only in White and Asian participants. To determine whether antidiabetes drugs confer consistent cardiovascular benefits in Black and other racial/ethnic participants requires more investigations in the future.

Project description:Background This study aimed to assess the effectiveness of sodium-glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta-analysis of randomized controlled trials comparing sodium-glucose cotransporter 2 inhibitors with placebo. We used meta-regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty-three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63-0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69-1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72-1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61-1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63-1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71-1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all-cause and cardiovascular mortality. There was no association between treatment effects for all-cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%-95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause and cardiovascular mortality versus placebo. Treatment effects of sodium-glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.

Project description:BackgroundGuidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes.Methods and findingsWe systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years).ConclusionsIntensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data.

Project description:ObjectiveTo assess the effects of finerenone and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus (T2DM), and the relative cardiovascular benefits in patients with or without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs.MethodsWe searched PubMed, the Cochrane Library, and Embase from January 1, 2000, to December 30, 2022, to identify randomized controlled trials. The primary outcomes were the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (MACE); hospitalization for heart failure (HHF); and a composite of renal outcomes. The results were reported as hazard ratios (HRs) with 95% confidence intervals (CIs).ResultsIn total, we identified 11 trials and 73,927 participants, 13,847 (18.7%) in finerenone trials and 60,080 (81.3%) in GLP1-RA trials. Finerenone reduced the risk of MACE by 13% (HR, 0.87; 95% CI, 0.79-0.95; P = 0.003), while GLP1-RA reduced the risk in a similar magnitude by 13% (HR, 0.87; 95% CI, 0.83-0.92; P < 0.001). For both drug classes, the effect on lowering the risk of MACE was restricted to approximately 14% in patients with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.82-0.90; P < 0.001), whereas no effect was observed in patients without established atherosclerotic cardiovascular disease (HR, 0.93; 95% CI, 0.85-1.02; P = 0.12). GLP1-RA reduced myocardial infarction, stroke and cardiovascular death more than finerenone (which appeared to have no effect). Only finerenone was beneficial for reducing the risk of HHF (HR, 0.78; 95% CI, 0.66-0.92; P = 0.003). Both finerenone (HR, 0.84; 95% CI, 0.77-0.92; P < 0.001) and GLP1-RA (HR, 0.81; 95% CI, 0.76-0.86; P < 0.001) reduced the risk of kidney disease progression, including macroalbuminuria, and finerenone was superior to GLP1-RA in delaying deterioration of kidney function.ConclusionsFinerenone and GLP1-RA lead to a risk reduction in MACE to a similar degree in patients with established atherosclerotic cardiovascular disease. For both drug classes, the effect on lowering the risk of progression of kidney disease was also in a similar magnitude in patients with T2DM, whereas only finerenone had a significant protective effect against HHF. Treatment decisions for patients with T2DM should consider the clinical benefit profiles of each drug.

Dataset Information

Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta-Regression Analysis.

Background

Methods and results

Conclusions

Publications

Potential Mediators for Treatment Effects of Novel Diabetes Medications on Cardiovascular and Renal Outcomes: A Meta-Regression Analysis.

Similar Datasets

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